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May 27-29, 2011
WOW Topkapı Palace
Antalya-TÜRKİYE
ABSTRACTS
Organized by
Hacettepe University
Medicinal Chemistry Research
Development & Application Center
www.drd.hacettepe.edu.tr
Dear Colleagues,
I would like to invite you to attend and contribute to the International
Symposium on Drug Research and Development “From Chemistry to
Medicine” DRD 2011 and New Horizons and Job Opportunities for Young
Scientists which is organized by Hacettepe University, Medicinal Chemistry
Research, Development and Application Center (MAGUM).
MAGUM, a subunit of Hacettepe University, was established in 1996 for
the purpose of realization of the drug design, structure-activity relationships,
synthesis, analysis and molecular quality control of synthetic and natural
drugs and drug raw materials in medicinal chemistry area with cooperation
of departments of Faculty of Pharmacy, Faculty of Medicine and other faculties to improve outputs of drug research, development and application by
multidisciplinary collaboration approaches.
The high quality performed scientific International Symposium on
Drug Research and Development “From Chemistry to Medicine” organized
by MAGUM every two years. In addition to DRD 2011 symposium, which will
be held on May 27-29, 2011, New Horizons and Job Opportunities for Young
Scientists” was also planned to conduct by MAGUM.
The mission of “International Symposium DRD 2011 and New Horizons and Job Opportunities for Young Scientists” will be to provide a scientific forum by the invitation of distinguished scientists having national /
international reputation in their areas, so the most recent advances will be
discussed and evaluated interactively and the exchange of interdisciplinary
knowledge from chemistry to medicine. The format of the scientific program
will also include oral and poster presentations on the concerning scientific
topics in addition to the invited lectures.
Members of the organizing committee and I cordially invite you to join
us at DRD 2011 in Antalya, May 27-29, 2011. It is important to note that
symposium venue Antalya is very famous with its archaeological and natural
riches and known as one of the most popular region of Turkish Riviera.
We are looking forward to see you in Antalya,Turkey.
With our kind regards,
Prof. Dr. Ünsal ÇALIŞ
Chair
ORGANIZING COMMITTEE
Honorary Chair
Prof. Uğur ERDENER, M.D.
President of Hacettepe University
Organizing Committee
Ünsal ÇALIŞ, Ph.D. (Chair)
Selma SARAÇ, Ph.D.
Sedef KIR, Ph.D.
Gülberk UÇAR, Ph.D.
Funda Nuray YALÇIN, Ph.D.
S. Kutay DEMİRKAN, Pharm.D.
ADVISORY BOARD
Prof. Melih ALTAN, Ph.D. (Ankara University, Türkiye)
Prof. Metin BALCI, Ph.D. (Middle East Technical University, Türkiye)
Prof. Erden BANOĞLU, Ph.D. (Gazi University, Türkiye)
Prof. A. Ahmet BAŞARAN, Ph.D. (Hacettepe University, Türkiye)
Prof. Erdem BÜYÜKBİNGÖL, Ph.D. (Ankara University, Türkiye)
Prof. Sevim DALKARA, M.D. (Hacettepe University, Türkiye)
Prof. Katerina GORACINOVA, Ph.D. (University of Sts Cyrill and Methodius, Macedonia)
Prof. Arzum Erdem GÜRSAN, Ph.D. (Ege University, Türkiye)
Prof. Selçuk GEÇİM, Ph.D. (Hacettepe University, Türkiye)
Prof. Emin KANSU, M.D. (Hacettepe University, Türkiye)
Prof. Hakan ORER, M.D. (Hacettepe University, Türkiye)
Prof. Seçkin ÖZDEN, Ph.D. (Ankara University, Türkiye)
Prof. Yekta ÖZER, M.D. (Hacettepe University, Türkiye)
Prof. Serhat ÜNAL, M.D. (Hacettepe University, Türkiye)
Prof. Metin TÜLÜ, Ph.D. (Yıldız Technical University, Türkiye)
Prof. Kemal YELEKÇİ, Ph.D. (Kadir Has University, Türkiye)
Prof. Nurşen ÜNLÜ, Ph.D. (Hacettepe University, Türkiye)
SCIENTIFIC SECRETERIAT
OFFICIAL SYMPOSIUM AGENCY
Prof. Selma SARAÇ, Ph. D.
Hacettepe University, Faculty of Pharmacy
Department of Pharmaceutical Chemistry
06100 Ankara-TÜRKİYE
Phone (Fax) : +90 312 305 30 15
[email protected]
DMR Congress Organization Services Tourism Inc.
Hollanda Cad. 696. sok. 22/9-10
06550 Yıldız Çankaya - Ankara, TURKEY
Phone : +90 312 442 01 50
Fax : +90 312 442 04 10
www.dmrturizm.com.tr
[email protected]
Prof. Sedef KIR, Ph. D.
Hacettepe University, Faculty of Pharmacy
Department of Analytical Chemistry
06100 Ankara-TÜRKİYE
Phone : +90 312 305 21 63
[email protected]
DRD 2011
CONTENTS
SCIENTIFIC PROGRAMME
6
SPONSORS
10
EXHIBITION
11
LECTURES
13
ORAL PRESENTATIONS
39
POSTER PRESENTATIONS
53
ındex
166
International Symposium on Drug Research & Development 2011
5
SCIENTIFIC PROGRAMME
DRD 2011
MAY 27, 2011
14.30-16.00
16.00-16.30
16.00-16.30
OPENING CEREMONY
Opening Lectures
Engineering Versatile Nano-carriers for Therapeutic Delivery
Woei Ping Cheng, University of Hertfordshire, United Kingdom
The Use of Novel Enabling Techniques to Overcome Drug Solubility Issues
Firas El-Saleh, ISP-International Specialty Products, Germany
Coffee Break
Coffee Break
16.30-18.00 SESSION I
New Trends and Methods in Drug Research and
Development
(All presentations will be in English)
Sponsored by
Chairpersons :
Rümeysa Demirdamar, Near East University, Turkish Republic of Northern
Cyprus
Nur Onar, Ondokuz Mayıs University, Türkiye
New Trends in Pharma: The Growth of Generics
Farhad Farshi, Abdi İbrahim Pharmaceutical R&D Center, Türkiye
In Silico Design of Novel and Highly Selective Monoamine Oxidase A and B
Inhibitors: Evaluation of Computational and Experimental Inhibition Values
Kemal Yelekçi, Kadir Has University, Türkiye
Nanomaterial Based Sensor Technology for Electrochemical Monitoring DrugDNA Interactions
Arzum Erdem Gürsan, Ege University, Türkiye
18.00-20.00 WELCOME RECEPTION
Sponsored by
MAY 28, 2011
09.00-10.30 SESSION II
Current Approaches for Development of Novel Drug
Delivery Systems
(All presentations will be in English)
Sponsored by
Chairpersons :
Nurşen Ünlü, Hacettepe University, Türkiye
Sema Çalış, Hacettepe University, Türkiye
Novel Excipients from Scratch to Launch
Nils Rottmann, BASF - The Chemical Company, Germany
Colloidal Carriers for Anticancer Drug Delivery – Formulation Approaches
Katerina Goracinova, University of Sts Cyrill and Methodius, Macedonia
Novel Nano-carriers Based on Self-assembling Polymers: A New Opportunity for
Improving Treatment of Diseases
Woei Ping Cheng, University of Hertfordshire, United Kingdom
10.30-11.00 Coffee Break
SCIENTIFIC PROGRAMME
International Symposium on Drug Research & Development 2011
6
DRD 2011
SESSION III-A
Experiences and Expectations of Clinicians: Diabetic Agents
(All presentations will be in Turkish)
Chairperson:
Gülberk Uçar, Hacettepe University, Türkiye
Supported by
İLADER
Insulin Therapy & Routes of Administration
Ercan Tuncel, Uludağ University, Türkiye
Oral Diabetic Therapy
Nilgün Güvener Demirağ, Başkent University, Türkiye
New Antidiabetic Agents
Bülent Okan Yıldız, Hacettepe University, Türkiye
LUNCH
SESSION III-B
Selected Oral Presentations on Research and Development in Pharmaceutical
Sciences
(All presentations will be in English)
Chairpersons :
Arzum Erdem Gürsan, Ege University, Türkiye
Katerina Goracinova, University of Sts Cyrill and Methodius, Macedonia
Monitoring Reovirus Entry and Endosomal Trafficking in Live Non-polarized and
Polarized Cells by Single Viral Particle Tracking
Cömert Kural, Harvard Medical School, USA
Computational Study of the Conformational Interconversion of 4,5-Dimethyl-1,3,4,5tetrahydro-2H-1,5-benzodiazepin-2-one
Sajid Jahangir, Karl Franzens University, Austria
Determination of Antioxidant Activity of Some Biologically Important Samples through
Cyclic Voltammetry
Haji Muhammad, Federal Urdu University of Arts, Science and Technology, Pakistan
Synthesis of Folate-PEG-Doxorubicin Conjugate, Radiolabelling with Technetium99m and Research into its Applications as an Imaging Agent in Cancer
Güliz Ak, Ege University, Türkiye
Bioengineering Technique Used to Study the Effects of Grapefruit Extract
Containing Emulsion on Human Skin Mechanical Parameters
Naveed Akhtar, The Islamia University of Bahawalpur, Pakistan
Study on a Commercial Anthelmentic Combination Efficacy against Fasciola Spp,
Dicrocoelium Dendriticum and Moniezia Spp in Small Ruminants in Urmia, Iran
Sohrab Rasouli, Islamic Azad University, Iran
Heavy Metals Toxicity in Root Vegetables Irrigated by Industrial Waste Water
Karachi
Kousar Yasmeen, Federal Urdu University of Arts, Pakistan
Formulation and Characterization of Two Bleach Creams of Mulberry Extract and
Comparison of their Effects on Human Skin Melanin and Erythema
Fatima Rasool, The University of the Punjab, Pakistan
12.30-14.00 Lunch
14.00-14.30 Poster Discussion & Exhibition
International Symposium on Drug Research & Development 2011
7
SCIENTIFIC PROGRAMME
11.00-12.30
12.30-14.00
11.00-12.30
SCIENTIFIC PROGRAMME
DRD 2011
14.30-16.00 SESSION IV
Interview Fear in Job Applications
(All presentations will be in Turkish)
Chairperson :
Buket Aksu, Santa Farma Pharmaceutical Company, Türkiye
Getting Ready for Interview and Get Over Your Fear
Nesrin Dilbaz, Ankara Numune Research And Training Hospital, Türkiye
Personal Behaviors During Job Interview
Aykut Bora, Bilim Pharmaceutical Company, Türkiye
Requirements of Scientific Background for Job Applications in Drug Research and
Development
A. Atilla Hıncal, İDE Pharmaceutical Consultancy, Türkiye
16.00-16.30 Coffee Break & Exhibition
Supported by
16.30-18.00
PANEL
New Horizons and Job Opportunities for Young Scientists
(All presentations will be in Turkish)
Moderator :
Selçuk Geçim, Hacettepe University, Türkiye
Tarık Çelik, The Turkish Academy of Sciences TÜBA, Türkiye
Tayfun Öner, Small & Medium Enterprises Development Organization
KOSGEB, Türkiye
Murat Yıldız, Republic of Turkey Ministry of Industry and Trade, Türkiye
Rıza Alagöz, Republic of Turkey Ministry of Industry and Trade, Türkiye
Tuğba Arslan Kantarcıoğlu, The Scientific & Technological Research
Council of Türkiye- TÜBİTAK
Emel Önder Fırat
The Scientific & Technological Research Council of Türkiye- TÜBİTAK
A.Tuncay Teksöz, Pfizer Inc. Pharmaceutical Company, Türkiye Farhad Farshi, Abdi İbrahim Pharmaceutical R&D Center, Türkiye
Sami Türkoğlu, Ulkar Holding, Türkiye
20:00-24:00 Gala Dinner
International Symposium on Drug Research & Development 2011
8
İLADER
DRD 2011
09.00-10.30
SESSION V
Recent Biochemical Approaches to Drug Development
(All presentations will be in English)
How to Change an Enzyme into a Cytotoxic Agent: Mechanisms of Targeting Top2 in
Cancer
John L. Nitiss, St. Jude Children’s Research Hospital, Memphis-USA Enhanced
Survival and Paracrine Activity of Bone Marrow Mesenchimal Stem Cells: Impact on
Cell Therapy of Ischemic Syndromes
Angelo Parini, Inserm Institut, France
Serotonergic Control of Cardiovascular Function
Nathalie Pizzinat, University of Toulouse, France
Sponsored by
Chairpersons :
Zeliha Büyükbingöl, Ankara University, Türkiye
Filiz Hıncal, Hacettepe University, Türkiye
10.30-11.00 Coffee Break
11.00-12.30 SESSION VI
Organic Synthesis and Analysis of Pharmaceutical
Molecules
(All presentations will be in English)
Sponsored by
Chairpersons :
Tuncel Özden, Gazi University, Türkiye
Erdem Büyükbingöl, Ankara University, Türkiye
Bisacylazides: A New Milestone for the Synthesis of Various Heterocycles
Metin Balcı, Middle East Technical University, Türkiye
Dendrimers as Potential Drug Carriers: Microwave-Assisted Synthesis of Pamam
Type Dendrimers
Metin Tülü, Yıldız Technical University, Türkiye
A Novel Polymorph of Zoledronic Acid and Process for its Preparation
Bekir Karlığa, Deva Holding API R&D, Türkiye
Synthesis of Ezetimibe: A Selective Cholesterol Absorption Inhibitor
Esen Bellur Atıcı, Deva Holding API R&D, Türkiye
12.30-14.00 Lunch
14.00-16.00 SEARCH CONFERENCE
Visualising the Future of Drug R & D:
Policies, Priorities and Strategies
(All presentations will be in Turkish)
Moderator:
İsmail Üstel, Consultant, Türkiye
16.00-16.30 Closing Remarks
International Symposium on Drug Research & Development 2011
9
Sponsored by
SCIENTIFIC PROGRAMME
MAY 29, 2011
SPONSORS
DRD 2011
SPONSORS
International Symposium on Drug Research & Development 2011
10
DRD 2011
1
ANAMED
EXHIBITION
STAND AREA
MEETING
HALL B
İNCEKARA
9
8
2
ISP
BAS-F
REDOKS
MEETING
HALL A
7
6
3
ANT TEKNİK
MEDSANTEK
INNOVA
5
POSTER
AREA
4
LABOR İLDAM
EXHIBITION
International Symposium on Drug Research & Development 2011
11
LECTURES
DRD 2011
ENGINEERING VERSATILE NANO-CARRIERS FOR THERAPEUTIC DELIVERY
Woei Ping CHENG
School of Pharmacy, University of Hertfordshire, College Lane, Hatfield, UK AL10 9AB
[email protected]
T
oday with the advancement of biotechnology, a
plethora of new therapeutic macromolecules such as
proteins/peptides and siRNA have been discovered
to treat a variety of diseases ranging from cancer, autoimmune diseases to metabolic diseases. Albeit their huge
potentials, one of the major hurdles has yet to overcome is
drug delivery problem. Unlike small drug molecules, these
drugs cannot be given orally because they are destroyed
extensively by enzymes in the gastrointestinal tract (GIT).
In addition, the large size and water soluble nature of
these drugs prevent them from being absorbed through
the GIT. For siRNA based therapeutics, another challenge to
overcome is the inability of these negatively charge molecules to cross the cell membrane and reach its target site,
which is the cytoplasm. We have designed a range of novel self-assembled polymers based on water soluble polyallylamine (PAA) for therapeutic delivery of proteins and
peptides. These self-assembled polymers formed nanocomplexes spontaneously with model proteins such as insulin1 and calcitonin (sCT)2 with the size ranging from 100250nm. The complexation took place due to electrostatic
and hydrophobic interaction between the polymer and
proteins. As a result, the fabrication of these complexes is
mild and unlike other conventional nanoparticles where
the use of organic solvents and high temperature might
degrade the labile proteins. Through grafting different
types of hydrophobic pendant groups such as cetyl, cholesteryl and palmitoyl chains onto PAA, we were able to
engineer different types of nano-complexes (i.e. vesicles,
nanoparticles) with different complexation efficiencies1,3.
REFERENCES
1. Thompson C, et. al. International Journal of Pharmaceutics 376: 46-55, 2009.
2. Cheng WP, et. al. Journal of Controlled Release 147: 289-297, 2010.
3. Thompson C, et. al. International Journal of Pharmaceu-
Addition of quaternary ammonium moieties onto these
self-assembled polymers have protected insulin and sCT
against in vitro enzymatic degradation1,2 and enhanced
the uptake of these complexes by CaCO2 cells via transcellular and paracellular pathways4. In vivo study using jejunal instillation has demonstrated the feasibility of using
these nano-complexes in oral protein delivery2. We have
also successfully designed pH triggered self-assembled
polymers based on poly-L-lysine (PLL) for siRNA delivery
in cancer therapy. Using a benzoic linker which is cleaved
in acidic pH, we were able to attach polyethylene glycol
(PEG) on PLL grafted with cholate hydrophobic pendant
groups. It is expected that PEG will maintain siRNA-polymer nanocomplexes’ long circulation in the blood. However, when these complexes are endocytosed by cancer
cells, the benzoic linker will be hydrolysed in the acidic endolysosomal compartment to detach PEG from the complexes. This will promote endosomal escape of siRNA into
the cytoplasm before it is being degraded in the endolysosome.
Using a confocal microscopy, we were able to demonstrate the
cellular uptake of these complexes by human prostate cancer
cells (PC-3) and endosomal escape of siRNA, which led to in vitro
reporter gene knockdown. In vivo result using tumour bearing
mice showed significant tumour suppression was achieved using VEGF siRNA-PEGylated complexes without marked toxicity
and undesirable immunological response5. In conclusion, by
tailoring the polymer architecture, we are able to design and
engineer a range of versatile nanocarriers based on self-assembled polymers which showed promising potential in the delivery of therapeutic macromolecules.
tics 383: 216-227, 2010.
4. Thompson C, et. al. Pharmaceutical Research, in press,
2011.
5. Guo J, et. al. manuscript in preparation, 2011.
International Symposium on Drug Research & Development 2011
15
LECTURES
I-01
 
ORAL PRESENTATIONS
LECTURES
DRD 2011
I-02
 
THE USE OF NOVEL ENABLING TECHNIQUES TO OVERCOME DRUG
SOLUBILITY ISSUES
Mohammed RAHMAN1, Firas EL-SALEH2,*, Tim BEE3
1
ISP Pharma Systems LLC, Columbia, Maryland, USA
ISP Global Technologies Deutschland GmbH, Cologne Germany
3
ISP, Wayne, New Jersey, USA
*
[email protected]
2
S
olubility of drugs has become a major issue in the
last few years. It has been estimated that 40–60%
of drugs in development have poor bioavailability
due to low aqueous solubility. This trend has driven increasing interest in technologies that help increase drug solubility
and / or drug dissolution rate and thus move the drugs from
BCS Class 2 (good permeability, poor solubility) into BCS
Class 1 (good permeability, good solubility), and thus overcome bioavailability issues, interpatient differences, food effects, etc.
This paper provides an overview of different excipients
and techniques necessary to serve this purpose. However,
the main focus is put on the technologies used in preparing
solid dispersions, namely Spray Drying and Hot Melt Extrusion (HME). Practical considerations and the main factors influencing the formation of solid dispersions supported with
examples are discussed as follows:
Based on the physicochemical properties of APIs, different formulation techniques and process technologies are
necessary to enhance drug solubility in vivo.
Polymers and API miscibility
Solubility in solvents
Influence of formulation on process technology
Thermal behavior, instability
Thermoreological characteristics
Process parameters and machine set-up
Factors influencing physical stability
International Symposium on Drug Research & Development 2011
16
DRD 2011
NEW TRENDS IN PHARMA: THE GROWTH OF GENERICS
Farhad FARSHI
Abdi İbrahim İlaç San. ve Tic. A.Ş.
Sanayi Mah. Tunç Cad. No:3 Esenyurt İstanbul, Türkiye
[email protected]
P
harma landscape is changing due to demographic,
epidemiological and economic shifts. Growing and
aging population, diseases and medical needs has
been offering some huge opportunities for Pharma. The
markets of the developing world are changing even more
radically than those of the developed world. While there
are significant opportunities in the developing world due to
health care awareness both of governments and individuals,
in case of developed countries, political compulsions to reduce health care budgets has a direct impact on profitability
of pharma sector.
The complex structure of current pharma R&D processes and studies needed to meet expectations of regulatory
agencies have made the big pharma less productive. Big
pharma started to lose their market share, growth and profitability in the markets they are strong for many years. Drug
pricing and reimbursement policies or legislations favoring
growth of generics have a major impact on profitability of innovator companies. They have been forced to change their
traditional business models and look for the opportunities to
compensate their loss in those markets.
How does this new pharmaceutical environment look like?
Multinational pharma companies have been challanged
for variety of issues in emerging, mature and developed markets. First, they strengthened their presence in those markets
with acquisitions and mergers. Since 1999, 60% of the top
25 generic companies from all around the world acquired.
Second, outsourcing some of their activities to different institutes, companies from all around the world. It is predicted
that 50% of Big Pharma R&D is outsourced to more capable
firms in order to maintain a strong pipeline for future drugs.
This will result in greater profitability and increased shareholder value for the early adopters of Big Pharma.
This presentation analyses the global pharmaceuticals market with respect to growing generics and emerging markets. It
is also aimed to show the challanges and the opportunities for
multinational companies along with big generic players.
International Symposium on Drug Research & Development 2011
17
LECTURES
I-03
 
ORAL PRESENTATIONS
LECTURES
DRD 2011
I-04
 
In Silico Design of Novel and Highly Selective Monoamine
Oxidase A and B Inhibitors: Evaluation of Computational and
Experimental Inhibition Values
Kemal Yelekçİ
Kadir Has University, Faculty of Arts and Sciences,Computational Biology and Bioinformatics Program
34083 Fatih- İstanbul, Türkiye
M
onoamine oxidases are flavoenzymes bound
to the mitochondrial outer membrane. There
are two isozymes named as MAO-A and MAOB. The basic difference in these two isozymes is in their selectivity for the oxidation of the various substrates and inhibitors. MAO-A oxidizes serotonin and norepinephrine and
any compound selectively inhibits this isozyme possesses
antidepressant activity. On the other hand, dopamine is
the substrate for MAO-B and selective inhibition of MAO-B
shows potent anti-Parkinson and plays important role in the
therapy of neurodegererative disorders. That is why, they are
the well known target for antidepressant, Parkinson’s disease and neuroprotective drugs. Recently published crystallographic structures of MAO-A and MAO-B paved the way for
computational modeling studies.
In the present work, starting from pyrazoline scaffolds,
and generating thousands of structures from these, potential inhibitors are obtained with their structural and physicochemical properties in order to increase both selectivity
and potency toward MAO-A and MAO-B isozymes. De novo
design software is used to generate the diverse structures
and, three docking tools, CDOCKER, Libdock and AutoDock,
are used to find the most probable potential inhibitor based
on its binding affinity. The dispositions of the candidate molecules within the organism are checked by ADMET_PSA_2D
(Polar Surface Area) versus ADMET_AlogP98 and their suitability is discussed. The MAO inhibition activities of the
candidates are compared with the properties of selegiline
and moclobemide, which are the two known inhibitors of
MAO-A and MAO-B respectively. Interaction of these candidate compounds in the active site of the isozyme will be
presented in detail.
R1
R4
R3
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H
R5
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R6
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This research was supported by The Scientific and Technological Research Council of Turkey with a grand number
108T232.
International Symposium on Drug Research & Development 2011
18
DRD 2011
NANOMATERIAL BASED SENSOR TECHNOLOGY FOR ELECTROCHEMICAL
MONITORING DRUG-DNA INTERACTIONS
Arzum ERDEM
Ege University, Faculty of Pharmacy, Analytical Chemistry Department, İzmir, Türkiye
[email protected]
A
fter the discovery of electroactivity in nucleic acids1, many electrochemical approaches have been
developed for analyzing, or quantification of
nucleic acids and its interactions with drugs, toxins and proteins2-12. Various type of advanced DNA biosensors have been
rapidly developed using different nanomaterials towards the
goal of simple and low-cost point-of-care detection of specific
biorecognition process using nucleic acids4, 9-12.
In the last decade, there has been an increasing attention on the binding of small molecules to nucleic acids.
Such studies have a key importance for the rational design
1.
2.
3.
4.
5.
6.
7.
8.
REFERENCES
Palecek E. Oscillographic Polarography of Highly Polymerized Deoxyribonucleic Acid. Nature 188: 656-657, 1960.
Wang J. From DNA biosensors to gene chips. Nucl. Acids
Res. 28: 3011-3016,2000.
Palecek E, Fojta M. Detecting DNA hybridization and
damage. Analytical Chemistry 73:74A-83A, 2001.
Erdem A. Nanometarial based electrochemical DNA sensing strategies. Talanta 74: 318-325, 2007.
Wang J, Kawde A-K, Erdem A., Salazar M. Magnetic beadbased label-free electrochemical detection of DNA Hybridization. Analyst 126: 2020-2024,2001.
Erdem A, Pividori MI, Lermo A, Bonanni A, del Vale M,
Alegret S. Genomagnetic assay based on label-free electrochemical detection using magneto-composite Electrodes. Sensors and Actuators B: Chem. 114: 591-598,
2006.
Wang J, Xu D, Erdem A, Polsky R, Salazar M. Genomagnetic electrochemical assays of DNA Hybridization. Talanta
56: 931-938, 2002.
Karadeniz H, Erdem A, Kuralay F, Jelen F. Indicator-based
of more-efficient gene-targeted agents3. The investigations
at chemistry side based on drug-DNA and protein-DNA interactions would provide novel compounds to be tested
for an effect on a biochemical target, or would provide new
approaches for the design of more effective DNA hybridization biosensors based on nanomaterials, which will further
become DNA microchip systems.
Acknowledgements: A.E would like to express her gratitude to the Turkish Academy of Sciences (TUBA) as the associate member of TUBA for their support.
and indicator-free magnetic assays connected with disposable electrochemical nucleic acid sensor system. Talanta 78: 187-192, 2009.
9. Erdem A, Papakonstantinou P, Murphy H. Direct DNA Hybridization at Disposable Graphite Electrodes Modified
with Carbon Nanotubes. Analytical Chemistry 78: 66566659, 2006.
10.Karadeniz H, Erdem A, Çalışkan A, Pereira CM, Pereira EM,
Ribeiro JA. Electrochemical sensing of silver tags labelled
DNA immobilized onto disposable graphite Electrodes.
Electrochem. Commun, 9: 2167-2173, 2007.
11.Erdem A, Karadeniz H, Çalışkan A. Single walled carbon
nanotubes modified graphite electrodes for electrochemical monitoring of nucleic acids and biomoleculer
interactions. Electroanalysis 21: 464-471, 2009.
12.Yapasan E, Çalışkan A, Karadeniz H, Erdem A. Electrochemical investigation of biomolecular interactions
between platinum derivatives and DNA by carbon
nanotubes modified sensors. Materials Science and Engineering B 169: 169-173, 2010
International Symposium on Drug Research & Development 2011
19
LECTURES
I-05
 
DRD 2011
ORAL PRESENTATIONS
LECTURES
I-06
 
NOVEL EXCIPIENTS – FROM SCRATCH TO LAUNCH
Nils Wilhelm ROTTMANN
BASF SE, Pharma Ingredients and Services, 67056 Ludwigshafen, Germany
[email protected]
T
he impact of excipients on modern pharmaceutical formulations has increased rapidly during the
past years. Reasons for this trend in the pharmaceutical industry are manifold: Due to numerous of patents
expiring in the next few years and at the same time a declining number of New Chemical Entities (NCE), life-cycle management and re-formulation of the existing products with
innovative excipients have gained a new importance.
For the development of new drug delivery systems and
the re-formulation of existing actives (API), innovative excipients and novel applications are required. Since many years,
BASF follows a strategy of developing novel and innovative
performance excipients to serve the markets needs.
A strict time-line has to be followed, when a new project
is started in the development laboratories. Basically such a
development is structured in the phases:
• Market evaluation
• Definition of project goal
•
•
•
•
•
•
Screening of suitable monomers
Screening of suitable polymerization techniques
Optimization of copolymer composition
Optimization of polymerization process
Scale up into pilot plant (1l to 4 m³)
Transfer into production ( > 4 m³ ).
During these phases, application experts keep on testing the performance and quality of the new products, trying to improve its characteristics constantly. Regulatory and
toxicology experts are involved in the projects from the very
beginning as well.
Developing a novel excipient for innovative formulations
has a similarity to the development of a new drug product.
Therefore, many parties are involved in the excipient development, within the raw material supplier as well as customers, universities and several authorities.
After launching a novel excipient, a lot of resources have
to be invested to facilitate an easy introduction and an easy
registration with the new excipient.
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DRD 2011
COLLODAL CARRIERS FOR ANTICANCER DRUG DELIVERY –
FORMULATION ASPECTS
Marija GLAVAŠ-DODOV1, Sema ÇALIŞ2, Maja SIMONOSKA1,Nikola GESKOVSKI1,
Katerina GORAČINOVA1*
Faculty of Pharmacy, University of Sts Cyril and Methodius, Skopje, Macedonia
2
Faculty of Pharmacy, University of Hacettepe, Ankara, Türkiye
*
[email protected]
1
C
hemotherapy has an important place in clinical
management of cancer and the molecular complexities associated with the drugs as well as inaccessibility of most physiological targets have resulted with
the development of alternative therapies as an approach
to medical intervention (Wang et al., 2009). On one hand,
genomics and proteomics research are identifying new tumor-specific molecular targets, and on the other, innovative
drug-delivery systems are being designed to guide drugs
more precisely to tumor cells, away from sites of toxicity and
to maintain drugs at therapeutic concentration over prolonged time periods1. The overall benefit of these improvements in disease treatment would be an increase in patient
compliance and quality of life. Nanoparticle (NP) delivery of
anticancer drugs to tumor tissue can be achieved by either
passive or active targeting. Passive targeting takes the advantage of inherent size, physico-chemical properties of NPs
and exploits the unique anatomical and patophysiological
abnormalities of tumor vasculature, which is regarded as a
gold standard in the design of new anticancer delivery systems1-3. It is hypothesized that phenomenon equivalent to
EPR (enhanced permeability and retention) effect for drug
targeting due to increased endothelial permeability, i.e. epithelial EPR effect, might be used as potential strategy that
enables inflamed tissue in GI tract to be targeted. Morphometric analysis of mucocellular layer overlying colorectal
cancer point that inflammatory cells are predominant in the
hypercellular mucocellular layer of colorectal cancer closely
resembling the abundance of monocytes, macrophages,
dendritic cells and T cells at the site of inflamation. This
means that epithelial EPR effect strategy and improved accumulation of specially designed nano/microparticles at the
site of inflammation might be useful for targeting GI cancer
as well.
The influence of different factors on the endothelial and
epithelial EPR mediated uptake of the colloidal particles is
however not fully understood. For the extravasation of the
drug loaded carrier more selectively at tumor tissues, at least
some properties of the nannocarriers are particulary important. To successfully take advantage of NP for drug delivery, a number of significant parameters, including stability,
drug loading capacity, size, size distribution, zeta potential,
surface hydrophilicity and/or hydrophobicity, and particle
decoration with specific and nonspecific ligands in order to
improve cell/tissue NP interaction and internalization have
to be carefully considered and optimized for each application. Also, introduction of in vivo biodistribution studies
and in vitro cell culture internalization and efficacy experiments, as early optimization tool for the design of targeted
colloidal drug carriers will properly evaluate the efficacy and
potential of surface modification for active targeting and
improved drug concentration and localization at the site
of action4. Following the principles of passive and nonspecific active targeting we have designed polyelectrolyte drug
delivery systems with pH dependent swelling and muco/
bioadhesivity. In vitro cell culture studies of micro/nanoparticulated 5-FU loaded and WGA functionalized bioadhesive
carriers designed using principles of epithelial EPR targeting
plus nonspecific ligand functionalizatioin point to increased
intracellular localization of the anticancer agent, which is
the major component for increased anticancer efficacy of
the drug delivery system5. In vivo biodistribution studies
for these carriers were in favor of increased localization and
concentration at the site of patophysiological abnormalities.
However, the primary concerns of any targeted drug delivery
system still stands for the abilities to successfully load and
deliver a desired therapeutic cargo to its target, and drug
loading can vary greatly with different carrier materials and
fabrication methods. Appropriate drug loading goes hand-
International Symposium on Drug Research & Development 2011
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ORAL PRESENTATIONS
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DRD 2011
in-hand with drug release kinetics and, hence, the overall effectiveness of the targeted therapy. Nanoparticles formulated using biodegradable PLGA:Poloxamer blends are among
the most intensively investigated drug delivery systems.
Available strategies for surface modification by adsorption
or covalent binding further increase the potential of these
systems for anticancer drug delivery. However, commonly
utilized techniques for nanoparticle preparation (emulsification solvent evaporation, emulsification solvent diffusion,
double emulsion solvent evaporation and nanoprecipitation
or solvent displacement) usually do not provide conditions
for good encapsulation efficiency of hydrophilic anticancer
drugs because of the rapid partitioning of the drug into the
external aqueous phase. However, there are only few attempts through the literature to establish modification of
nanoprecipitation method for production of hydrophilic
drug loaded particles, but with even less success compared
to the emulsification diffusion methods. Formation of submicrone particles during the nanoprecipitation method depends on the differences in the surface tension between the
solvents, which leads to interfacial turbulence resulting with
breaking up the organic phase and dispersing it as a drops
in the aqueous phase6. These droplets continuously brake
down into smaller submicrone droplets due to the interfacial convective flow which contributes to renewing the interfacial surface increasing the mass-exchange rate between
the phases. During the diffusion of the organic solvent into
the water dissolved polymer chains are also dragged into
the water medium which is followed by aggregation and
NP formation. In the standard procedure the organic phase
containing the polymer that will form the nanoparticles is
poured into the aqueous phase under slight magnetic stirring. Logical approach to improve hydrophilic drug loading
1.
2.
3.
4.
REFERENCES
Acharya S, Sahoo SK. PLGA nanoparticles containing various anticancer agents and tumour delivery by EPR effect.
Adv Drug Deliv Rev doi:10.1016/j.addr.2010.10.008, 2010.
Muggia FM. Doxorubicin-polymer conjugates: further
demonstration of the concept of enhanced permeability
and retention. Clin Cancer Res 5: 7–8, 1999.
Maeda H. SMANCS and polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy. Adv
Drug Deliv Rev 46: 169–185, 2001.
imonoska-Crcarevska M, Glavas-Dodov M, Petrusevska
G, Gjorgoski I, Goracinova K. Bioefficacy of budesonide
loaded crosslinked polyeletrolyte microparticles in rat
might be rapid micromixing to induce faster supersaturation, polymer agregation and particle formation. Also we
hypothesized that dispersing the drug water solution into
the organic polymer solution (nonsolvent for the drug substance) prior nanoprecipitation, might delay the hydrophilic
drug partitioning into the outer water phase during nanopricipitation. Including these principles we developed modified
nanoprecipitation method for Irinotechan HCl loading into
amphiphilic PLGA nanocarriers. First Irinotechan HCl was dissolved in small quantity of water and dispersed in polymeric
(PLGA/amphiphillc polymers) acetone solution (ultraturax,
6500 rpm, Irinotechan is practically insoluble in water) which
was consequently mixed in water to induce nanoprecipitation (ultraturax 6500 rpm). The method was highly reproducible with nanoparticle size of d(0.5) 100 nm and efficacy of
loading ranging from 52 – 67% depending on the concentration of Irinotecan HCl solution dispersed within polymeric
acetone solution. Application of other solvents like ethanol
and acetonitrile resulted with very poor incorporation efficacy compared to water probably because of the difference
in surface tension, mixing and diffusion among water (71.99
mN/m) and aceton (22.73 mN/m), compared to acetonitrile
(28.34 mN/m) and ethanol (21.80 mN/m) (Irinotechan HCL
is sparingly soluble in water, ethanol and slightly in acetonitrile).
Increased plasma residence time and targeting due to
endothelial EPR effect is well documented in literature, and
was confirmed for these systems through our experiments.
Further comparative studies will be done for comparison of
localization of nanoparticles due to EPR effect and due to
active targeting after attachment of specific ligand at the
nanopaticle surface.
model of induced colitis. J Drug Target 17 (10): 788-802,
2009.
5. Glavas-Dodov M, Calis S, Simonoska-Crcarevska M,
Geskovski N, Petrovska V, Goracinova K. Wheat germ
agglutinin-conjugated chitosan-Ca-alginate microparticles for local colon delivery of 5-FU: Development and in
vitro characterization. Int J Pharm 381: 166-175, 2009.
6. Mora-Huertas CE, Fessi H, Elaissari A. Influence of process
and formulation parameters on the formation of submicronparticles by solvent displacement and emulsification
diffusion methods. Critical comparison. Adv Colloid Interface Sci doi:10.1016/j.cis.2011.02.005, 2011.
International Symposium on Drug Research & Development 2011
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NOVEL NANO-CARRIERS BASED ON SELF-ASSEMBLING POLYMERS: A
NEW OPPORTUNITY FOR IMPROVING TREATMENT OF DISEASES
Woei Ping CHENG
School of Pharmacy, University of Hertfordshire, College Lane, Hatfield, UK AL10 9AB
[email protected]
I
t has been estimated that 40% of the current drug
candidates in development and marketed drugs consist of hydrophobic drugs1. Poorly water-soluble drugs
present a major challenge to the pharmaceutical industry
as it can hinder or even prevent the progress of the drug
into clinical use. Self-assembling polymers consisting of hydrophilic and hydrophobic segments are being explored as
potential drug delivery systems for hydrophobic drugs since
1990s. They form different types of nano-size self-assemblies
such as polymeric micelles, vesicles, nanoparticles, disc-like
structures in aqueous environment upon the aggregations
of hydrophobic moieties. The hydrophobic core can be used
to encapsulate hydrophobic drugs for improving drug solubility and stability. Today the most widely explored self-assembled polymer architecture is block copolymer while graft
polymer is less reported in the literature. Our work focus on
the design of novel graft polymers consisting of water soluble polymer backbone, polyallylamine (PAA) grafted with hydrophobic pendant groups2. Generally, nano-carriers formed
by self-assembling polymers are mainly investigated for intravenous delivery. Here, we investigate their potential as
hydrophobic drug solubilisers for oral, ocular as well as parREFERENCES
1. Kilpatrick P. Nature Reviews Drug Discovery 2, 337, 2003.
2. Hoskins C, et. al. Polymers for Advanced Technologies, in
press, 2011.
enteral delivery. PAA grafted with aromatic pendant groups
and cholestryl pendant groups enhanced the encapsulation
of a range of hydrophobic drugs such as etoposide, griseofulvin, prednisolone, triamcinolone acetonide, propofol and
estradiol. The drug water solubility increased from 13 to 557fold depending on the type of the drug or the hydrophobic
pendant group attached to PAA. In vivo study showed the
ability of these nano-carriers in promoting oral absorption
of griseofulvin in rats3. We also investigated the potential
of these nano-carriers in pancreatic cancer therapy. Our result showed that cholesteryl- PAA was able to encapsulate a
novel hydrophobic anticancer drug and enhanced the drug
cytotoxic effect on human pancreatic carcinoma cells at a
non-cytotoxic concentration. In vivo result demonstrated
the ability of this formulation to impede tumour growth on
xenograft mice with results comparable to gemcitabine, the
gold standard therapy for pancreatic cancer when administered peritoneally4. In conclusion, nano-carriers based on
self-assembling polymers show promising potential in enhancing hydrophobic drug solubility and provide a new opportunity to improve the treatment of diseases.
3. Hoskins C, et. al. manuscript in preparation, 2011.
4. Hoskins C, et. al. Pharmaceutical Research 27, 2694-2703,
2010.
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ORAL PRESENTATIONS
LECTURES
I-09
 
INSULIN THERAPY & ROUTES OF ADMINISTRATION
Ercan TUNCEL
Uludağ University, School of Medicine, Department of Endocrinology and Metabolism, Bursa, Türkiye
I
nsulin and insulin treatment, in general, the problems
of production, oscillation and the effect can be examined on the topic.
1.
2.
3.
4.
5.
Production
Coordination with other cells of the islet
Oscillation dynamics
Delivery to the circulation
Impact the formation and termination of the effect
Forms of insulin therapy applied today, the first in the
beta cell insulin production and stored in vesicles outside
the cell to be synchronized with other cells is not provided.
Insulin molecule in vitro conditions applied to the original
molecule imitation by parenteral route. Pulsatile release of
insulin and other hormones levels in a situation according
to the balance of construction-oscillation. Therefore, the efREFERENCES
1. Rhodes CJ, Shoelson S, Halban P. Insulin biosynthesis,
processing and chemistry. In: Kahn RC (editor), Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams and Wilkins
Co, Philadelphia, 2005, p. 65-82
2. Manesso E, Toffolo GM, Saisho Y, Butler AE, Matveyenko
AV, Cobelli C, Butler PC. Dynamics of beta-cellturnover:
Evidence for beta-cell turn over and regeneration from
sources of beta-cells other than beta-cell replication in
the HIP rat. Am J Physiol Endocrinol Metab 297 (2): 32330, 2009.
3. Farmer TG, Edgar TF, Peppas NA. Effectiveness of intravenous infusion algorithms for glucose control in diabetic
fect of parenteral insulin at cellular level is decreasing, and in
particular according to the circadian rhythm can not be an
adaptation. Today, the most important problem of applied
insulin therapy which insülin normally reach to the liver from
the portal vein, these effects of insulin provided by giving
the caval system. In parenteral treatment, hepatic physiological insulin levels more than 5-10 times the amount of insulin
but can pose with the effect. In other case, half life of venous
insulin is around 5 minutes, the effect of treatment, subcutaneous and intramuscular applications, such as watches
on going and life-threatening complications of hypoglycemia is important issue. New treatment methods (pancreas
transplantation, islet replacement, intraperitoneal injection
pumps, subcutaneous pump systems with glucose sensor,
insulin molecule changes) is to resolve all the problems mentioned above as intense. Today, however, at this point is still
not obtained complete success.
patients using different simulation models. Ind Eng Chem
Res 48 (9): 4402-4414, 2009.
4. Hanley SC, Austin E, Assouline-Thomas B, Kapeluto J, Blaichman J, Moosavi M, Petropavlovskaia M, Rosenberg L.
{beta}-Cell mass dynamics and islet cell plasticity in human type 2 diabetes. Endocrinology 151 (4): 1462-72,
2010.
5. Monte SV, Schentag JJ, Adelman MH, Paladino JA. Glucose supply and insulin demand dynamics of antidiabetic
agents. J Diabetes Sci Technol 4 (2): 365-81, 2010.
International Symposium on Drug Research & Development 2011
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ORAL ANTIDIABETIC DRUGS
Nilgün Güvener DEMİRAĞ
Başkent University, Department of Internal Medicine, Divison of Endocrinology and Metabolism, Ankara, Türkiye
[email protected]
T
he incidence of type 2 diabetes is epidemically increasing worldwide. Developments of appropriate
strategies to prevent and to treat the diabetes become more important and challenging. Main goal of our treatment is to have the best glycemic control. While achieving this
goal, side effects, weight changes, hypoglycemic symptoms
should be in acceptable range. In addition to these, we also
expect these drugs to reserve or even increase the pancreatic
b cell functions and provide advantages such as prevention
or control of hypertension, hyperlipidemia, cardiovascular diseases which are commonly seen in diabetics and should be
cost effective. Characteristics of currently used antidiabetic
medications are summarized in the table below.
Although the large number of therapeutic choices now
available, it has been shown that HbA1c level still above 7%
for many diabetic patients. Oral antidiabetic therapy is the
main treatment of choice for diabetic patients regardless of
duration of disease, metabolic control, complications and
presence of cardiovascular risk factors and intensification of
treatment is usually not good enough.
Type 2 diabetes is a progressive disease therefore; preservation of b cell function must be the one of the main treatment goals while developing new treatment strategies. As
we understand the pathogenesis of diabetes, we would be
able to develop new treatment goals and alternatives.
Interventions
Expected decrease in HbA1c
Advantages
Disadvantages
Lifestyle
modifications
1-2
Low cost, many benefits
Most patients fail within 1 year
Metformin
1-1.5
Weight neutral,
inexpensive
GI distress, lactic acidosis
Sulfonylureas
0.8-1.5
Inexpensive
Hypoglycemia, weight
gain, insufficient effect on
preservation of β cell function,
adverse effects on ischemic
remodelling?
Thiazolidinediones
(glitazones)
0.8-1.0
Improved lipid profile
Weight gain, edema, anemia,
osteoporosis, possible CV risks,
expensive
GLP-1 analogs
0.8-1.2
Weight loss
GI side effects, injection,
expensive
DPP-4 inhibitors
0.5-0.9
No need for dose
adjustment, high
tolerability, weight neutral
Expensive, short duration of
experience
Alpha-glucosidase
inhibitors
0.5-0.8
Weight neutral
Frequent GI side effects, threetimes daily dosing
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ORAL PRESENTATIONS
LECTURES
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NEW ANTIDIABETIC AGENTS
Bülent Okan YILDIZ
Hacettepe University, School of Medicine, Department of Internal Medicine,
Endocrinology and Metabolism Unit, 06100 Sıhhiye, Ankara, Türkiye
I
ncreasing realization of the need for optimal glycemic
control and the shortcomings of available therapeutic
options in diabetes have led to active search for newer and improved therapeutic modalities. Physicians have
high expectations for the efficacy and safety of new drugs.
New antidiabetic agents should offer clear advantages over
available agents, lowering glucose via mechanisms ideally
associated with beneficial cardiovascular effects. Over the
past decade, increased understanding of the broader pathophysiology of type 2 diabetes has led to the development
of new agents. Incretin-based therapies represent one such
group of drugs in the pharmacotherapy of diabetes. Several
novel classes of drugs with different mechanism of action are
under development. Potential molecular targets in adipose
tissue and kidney receive particular attention.
International Symposium on Drug Research & Development 2011
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DRD 2011
TO OVERCOME THE FEAR OF JOB INTERVIEW: APPROACHES WITH SOCIAL
EFFECTIVENESS AND DIALECTICAL BEHAVIOR
Nesrin DİLBAZ
Ankara Numune Research and Training Hospital, Türkiye
P
reparing for job interview can be stresful. The fear
of negative evaluation can be basic emotion during interview. The ways to overcome fear during
job interview, To avoid nervousness during interview, How
to feel prepared for job interview are the most frequent programs that are prepared for succesful interview.
level goes up and make a peak and takes more time to return
base. This is why some people are experiencing more crises
than others. They dont have enough methods for coping
with these emotions. DBT is a method for teaching coping
and social effectiveness that will be helpful for improving the
lifes of these individuals.
Dialectical Behavior Therapy (DBT) is built by modifying
components of Cognitive Behavior Therapy and adding Zen
and mindfullness. According to DBT some people react abnormally to emotional stimulation due to environments during upbringing and due to biological factors. Their arousal
The aim of this presentation is teaching individuals to
cope with negative evaluation anxiety and fear and also
training them about social effectiveness and social skills that
will help these individuals to improve their lives.
REFERENCES
1. McKay et al. Dialectical Behavior Therapy Skills Workbook: Practical DBT Exercises for Learning Mindfulness,
Interpersonal Effectiveness, Emotion Regulation, & Distress Tolerance (2007).
2. Samuel MT, Deborah CB, Michele RC. Social effectiveness
therapy: A program for overcoming social anxiety and social phobia: A therapist guide (1997).
3. Blonna R. Maximize Your Coaching Effectiveness with Acceptance and Commitment Therapy (2011).
International Symposium on Drug Research & Development 2011
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ORAL PRESENTATIONS
LECTURES
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PERSONAL BEHAVIORS DURING JOB INTERVIEW
Aykut BORA
Bilim Pharmaceutical Company, Türkiye
T
he range of tasks in a pharmaceutical company
spans a wide area of different job descriptions and
expert knowledge, from the development of medicines to their production, the application for the necessary
permits, their marketing and communication, to the evaluation and reporting on the effects of new pharmaceuticals.
When a new product is defined a team needs to be established to design it and a process for its cost-efficient
manufacture for a large customer group. When setting up
such teams, successful and leading companies that are the
preferred choice of employees also successfully apply competency management. At Bilim İlaç one of our HR priorities
is competency management. Our competency management
process, which has been designed in line with our company’s
strategies and objectives, is based not only on the principle
of identifying the best employees and leadership personnel
of the future, but also on the principles of defining, acquiring
and retaining the competencies the company needs in order
to realise its future goals.
Our competency management process comprises the activities of recruitment of candidates with the defined skill and
qualifications, of monitoring their performances, of personal
development, motivation and retention in the company.
With the various practical implementations at our company, we pursue the objective of developing the skills of new
team members and of our present staff. With this approach
we support in particular university students with an interest in our trainee programme. Every year, our company accepts trainees from different university departments. Once
we have reached the employment stage, those among them
who stand out in terms of performance and potential are
subject to our selection and recruitment process which ensures that their current potential is fully appreciated.
International Symposium on Drug Research & Development 2011
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ABOUT THE REQUIREMENTS OF SCIENTIFIC BACKGROUND FOR JOB
APPLICATION IN DRUG RESEARCH AND DEVELOPMENT
A. Atilla HINCAL
Dean of Hacettepe University Faculty of Pharmacy (1981-94); Head of Institute of Health Sciences (1994-97)
İDE Drug Information Consultancy and Education Ltd. Co., Ankara, Türkiye
İDE Pharmaceutical Consultancy Ltd. Co., Kavaklıdere, Ankara, Türkiye
[email protected], [email protected]
O
bviously, educational background is among top
factors that impact on how successfully a candidate can perform at an R&D position. However,
several other parameters also factor in, including work performance, attitudes, image, achievements and efficiency of
the candidate in the school and thereafter, if applicable, in
the workplace, albeit short. An indispensable point that must
not be overlooked is the quality of the education received,
and whether the person in question will be able to apply his
or her attributes in the most appropriate and effective way to
perform in a manner that will best respond to the expectations of both himself and the company/establishment that
intends to employ him or her.
What we all know, or should now, that at the end of the
day the success and the returns on such success belongs
primarily to the individual. In fact, achievements of successful individuals that a county is able to generate are a major
driver of growth and development for countries. A candidate
to a position should therefore carefully weigh whether he or
she is possessing the necessary competencies; more so in
pharmaceutical R&D, which is highly versatile and where it
carries much more relevance. Main expectations from those
who intend to get into R&D include the ability to instill trust
in others, and possessing the essential characteristics of a
person of science. And for newcomers this means not letting
the years in school go to waste, and learning, and understanding that learning is the most important gain and that
success, not only in sciences but in every aspect of life, will
come only if learnings can be put to appropriate use, and in
the benefit of society.
Persons considering getting into R&D should, before
anything else, know themselves very well. They should be
well positioned to accurately weigh their own potential for
success in a given field. It should be never overlooked that
wanting something and achieving it successfully are not the
same thing. A person’s success is proportional to the degree
by which such person is able to accurately identify the areas
and issues in which he or she will be able to perform research
tasks or any other job as best as he or she can, while loving it
dearly and when circumstances warrant it, by making a sacrifice. And for persons intending to pursue a career in R&D, this
means performing a seriously thorough and down-to-earth
analysis of both themselves and of the job they are seeking to get, weighing it physically, mentally, and financially
to decide whether they are in fact up to it. They must know
that scientific research and development is a marathon of an
undertaking that requires sacrifice, constantly working, observing, performing new analyses and syntheses using all of
these inputs, while building and showcasing a creative side.
Scientific methodology requires a knowledge of past work
in the field and of comparables before embarking on a research undertaking in a specific field. Nevertheless, it must
be understood, absorbed, acknowledged and never forgotten that science cannot be constructed on replicates, errors,
and false findings.
What do we do, think, want to do, can do and what should
be look out for in this speech, when applying for a job/a
position at a science institute, in the school, during youth,
mid-life and maturity? Had it been possible to know all of
these before applying for a job, surely we would be living in
a vastly different world than what we have now. And what
have we done, what are we doing, and what will we do to
learn of these? We will address these issues using examples
from actual events and experiences.
International Symposium on Drug Research & Development 2011
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ORAL PRESENTATIONS
LECTURES
DRD 2011
I-15
 
HOW TO CHANGE AN ENZYME INTO A CYTOTOXIC AGENT: MECHANISMS
OF TARGETING TOP2 IN CANCER
John L. NITISS*, Anna ROGOJINA, Karthik SHANMUGANATHAM, Karin C. NITISS
Molecular Pharmacology Department, St. Jude Children’s Research Hospital, Memphis, TN 38105 USA
*[email protected]
D
NA topoisomerases are ubiquitous enzymes that
are required for replication, transcription, and
many other chromosomal processes1. DNA topoisomerases make transient breaks in DNA using a unique
mechanism that includes the creation of a transient enzyme/
DNA covalent intermediate. Many small molecules targeting these enzymes have been identified that exploit this
enzymatic mechanism and increase the level of enzyme covalently bound to DNA. The generation of elevated levels of
enzyme/DNA covalent complexes is the key event in cell killing by drugs targeting DNA topoisomerases, and agents that
enhance levels of topoisomerase/DNA covalent complexes
are termed topoisomerase poisons. Topoisomerase poisons
are important anti-cancer drugs, and include the camptothecins (targeting topoisomerase I) and agents such as etoposide and doxorubicin (targeting topoisomerase II)2. While
topoisomerase poisons are active anti-cancer drugs, there
are only limited tools available to predict which patients will
respond to this class of agents.
Most topoisomerase poisons are a class of inhibitors
termed interstitial inhibitors3. This mode of inhibition
depends on both the enzyme and DNA to form a drug
binding site. There is limited information about how
topoisomerase II and DNA combine to form a drug
binding site for agents such as etoposide and doxorubicin. We have combined genetic and structural approaches to identify regions of topoisomerase II that
are important for drug action. We identified sites near
the active site tyrosine that contribute to drug sensitivity. Interestingly, we also identified a domain near the
C-terminal dimerization domain that also controls DNA
cleavage. This result suggests that it may be possible to
identify potent allosteric inhibitors of topoisomerase II
that may have unique therapeutic potential.
Since topoisomerase II poisons kill cells by the generation of DNA damage, we hypothesized that understanding mechanisms for repairing or tolerating this
type of enzyme mediated DNA damage would increase
our ability to predict which tumors might be sensitive
to topoisomerase poisons, and to design safer rational
combinations of topoisomerase poison with other anticancer drugs. We were particularly interested in genes
that were important for repair of protein/DNA adducts,
Therefore, we concentrated on proteins that may be involved in nucleolytic repair of this unique adduct. We
demonstrated that yeast and human Tdp1 could hydrolyze 5’ as well as 3’ phosphotyrosyl linkages, and play
a functional role in repairing topoisomerase II mediated DNA damage4. Genetic and biochemical analysis
of the MRN complex (Mre11/Rad50/Nbs1) implicated
this protein in the removal of the topoisomerase–like
protein Spo11 from the ends of DNA during meiotic recombination. The Mre11 protein carries both endonuclease and exonuclease activities. We used an assay for
quantitating topoisomerase II/DNA covalent complexes in mammalian cells, and showed that in the absence
of the MRN complex, levels of topoisomerase II/DNA
covalent complexes were substantially elevated. These
results show at least two pathways that are involved in
nucleolytic repair of topoisomerase II mediated DNA
damage. Our studies with Tdp1 and the MRN complex
provide a strong validation for the use of genome wide
screens in model organisms to study anti-cancer drug
action, coupled with the development of specific biochemical assays that can be used to functionally assess
the importance of specific proteins in drug effects.
International Symposium on Drug Research & Development 2011
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3. Pommier Y, Cherfils J. Interfacial inhibition of macromolecular interactions: nature’s paradigm for drug discovery.
Trends in Pharmacological Sciences 26: 138-145, 2005.
4. Nitiss KC, Malik M, He X, White SW, Nitiss JL. Tyrosyl-DNA
phosphodiesterase (Tdp1) participates in the repair of
Top2-mediated DNA damage. Proc Natl Acad Sci USA
103: 8953-8958, 2006.
International Symposium on Drug Research & Development 2011
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LECTURES
REFERENCES
1. Nitiss JL. DNA topoisomerase II and its growing repertoire of biological functions.DNA topoisomerase II and its
growing repertoire of biological functions. Nat Rev Cancer 9: 327-337, 2009.
2. Nitiss JL. Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer 9: 338-350, 2009.
ORAL PRESENTATIONS
LECTURES
DRD 2011
I-16
 
ENHANCED SURVIVAL AND PARACRINE ACTIVITY OF BONE MARROW
MESENCHIMAL STEM CELLS: IMPACT ON CELL THERAPY OF ISCHEMIC
SYNDROMES
Angelo PARINI1,*, Céline MIAS1, Chiara ALFARANO1, Philippe BOURIN2, Jérôme RONCALLI1,
Daniel CUSSAC1
Inserm UMR U 1048 – Institute of Metabolic and Cardiovascular Diseases Toulouse
2
Laboratoire de Thérapie Cellulaire EFS, Pyrénées-Méditerranée, Toulouse
*
[email protected]
1
S
everal studies have shown that Bone Marrow Mesenchymal Stem Cells (BMMSCs) administration
enhances structural and functional recovery of injured organs. The beneficial effects of injected BMMSCs have
been related, in part, to their transdifferentiation in the cell
phenotype of host organs. More recently, it has been suggested that BMMSCs improve tissue regeneration through
secretion of a variety of paracrine factors. Approaches to improve the ability of grafted BMMSCs to survive and secrete
paracrine factors represent one of the challenges for the
further development of these novel therapies. In our laboratory, we designed a strategy of ex-vivo pretreatment with the
pineal hormone melatonin to improve survival, paracrine activity and efficiency of BMMSCs.
Experiments in vitro showed that, through stimulation
of specific MT receptors, melatonin induced an overexpression of the antioxidant enzyme catalase and superoxyde
dismutase-1 and increased the resistance of BMMSCs to hy-
drogen peroxide-dependent apoptosis. Using rat models of
ischemic heart or renal failure, we showed that melatonin
pretreatment in vitro strongly increased survival of BMMSCs
after intraparenchymal injection. This effect was concomitant
to increased angiogenesis, decreased fibrosis and improved
recovery of cardiac and renal functions. In order to determine whether the effects observed in vivo where related to
the secretion of paracrine factors, we tested conditioned
culture media from melatonin-treated MSCs on endothelial progenitor cells and fibroblasts. Our results showed that
conditioned media from melatonin-treated MSCs stimulate
tube formation by endothelial progenitor cells and decrease
extracellular matrix accumulation by fibroblasts.
In conclusion, our results show that melatonin behaves
as a preconditioning agent increasing survival, paracrine activity and efficiency of BMMSCs. The use of this molecule for
pretreatment of BMMSCs may represent a novel and safe approach for improving the beneficial effects of cell therapy of
solid organs.
International Symposium on Drug Research & Development 2011
32
DRD 2011
Serotonergic Control of Cardiovascular Function
Nathalie Pizzinat
Institute of Metabolic and Cardiovascular Diseases (I2MC), INSERM, Toulouse, France
S
erotonin, or 5-hydroxytryptamine (5-HT), is a naturally-occurring vasoactive substance synthetised
from L-tryptophan, primarily by central and peripheral monoaminergic neurons and the gastro -enterochromaffin cells. Serotonin released from gastrointestinal tract is
avidly taken up and stored by circulating platelets. The cardiovascular system is mostly exposed to free serotonin, the
level of which is largely controlled by platelets.
Numerous studies have demonstrated the implication of
serotoninnergic receptors in the control of vascular tone and
cardiac function. Serotonin produces complex responses on
blood pressure including vasoconstrictive and vasodilatory effects. The vasopressor response is a consequence of vasoconstriction mainly mediated by 5-HT2a receptors located on vascular smooth muscle cells. The vasodepressor response may
involve different mechanisms: vasodilatation by endothelium
release of nitric oxide and inhibition of the vasopressor sympathetic outflow by sympatho-inhibitory 5HT1 receptors.
Serotonin regulates cardiac function by inducing chronotropic and inotropic effects mediated by 5HT4 or 5HT2A
receptors. This ventricular positive inotropic responsiveness
to serotonin exacerbates in conditions of heart failure both
in rat and human ventricles. We have also underlined the
relevance of platelet derived serotonin on cardiac fibroblast
phenotype. Serotonin released by platelets, occuring principally during thrombotic events, promotes cardiac fibroblast
activation through stimulation of 5-HT2A receptors. These
effects of platelet derived serotonin may have particular relevance in acute events following ischemic injury and in the
early ventricular remodeling.
Recently, an up regulation of circulating serotonin has
been described in patients with cardiopathy and heart fail-
ure. The same observation has been made in rat submitted
to cardiac hypertrophy by pressure overload suggesting a
targeted effect of serotonin during cardiovascular pathologies. In order to address the question of serotonin function
during pathological heart remodeling, we used KO mice for
the limiting enzyme of serotonin biosynthesis (tryptophan
hydroxylase 1) TPH1. This enzyme converts L-Tryptophan to
5-hydroxy-L-tryptophan (5-HTP) which is then transformed
into 5HT by the L-aromatic amino acid decarboxylase (LAAD).
The KO TPH1 mice exhibited low level of circulating and cardiac serotonin. We submitted KO TPH1 mice and their WT littermates to a mild transverse aortic constriction (TAC). Echocardiographic analysis revealed in banded KO compared to
WT mice an exacerbated left ventricular dilatation and a decrease in fractional shortening indicating a decompensated
cardiac function. In this model of pressure overload hypertrophy induced by TAC, it appears that low level of serotonin
worsen progression to cardiac failure.
To further investigate this hypothesis, we restored 5HT
level in KO TPH1 mice by supplementation with the serotonin precursor 5-HTP. Preliminary analysis have shown that
treatment with 5-HTP induced a significant decrease in ventricular dilatation without affecting hypertrophy, measured
by echocardiography. Moreover fibrosis was decreased in
ventricle indicating a beneficial effect of 5-HTP treatment.
Fractional shortening was fully preserved in the KO TPH1
mice treated group. These data indicate that in vivo, normal
serotonin concentrations are required to prevent transition
from hypertrophy to heart failure.
These findings underline the role of serotonin in regulation of cardiovascular function and offer new prospects for
the use of serotoninergic drugs in therapies for cardiovascular diseases.
International Symposium on Drug Research & Development 2011
33
LECTURES
I-17
 
DRD 2011
ORAL PRESENTATIONS
LECTURES
I-18
 
BISACYLAZIDES: A NEW MILESTONE FOR THE SYNTHESIS OF VARIOUS
HETEROCYCLES
Metin BALCI
Department of Chemistry, Middle East Technical University, 06531 Ankara, Türkiye
[email protected]
I
socoumarins, indoles, benzoazepines represent an important class of naturally occurring compounds that
display a wide range of biological activities. Our investigation began with an attempted synthesis of the diazide
derived from the homophthalic acid1. Homophthalic acid 1
was reacted with thionyl chloride, dimethy formamide and
sodium azide in the presence of tetrabutyl ammonium bromide as a catalyst. Only, 6H-dibenzo[c,h]chromen-6-one (2)
was formed in 41% yield 1,2.
The azide derived from the half ester 3 was synthesized.
Conversion of the formed azide into the corresponding urethane in methanol followed by cyclization and acetylation
gave the indol derivative4. On the other hand, the reaction
of homophthalic anhydride with hydrazine in dimethyl formamide resulted in the formation of a new pyrazole derivative5.
O
NH
R
N
R
N
O
NR
O
NR
O
NH
O
O
O
O
N C
O
O
N
O
O
COOH
COOH
SOCl2, DMF
O
Furthermore, the synthesis of benzodiazepinone and
dihydrofuropyrimidinone3, isoquinolinone and furopyrrol
starting from the corresponding diacids will be discussed4-7.
Bu4NBr, NaN3
3
COOCH3
1
COOMe
N
OH
4 H3 C
COOH
2
O
O
O
5
N
NH
REFERENCES
1. Özcan S, Şahin E, Balcı M. The synthesis of unusual isocoumarin derivatives: the chemistry of homophthalic acid.
Tetrahedron Lett 48: 2151-2154, 2007.
2. Özcan S, Balci M. The Chemistry of Homophthalic Acid:
A New Synthetic Strategy for Construction of Substituted Isocoumarine and Indole Skeletons. Tetrahedron 64:
5531-5540, 2008.
3. Koza G, Özcan S, Şahin E, Balci M. Regioselective Synthesis of Dihydrofuro[3,2-d]pyrimidin-2(1H)-one Skeleton:
A New Class of Compounds. Tetrahedron 65: 5973-5976,
2009.
4. Dengiz Ç, Özcan S, Şahin E, Balcı M. A new synthetic
Methodology for the construction of 1,3,4,5-tetrahydro2H-1,3-benzodiazepin-2-one skeleton. Synthesis: 13651370, 2010.
5. Deliömeroglu MK, Özcan S, Balci M. A short and efficient
construction of the dibenzo[c,h]chromen-6-one skeletone. Arkivoc 148-160, 2010.
6. Koza G, Karahan E, Balci M. Helv Chim Acta 93: 1698-1704,
2010.
7. Özcan S, Çağatay D, Deliömeroğlu KM, Şahin E, Balci M.
A novel one-pot three component reaction: Synthesis of
isocoumarin-condensed pyrazols. Tetrahedron Lett 52:
1495-1497, 2011.
International Symposium on Drug Research & Development 2011
34
DRD 2011
Dendrimers as potential drug carriers; MICROWAVE-ASSISTED
SYNTHESIS OF PAMAM TYPE DENDRIMERS
Cemil DIZMAN1, Tezcan PARALI1, Ali Serol ERTÜRK1, Metin TÜLÜ1,2,*
1
Department of Chemistry, Fatih University, 34500 İstanbul, Türkiye
Department of Chemistry, Yıldız Technical University, 34210 İstanbul, Türkiye
*
[email protected], [email protected]
2
P
oly(amido amine) (PAMAM) type dendritic
macromolecules have become significant impact in the field of material sciences and are
one of the major starting points for nanotechnology
as a result of the numerous modifications that can be
conducted, either on the surface or within their molecular infrastructure, thus taking advantage of their
unimolecular micelle properties1. These host cavities,
maintained by the dendritic branches, allow for the incorporation of nanoparticles as well as metal particles,
which make these attractive in catalysis and imaging
studies. Especially Dendritic hosts with hydrogen bonding receptors have been made by Newkome et al.2
The poly(amidoether) dendrimers contain (2,6-diacylamino)pyridine moieties that serve as donor-acceptordonor (DAD) H-bonding units. Barbituric acid, a guest
that contains two ADA arrays, is bound to the dendrimer, as evidenced by 1H NMR measurements. For the
higher generation dendrimers, intramolecular selfassociation competes with guest binding. The solubility
of these fractal constructs can be tailored depending
on their surface modifications. Highly water-soluble,
neutral dendrimers appended with, grown from, or acting as hosts to specific molecules give rise to a wide
variety of biomedical applications such as drug delivery systems and MRI imaging agent3. The inherent
supramolecular or supramacromolecular chemistry has
been exploited but the design and construction of uniquely tailored macrostructures have just begun. Laser
dyes, as well as electron and energy donor and acceptor functionality, have also been paired with these fractal constructs in order to probe their uses in the field
of molecular electronics. With their synthetic control,
appearently unlimited modifications and wide variety
of potential applications, as well as their commercial4,5
availability, these 1à 2 or 1à 3 branched dendrimers
have become an important nanostructured tools for
diverse pratical applications. Present study6 mainly covers 1 à 3 branched non-chiral dendrimers prepared by
a divergent process but selected functional surfaces
having antibacterial or antimicrobial properties. As a
synthetic method Microwave Assisted Technique has
been applied. More detailed; ethylenetriamine (ETA) or
trimethylolpropane tris[poly(propylene glycol), amine
terminated] ether were selected as cores and methyacrylate (MA) and ethylenediamine (EDA) were alternatively used as building blocks. Novel PAMAM type dendrimers were synthesized up to the 4th. generations.
In order to make the molecules water soluble, surface
groups were modified by 2-amino-2-(hydroxymethyl)
propane-1, 3-diol (AT). The syntheses were carried out
mostly by applying microwave irradiation technique
and correlated with conventional methods. The products were characterized via Elementary Analysis (EA),
Fourier Transform Infra Red (FT-IR) and 1H NMR-13C NMR
spectroscopy. Since all dendrimer/substrate complexes
were completely miscible with water in all proportions.
When the bound substrates are drug moieties, then the
resulting complexes could be considered as potential
drug delivery systems. In the similiar studies (Scheme
1),7 flow calorimetry demonstrates that dendrimers
were able to release their hydrophobic guests when in
contact with a biological cell.
International Symposium on Drug Research & Development 2011
35
LECTURES
I-19
 
ORAL PRESENTATIONS
LECTURES
DRD 2011
HO OH
HO
HN O
HO
HO
NH
HO
N
O
NH
O OH
HO
HO
HO
N O
H
H
N
HO
N
HO
O
HO
OH OH
OH
O NH
OH
OH
HN
OH
N
O
HN
O
O
N
N
H
N
N
HN O
N
NH
HN
O
O
NH
HO
HO OH
HO
O
H
N
OH
OH
OH
OH
HO
HO
O
-
-
HO
HOHO
O O
O
N
N
H
N
N
N
HN O
HN
N
O
O
NH
HO
HO OH
A
O
OH
OH
NH OH
O
H
N
O NH
N
NH
OHOH
O
O
N
N
H
O
OH
HN
O
O
OH OH
OH
O NH
OH
OH
HN
OH
N
O
N
O
HO
HO
HO
N O
H
H
N
HO
N
HO
O
HO
O
HN
NH
NH
OH
OH
O
NH OH
O NH
N
O
HO
HOHO
OH O
O
N
N
H
N
O
HO
HO
HO OH
HO
HN O
OH
OH
OH
O
HN
OH
HO
HO
OH
OHOH
B
Scheme 1. Possible interactions: Unlikely hydrogen
REFERENCES
1. Yang H, Lopina ST. Penicillin V-conjugated PEG-PAMAM
star polymers. J Biomater Sci Polymer Edn 14(10), 1043–
1056, 2003.
2. Newkome GR, Woosley BD, He E, Moorefield CN, Guther
R, Baker GR, Escamilla GH, Merril J, Luftmann H. Cascade
Polymers: Synthesis and characterization of one directional arborols based on adamantane. Chem Commun
2737-2738, 1996.
3. Newkome GR, Shreiner CD. Poly(amidoamine), polypropylenimine, and related dendrimers and dendrons possessing different 1 à2 branching motifs: An overview of
the divergent procedures. Polymer 49, 1-173, 2008.
4. http://www.dendritech.com/
5. http://www.frontiersci.com/
6. Tulu M, Aghatabay NM, Senel M, Dızman C, Paralı T, Dülger B. Synthesis, characterization and antimicrobial activity of water soluble dendritic macromolecules, European
Journal of Medicinal Chemistry 44, 1093-1099, 2009. 7. Beezer AE, King ASH, Martin IK, Mitchel JC, Twyman LJ,
Wain CF. Dendrimers as potential drug carriers; encapsulation of acidic hydrophobes within water soluble
PAMAM derivatives. Tetrahedron 59, 3873-3880, 2003.
International Symposium on Drug Research & Development 2011
36
ORAL PRESENTATIONS
DRD 2011
Monitoring Reovirus entry and endosomal trafficking in live
non-polarized and polarized cells by single viral particle
tracking
Cömert Kural1, Steeve Bulant1, Tomas Kirchhausen1,2
Immune Disease Institute, Harvard Medical School, Boston, MA.
Department of Cell Biology, Harvard Medical School, Boston, MA.
1
2
O
ncolytic viruses infect and kill cancer cells preferentially; either by direct lysis of the tumour
cells or by serving vectors for delivery of genes
encoding enzymes that convert non-toxic pro-drugs into
cytotoxins, e.g., ganciclovir. Recently, reoviridae family virions have been shown to have oncolytic properties and proposed as a possible tumor-killing therapy for cancer treatment. However, generation of tumour selectivity is a critical
factor for constraining the oncolytic activity to cancerous
cells without affecting the healthy tissue. Here we employed
high-resolution fluorescence microscopy to study internalization and trafficking of reovirus particles in polarized
epithelium and non-polarized cells. We controlled the viral
entry routes by drugs such as amiloride and dynasore in order to repress macropinocytosis or clathrin-mediated endocytosis, respectively. Our results indicate that virions entered
non-polarized cells very inefficiently both by clathrin-mediated endocytosis and by macropinocytosis-like mechanism.
In contrast, efficient entry of virions at the apical surface of
polarized cells was strictly mediated by clathrin-mediated
endocytosis. Our data provide the first real-time analysis of
virus entry into polarized cells and define the entry mechanism of reovirus. More generally, our observations emphasize the importance of studying virus entry in relevant cell
types, especially for pathogens that invade hosts through
the polarized epithelium.
International Symposium on Drug Research & Development 2011
41
ORAL PRESENTATIONS
O-01
ORAL PRESENTATIONS
DRD 2011
O-02
Computational study of the conformational interconversion
of 4,5-dimethyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one
Sajid Jahangir1,2,* , Walter M. F. Fabian1
1
Institute of Chemistry, Karl Franzens University, Graz, Heinrichstrasse 28, A-8010 Graz, Austria,
Department of Chemistry, Federal Urdu University of Arts, Science and Technology, Gulshan-e-Iqbal Science
Campus, Karachi, Sindh, Pakistan
*[email protected]
2
I
nterconversion barriers between different conformations of R and S enantiomer of 4,5-dimethyl-1,3,4,5tetrahydro-2H-1,5-benzodiazepin-2-one were
calculated. Starting structures of (R) and (S) enantiomer of
4,5-dimethyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one were created with the Sybyl molecular modeling package. Ten conformations of each compound were
obtained by Sybyl simulated annealing using the force field
MMFF94s followed by B3LYP/6-31G(d) optimization. After
optimization, four unique conformations (Figure 1) of each
analogue were selected for further calculations. The ground
state structure and the transition state geometries were fully
optimized, and each stationary point found was characterized by a frequency calculation followed by IRC calculations.
Transition state structures were characterized by one imaginary frequency. The interconversion barrier was calculated
by the difference between the total energies, including the
zero-point and thermal corrections, of the minimum and the
transition state (Figure 2). The minimum calculated interconversion barrier, DG≠ = 1.77 kcal/mol, was observed for interconversion of 3rd conformation of 1S to 4th conformation
of 1S whereas the maximum interconversion barrier, DG≠ =
7.48 kcal/mol, for corresponding conformation of 1R. These
results are unexpected and more investigations are required
to get in depth information about interconversion barriers of
these types of compounds.
Figure 1
Figure 2
International Symposium on Drug Research & Development 2011
42
DRD 2011
DETERMINATION OF ANTIOXIDANT ACTIVITY OF SOME BIOLOGICALLY
IMPORTANT SAMPLES THROUGH CYCLIC VOLTAMMETRY
Haji Muhammad*, Iftikhar Ahmad Tahiri,, Mohammad Ali Versiani, Obaid Khaliq,
Fahad Hassan, M. Latif , M. Samiuddin Qadri
Department of Chemistry, Federal Urdu University of Arts, Science and Technology, Gulshan-e-Iqbal Campus,
Karachi-75300, Pakistan
*[email protected]
T
raditional herb medicines are an important part of
the health care system of Subcontinent of South
Asia. Ayurveda, supposed to be the oldest medical system in the world, provides potential leads to find active and therapeutically useful compounds from plants. In
the present work eleven natural samples (Turmeric, Orange
juice, Almond, Pistachio, Tea, Ginsing, Green Tea, Olive oil,
Vinegar, Narrium indicum Extract, Glucose) were selected to
explore their antioxidant activities through cyclic voltammetry (CV). Although most of them are already known for
their antioxidant activities but this is the first time that their
antioxidant properties have been investigated through CV.
Superoxide free radical was generated by the run of CV of
0.1M tetrabutylammonium perchlorate (TBAClO4) in acetonitrile at 100mV scan rate, where Glassy Carbon (GC) was used
as working electrode. In the presence of natural samples the
oxidation peaks of superoxide were obtained in decreased
anodic current. The decreased or diminished oxidation peak
current is a clear indication of antioxidant activity of the
studied samples. Out of eleven sample, eight samples (Ginsing, Turmeric, Orange juice, Almond, Pistachio, Tea, Green
Tea, Olive oil) have shown high antioxidant activity whereas three sample (Vinegar, N. indicum Extract, Glucose) have
shown low antioxidant activity.
International Symposium on Drug Research & Development 2011
43
ORAL PRESENTATIONS
O-03
ORAL PRESENTATIONS
DRD 2011
O-04
SYNTHESIS OF FOLATE-PEG-DOXORUBICIN CONJUGATE,
RADIOLABELLING WITH TECHNETIUM-99m AND RESEARCH INTO ITS
APPLICATIONS AS AN IMAGING AGENT IN CANCER
Güliz AK*, Şenay ŞANLIER
Ege University, Faculty of Science, Biochemistry Department, 35100 Izmir, Türkiye
*[email protected]
P
rostate cancer is a significant problem, reported as
the leading cancer diagnosed in males1. Folat receptors (FR) exhibit limited expression on healthy
cells, but are often present in large numbers on cancer cells.
For example, FRs are overexpressed on epithelial cancers
of the ovary, mammary gland, colon, lung, prostate, nose,
throat, and brain. FR has the ability to transport both folic
acid and folate-linked cargos of many sorts (i.e., chemotherapeutics, imaging agents, proteins, liposomes, nanoparticles,
etc.)2. Therefore folic acid displays multiple desirable characteristics for use in the targeting of cytotoxic drugs and imaging agents to cancer tissue3. The anthracycline antibiotic
doxorubicin has a broad spectrum of antineoplastic action
and the clinical use of doxorubicin shows a large-spread field
of toxicities, the most important is the cardiotoxicity, but also
palmar plantar erythrodysesthesia is a dose-limiting severe
side-effect4. The aim of this work is synthesis of folate-PEGdoxorubicin conjugate, labelling with technetium-99m and
research into its radiopharmaceutical potential as a cancer
imaging agent for targeting. Folate-poly(ethylene glycol)doxorubicin (FOL-PEG-DOX) conjugate was prepared as
described in a previous study and this nanoconjugate was
characterized by NMR spectroscopy, zetasizer and SEM5.
Radiolabelling of FOL-PEG-DOX with technetium-99m was
performed adjusting of pH between 3 and 4. After the quality control tests,99mTc-FOL-PEG-DOX and the control groups
(99mTc-PEG-DOX and 99mTc-DOX) were used in biodistribution
studies on male rats and the animal experiments were ap-
proved by the Institutional Animal Review Committee of Ege
University. Obtained datas showed that uptake of kidney
and prostate which overexpress folate receptor was higher.
In addition, target/non-target organ ratio was 160. As a consequent, it was believed that 99mTc-FOL-PEG-DOX radiolabelled conjugate has a high radiopharmaceutical potential
as a prostate cancer imaging agent and treatment response
monitoring agent.
1.
2.
3.
4.
5.
REFERENCES
Hattori Y., Maitani Y. Enhanced in vitro DNA transfection
efficiency by novel folate-linked nanoparticles in human
prostate cancer and oral cancer. Journal of Controlled Release 97:173–183, 2004.
Hilgenbrink A.R., Low P.S. Folate Receptor-Mediated Drug
Targeting: From Therapeutics to Diagnostics. Journal of
Pharmaceutical Sciences 94 (10): 2135-2146, 2005.
Low P.S., Kularatne S.A. Folate-targeted therapeutic and
imaging agents for cancer. Current Opinion in Chemical
Biology 13:256–262, 2009.
Jung K., Reszka R. Mitochondria as subcellular targets for
clinically useful anthracyclines. Advanced Drug Delivery
Reviews 49:87–105.
Yoo H.S., Park T.G. Folate-receptor-targeted delivery of
doxorubicin nano-aggregates stabilized by doxorubicin–PEG–folate conjugate. Journal of Controlled Release
100:247–256, 2004.
International Symposium on Drug Research & Development 2011
44
DRD 2011
Bioengineering technique used to study the effects of
grapefruit extract containing emulsion on human skin
mechanical parameters
Naveed AkhtaR*, Gulfishan, Haji M Shoaib Khan, Tariq Mahmood, Barkat A Khan
Department of Pharmacy, Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur,
63100, Bahawalpur, Pakistan
*
[email protected]
T
he Cutometer equipped with a 2-mm diameter
suction probe is a device suitable for assessing
mechanical parameters of the skin. The objective of this study was to determine the effect of grapefruit
extract containing emulsion on mechanical parameters of
skin while applied by healthy human volunteers. The noninvasive method applied can be useful for investigation of
age-related changes.
For this purpose, base containing no active material and a
formulation containing concentrated crude extract of grapefruit (2%) in the internal aqueous phase (W/O emulsion)
were tested. Both base and formulation were applied to the
cheeks of human volunteers for a period of four weeks. Different mechanical parameters of skin like R0, R1, R2, R3, R4,
R5, R6, R7, R8 and R9 were measured by the cutometer and
results were evaluated statistically to justify any effect produced by these emulsion. Applying ANOVA with respect to
time, it was found that results for R0, R1, R3, R4, R5, R6 and R8
were significant after the application of formulation while R3
and R8 values after the application of base were significant.
In this study, the instrumental measurements produced
by the formulation regarding various skin mechanical parameters were comparable to that of base.
International Symposium on Drug Research & Development 2011
45
ORAL PRESENTATIONS
O-05
ORAL PRESENTATIONS
DRD 2011
O-06
STUDY ON A COMMERCIAL ANTHELMENTIC COMBINATION EFFICACY
AGAINST FASCIOLA spp, DICROCOELIUM DENDRITICUM AND MONIEZIA
spp IN SMALL RUMINANTS IN URMIA, IRAN
Sohrab Rasouli1,*, Mohammad Sadaghian2
1Islamic Azad University- Urmia Branch, Faculty of Veterinary Medicine, Dept. of Pathobiology, Urmia, Iran
2Islamic Azad University- Shabestar Branch, Faculty of Veterinary Medicine, Dept. of Pathobiology, Shabestar, Iran
*[email protected]
G
astrointestinal parasites (GIP) and especially liver
trematodes cause marked production losses to
livestock throughout the world. Control of ruminants GIP over the past decades has been achieved by the
use of anthelmintic drugs, but control of GIP is becoming
more difficult due to the increased resistance of parasites to
common anthelmintics, which has been reported from all
over the world1. This study was performed to evaluate the effectiveness of a commercial anthelmintic combination (Felonil®, 37.5 mg Levamisole HCl and 50 mg Triclabendazole/ml)
against Fasciola spp, Dicrocoelium dendriticum and Moniezia
spp of small ruminants in Urmia surroundings, northwest of
Iran.
One thousand free grazing sheep and goats of both
sexes aged above 4 month were primarily subjected to
faecal examination using Mc master technique2 then
100 naturally infected sheep and goats were randomly
selected for the study and were divided into two equal
groups. Then treatment group animals were drenched
1ml/5 kg BW of Felonil® whereas the others received
similar amounts of normal saline as placebo. Faecal
REFERENCES
1. Min BR. and Hart SP. Tannins for suppression of internal
parasites. J Animal Sci 81: E102-109, 2010.
samples were taken directly from rectum at day 1, 3,
7 and 14 after treatment from both groups’ subjects.
Parasites’ egg per gram of faeces (EPG) was examined
using mentioned technique. Also, at the end of period,
5 animals from each group were necropsied to investigate adult worms.
Dominant effect of treatment on Fasciola spp EPG
was observed from 3rd day and there was significant
decrease in EPG levels of the other sampling sessions
up to the end of study (P<0/05), but no similar significant reduction were observed about Dicrocoelium dendriticum and Moniezia spp. According to results, administration of the dose recommended by Manufacturer
Company, has not appropriate efficacy against all adult
flatworms and it is impossible to rely on this combination as a broad spectrum anthelmintic drug at least in
recommended dose. So it can be concluded that field
evaluation of each new product, about every area parasites population is necessary to sufficient control of
these parasites.
2. Urquhart GM. and others. Veterinary Parasitology.
2nd ed. United Kingdom: Blackwell Publishing, 2003,
p. 276-281.
International Symposium on Drug Research & Development 2011
46
DRD 2011
Heavy Metals Toxicity in Root Vegetables Irrigated by
Industrial Waste Water Karachi
Kousar Yasmeen*, Muhammad Ali Versiani, Rafee Arain, Qamarul Haque, Sajid Jahangir,
Iftikhar Ahmed Tahiri
Department of Chemistry, Federal Urdu University of Arts, Science and Technology, Gulshan-e-Iqbal Campus,
Karachi-75300, Pakistan
*
[email protected]
I
n Karachi city, waste water is used for irrigating vegetables fields. Long-term use of wastewater may cause
accumulation of heavy metals in agricultural soils and
vegetables. Heavy metals such as Cd, Cr, Zn and Mn act as
micronutrients at lower concentrations but they become
toxic at higher concentration. To elucidate the effect of waste
water on heavy metal concentration in vegetables, soil and
water, a region fertilized with industrial waste water in Malir
was selected for study. The present study is undertaken to
determine concentrations of Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb
and Zn in waste water, soil and six root vegetables by using the atomic absorption spectrophotometer (AAS). The
six vegetables investigated include: beet, carrot, turnip, radish, potato and sweet potato. Industrial waste water (IWW)
samples were examined for pH, Conductivity, Total Dissolved
Solids, Alkalinity, Acidity, Hardness, SO4-2,Cl-, Biological Oxygen Demand, Chemical Oxygen Demand, Dissolved Oxygen
and heavy metals (Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb and Zn). The
samples were collected over a three year period, 2007-2009.
The results revealed that metals were in the following order
(three year average) in IWW Malir: Ni < Cd < Mn < Pb < Cr <
Co < Cu < Zn < Fe. Root vegetable and soil irrigated with IWW
Malir showed elevated levels of metals except Zn in three
year study and Pb in radish (0.046 mg·L-1) and in turnip (0.020
mg·L-1) in 2008 and 2009, respectively. Maximum concentration of Fe was found in beet leaf 3.798 mg·L-1(2007), 5.980
mg·L-1(2008) and 6.80 mg·L-1 in 2009.
International Symposium on Drug Research & Development 2011
47
ORAL PRESENTATIONS
O-07
ORAL PRESENTATIONS
DRD 2011
O-08
Formulation And Characterization Of Two Bleach Creams Of
Mulberry Extract And Comparison Of Their Effects On Human
Skin Melanin And Erythema
Fatima RASOOL1,*, Shams UL-HASSAN2, Haji Muhammad Shoaib KHAN2, Naveed AKHTAR2,
Barkat Ali KHAN2, Atif ALİ2, Asadullah MADNİ2
1University College of Pharmacy, The University of the Punjab, Lahore, Pakistan
2Department of Pharmacy, Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur
*[email protected]
T
he aim of the study was to formulate two stable
creams containing different concentrations of
mulberry extract and comparison of their effects
on human skin.
weeks. Both formulations were applied to the cheeks of human volunteers for four weeks. Different skin parameters like
skin melanin, erythema and skin pH were monitered every
week to compare any effect produced by these creams.
Concentrated ethanolic extract of the bark of shoots of
Morus alba tree, was entrapped in the inner aqueous phase
of w/o emulsion.. Formulation 1 containing 1% extarct and
formulation 2 containing 3% extarct in the internal aqueous
phase were prepared. Samples of both formulations were
stored at different accelerated conditions i.e., 8oC, 25oC, 40oC,
Significant (p≤0.05) changes in the pH of both formulations were observed at different storage conditions with the
passage of time. Similar effects on skin melanin i.e., decrease
in melanin and erythema were produced by both formulations. Statistically insignificant effects on skin pH were produced by both the formulations.
40oC+75% RH for a period of four weeks to predict the stability of these creams. Different stability parameters like color,
liquefaction, phase separation, centrifugation, electrical conductivity and pH were measured at all different storage conditions at different time intervals for a study period of four
It can be concluded that the effects of ethanolic extract
of Morus alba (L.) in different concentrations i.e., 1% and 3%
are same on human skin. Both the creams were good with
respect to sensory evaluation.
International Symposium on Drug Research & Development 2011
48
DRD 2011
A NOVEL POLYMORPH OF ZOLEDRONIC ACID AND PROCESS FOR ITS
PREPARATION
Bekir KARLIĞA
Deva Holding A.Ş. Çerkezköy API Üretim Tesisi, Organize Sanayi Bölgesi Atatürk Mh., Fatih Blv. No: 26, Karaağaç
59500, Çerkezköy, Tekirdağ, Türkiye
[email protected]
Z
oledronic acid1 (or zoledronate) is a type of
bisphosphonate which is designated chemically
as (1-hydroxy-2-imidazol-1-yl-1-phosphono-ethyl) phosphonic acid of the Formula I.
N
N
O
N
The discovery of new polymorphic forms2 of a pharmaceutically useful compound provides a new opportunity to
improve the performance characteristics of a pharmaceutical product.
HCl
OH
2-imidazole acetic acid HCl
1) Phosphorus acid, PCl3
Sunfloweroil
2) H2O
3) Acetone
OH
OH
P O
HO P OH
O OH
N
Zoledronic Acid
Formula I
It is used in the treatment of bone disorders, such as
hypercalcemia caused by cancer, Paget’s disease and osteoporosis and also used to prevent patients from skeletal
fractures.
REFERENCES
1. Jaegg Knut A, Widler L, inventors; Basel and Muchenstein. Substituted alkanediphosphonic acids and pharmaceutical use. US patent 4,939,130. 1987 February 27.
The present study aims to provide a novel polymorph of
zoledronic acid denominated as Form Y, which has considerably good flow properties and stability due to low hygroscopicity. A further purpose of the study is to provide a process for producing Form Y with higher reproducibility and
material economy.
2. Aronhime Judith, Lifshitz-liron, inventors; Teva Pharmaceutical. Zoledronic acid a crystal forms, Zoledronate
sodium salt crystal forms, Amorphous Zoledronate sodium salt, and processes for their preparation. EP patent
200440756693. 2004 Jun 07.
International Symposium on Drug Research & Development 2011
49
ORAL PRESENTATIONS
O-09
DRD 2011
ORAL PRESENTATIONS
0-10
SYNTHESIS OF EZETIMIBE: A SELECTIVE CHOLESTEROL ABSORPTION
INHIBITOR
Esen BELLUR ATICI1,*, Mustafa ADIYAMAN2
Deva Holding A.Ş., Çerkezköy API Production Plant, Organize Sanayi Bölgesi, Atatürk Mh. Fatih Blv. No: 26
Karaağaç, 59500 Çerkezköy – Tekirdağ, Türkiye
2
Zentiva Health Products, Küçükkarıştıran, 39780 Lüleburgaz – Kırklareli, Türkiye
*
[email protected]
1
H
igh blood-cholesterol levels constitute a major
risk factor for cardiovascular disease1. The total
blood cholesterol level is primarily regulated by
two complementary mechanisms: (1) cholesterol biosynthesis in the liver and (2) absorption of dietary cholesterol in the
small intestine2. Since their introduction in the late 1980s,
statins have by far become the predominant class of current
lipid-lowering drugs3. Statins inhibit HMG-CoA reductase,
the enzyme that catalyzes the rate-limiting step of cholesterol biosynthesis in the liver. However, the patient response to
statins varies greatly, with half of all patients on statin therapies failing to reach their cholesterol goals 1.
Ezetimibe, designated as 1-(4-fluorophenyl)-3(R)-[3-(4fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxy phenyl)-2azetidinone, which was approved in late 2002 for use either
alone and in combination with a statin, is the only example to
date of a drug that involves inhibition of intestinal cholesterol
absorption. Ezetimibe, alone or in combination with statins,
is indicated as adjunctive therapy to diet for the reduction of
elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (Apo B) in patients with
primary hypercholesterolemia; and for the reduction of sitosterol and campesterol levels in patients with homozygous fa1.
2.
3.
4.
REFERENCES
Bruckert E. New advances in lipid-modifying therapies for
reducing cardiovascular risk. Cardiology 97: 59-66, 2002,
and references therein.
Bays H. Ezetimibe. Expert Opin Investig Drugs 11: 15871604, 2002, and references therein.
Earl J, Kirkpatrick P. Ezetimibe. Nat Rev Drug Discovery 2:
97-98, 2003.
Kværnø L, Werder M, Hauser H, Carreira EM. Synthesis and
in vitro evaluation of inhibitors of intestinal cholesterol absorption. J Med Chem 48, 6035-6053, 2005, and references
milial sitosterolemia. Ezetimibe, in combination with statins, is
indicated for the reduction of TC and LDL-C in patients with
homozygous familial hypercholesterolemia4.
The novel structure and potent biological activity of Ezetimibe has prompted intense synthetic interest in the synthetic
community which led to the development of several syntheses
for this molecule. Many of these routes have utilized chiral auxiliary based synthesis and used flash chromatography or chiral
HPLC for the purification of the intermediates5. Impurity profile
of a drug substance is critical for the safety assessment of Active
Pharmaceutical Ingredients (API) and it is mandatory to identify and characterize the present impurities above the accepted
limits of 0.1%6. As three asymmetric carbons in the ezetimibe
molecule give rise to eight stereoisomers, the synthesis of the
final product with the required stereochemistry is a significant
challenge. Although different synthetic routes of ezetimibe and
the intermediates have been discussed in literature, we have
developed a process allowed us to obtain ezetimibe with high
stereochemical and chemical purity on a large-scale7.
therein.
5. Castañer RM, Sorbera LA, Castañer J. Ezetimibe. Drugs of
the Future 25: 679–685, 2000, and references therein.
6. ICH Guideline, Impurities in New Drug Substances Q3A
(R2), October 25, 2006.
7. Bellur Atıcı E, Adıyaman M. Zentiva. Novel intermediates useful for the preparation of (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)
azetidin-2-one and processes for producing the same. Appl.
No: TR 2010 00116. 2010 Jan 08, and references therein.
International Symposium on Drug Research & Development 2011
50
POSTER PRESENTATIONS
DRD 2011
SYNTHESIS OF 1-(4-HYDROXY-3-AMINO-1-YL-METHYL-PHENYL)-3PYRIDINE-3-YL-PROPENONES
Sinan BİLGİNER, Halise İnci GÜL*
Atatürk University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Erzurum, Türkiye
*
[email protected]
C
halchone compound, 1-(4-hydroxy-3-amino-1ylmethyl-phenyl)-3-pyridin-3-yl-propenone, was
synthesized using p-hyrdoxyacetophenone and
pyridine-3-carbaldehyde in ethanol at 800C. Corresponding
Mannich bases with morpholine (1), piperidine (2), 4-methylpiperazine (3), and pyrolidine were synthesized by conventional method. The mixture of chalcone compound, paraformaldehyde and corresponding amine was heated in ethanol
for sometime. It was 39.5 h for 3 and 4, 51 h for 1 and 84 h
for 2). Heating period was stopped according to TLC and 1H
Crude compounds were purified by column chromatography by using (diisopropyl ether:methanol (80:20) for 1,
ethylacetate:methanol (90:10) for 2, chloroform:methanol
(95:5) for 3 and 4. Chemical structures of the compounds
were confirmed by 1 H NMR and 13C NMR spectra.
Acknowledgement: This study was supported by
Ataturk University Research Foundation (Project Number:
2009/317).
NMR results.
International Symposium on Drug Research & Development 2011
55
POSTER PRESENTATIONS
P-001
POSTER PRESENTATIONS
DRD 2011
P-002
CYTOTOXICITY OF N,N’-BIS[1-ARYL-3-(PIPERIDINE-1’-YL) PROPYLIDENE]
HYDRAZINE DIHYDROCHLORIDES AGAINST BREAST CANCER CELLS
(T47D)
Halise İnci Gül1, Kaan Küçükoğlu1,*, Rengül-Çetin Atalay2
Atatürk University, Faculty of Pharmacy, Dept. of Pharmaceutical Chemistry, 25240 Erzurum, Türkiye)
Bilkent University, Faculty of Science, Dept. of Molecular Biology and Genetics, Faculty of Science, Bilkent
University, 06800 Ankara, Türkiye
*
[email protected]
1
2
B
reast cancer is the leading cause of cancer death
among women with approximately a million new
cases each year1,2. Despite there are some therapy
options such as surgery, chemotherapy, endocrine and radiation therapy in the treatment of breast cancer, several side
effects and drug resistance to chemotherapeutic agents are
often encountered problems in the course of therapy3.
Hydrazones of Mannich bases are formed by the reaction
of Mannich bases with hydrazine. A few studies report the cytotoxic activities of them4,5. In the present study, N,N’-bis[1-aryl-3-(piperidine-1’-yl)propylidene]hydrazine dihydrochlorides
(compounds P1-P8) were synthesized and their cytotoxic
activities were evaluated against breast cancer cells (T47D).
Alterations in biological activity depending on modifications
in chemical structure were also followed. The aryl part was
changed as phenyl in P1, 4-methylphenyl in P2, 4-methoxyphenyl in P3, 4-hydroxyphenyl in P4, 4-chlorophenyl in P5,
3-methoxyphenyl in P6, 4-fluorophenyl in P7 and 4-bromophenyl in P8. Cytotoxicities of the compounds were determined as described6,7 and shown at Table 1 (IC50, µM).
REFERENCES
1. McPherson K, Steel CM, Dixon JM. ABC of breast diseases,
breast cancer-epidemiology, risk factors, and genetics.
BMJ 321: 624-628, 2000.
2. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 55: 74-108, 2005.
3. Bange J, Zwick E, Ullrich A. Molecular targets for breast
cancer therapy and prevention. Nat Med 7: 548-551, 2001.
4. Gul HI, Das U, Pandit B, Li PK. Evaluation of the cytotoxicity of some mono-Mannich bases and their corresponding
azine derivatives against androgen-independent prostate
cancer cells. Arzneimittelforschung 56: 850-854, 2006.
Table 1: Cytotoxic activity of P Series against breast cancer cells (T47D)
Compound
Ar
Cytotoxicity (IC50), (µM)
P1
C6H5
19.90
P2
4-CH3C6H4
4.83
P3
4-CH3OC6H4
*
P4
4-HOC6H4
51.59
P5
4-ClC6H4
114.93
P6
3-CH3OC6H4
229.82
P7
4-FC6H4
10.05
P8
4-BrC6H4
16.09
5-FU
7.0
*: No inhibition
Acknowledgement: This study was supported by the
Research Foundation of Ataturk University (Project Number:
2007/58), Erzurum (Turkey).
5. Dimmock JR, Erciyas E, Kirkpatrick DL, King KM. Evaluation of some azines of aminomethylacetophenones and
related quaternary ammonium compounds versus the
EMT6 tumour. Pharmazie 43: 614-616, 1988.
6. Hansen HB, Nielsen SE, Berg K. Re-examination and further development of a precise and rapid dye method for
measuring cell growth/cell kill. J Immunol Methods 119:
203-210, 1989.
7. Freshny RI. Culture of animal cells: a manual of basic technique. New York: John & Wiley Sons, Inc; 2005.
International Symposium on Drug Research & Development 2011
56
DRD 2011
EVALUATION OF THE CYTOTOXICIY OF SOME NEW N,N’-BIS[1-ARYL-3(PYRROLIDINE-1’-YL)PROPYLIDENE] HYDRAZINE DIHYDROCHLORIDES
AGAINST HUMAN HEPATOMA CELLS (HUH7)
Kaan Küçükoğlu1,*, Halise İnci Gül1, Rengül-Çetin Atalay2
Ataturk University, Faculty of Pharmacy, Dept. of Pharmaceutical Chemistry, 25240 Erzurum, Türkiye
Bilkent University, Faculty of Science, Dept. of Molecular Biology and Genetics, Faculty of Science, Bilkent
University, 06800 Ankara, Türkiye
*
[email protected]
1
2
H
ydrazones are a special group of compounds in
organic chemistry. They have various biological activities including anticancer and cytotoxic
activities [1-5]. Some new hydrazone compounds, N,N’bis[1-aryl-3-(pyrrolidine-1’-yl)propylidene]hydrazine dihydrochlorides, were designed and synthesized to find a new
leader compounds to develop new cytotoxic/anticancer
compounds. The aryl part was changed as phenyl in R1,
4-methylphenyl in R2, 4-methoxyphenyl in R3, 4-hydroxyphenyl in R4, 4-chlorophenyl in R5, 3-methoxyphenyl in R6,
4-fluorophenyl in R7. Different substituents at different positions of the phenyl ring may govern the bioactivity, since
they have different electronic natures with different Hammett values.
Cytotoxic activities of the compounds synthesized were
investigated against human hepatoma cells (Huh7) since
hepatocellular carcinoma (HCC) cells have the high resistance against chemotherapeutic agents, treatment options
of HCC is very limited and surgery is the only curative treatment procedure for most patients with HCC [6]. R2, R6, and
R7 had more powerful activity than the reference compound
5-FU. The IC50 value of 5-FU was 42.12 µM. The information
Acknowledgement: This study was supported by the
Research Foundation of Ataturk University (Project Number:
2007/58), Erzurum (Turkey).
REFERENCES
1. Pandey J, Pal R, Dwivedi A, Hajela K. Synthesis of some
new diaryl and triaryl hydrazone derivatives as possible
estrogen receptor modulators. Arzneimittelforschung 52:
39-44, 2002.
2. Savini L, Chiasserini L, Travagli V, Pellerano C, Novellino E,
Cosentino S, Pisano MB. New alpha-(N)-heterocyclichydrazones: evaluation of anticancer, anti-HIV and antimicrobial activity. Eur J Med Chem 39: 113-122, 2004.
3. Cocco MT, Congiu C, Lilliu V, Onnis V. Synthesis and in
vitro antitumoral activity of new hydrazinopyrimidine-5carbonitrile derivatives. Bioorg Med Chem 14: 366-372,
2006.
4. Gul HI, Das U, Pandit B, Li PK. Evaluation of the cytotoxicity of some mono-Mannich bases and their corresponding azine derivatives against androgen-independent
prostate cancer cells. Arzneimittelforschung 56: 850-854,
2006.
5. Dimmock JR, Erciyas E, Kirkpatrick DL, King KM. Evaluation of some azines of aminomethylacetophenones and
related quaternary ammonium compounds versus the
EMT6 tumour. Pharmazie 43: 614-616, 1988.
6. Schwartz M, Roayaie S, Konstadoulakis M. Strategies for
the management of hepatocellular carcinoma, Nat Clin
Pract Oncol 4: 424-432, 2007.
obtained by this study may give direction for further design
of cytotoxic compounds.
International Symposium on Drug Research & Development 2011
57
POSTER PRESENTATIONS
P-003
POSTER PRESENTATIONS
DRD 2011
P-004
CYTOTOXICITIES OF SOME 1-ARYL-2-(4-METHYLPIPERAZINE-1-YLMETHYL)-2-PROPENE-1-ONE DIHYDROCHLORIDES AGAINST HEP-3B
CELLS
Mehtap TUĞRAK1, Halise İnci GÜL1,*, Neşe BAŞAK2, Mustafa GÜL3, Fikrettin ŞAHİN2
Ataturk University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 25240 Erzurum, Türkiye
Yeditepe University, Faculty of Engineering and Architecture, Department of Genetics and Bioengineering, Istanbul,
Türkiye
3
Ataturk University, Faculty of Medicine, Department of Physiology, 25240 Erzurum, Türkiye
*
[email protected]
1
2
I
t is known that α,β- unsaturated ketones and their
Mannich bases have cytotoxic, anticancer activities1.
Synthesis of 1-aryl-2-(4-methylpiperazine-1-yl-methyl)2-propene-1-one dihydrochlorides and evaluation of their
cytotoxicities against liver cancer cell line, HEP-3B, were aimed in this study. A major goal in our laboratories is the discovery of novel compounds which can alleviate the devastating effects of liver cancers. The importance of such goals
is axiomatic when one considers, for example, that approximately 20% of cancer-related deaths in the United States are
due to primary liver tumours (arising from the hepatobiliary
system) or secondary malignancies (tumours of extrahepatic
origins which metastasis in the liver)2. The most common
primary liver cancers are hepatocellular carcinomas which
are often referred to as hepatomas. Hence the first step in
our long-term strategy is to find some prototypic molecules
which are cytotoxic to a human hepatoma cell line.
Aryl part was C6H5 (1), 4-CH3C6H4 (2), 4-CH3OC6H4 (3),
4-ClC6H4 (4), C4H3S (2-il) (5) in our series. Compounds were
synthesized by conventional heating and cytotoxicities of
the compounds were determined by MTS method. Cytotoxicity results were shown at Table 1(LC50, µM).
Table 1. Cytotoxicity of the compounds (1-5) against
HEP-3B cell line
Compound
Ar
Cytotoxicity (LC50), (µm)
1
C6H5
48.56
2
4-CH3C6H4
24.56
3
4-CH3OC6H4
40.88
4
4-ClC6H4
54.93
5
C4H3S (2-yl)
41.49
5-FU
73.44
Acknowledgement: This study was supported by
Ataturk University Research Foundation (Project Number:
2010/166), Erzurum (Turkey).
REFERENCES
1. Dimmock JR, Kumar P. Anticancer and and cytotoxic properties of Mannich bases. Curr Med Chem 4: 1-22, 1997.
2. Stragg RJ, Chang JT. In Textbook of Therapeutics: Drug
and Disease Management, 7 th ed.In: Herfindal ET, Gourley DR (editors), Lipincott Williams and Wilkins, Philadelphia, p. 1787, 2000.
International Symposium on Drug Research & Development 2011
58
DRD 2011
EFFECT OF PREGNANCY ON THE PHARMACOKINETIC PROFILES
OF CEFEPIME USING A FULLY VALIDATED ULTRAFAST LIQUID
CHROMATOGRAPHIC METHOD
Ayşegül Doğan1,*, Emirhan Nemutlu1, Tuba Reçber1, Hakan Eroğlu2, M. Aykut Özek3
Pınar Çalış3, Sedef Kır1, M. Sinan Beksaç3
Hacettepe University, Faculty of Pharmacy, Analytical Chemistry Department, Sıhhiye, Ankara, Türkiye
Hacettepe University, Faculty of Pharmacy, Basic Pharmaceutical Sciences Department, Sıhhiye, Ankara, Türkiye
3
Hacettepe University, Faculty of Medicine, Obstetrics and Gynecology Department, Sıhhiye, Ankara, Türkiye
*[email protected]
1
2
P
regnancy alters pharmacokinetic profile of many
drugs, because of changing body volume and metabolism rate1,2. Therefore dosage rates and concentration of drugs must be controlled during pregnancy.
Here, we identified pharmacokinetic profile of cefepime
in caesarean and non-pregnant sectioned women using a
simple, rapid, cost-effective and valid ultrafast liquid chromatographic method. The chromatographic separation was
performed using 40 mM, pH 3.2 phosphate buffer containing 6% methanol as mobile phase at 0.30 mL/min flow rate.
Gradient elution with methanol was applied to get shorter
analysis time without any interference from plasma endogens. During analyses, temperature of column, samples
and detector were set as 30 °C, 10 °C and 40 °C, respectively.
The detection wavelength was 260 nm and ceftizoxime was
used as internal standard. At the optimum conditions, the
cefepime analysis from plasma samples was completed in
7 min. Cefepime were extracted from plasma samples using
perchloric acid with very high recovery (99.3%). The method
REFERENCES
1. Little B. B. Pharmacokinetics During Pregnancy: EvidenceBased Maternal Dose Formulation. Obstet Gynecol 93:
858-868, 1999.
2. Dawes M, Chowienczyk P. J. Pharmacokinetics in pregnancy. Best Pract Res Cl Ob. 15: 819-826, 2001.
was fully validated according to the Food and Drug Administration guidelines for bioanalytical method validation3 and
found linear, repeatable, reproducible and robust.
After validation studies, the method was applied to five
caesarean-sectioned women treated/exposed with single
intravenous dose of cefepime (1 g Maxipime®) and pharmacokinetic profile of cefepime was obtained. Peak serum
concentrations of cefepime in caesarean-sectioned women
at the arterial port after infusion was 69.23 ± 11.93 µg/mL.
The mean elimination half-life, volume of distribution and
calculated area under the concentration-time curve (AUC)0–∞
were1.06 ± 0.26 h, 14.35 ± 2.55 L and 102.41 ± 12.21 µg·h/mL
for caesarean-sectioned women, respectively.
Acknowledgement: This project was supported by
Hacettepe University Scientific Research Fund (07 01 301
006).
3. US Department of Health and Human Services, Food and
Drug Administration, Center for Drug Evaluation and
Research (CDER), Center for Veterinary Medicine (CVM):
Guidance for Industry, Bioanalytical Method Validation;
2001.
International Symposium on Drug Research & Development 2011
59
POSTER PRESENTATIONS
P-005
POSTER PRESENTATIONS
DRD 2011
P-006
PYRAZOLINE BASED MAO INHIBITORS: SYNTHESIS, BIOLOGICAL
EVALUATION AND SAR STUDIES
Kiran BOPPANA1, Açelya YALOVAÇ ASLAN2,*, Samiye YABANOGLU ÇİFTÇİ2, Jagannath BEHERA3,
P.K. DUBEY4, Vadivelan SANKARAN5, Barij N. SINHA3, Arijit BASU3, Venkatesan JAYAPRAKASH3,
Gülberk UÇAR1
GVK Biosciences Pvt. Ltd., S-1, Phase-1, T.I.E., Balanagar, Hyderabad 500 037, Andhra Pradesh, India
2
Dept. Of Biochemistry, Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Türkiye
3
Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India
4
Department of Chemistry, J.N.T. University, Kukatpally, Hyderabad 500 085, Andhra Pradesh, India
5
Informatics, GVK Biosciences Private Limited, 37 Sterling Road, Chennai, India
*
[email protected]
1
S
ince our group has previously reported that some
3, 5-diaryl carbothioamide pyrazolines inhibited
rat liver MAO isoforms1, twenty–two newly synthesized pyrazolines were tested for their human monoamine
oxidase (hMAO) inhibitory activities2. Twelve molecules with
unsubstituted ring A and substituted ring C (5-16) were
found to be potent inhibitors of hMAO-A isoform with se-
lectivity index for MAO-A (SIMAO-A ) in the order 103-104. Ten
molecules with unsubstituted ring A and without ring C (2130), in which eight molecules (21,23-26, 28-30) were selective for hMAO-A, one for hMAO-B (22) and the other one
non-selective (27). Presence of ring C appeared to increase
inhibitory potency as well as SI towards hMAO-A; however it
decreases both potency and SI towards hMAO-B.
Compound
R
R’
Compound
X
R
Y
5
2-OH
4-0CH3
21
C
-CH3
O
6
2-OH
4-CH3
22
N
-
O
7
2-OH
3-OCH3
23
C
-OCH3
O
8
2-OH
3-CH3
24
C
-Cl
O
9
2-OH
2-OCH3
25
C
-CH3
S
10
2-OH
2-CH3
26
N
-
S
11
4-OH
4-OCH3
27
C
-Cl
S
12
4-OH
4-CH3
28
C
-CH3
NH
13
4-OH
3-OCH3
29
N
-
NH
14
4-OH
3-CH3
30
C
-Cl
NH
15
4-OH
2-OCH3
16
4-OH
2-CH3
REFERENCES
1. Venkatesan, J., Sinha, B. N., Ucar, G., Ercan, A. Pyrazolinebased mycobactin analogues as MAO-inhibitors, Bioorg
Med Chem Lett 18: 6362–6368, 2008.
2. Zhou M., Panchuk-Voloshina N. A one-step fluorometric
method for the continuous measurement of monoamine
oxidase activity. Anal Biochem 253: 169-174, 1997.
International Symposium on Drug Research & Development 2011
60
DRD 2011
SYNTHESIS AND STRUCTURAL ELUCIDATON OF NEW 2-(1H-IMIDAZOL1-YL)-1-(NAPHTH-2-YL)ETHANOL ESTER DERIVATIVES AS POTENTIAL
ANTIMICROBIAL COMPOUNDS
Mustafa Fahir ACAR1, Didem KART2, Sevim DALKARA1
Department of Pharmaceutical Chemistry,
Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Türkiye
1
2
A
ntifungal infections are the frequent and life
threatening problem for transplant recipients,
cancer and AIDS patients receiving broad spectrum antibiotics. Therefore, the efforts to develop more effective and safer systemic antifungal agents are popular area
for medicinal chemists1.
Nafimidone alcohol was prepared by the reduction of keton group in nafimidone. Esters of nafimidone alcohol were
synthesized by acylation of the alcohol group with carboxylic acids.
Purification of the products was realized by column chromatography and crystallography. Structural elucidation of
the purified compounds was realized by IR, 1H-NMR, MASS
spectral and elementary analysis data. Antifungal and antibacterial activities of the compounds were tested by microdulution method against three fungi and four bacteria, two
are Gr (+) and two are Gr (-). Ampicilin and fluconazole were
used as reference compounds for antibacterial and antifungal activities respectively. Most of the compounds showed
antimicrobial activities.
Nafimidone (I) and its active metabolite nafimidone alcohol (II) are the well-known representatives of (arylalkyl)
imidazole anticonvulsant compounds2. Structural similarities
of these compounds with 1H-azole antifungals prompted us
to study on their antifungal/antibacterial activities; we found
that various derivatives of nafimidone and nafimidone alcohol
exhibit antimicrobial activities 3,4. In this study, as a continuation of our interest on (arylalkyl)imidazole derivatives, we described some new alkyl/arylalkyl/aryl ester derivatives of nafimidone alcohol as potential antimicrobial compounds (III).
O
OH
C
CH
CH2
NaBH4
N
OR
CH2
.HCl
CH
1) DCC/DMAP/RCOOH
N
N
(I)
Acknowledgement: This project was supported by
Hacettepe University Scientific Research Fund (HÜBAB
010D06301003).
N
(II)
CH2
N
N
2) gHCl
(III)
.HCl
R: -CH3; -CH2C6H5; -C6H4C6H5; -CH(C6H5)2
REFERENCES
1. Emami S, Falahati M, Banifatemi A, Shafiee A. Stereoselective sythesis and antifungal activity of (Z)- trans-3azolyl2-methylchromanone oxime ethers. Bioorg & Med Chem
12: 5881-5889, 2004.
2. Walker K.A.M, Wallach M.B, Hirschfeld D.R.
1-(Naphthylalkyl)-1H-imidazole derivatives, a new class
of anticonvulsant agents. Eur J Med Chem 24(1): 67-74,
1981.
3. Karakurt A, Dalkara S, Özalp M, Kendi E, Stables J.P. Synthesis of some 1-(2-naphyl)-2-(imidazole-1yl)etanon Oxime
and Oxime Ether Derivatives and Their Anticonvulsant and
Antimicrobial Activities. Eur J Med Chem 36: 421-433, 2001.
4. Karakurt A, Özalp M, Işık Ş, Stables J.P, Dalkara S. Synthesis, anticonvulsant and antimicrobial activities of some
new 2-acetylnaphthalene derivatives. Bioorg & Med
Chem 18(8): 2902-2911, 2010.
International Symposium on Drug Research & Development 2011
61
POSTER PRESENTATIONS
P-007
POSTER PRESENTATIONS
DRD 2011
P-008
OPTIMIZATION AND COMPARATION OF NESTED AND SEMI NESTED PCR
WITH CONVENTIONAL PCR FOR ISOLATION OF PLASMODIAL ENOLASE
GENES
Venhar Çelİk1,*, Irmak İçen1, Jose Miguel Rubio2, Ömer MunzuroĞlu1
Department of Biology, Faculty of Sciences, Firat University, Elazığ 23119, Türkiye
Malaria&Emerging Parasitic Diseases Laboratory, Parasitology Department, National Centre of Microbiology,
Instituto de Salud Carlos III, Cra. Majadahonda Pozuelo Km. 2, Majadahonda, 28220 Madrid, Spain
*
[email protected]
1
2
M
alaria is one of the world’s most prevalent parasitic infections and so the development of new
tools to contribute to its control is necessary.
Currently, the main objective of malaria control programs
is adequate treatment in addition to rapid diagnosis. Thus,
drug discovery is noteworthy. Exploration of new proteins
which is important for metabolism of Plasmodium offers
unique opportunities for drug discovery. For that, isolation
and cloning of gene, and then its expression is the first step
of it. However, sometimes, a difficulty in achieving this goal
is represented by the occurrence of lack of genomic DNA
concentration depending on low parasitemia levels. Thus,
we have tried nested and seminested PCR in addition to conventional PCR. We succesfully could isolate enolase genes of
Plasmodium falciparum and P. vivax, which are the first and
second most common malaria parasites worldwide among
the five species of Plasmodium that infect humans, with nested and semi nested PCR, although we couldn’t take result
with conventional PCR. At the same time, we have optimized
nested and semi nested PCR for isolation of Plasmodial enolase gene.
International Symposium on Drug Research & Development 2011
62
DRD 2011
THE USE OF SITE-DIRECTED MUTAGENESIS FOR REMOVAL OF THE
INTRONS IN APICOMPLEXAN’S GENES: A NEW APPROACH FOR GEN
EXPRESSION
Irmak İçen*, Venhar Çelİk, Ömer MunzuroĞlu
Department of Biology, Faculty of Sciences, Firat University, Elazığ 23119, Türkiye
*
[email protected]
T
he phylum Apicomplexan’s members such as Plasmodium spp., which cause severe human malaria,
and Theileria, Eimeria, Babesia spp. which are responsible for economic losses, result in profound medical,
social, and economic effects. The development of drug resistance in Apicomplexan mean that more effective drugs are
urgently needed. The gen expression is an important stage
to identify proteins which can be potential drug targets in
Apicomplexan parasites. RNA analysis and therefore RNA extraction are required for studies on gen expression. However,
RNA molecules are generally less stable than DNA. In addition, although both of DNA and RNA are degraded enzimati-
cally by DNA- and RNA-specific nucleases, it is much more
difficult to work with native RNA molecules in the laboratory
because RNAases are nearly ubiquitous. Thus, we prefered
to genomic DNA instead of RNA for gene cloning and then
its expression. But, there are introns in most of genes in Apicomplexan. We used PCR based site-directed mutagenesis
for removal of the introns in genes. Initially, we generated
exon fragments by PCR, then we connected exon fragments
to one another by a short PCR cycle. The resulting fusion
product amplified further by PCR. This approach especially
can be used for isolation of genes from parasites which is difficult to be obtained their RNA.
International Symposium on Drug Research & Development 2011
63
POSTER PRESENTATIONS
P-009
POSTER PRESENTATIONS
DRD 2011
P-010
 
development of lıposome formulatıon of doxycylıne and
ınvestıgatıon transport propertıes through caco-2 cell lıne
Çiğdem YÜCEL1,*, Zelihagül DEĞİM2, Şükran YILMAZ3
Erciyes University, Faculty of Pharmacy, Dept. of Pharmaceutical Technology, 38039 Kayseri, Türkiye
2
Gazi University, Faculty of Pharmacy, Dept. of Pharmaceutical Technology, 06330 Ankara, Türkiye
3
Food and Mouth Diseases Institute, 06520 Ankara, Türkiye
*
[email protected]
1
D
oxycycline is a semi-synthetic antibiotic, derived
from tetracycline. It has been used to overcome
various type of infections.1,2 . Caco-2 cells are
human colon cancer cells, which are widely used to make
oral drug absorption, that are increasingly used as an in vitro blood-brain barrier (BBB) model in passive permeability
and membrane transport studies.3,4,5. In this study, Caco-2
cells were used as model cell cultures. The cytotoxic effects
of doxycycline on Caco-2 cells, transport studies of doxycycline solution and liposome formulations through Caco-2
cells were investigated. MTT test was performed for studying
doxycycline effect on the viability of Caco-2 cells. According
REFERENCES
1. D.Vargas-Estrada,J.Gracia-Mora.Pharmacokinetic study of
an injectable long-acting parenteral formulation of doxycycline hyclate in calves. Researchin Vet. Sci. 84: 477-482, 2008.
2. Kelly Smith,MD, James J.Leyden,MD. Safety of doxycycline and minocycline: A systematic review. Clin. Therap.
27(9): 1329-1342, 2005.
3. Beck RCR, Pohlmann AR, Hoffmeister C, Gallas MR, Collnot E,
Svhaefer EF, Guterres SS, Lehr CM. Dexamethasone-loaded
nanoparticle-coated microparticles: Correlation between
to the MTT test results, cell viability was found to be efficient
in 10 µg/mL doxycycline concentration.
The cumulative amount of doxycycline solution and liposome formulations transported through apical to basolateral
side of Caco-2 cells was found to be 74.5%, 67.4% and 77%,
76.5% (n=3). Apparent permeability coefficients (k) were calculated as 0.881±0.030, 2.82±0.15 ( n=3) respectively.
For conclusion, the use of Caco-2 cell monolayer as a BBB
model for in vitro experiments was found to be useful and
predictive.
in vitro drug release and drugtransport across Caco-2 cell
monolayers. Eur J of Pharm and Biopharm 67: 18–30, 2007.
4. Garberg P, Ball M, Borg N, Cecchelli R, Fenart L, Hurst
RD, Lindmark T, Mabondzo A, Nilsson JE, Raub TJ, Stanimirovic D, Terasaki T, Öberg JO, Österberg T, et al. In vitro
models fort he blood-brain barriers. Toxicology in Vitro
19: 299-334, 2005.
5. Artursson P, Palm K, Luthman K. Caco-2 monolayers in experimental and theoretical predictions of drug transport.
Adv Drug Del Reviews 46: 27-43, 2001.
International Symposium on Drug Research & Development 2011
64
DRD 2011
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL PROPERTIES OF
CANNABIMIMETIC AMINOALKYLINDOLE BASED NAPHTHYLAMINE
DERIVATIVES
Gülay ZENGİN, Adem MERT*, Hüseyin ZENGİN, Dürdane ÇANDAR
Gaziantep University, Faculty of Science and Literature, Department of Chemistry, 27310 Gaziantep, Türkiye
*[email protected]
T
he synthesis of cannabimimetic aminoalkylindole
based naphthylamine derivatives is in progress,
where substituents at the 5- and 8-positions of
the naphthalene ring will be examined and manipulated in
accordance to their size and electronic effects. Thus far as a
result of early molecular studies of D9-tetrahydrocannabinol
(D9-THC) and aminoalkylindoles (AAI), three discrete regions
of interaction with cannabinoid receptors have been identified.1,2 The steric requirement for receptor interaction of the
cyclohexene ring of D9-THC is fulfilled by the naphthalene
ring of AAIs. Potential hydrogen bonding by phenolic hydroxyl group of D9-THC overlaps with the carbonyl moiety of
AAIs and a C-3 alkyl chain of D9-THC allows for hydrophobic
interaction which may be facilitated by the morpholinoethyl
group of AAIs. Further this morpholinoethyl group may be
replaced by carbon chains as chains of four to six carbons
produce optimal affinity.
REFERENCES
1. Huffman, J.W.; Dai, D.; Martin, B.R.; Compton, D.R. Bioorg
Med Chem Lett 4, 563, 1994.
Chemical structures of ∆9-THC (1) and the AAI WIN 55,2122 (2) showing the proposed overlapping moieties involved
in receptor interaction, denoted as a, b and c.
These features have been used in the design of our
cannabimimetic aminoalkylindole based naphthylamines,
where our compounds consist of a naphthalene ring, carbonyl group and a second naphthalene ring with substituents at the 5- and 8-positions, instead of a morpholinoethyl
group or carbon chain. The rationale for this study is to focus
the specific effects of 5- and 8-substitution, and eventually
examine the resulting physiochemical and biological properties. The synthesized compounds will be characterized
using spectroscopic techniques including UV-Vis, FTIR and
photoluminescence.v
2. Aung, M.M.; Griffin, G.; Huffman, J.W.; Wu, M.-J.; Keel, C.;
Yang, B.; Showalter, V.M.; Abood, M.E.; Martin, B.R. Drug
Alcohol Depend 60, 133, 2000.
International Symposium on Drug Research & Development 2011
65
POSTER PRESENTATIONS
P-011
POSTER PRESENTATIONS
DRD 2011
P-012
ProductIon of recombInant D-arabInol dehydrogenase In
EscherIchIa ColI
Kevser Bİberoğlu, Özden TACAL
Department of Biochemistry, School of Pharmacy, University of Hacettepe, 06100Ankara,Türkiye
I
ncidence of invasive candidiasis has dramatically increased in recent years. Therefore, early and accurate
diagnosis of invasive candidiasis is very important. Darabinitol, five carbon sugar alcohol is a metabolite of several
pathogenic Candida species. Several studies have shown
that serum D-arabinitol concentrations are higher in humans with invasive candidiasis than in uninfected controls
and the concentration of serum D-arabinitol decreases with
antifungal therapy. Based on these findings, D-arabinitol is
described as an important diagnostic marker. In this study,
we produced functionally active recombinant D-arabinitol
dehydrogenase (rArDH) in E.coli for enzymatic detection of
serum D-arabinitol levels. rArDH was purified by dye-ligand
affinity chromatography (Purification fold, 5000- fold; specific activity, 25 U/mg). Analysis of the purified recombinant enzyme by SDS-PAGE showed a band at 30 kDa. These results
suggest that recombinant enzyme, produced in E.coli can be
used for determination of D-arabinitol levels in serum.
Acknowledgement: This study was supported by a
grant (05 01 301 002) from the Hacettepe University Research Fund.
International Symposium on Drug Research & Development 2011
66
DRD 2011
THE EFFECTS OF ORGANIC DRIED APRICOT ON THE HEMATOLOGIC
PARAMETERS IN RATS
İsmet YILMAZ
Department of Pharmacology, Faculty of Pharmacy, University of İnönü, 44280 Malatya, Türkiye
[email protected]
T
he main purpose of this study was to investigate
the medicinal importance of organic dried apricot
(Prunus armeniaca L. Kabaaşı spp.) consumption
based on hematologic parameters and the second purpose
was to determine best ratio and/or period of organic dried
apricot supplementation of diet in rats and/or human. In this
study, 120 male and 120 female Sprague Dawley rats were
used. From each gender, twentyfour rats were randomly divided into five groups (n=24/groups) as follows: Group I (control) were fed with standard rat chow, group II were fed with
1 %, group III were fed with 2.5 %, group IV were fed 5 % and
group V were fed 10 % organic dried apricot supplemented
to standard diet were given for 120 days study period. The
REFERENCES
1. Akın, E.B., Karabulut, I., Topcu, A. 2008. Some compositional properties of main Malatya apricot (Prunus armeniaca
L.) varieties. Food Chem 107: 939–948. doi:10.1016/j.
foodchem.2007.08.052.
2. Celık, I., Suzek, H. 2008. The hematological effects of
methyl parathion in rats. J Hazard Mater 153: 1117–1121.
doi:10.1016/j.jhazmat.2007.09.067. PMID: 17964717.
3. El-Demerdash, F.M., Yousef, M.I., Kedwany, F.S. et al. 2004.
Cadmium-induced changes in lipid peroxidation, blood
hematology, biochemical parameters and semen quality
of male rats: protective role of vitamin E and β-carotene.
body weights of rats were determined, as 320.6 g for male
rats (n=120), and 209.7 g for female rats (n=120) at the beginning of study. At 30th, 60th and 120th days, in each gender
and group, 8 rats were sacrified and then 1-1.5 ml of fresh
blood samples were used at automatic hematological assay
analyzer for complete blood counts. Among control and other groups and/or periods (30th, 60th and 120th days) based
on hematologic parameters, statistical significances were
determined and tabulated in accordance to their gender and
group differences. This study shown that, minimum 1 % rate
and at least 30 days period or briefly 3-5 apricot/day (~25-40
g/day) consumption of organic dried apricot may be remarkably benefical for human health for each gender.
Food Chem Toxicol 42: 1563–1571. doi:10.1016/j.
fct.2004.05.001. PMID:15304303.
4. Georgıou, N.A., Garssen, J., Wıtkamp, R.F. 2011. Pharma–
nutrition interface: The gap is narrowing. Eur J Pharmacol 651: 1–8. doi:10.1016/j.ejphar.2010.11.007. PMID:
21114994.
5. Petterino, C., Argentino-Storino, A. 2006. Clinical chemistry and hematology historical data in control SpragueDawley rats from pre-clinical toxicity studies. Exp Toxicol
Pathol 57: 213–219. doi:10.1016/j.etp.2005.10.002. PMID:
16343876.
International Symposium on Drug Research & Development 2011
67
POSTER PRESENTATIONS
P-013
POSTER PRESENTATIONS
DRD 2011
P-014
THE EFFECTS OF APRICOT ON BIOCHEMICAL PARAMETERS AND TOTAL
ANTIOXIDANT CAPACITY LEVELS IN RATS
İsmet YILMAZ1,*, Yusuf TÜRKÖZ2, İsmail TEMEL2, Şule GÜRSOY2, Zümrüt DOĞAN3
Department of Pharmacology, Faculty of Pharmacy University of İnönü, 44280 Malatya, Türkiye
2
Department of Biochemistry, Faculty of Medicine University of İnönü, 44280 Malatya, Türkiye
3
Center of Experimental Animals Research and Production, University of İnönü, 44280 Malatya, Türkiye
*
[email protected]
1
T
he main purpose of this study was investigate the
effects of dried organic apricot (Prunus armeniaca
L. Kabaaşı spp.) at different ratios and/or periods
on serum biochemical parameters and total antioxidant capacity levels in rats. In this study, 120 male and 120 female
Sprague Dawley rats were used. From each gender, 24 rats
were randomly divided into five groups as follows: Group
I (control, n=24) were fed with standard rat chow, Group II
(n=24) were fed with 1 %, Group III (n=24) were fed with 2.5
%, Group IV (n=24) were fed 5 % and Group V (n=24) were
fed 10 % organic dried apricot (ODA) supplemented to standard diet were given for 120 days study period. At the beginning of study, the body weights of male and female rats
were determined 320.6 g and 209.7 g respectively. At 30th.
1.
2.
3.
4.
REFERENCES
Akın EB, Karabulut I, Topcu A Some compositional properties of main Malatya apricot (Prunus armeniaca L.) varieties. Food Chem 107: 939–948, 2008.
Al-Shinnawy MS Physiological effect of a food additive
on some hematological and biochemical parameters of
male albino rats. Egypt Acad J Biolog Sci 2(1): 143-151,
2009.
American Diabetes A Nutrition recommendations and
interventions for diabetes: a position statement of the
American Diabetes Association. Diabetes Care 31: 61-78,
2008.
Bazzano LA, Li TY, Joshipura KJ, Hu FB Intake of fruit, vegetables, and fruit juices and risk of diabetes in women.
Diabetes Care 31: 1311-1317, 2008.
60th and 120th days each gender and groups, 8 rat were sacrified, 7-10 ml blood were drawn by intracardiac puncture and
collected into centrifuge tubes without any anticoagulant,
then blood samples centrifuged at 3000 r.p.m. for 5 min and
obtained serum samples were used for biochemical analysis.
Among controls and other groups and/or periods (30, 60 and
120 days) based on biochemicaal parameters statistical significance were determined and tabulated in accordance to
their gender and group differences (Table2, 3).
This study results shown that, minimum 1% rate and at
least 30 days period or briefly 3-5 apricot/day (~25-40 g/day)
consumption may be based on important biochemical parameters, remarkably benefical for each gender.
5. Celık I, Suzek H The hematological effects of methyl parathion in rats. J Hazard Mater 153: 1117–1121, 2008.
6. Diabetes Prevention Program Group Reduction in the incidence of type 2 diabetes with lifestyle intervention or
metformin. N Engl J Med 346: 393–403, 2002.
7. El-Demerdash FM Antioxidant effect of vitamin E and
selenium on lipid peroxidation, enzyme activities and
biochemical parameters in rats exposed to aluminium. J
Trace Elem Med Biol 18: 113–121, 2004.
8. Georgıou NA, Garssen J, Wıtkamp RF Pharma–nutrition
interface: The gap is narrowing. Eur J Pharmacol 651: 1–8,
2011.
9. Kahlon TS, Smith GE In vitro binding of bile acids by bananas, peaches, pineapple, grapes, pears, apricots and
nectarines. Food Chem 101: 1046–1051, 2007.
International Symposium on Drug Research & Development 2011
68
DRD 2011
SYNTHESIS AND CHARACTERIZATION SOME NOVEL THIOUREA
DERIVATED FROM RHODANINE
İnci Nejla DAĞDEVİREN1, Emine Elçin ORUÇ EMRE1, Ayşegül KARAKÜÇÜK İYİDOĞAN1,*
Bedia KOÇYİĞİT KAYMAKÇIOĞLU2
,
1
Gaziantep University, Faculty of Arts and Sciences, Department of Chemistry, 27310 Gaziantep, Türkiye
Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 81010 İstanbul, Türkiye
*[email protected]
2
I
t is well known that compounds containing substitue
thiourea have been reported to posses antimicrobial,
antidiabetic, antibacterial, anticancer activities [1-3].
Also, it was thought that thiourea compounds combining
with rhodanine ring could exhibit suitable pharmaceutical
properties and avoid undesirable side effects.
the literature, then substitue isothiocyanates were added to
the biologically active amines due to obtain thiourea derivates. The chemical structures of compounds were elucidated using IR, 1H-NMR, mass spectroscopy and elemental
analysis.
O
In this research was composed of two parts by using general synthesis methods. In this first part of study,
5-(4-nitrobenzilydene)-2-thioxo-1,3-thiazolidine-4-one was
synthesized by the condensation rhodanine with 4-nitrobenzaldehyde according to the literature [4]. After the reduction
of nitro group of compound to corresponding amines, thiourea derivatives were obtained by the addition to substituted
isothiocyanates. In second part of study, 3-(2-aminoethyl)-2thioxo-1,3-thiazolidine-4-on was synthesized by reactions
rhodanine and 2-chloroethylamine hydrochloride according
REFERENCES
1. Cutshall NS, O’Day C, Prezhdo M. Rhodanine derivatives
as inhibitors of JSP-1. Bioorg Med Chem Lett 15: 33743379, 2005.
2. Doub L, Richardson LM, Herbst DR, Black ML, Stevenson
OL, Bambas L, Youmans GP, Youmans AS. Some phenylthiourea derivates and their antituberculos activity. J Am
Chem Soc 80: 2205-2217, 1958.
H
N
R NH C NH
S
S
S
S
CH2CH2 NH C NH R
O
N
S
S
3. Habib NS, Ridal SM, Badaweyl EA, Fahmyl HTY, Ghozlanz
HA. Synthesis and antimicrobial activity of rhodanine derivatives. Eur J Med Chem 32: 759-762, 1997.
4. Tang E, Yang G, Yin J. Studies on the synthesis of 5-(paminobenzylidene)-rhodanine and its properties. Spect
Chim Acta Part A 59: 651-656, 2003.
International Symposium on Drug Research & Development 2011
69
POSTER PRESENTATIONS
P-015
POSTER PRESENTATIONS
DRD 2011
P-016
SYNTHESIS AND CHARACTERIZATION SOME NOVEL THIOUREAS
DERIVATED FROM HETEROCYCLIC AMINES
İnci Nejla DAĞDEVİREN, Emine Elçin ORUÇ EMRE, Ayşegül KARAKÜÇÜK İYİDOĞAN*
Gaziantep University, Faculty of Arts and Sciences, Department of Chemistry, 27310 Gaziantep, Türkiye
*[email protected]
D
uring recent years there have been intense investigations on the different classes of thiourea
compounds, many of which known to possess
interesting biological properties such as antimicrobial, antibacterial, analgesic, antiflammatory, anticancer, antifungal,
antituberculosis, anti-HIV, anticonvulsant and antihypertensive activities1-4.
condensation of heterocyclic amines such as pyrimidine,
isoxazole and benzoxazol with different isothiocyanates.
Chemical structures of compounds were illuminated using
IR, 1H-NMR, mass spectroscopy and elemental analysis.
N
O
NH
Cl
In this research, original thiourea derivatives were synthesized with the aim of new drug development. Therefore,
a series of new thiourea derivatives were obtained by the
N
C
NH R Cl
NH
N
S
NH
F
O
N
C
C
NH R
S
NH R
S
REFERENCES
1. Glasser AC, Doughty RM. Substitued heterocyclic
thioureas. I.Antitubercular activity. J Pharm Sci 51:
1031-1033, 1962.
2. Heinisch G, Matuszczak B, Ralkowitz D, Tantisira B.
Synthesis of N-aryl-N-heteroaryl-substituted urea
and thiourea derivatives and evaluation of their anticonvulsant activity. Archiv der Pharmazie 330: 207210, 1997.
3. Karakuş S, Kaymakçıoğlu B, Toklu HZ, Arıcıoğlu F,
Rollas S. Synthesis and antituberculosis activity of
new N-phenyl-N-[4-(5-alkyl/arylamino-1,3,4-thiadiazole-2-yl)phenyl]thioureas. Archiv der Pharmazie
Chem Life Sci 342: 48-53. 2009b.
4. Tian Z, Plata DJ, Wittenberger SJ, Bhatia AV. A general synthesis of N-aryl- and N-alkyl-2-aminobenzoxazoles. Tetrahedron Lett 46: 8341-8343. 2005.
International Symposium on Drug Research & Development 2011
70
DRD 2011
THE NOVEL THIOSEMICARBAZONES: SYNTHESIS, CHARACTERIZATION
AND ANTIBACTERIAL ACTIVITY
Zeliha MERCAN1, Ayşegül KARAKÜÇÜK İYİDOĞAN1,*, Emine Elçin ORUÇ EMRE1,
İbrahim Halil KILIÇ2, Derya İŞLER2, Mehmet ÖZASLAN2
Gaziantep University, Faculty of Arts and Sciences, Department of Chemisty, 27310 Gaziantep, Türkiye
2
Gaziantep University, Faculty of Arts and Sciences, Department of Biology, 27310 Gaziantep, Türkiye
*
[email protected]
1
T
hiosemicarbazones are belong to a large group of
thiourea derivatives whose biological activities are
a function of parent aldehyde and ketone moiety.
Especially, heterocyclic and aromatic thiosemicarbazones
have attracted considerable pharmaceutical interest due to
their antimicrobial, antiviral, antitumor, antimalarial, antiprotozoal, anticonvulsant and antituberculosis activities1-5.
against bacteria Gram-negative (Escherichia coli ATCC 25322,
Psedoumanas aeruginosa ATCC 25853) and Gram-positive
bacteria (Enterococcus faecalis ATCC 25923, Staphylococcus
aureus ATCC 29212) was determined by microdilution broth
method. The minimum inhibitory concentrations (MIC) were
defined as the lowest concentrations of the compounds that
prevented visible growth.
In this study we prepared thirteen thiosemicarbazone
derivatives in good yields by the reaction of corresponding 4-substituted phenylthiosemicarbazides with various
heterocyclic and aromatic aldehydes in appropriate solvent.
Structures of synhesized compounds have been characterized by UV, IR, 1H NMR, 13C NMR spectral data and elemental
analysis. In vitro antibacterial activity of these compounds
REFERENCES
1. Hu K., Yang ZH., Pan SS., Xu HJ., Ren J. Synthesis and antitumor activity of liquiritigenin thiosemicarbazone derivatives. Eur J Med Chem 45, 3453-3458, 2010.
2. Bal TR., Anand B., Yogeeswari, P. Sriram D. Synthesis and evaluation of anti-HIV activity of isatin
β-thiosemicarbazone derivatives. Bioorg Med Chem Lett
15, 4451-4455, 2005.
3. Bharti N., Husain K., Garza MTG., Vega DEC., Garza JC.,
Cardenas BDM., Naqvi F. Azam A. Synthesis and in vitro
antiprotozoal activity of 5-nitrothiophene-2-carboxaldehyde thiosemicarbazone derivatives. Bioorg Med Chem
Lett 12, 3475-3478, 2002.
R
H
H
N
N
H
N
R
1
S
R ,R '= various substituents
4. Halve AK., Bhashkar B., Sharma V., Bhadauria R., Kankoriya
A., Soni, A., Tiwari K., (). Synthesis and in vitro antimicrobial studies of some new 3-[phenyldiazenyl] benzaldehyde
N-phenyl thiosemicarbazones. J Enzym Inhib Med Chem
23(1), 77-81, 2008.
5. Karkı SS., Bahadurıa VS., Rana V., Kumar S., Subbaro PG.,
Das U., Balzarini J., De Clercq, E., Dimmock, J. R., (). 1-arylmethyl-2,3-dioxo-2,3-dihydroindole thiosemicarbazones
as leads fro developing cytotoxins and anticonvulsants. J
Enzym Inhib Med Chem 24(2), 537-544. 2009.
International Symposium on Drug Research & Development 2011
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POSTER PRESENTATIONS
P-017
POSTER PRESENTATIONS
DRD 2011
P-018
SYNTHESIS NEW HYDRAZONES DERIVATED FROM L-CYSTEIN ETHYL
ESTER HYDROCHLORIDE
Yusuf SICAK1, Emine Elçin ORUÇ EMRE1, Ayşegül KARAKÜÇÜK İYİDOĞAN1,*,
Bedia KOÇYİĞİT KAYMAKÇIOĞLU2
1
Gaziantep University, Faculty of Arts and Sciences, Department of Chemistry, 27310 Gaziantep, Türkiye
Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 81010 İstanbul, Türkiye
*[email protected]
2
T
he hydrazone is a special class of schiff bases as
oxime and shows a wide range of pharmacological properties including antibacterial, anticancer,
antifungal, analgesic, antiinflammatory, antitubercular activities1-4. In this study, our aim is to gain of new active agents.
Therefore, a new series of 4-substituted N-{1-[2- (4-substitutedbenzylidene)hydrazinyl]-1-oxo-3-sulfanylpropan-2-yl}
benzamide derivatives were synthesized to evaluate antimicrobial activite. These derivatives have been obtained from
condensation with 4-substitued benzaldehyde and hydrazides, which synthesized by reaction of ethyl 2-{[(4-substituREFERENCES
1. Koçyiğit-Kaymakçıoğlu B, Oruç E, Unsalan S, Kandemirli
F, Shvets N, Rollas S, Dimoglo A. Synthesis and characterization of novel hydrazide-hydrazones and the study of
their structure-antituberculosis activity. Eur J Med Chem
41(11): 1253-1261, 2006.
2. Bhandari SV, Bothara KG, Raut MK, Patil AA, Sarkate AP,
MokaleVJ. Desing, Synthesis and Evaluation of Antiinflammatory, Analgesic and Ulcerogenicity studies of
Novel S-Subtituted phenacyl-1,3,4-oxadiazole-2-thiol
and Schiff bases of Diclofenac acid as Nonucerogenic De-
tedphenyl)carbonyl]amino}-3-sulfanylpropanoate derivatives and hydrazine monohydrate. The structure of the new
synthesized hydrazide-hydrazones derivatives have been
illuminated by using UV, IR, 1H NMR spectroscopy and elemental analysis. Antimicrobial activities of these compounds
are screened.
O
R
C
CH2
NH
SH
HC
C
NH
N
CH
R1
O
rivatives. Bioorg Med Chem 16: 1822-1831, 2008.
3. Raparti V, Chitre T, Bothara K, Kumar V, Dangre S,
Khachane C, Gore S, Deshmane B. Novel 4-(morpholin4-yl)-N’-(arylidene)benzohydrazide: Synthesis, antimycobacterial activity QSAR investigations. Eur J Med Chem
44: 3954-3960, 2009.
4. Koçyiğit-Kaymakçıoğlu B, Oruç EE, Unsalan S, Rollas S.
Antituberculosis activity of hydrazones derived from
4-fluorobenzoic acid hydrazide”. Med Chem Res 18: 277286, 2009.
International Symposium on Drug Research & Development 2011
72
DRD 2011
SYNTHESIS AND CHARACTERIZATION OF NOVEL AROMATIC
THIOSEMICARBAZONE DERIVATIVES
Bilal AYDINÖZ, Ayşegül KARAKÜÇÜK İYİDOĞAN*, Özgül GÜNER, Emine Elçin ORUÇ EMRE
Gaziantep University, Faculty of Arts and Sciences, Department of Chemistry, 27310 Gaziantep, Türkiye
* [email protected]
T
hiosemicarbazones are obtained by condensation of the corresponding thiosemicarbazide with
aldehydes or ketones1. Biological activities of thiosemicarbazones have been studied since 1946, when their
activity against Mycobacterium tuberculosis was reported
by Domagk2. The other biological activities of thiosemicarbazone derivatives such as antimicrobial, antiprotozoal, anticonvulsant, antiviral and antitumor activity have been described3-5.
H
H
N
N
N
S
R
In the present work, we have synthesized twelve thiosemicarbazone derivatives bearing aromatic ring. All
reactions were monitored by TLC used appropriate solvent system. The chemical structures of thiosemicarbazones were identified by UV-vis, FTIR, 1H NMR, 13C NMR,
MS spectral data and their purities were determined by
TLC, melting point and elemental analyses. Their antimicrobial, cytotoxic and antiviral activities are evaluated in future studies.
R'
R, R' = varios substituents
REFERENCES
1. Finkielsztein LM., Castro EF., Fabian LE., Moltrasio
GY., Campos RH., Cavallaro LV., Moglioni AG. New
1-indanone thiosemicarbazone derivatives active
against BVDV. Eur J Med Chem 43, 1767-1773, 2008.
2. Domagk G., Behnisch R., Mietzch F., Schmidt H. On
a new class of compounds effective in vitro against
tubercle bacilli. Naturwissenschaften 10, 315, 1946.
3. Finch RA., Liu MC., Cory AH., Cory JG., Sartorelli AC.
Trıapıne (3-aminopyridine-2-carboxaldehyde thiosemicarbazone; 3-AP): An inhibitor of ribonucleotide
reductase with antineoplastıc activity. Advance Enzyme Regulation 39, 3-12, 1999.
4. Aquino TM., Liesen A., Silva REA., Lima VT., Carvalho
CS., Faria AR., Araujo JM., Lima JG., Alves A., Melo
E., Goes A. Synthesis, anti-Toxoplasma gondii and
antimicrobial activities of benzaldehyde 4-phenyl3-thiosemicarbazones and 2-[(phenylmethylene)
hydrazono]-4-oxo-3-phenyl-5-thiazolidineacetic acids. Bioorg Med Chem 16, 446-456, 2008.
5. Bal TR., Anand B., Yogeeswari P., Sriram D. Synthesis and evaluation of anti-HIV activity of isatin
β-thiosemicarbazone derivatives. Bioorg Med Chem
Lett 15, 4451-4455, 2005.
International Symposium on Drug Research & Development 2011
73
POSTER PRESENTATIONS
P-019
POSTER PRESENTATIONS
DRD 2011
P-020
SYNTHESIS AND BIOLOGICAL ACTIVITIES OF SOME NEW HYDRAZIDEHYDRAZONE DERIVATIVES
Şenel TEKE, Ayşegül KARAKÜÇÜK İYİDOĞAN*
Gaziantep University, Faculty of Arts and Sciences, Department of Chemistry, 27310 Gaziantep, Türkiye
*[email protected]
H
ydrazones are a class of important compounds
for drug synhesis, as ligands for metal complexes
and preparation of cyclic rings1-2. The hydrazidehydrazones are also compounds which posses great biological activites such as antimicrobial, antituberculosis, anticonvulsant, anticancer and antiviral activities3-5.
N
O
In this study, synthesis of eight (S)-2-[(4substitutedbenzamido)-N’-(4-substitutedbenzylidene)-3phenyl]propanoic acid hydrazide which have a chiral center
have been realised to investigate their antimicrobial and anticancer activities in future. The purities and chemical structures of these compounds have been confirmed by UV, IR, 1H
NMR, 13C NMR, MS spectroscopies and elemental analysis.
REFERENCES
1. Singh VP. Synthesis, electronic and ESR spectral studies
on copper(II) nitrate complexes with some acylhydrazines and hydrazones. Spect Chim Acta Part A 71, 17–22,
2008.
2. Ciesielski, M., Pufky, D., Döring, M. A convenient new synthesis of fused 1,2,4-triazoles: the oxidation of heterocyclic hydrazones using copper dichloride. Tetrahedron 61,
5942–5947, 2005.
3. Metwally, KA., Abdel-Aziz, LM., Lashine, MES., Husseinyb, MI., Badawya, RH. Hydrazones of 2-aryl-quinoline4-carboxylic acid hydrazides:Synthesis and preliminary
R'
O
H
N
H
N
R
evaluation as antimicrobial agents. Bioorg Med Chem 14,
8675–8682, 2006.
4. Koçyiğit-Kaymakçıoğlu, B., Oruç E., Unsalan, S., Kandemirli, F., Shvets, N., Rollas, S., Anatholy, D. Synthesis and
characterization of novel hydrazide–hydrazones and the
study of their structure–antituberculosis activity. Eur J
Med Chem 41, 1253–1261, 2006.
5. Kaushik, D., Khan, SA., Chawla, G., Kumar, S. N’-[(5-chloro3-methyl-1-phenyl-1H-pyrazol-4-yl)methylene] 2/4-substituted hydrazides: Synthesis and anticonvulsant activity. Eur J Med Chem 45, 3943-3949, 2010.
International Symposium on Drug Research & Development 2011
74
DRD 2011
THE SYNTHESIS OF NOVEL CHALCONE DERIVATIVES FROM N-(4ACETYLPHENYL)-3-NITROBENZAMIDE AND THEIR STRUCTURAL
CHARACTERIZATION
Erdem ERGAN1, Emine Elçin ORUÇ EMRE1, Ayşegül KARAKÜÇÜK İYİDOĞAN1,*,
İbrahim Halil KILIÇ2, Derya İŞLER2, Mehmet ÖZASLAN2
Gaziantep University, Faculty of Arts and Sciences, Department of Chemistry, 27310 Gaziantep, Türkiye
2
Gaziantep University, Faculty of Arts and Sciences, Department of Biology, 27310 Gaziantep, Türkiye
*[email protected]
1
C
halcones are 1,3-diphenyl-2-propene-1-one, in
which two aromatic rings are linked by a three
carbon α,β-unsaturated carbonyl system. Chalcones possess conjugated double bonds and a completely
delocalized π-electron system on both benzene rings. Chalcones are synthesized by Claisen-Schmidt condensation of
aldehyde and ketone by base catalyzed or acid catalyzed
followed by dehydration. In the result of literature studies,
it is known that the chalcones show a wide range of pharmacological properties including antibacterial, anticancer,
antifungal, antiinflammatory, antitubercular, antitrombosit,
antimalarial, antiparasitic, antidiabetic, antileishmanial, antiplatelet activities1-5.
REFERENCES
1. Cheng JH, Hung CF, Yang SC, Wang JP, Won SJ, Lin CN. Synthesis and cytotoxic, anti-inflamatory, and anti-oxidant
activities of 2’,5’-dialkoxylchalcones as cancer chemopreventive agents. Bioorg Med Chem 16: 7270-7276, 2008.
2. Bandgar BP, Gawande SS, Bodade RG, Totre JV, Khobragade
CN. Synthesis and biological evaulation of simple methoxylated chalcones as anticancer, anti-inflammatory and antioxidant agents. Bioorg Med Chem 18: 1364-1370, 2010.
3. Modzelewska A, Pettit C, Achanta G, Davidson NE, Huang
P, Khan SR. Anticancer activities of novel chalcone and bischalcone derivaties. Bioorg Med Chem 14: 3491-3495, 2006.
In this study, N-(4-acetylphenyl)-3-nitrobenzamide which
were reacted with 4-aminoacetophenone and 3-nitrobenzoil
chloride and then this compound were treated with suitable substitue aldehydes in order to obtain new N-(4-{3-[4substituephenyl]prop-2-enoyl}phenyl)-3-nitrobenzamide
derivatives. The structures of synthesized compounds were
identified from appropriate. The structures of synthesized
compounds were identified by UV, IR, 13C NMR, 1H NMR and
elemental analysis (C, H, N, S). All compounds were evaulated for antimicrobacterial activity against Gram-pozitive
(Pseudomonas aeruginosa ATCC 25853, Escherichia coli
ATCC 25322) ve Gram-negative (Enterococcus faecalis ATCC
25923, Stafilococcus aureus ATCC 29212) with microdilution
broth process.
4. Satyanarayana M, Tiwari P, Tripathi BK, Srivastava AK, Pratap R. Synthesis and antihyperglycemic activity of chalcone based aryloxypropanolamines. Bioorg Med Chem
12: 883-889, 2004.
5. Saxena HO, Faridi U, Kumar JK, Luqman S, Darokar MP,
Shanker K, Chanotiya CS, Gupta MM, Negi AS. Sythesis of
chalcone derivaties on steroidal framework and their anticancer activities. Steroids 72: 892-900, 2007.
International Symposium on Drug Research & Development 2011
75
POSTER PRESENTATIONS
P-021
POSTER PRESENTATIONS
DRD 2011
P-022
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL ACTIVITIY OF NEW
1,2,4-TRIAZOLE-3-THIONES AND 1,3,4-THIADIAZOLES DERIVED FROM
ETHYL-2-AMINO-3-PHENYLPROPANOATE
Eyüp BAŞARAN, Ayşegül KARAKÜÇÜK İYİDOĞAN*
Gaziantep University, Faculty of Arts and Sciences, Department of Chemistry, 27310 Gaziantep, Türkiye
*[email protected]
N
owadays, five-membered heterocyclic rings such
as 1,2,4-triazole and 1,3,4-thiadiazole that occur
the structure of many organic compounds used
in drugs. The ring systems of the activity studies on antibacterial, antimycobacterial, antimycotic, antifungal1,2, anticonvulsant and antiviral3, biological activity was observed. Even re-
synthesized compounds were elucidated with UV-vis, IR, 1H
NMR, 13C NMR, MS spectral data and elemental analysis. Antimicrobial, anticancer and anticonvulsant activities of these
compounds will be screened.
R
cent studies has established for these heterocycles analgesic4
and anti-inflammatory5 activities.
R
NH
O
N N
S
R
1
NH
In this study, some novel 1,2,4-triazole-3-thiones and
1,3,4-tiadiazoles derivated from ethyl-2-amino-3-phenylpropanoate have been synthesized. Chemical structure of the
REFERENCES
1. Varvarason A, Tantili-Kakoulidou A, Siatra-Papastasikoudi
T, Tiligada E. Synthesis and biological evaluation of indole
containing derivatives of thiosemicarbazide and their cyclic 1,2,4-triazole and 1,3,4-thiadiazole analogs. Arzneim
Forsch 50: 48-54, 2000.
2. Mamolo MG, Falagiani V, Zanpier D, Vio L, Banfi F. Synthesis and antimycobacterial activity of 5-(pyridin-2-1,3,4thiadiazol-2-yl-thio)]-acetic acid arylidene-hydrazide derivatives. Farmaco 56: 587-592, 2001.
3. Kritsanida M, Mouroutsou A, Marakos P, Pouli N, Papakonstantinou-Garoufalias S, Pannecouque C, Witvouw M, De
NH
O
N
HN
N
R
1
S
Clercq E. Il Farmaco 57: 253–257, 2002.
4. Shenone S, Bruno O, Ranise A, Bondavalli W, Falcone G,
Giordano L, Vitelli M,3- Arylsulphonyl-5-arylamino-1,3,4thiadiazol-2(3H)ones as anti-inflammatory and analgesic
agents. Bioorg Med Chem 9: 2149-2153, 2001.
5. Labanauskas L, Kalcas V, Uderenaite E, Gaidelis P, Brukstus
A, Dauksas V. Synthesis of 3-(3,4-dimethoxyphenyl)-1H1,2,4-triazole-5-thiol and 2-amino-5-(3,4-dimethoxyphenyl )-1,3,4-thiadiazole derivatives exhibiting anti-inflammatory activity. Pharmazie 56: 617-619, 2001.
International Symposium on Drug Research & Development 2011
76
DRD 2011
ANTIBACTERIAL ACTIVITY OF SOME NEW AROMATIC
THIOSEMICARBAZONES
Bilal AYDINÖZ1, Ayşegül KARAKÜÇÜK İYİDOĞAN1,*, Demet TAŞDEMİR1, Mehmet SÖNMEZ1,
Emine Elçin ORUÇ EMRE1, İsmet BERBER2
Gaziantep University, Faculty of Arts and Sciences, Department of Chemistry, 27310 Gaziantep, Türkiye
2
Sinop Unıversity, Faculty of Arts and Sciences, Department of Biology, 57000 Sinop, Türkiye
*[email protected]
1
T
hiosemicarbazones are universal ligands because
they can coordinate as neutral ligands or their deprotonated forms so these group crucial for coordination chemistry .Thiosemicarbazones coordinate to the
metal ion by the sulphur and nitrogen atoms. Consequently
recently thiosemicarbazones and their metal complexes are
considerable interest. They have been important biological
activity such as antiviral1, antineoplastic2, antimalarial3 and
antimicrobial 4. In this study, we have syntesized Cu(II), Ni(II),
Zn(II), Co(II) complexes of thiosemicarbazone derivated from
4-substitutedbenzaldehydes and N-phenylhyhidrazinecarbothioamide.
R
H
H
N
N
The puritiy and chemical structure of the ligands were
determined by UV-vis, IR, 1H NMR, 13C NMR, MS spectroscopies and elemental analysis. Their complexes with Cu(II),
Ni(II), Zn(II) and Co(II) were proposed from combination of
UV-Vis, IR, MS spectra, elemental analysis and TGA. These
studies revealed that thionic sulphur and azomethine nitrogen of thiosemicarbazones were coordinated to metal
ion. In vitro antibacterial activity of thiosemicarbazones and
their complexes against bacteria Gram-negative and Grampositive bacteria (E. coli ATCC 4230, S. aureus ATCC 6538, S.
aureus ATCC 25923, M. luteus ATCC 9345) was investigated
by microdilution broth method. Ampicillin was used as the
standart for antibacterial test and the minimum inhibitory
concentrations of these compounds (MIC) were determined.
N
S
R'
M
R'
R
S
N
N
N
H
H
REFERENCES
1. Horton D., Varela O. Cu, Pt, and Pd complexes of the 3-deoxy-1,2-bis(thiosemicarbazone) derived from D-glucose.
Carbohyd Res 328: 425-429, 2000.
2. Afrasiabi Z., Sinn E., Che, J., Ma Y., Rheingold AL., Zakharov
LN., Rath N., Padhye S. Appended 1,2-naphthoquinones
as anticancer agents 1:synthesis, structural, spectral and
antitumor activities of ortho-naphthaquinone thiosemicarbazone and its transition metal complexes. Inorg
Chim Acta 357: 271–278, 2004.
3. Oliveira R., Souza-Fagundes E.M., Soares RP., Andrade AA.,
Krettli AU., Zani CL. Synthesis and antimalarial activity of
semicarbazone and thiosemicarbazone derivatives. Eur J
Med Chem 43: 1983-1988, 2008.
4. Cocco A., Cenzo Congiu C., Onnis V., Pellerano M. Synthesis and antimycobacterial activity of new S-alkylisothiosemicarbazone derivatives. Bioorg Med Chem 10:
501–506, 2002.
International Symposium on Drug Research & Development 2011
77
POSTER PRESENTATIONS
P-023
POSTER PRESENTATIONS
DRD 2011
P-024
ANTIVIRAL AND CYTOTOXIC ACTIVITIES OF PLATINUM(II) AND
PALLADIUM(II) COMPLEXES DERIVED FROM 5-SUBSTITUTED-2THIOPHENE CARBOXALDEHYDE THIOSEMICARBAZONES
Demet TAŞDEMİR1, Ayşegül KARAKÜÇÜK İYİDOĞAN1,*, Emine Elçin ORUÇ EMRE1, Jan BALZARINI2
Gaziantep University, Faculty of Science, Department of Chemistry, 27310 Gaziantep, Türkiye
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Katholieke Universtiteit Leuven,
3000 Leuven, Belgium
* [email protected]
1
2
R
ecently, thiosemicarbazones and their metal complexes have achieved importance due to their application in pharmaceutical chemistry and have
proved as chemotherapeutic agents potentially useful for
inhibiting the activities of cancer cells. For evample, 3-aminopyridine-2-carboxaldeyde thiosemicarbazone (Triapine®;
Vion Pharmaceuticals Inc. New Haven, CT) inhibit to the
biosynthesis of DNA in leukemia L1210 cells by blocking activity of ribonucleotide reductase1. Many heterocyclic thiosemicarbazone derivatives and their platinum and palladium
complexes have a wide range of pharmacological activities,
such as antituberculosis2, antimicrobial3, antitumor4, antimalarial5, antiviral6 so that many research groups are interested
in these compounds. In this study, we have syntesized Pt(II)
and Pd(II) complexes of thiosemicarbazone derivated from
5-substitutedthiophene-2-carboxaldehydes and N-phenylhyhidrazinecarbothioamide.
REFERENCES
1. Finch RA., Liu MC., Gril SP., Rose WC., Loomis R., Vasquez
KM., Cheng YC., Sartorelli AC. Triapine (3-aminopyridine2-carboxaldehyde-thiosemicarbazone): a potent inhibitor
of ribonucleotide reductase activity with broad spectrum
antitumor activity. Biochem Pharmacol 59: 983-991, 2000.
2. G. Domagk., R. Behnisch., F. Mietzsch., H. Schmidt. Uber
eine neue gegen Tuberkelbazillen in vitro wirksame
Verbindungsklasse. Naturwis-senschaften 10: 315, 1946.
3. Zahínos E., Luna-Giles F., García P., Calderón M. Co(III),
Ni(II), Zn(II) and Cd(II) complexes with 2-acetyl-2-thiazoline thiosemicarbazone: Synthesis, characterization, Xray structures and antibacterial activity. Eur J Med Chem
46: 150-159, 2011.
H
N
N
R
S
N
R'
S
M
Cl
Cl
M=Pt(II) or Pd(II)
The puritiy and chemical structure of the ligands were
determined by UV-vis, IR, 1H NMR, 13C NMR, MS spectroscopies and elemental analysis. Their complexes with Pt(II), Pd(II)
were proposed from combination of UV-Vis, IR, MS spectra,
elemental analysis and TGA. These studies revealed that
thionic sulphur and azomethine nitrogen of thiosemicarbazones were coordinated to metal ion. The in vitro cytotoxic
and antiviral activity of all thiosemicarbazones and their
metal complexes were also evaluated.
4. Hu K., Yang Z., Pan S., Xu H., Ren J. Synthesis and antitumor activity of liquiritigenin thiosemicarbazone derivatives. Eur J Med Chem 45: 3453-3458, 2010.
5. Walcourt A., Loyevsky M., Lovejoy D., Gordeuk V., Richardson R. Novel aroylhydrazone and thiosemicarbazone iron
chelators with anti-malarial activity against chloroquineresistant and -sensitive parasites. The Int J Biochem & Cell
Biol 36: 401–407, 2004.
6. Quenelle D., Keith K., Kern E. In vitro and in vivo evaluation of isatin-thiosemicarbazone and marboran against
vaccinia and cowpox virus infections. Antiviral Research
71, 24-30, 2006.
International Symposium on Drug Research & Development 2011
78
DRD 2011
SYNTHESIS AND CHARACTERIZATION OF NEW 1-(4-CHLOROPHENYL)2-(1H-IMIDAZOLE-1-YL)ETHANOL ESTERS AS POTENTIAL
ANTICONVULSANT AND ANTIFUNGAL COMPOUNDS
İnci Selin DOĞAN1, 2, Selma SARAÇ1, *, Sevim DALKARA1
Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06100 Ankara, Türkiye
Permanent address: Süleyman Demirel University, Faculty of Medicine, Research and Implementation Hospital,
Çünür-Isparta, Türkiye
*
[email protected]
1
2
D
enzimol (α-[4-(2-phenylethyl)phenyl]-1H-imidazole1-ethanol), nafimidone [1-(2-naphthyl)-2-(imidazol1-yl)ethanone] and its major metabolite nafimidone
alcohol are known the examples of (arylalkyl)azole anticonvulsant compounds. The structure-activity relationship (SAR)
studies showed that the most desirable anticonvulsant activity appeared with a lipophilic aryl group, oxygen containing
small substituent in the alkylene bridge and imidazole ring1,2.
In addition to their anticonvulsant activity, many of these compounds also show antifungal and/or antibacterial activities because of their structural similarities to 1-substituted-1H-azole
antifungals, which have an important place among the other
antifungal compounds. Azole antifungals generally possess an
imidazole or triazole ring (seen with miconazole, ketoconazole,
N
O
N
In this study we aimed to synthesize some new 1-(4-chlorophenyl)- 2-(1H-imidazole-1-yl)ethanol esters (II) to find more
active and less toxic anticonvulsant and antifungal compounds
and to establish new SARs for this group. In these compounds
the phenyl ring was substituted at p-position with chlorine atom.
Compounds were prepared by esterification of the appropriate
alcohol (I) with various aliphatic carboxylic acids in the presence
of dicyclohexylcarbodiimide/4-dimethylaminopyridine (DCC/
DMAP). The structure of the compounds was confirmed by IR, 1HNMR, mass spectral data and elemental analysis.
N
OH
NaBH4
N
Cl
Cl
and aliphatic carboxylic acid ester derivatives of 1-phenyl-2(imidazol-1-yl)ethanol carrying phenyl ring as a lipophilic aromatic group instead of naphthalene have been described5,6.
(I)
OCOR N
N
R-COOH
Cl
. HCl
(II)
R: -CH3, -CH2CH3, -CH2CH2CH3, -CH2(CH2)2CH3, -CH2CH(CH3)2
fluconazole and itraconazole) as an azole group3,4. In our previous studies some carboxylic acid esters of nafimidone alcohol
Acknowledgement: This project was supported by Hacettepe University Scientific Research Fund (HÜBAB 010D06301004).
REFERENCES
1. Walker KAM, Wallach MB, Hirschfield DR, 1-(Naphthylalkyl)-1Himidazole derivatives, a new class of anticonvulsant agents. J
Med Chem 24: 67-74, 1981.
2. Nardi D, Tajana A, Leonardi A, Pennini R, Portioli F, Magistretti MJ, Subissi A. Synthesis and anticonvulsant activity of N-(benzoylalkyl)imidazoles and N-(ω-phenyl-ωhydroxyalkyl)imidazoles. J Med Chem 24: 727-731, 1981.
3. Karakurt A, Dalkara S, Özalp M, Özbey S, Kendi E, Stables JP.
Synthesis of some 1-(2-naphthyl)-2-(imidazole-1-yl)ethanone
oxime and oxime ether derivatives and their anticonvulsant
and antimicrobial activities. Eur J Med Chem 36: 421-433, 2001.
4. Karakurt A, Aytemir MD, Stables JP, Özalp M, Kaynak FB,
Özbey S, Dalkara S. Synthesis of some oxime ether deriva-
tives of 1-(2-naphthyl)-2-(1,2,4-triazol-1-yl)ethanone and
their anticonvulsant and antimicrobial activities. Arch.
Pharm. (Weinheim) 339: 513-520, 2006.
5. Karakurt A, Özalp M, Işık Ş, Stables JP, Dalkara S. Synthesis,
anticonvulsant and antimicrobial activities of some new
2-acetylnaphthalene derivatives. Bioorg & Med Chem
18(8): 2902-2911 (2010).
6. Doğan İS, Saraç S, Dalkara S. Studies on aliphatic esters of
1-phenyl-2-(1H-imidazol-1-yl) ethanol. 4th International
Meeting on Medicinal and Pharmaceutical Chemistry
(IMMPC)-6th International Symposium on Pharmaceutical
Chemistry (ISPC) Joint Meeting, Ankara-Türkiye, September 30-October 2, 2010, Abstract Book p. 90, 2010.
International Symposium on Drug Research & Development 2011
79
POSTER PRESENTATIONS
P-025
POSTER PRESENTATIONS
DRD 2011
P-026
SYNTHESIS AND ANTINOCICEPTIVE ACTIVITY OF SOME 2-PYRAZOLINE
DERIVATIVES
Ahmet ÖZDEMIR1,* , Ebru ÇINAR2, Mehlika Dilek ALTINTOP1, Zafer Asım KAPLANCIKLI1,
Gülhan Turan ZITOUNI1, Özgür Devrim CAN3
Anadolu University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 26470 Eskişehir, Türkiye
2
Anadolu University, Faculty of Pharmacy, 26470, Eskişehir, Türkiye
3
Anadolu University, Faculty of Pharmacy, Department of Pharmacology, 26470 Eskişehir, Türkiye
*
[email protected]
1
T
he new 1,3,5-trisubstituted-2-pyrazoline derivatives were synthesized by reacting various chalcones with hydrazine hydrate in glacial acetic
1
acid . The structures of the synthesized compounds were
proved by means of their IR, 1H-NMR and FAB+-MS spectroscopic data and and Elemental Analyses. Antinociceptive
activities of the test compounds (100 mg/kg) were investigated by hot plate, tail-clip and acetic acid induced writhing tests in mice. Morphine sulphate (10 mg/kg) was used
as a reference drug. Rota-rod tests were performed to check
the presence of any motor abnormalities induced by the
test compounds. Reaction times of mice in hot-plate and
tail-clip tests were significantly increased and numbers of
acetic acid-induced writhing and stretching behaviors were
significantly decreased following the administration of the
test compounds, indicating the presence of antinociceptive
activity. The compounds did not impair the motor performance in Rota-Rod test, indicating that the observed antinociception unlikely occurred due to motor abnormalities. In
conclusion, tested compounds exhibited different levels of
antinociceptive activities and these antinociception involves
both peripheral and central mechanisms. Further studies are
needed to clarify the exact mechanism of action.
R
S
N
N
O
R= -CH2-O-CH2, -OC2H5, -N(C2H5)2, -OH, -CH(CH3)2, -CN, -CF3, -Br, -CH3, -OCF3
REFERENCES
1. Srinath N., Prasad Y.R., Mukkanti K., Synthesis and analgesic activity of some 1,3,5-trisubstituted-2-pyrazolines, Int
J Curr Pharm Res 3(1), 76-80, 2010.
International Symposium on Drug Research & Development 2011
80
DRD 2011
SYNTHESIS AND CHARACTERIZATION OF PYRAZOLE DERIVATIVES FROM
SOME HYDRAZIDES
Ş.Güniz Küçükgüzel1, Sevil Aydın1,*, Neerja Kaushik-Basu2,
Guru Kumar Kollongod RAMANATHAN2
Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Haydarpaşa 34668 İstanbul,
Türkiye
2
Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue,
Newark, NJ 07103
*
[email protected]
1
P
yrazole-containing compounds were re- proved to be a selective inhibitor of HCV replication [5].
ported to exhibit neovascularization, decrease
in VEGF production and increase in apoptosis of
tumor cells and antiproliferative activity [1-4]. Pyrazofurin;
the natural 4-hydroxypyrazole C-glycoside has antimicrobial and antiviral activities against many RNA and DNA viruses. In addition, this drug has been used clinically as an
anticancer agent. 5-(4-Chlorophenyl)-1-(4-methoxyphenyl)3-(trifluoromethyl)-1H-pyrazole (SC-560) was reported to
be active against bovine viral diarrhoea virus (BVDV) and
REFERENCES
1. Leahy KM, Koki AT, Masferrer JL. Role of Cyclooxygenases
in Angiogenesis. Curr Med Chem 7: 1163-1170, 2000.
2. Abadi AH, Eissa AA, Hassan GS. Synthesis of novel 1,3,4-trisubstituted pyrazole derivatives and their evaluation as
antitumor and antiangiogenic agents. Chem Pharm Bull
(Tokyo) 51(7): 838-844, 2003.
3. Abdel-Aziz HA, Gamal-Eldeen AM, Hamdy NA, Fakhr IMI.
Facile synthesis and in-vitro antitumor activity of some
pyrazolo[3,4-b]pyridines and pyrazolo[1,5-a]pyrimidines
linked to a thiazolo[3,2-a]benzimidazole moiety. Arch
Pharm Chem Life Sci 342: 230-237, 2009.
In view of the above observations, the green synthesis
of novel 1-aroyl-3,5-dimethyl-1H-pyrazole derivatives using
microwave irradiation were aimed at investigating biological
activities of these compounds.
Acknowledgement: This study was supported by Scientific Research Project Commission of Marmara University
(Project number: SAĞ.A.310510 / 0175).
4. Rostom SAF. Polysubstituted pyrazoles, part 6. Synthesis
of some 1-(4-chlorophenyl)-4-hydroxy-1H-pyrazol-3-carbonyl derivatives linked to nitrogenous heterocyclic ring
systems as potential antitumor agents. Bioorg Med Chem
18, 2767-2776, 2010.
5. Okamoto M, Sakai M, Goto Y, Salim MT, Baba C, Goto K,
Watashi K, Shimotohno K, Baba M. Anti-bovine viral diarrhoea virus and hepatitis C virus activity of the cyclooxygenase inhibitor SC-560. Antivir Chem Chemother 20 (1):
47-54, 2009.
International Symposium on Drug Research & Development 2011
81
POSTER PRESENTATIONS
P-027
POSTER PRESENTATIONS
DRD 2011
P-028
Determination with HPLC-UV Method of Etodolac in
Pharmaceutical Preparations
Alptuğ ATİLA, Ö. Faruk KOÇAK, Yücel KADIOĞLU
Department of Analytical Chemistry, Faculty of Pharmacy, Atatürk University, 25240 Erzurum, Türkiye
N
on-steroidal anti-inflammatory drugs (NSAIDs)
are used in humans and domestic animals due to
their anti-inflammatory, analgesic and anti-pyretic effect1. Etodolac (1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4b]-indole-1-acetic acid) is an effective and well-tolerated
NSAID, and is indicated for the treatment of analgesia and
for the signs and symptoms of rheumatoid arthritis and osteoarthritis2.
Etodolac was kindly supplied from Novagenix Pharmaceutical Industry (Ankara, Turkey). Acetaminophen used as
internal standard (IS) was obtained from Sigma-Aldrich (USA).
An Agilent 1200 series HPLC system, consisting of a degasser,
quaternary pump, autosampler, and a variable wavelength
UV detector with a thermostatted column compartment was
used in this study. Separation was carried out on reversedphase ACE C18 column. The mobile phase contained a mixture of acetonitrile-water (80:20, v/v). The UV detector was
REFERENCES
1. Zaher A. R, Nasir K. Khan. Effects of cyclooxygenase inhibition on the gastrointestinaltract.Experimental and Toksicologic Pathalogy 58:163-173,2006.
set at 272 nm and peak areas were integrated using Agilent
ChemStation software program. Etodolac working solution
was used to prepare the spiking stock solutions for construction of six-point calibration curve (0.08–10 µg mL−1) and QC
samples at three different levels (0.1, 4.5, 9.5 µg mL−1). The
working IS solution (1 µg mL−1) was prepared by diluting the
stock solution. The calibration equation from six replicate
experiments, y = 1,530x-0,057 (r = 0.9996), demonstrated the
linearity of the method.
A simple and quick analytical method has been developed to be applied in determining etodolac in tablets. The
present methods are specific, accurate, precise, linear and
sensitive. There is an excellent correlation between peak area
and concentration. This method can be applicable in routine
quality control laboratories because of short analysis and
low cost of analyse.
2. Joseph P. B., Joan M. K.B., Patrick M., Donna K. S., Lyeite S.
R., Robert R., Philip D. W., Pharmacokinetics of Etodolac
in Patients with Stable Juvenile Rheumatoid Arthritis
21:1715-1724, 1999.
International Symposium on Drug Research & Development 2011
82
DRD 2011
Determination of pKa Values OF SOME BASıC DRUGS (Salmeterol
xınafoate, Flutıcasone propıonate and Thioridazine) By lıquıd
chromatography
Bediha Yalçın1,2,*, Senem Şanlı1, Nurgül Karadaş1, Nurullah Şanlı1, Adem Asan2
Department of Chemistry, Faculty of Science and Arts, Hitit University, Çorum, Türkiye
Department of Analytical Chemistry, Faculty of Science and Arts, Ondokuz Mayıs University, Kurupelit, Samsun,
Türkiye
*
[email protected]
1
2
F
luticasone propionate is a glucocorticoid with potent anti-inflammatory activity used in the prevention of asthma. It is very poorly water soluble and
also displays a high degree of binding to lung tissue. Salmeterol xinafoate dissociates in solution to yield salmeterol
base and hydroxynaphthoate, and displays poor aqueous
solubility. Thioridazine is a piperidine typical antipsychotic
drug belonging to the phenothiazine drug group and was
previously widely used in the treatment of schizophrenia
and psychosis1,2.
REFERENCES
1. Murnane D, Martin GP, Marriott C, Validation of a reverse-phase high performance liquid chromatographic
method for concurrent assay of a weak base (salmeterol
xinafoate) and a pharmacologically active steroid (fluticasone propionate). J Pharm and Biomed Anal 40:11491154, 2006.
The ionization constant (pKa) is an important physicochemical parameter of a drug and the knowledge of this
parameter is of fundamental importance in a wide range
of applications and research areas. The use of high performance liquid chromatography (HPLC) retention parameters
to determine pKa values is widely used in recent years. In this
study, pKa values of some basic drugs, namely; fluticasone
propionate, salmeterol, xinafoic acid and thioridazine were
determined at different acetonitrile-water mixtures, ranging between 55-65% (v/v), using LC-UV method. X-Terra RP18 column (250 x 4.60 mm ID x 5m) was used and column
temperature was 25 0C.
2. Robertson A, MacDonald C, A typical neuroleptics clozapine and thioridazine enhance amphetamine-induced
stereotypy. Pharmacol Biochem Behav 21:97–101, 1984.
International Symposium on Drug Research & Development 2011
83
POSTER PRESENTATIONS
P-029
POSTER PRESENTATIONS
DRD 2011
P-030
SIMULTANEOUS ASSAY of FLUTICASONE PROPIONATE AND
SALMETEROL XINAFOATE ın Pharmaceutical Dosage Forms By Hplc
Bediha Yalçın1,2, Senem Şanlı1,*, Nurullah Şanlı1, Adem Asan2
1
Department of Chemistry, Faculty of Science and Arts, Hitit University, Çorum, Türkiye
Department of Analytical Chemistry, Faculty of Science and Arts, Ondokuz Mayıs University, Kurupelit, Samsun,
Türkiye
*
[email protected]
2
F
luticasone propionate is a novel androstane glucocorticosteroid having potent pulmonary antiinflammatory activity. It has been shown to exhibit
improved therapeutic efficacy in the treatment of asthma
and rhinits compared with other available inhaled corticosteroids. Salmeterol is a long-acting potent β-2 adrenoceptor agonist used via inhalation to improve lung function,
reduce symptoms and provide a better quality of life for patients with asthma.
These two drugs are formulated as dry powder inhalers
or pressurized metered dose inhalers individually or in combined formulation1,2,3. A simple, accurate, precise and fully
validated liquid chromatographic method have been developed for the simultaneous determination of fluticasone propionate and salmeterol xinafoate in pharmaceutical dosage
form. Separation was performed on X-Terra RP-18 column
(250 mm x 4.60 mm ID x 5m) at 25 0C with the mobile phase
of acetonitrile:water 60:40 (v/v) adjusted to pH 3.75 with 25
mM ortophosphoric acid.
REFERENCES
1. Li YN, Tattam BN, Brown, KF, Seale, JP, A sensitive method
for the quantification of fluticasone propionate in human
plasma by high-performance liquid chromatography/atmospheric pressure chemical ionisation mass spectrometry. J Pharm Biomed Anal 16:447-452, 1997.
2. Murnane D, Martin GP, Marriott C, Validation of a RP-HPLC
method for concurrent assay of a weak base (salmeterol
xinafoate) and a pharmacologically active steroid (fluticasone propionate). J Pharm Biomed Anal 40:1149-1154,
2006.
3. Zhang M, Fawcett, P, Shaw, JP, Rapid chiral HPLC assay for
salmeterol and a-hydroxysalmeterol. Application to in
vitro metabolism studies. J Chromatogr B 729:225-230,
1999.
International Symposium on Drug Research & Development 2011
84
DRD 2011
SYNTHESIS AND EVALUATION OF ANTIMICROBIAL ACTIVITIES OF SOME
NEW BENZIMIDAZOLE DERIVATIVES
Özden Tarı1,*, Nizami Duran2, Öztekin Algül1
Mersin University Faculty of Pharmacy Department of Pharmaceutical Chemistry, Mersin, Türkiye
2
Mersin University Faculty of Medicine Department of Microbiology, Hatay, Türkiye
*
[email protected]
1
T
herapy of bacterial and fungal infections is limited
because of the increasing number of multi-drug
resistance pathogens, such as methicillin-resistant Staphylococcus aureus [1,2]. Drug resistance is also increased by the irrational use of antimicrobial drugs. Hence,
there is a need for effective alternative antimicrobial compounds such as vancomycin, methicillin for the treatment of
these infections.
Benzimidazoles carrying different substituents have various biological activities, i.e. anticancer, antiviral, antifungal,
antihelmintic, anti-inflammatory, antihistaminic and antibacterial [3]. Also, benzimidazoles still remain one of the
most versatile classes of compounds against microorganisms. Recently, it was shown that substitutions in N-1 and C-2
positions of benzimidazole ring were important for antimicrobial activities [4,5].
In this study, ten new 1,2-disubstituted benzimidazole
derivatives were synthesized by conventional and microwave
synthesis methods and antimicrobial effects of these compounds were tested by Microdilution Broth Method in vitro. REFERENCES
1. Pfaller M, Diekema D. Rare and Emerging Opportunistic
Fungal Pathogens: Concern for Resistance beyond Candida albicans and Aspergillus fumigatus. J Clin Microbiol
42: 4419, 2004.
2. Graffunder EM, Venezia RA. Risk factors associated with
nosocomial methicillin-resistant Staphylococcus aureus
(MRSA) infection including previous use of antimicrobials. J Antimicrob Chemoth 49: 999–1050, 2002.
3. Pathak D, Siddiqui N, Bhrigu B, Ahsan W, Alam MS. Benzimidazoles: A New Profile of Biological Activities. Der
The most potent antibacterial effective compounds were
1,2-bis(4-chlorophenyl)-1H-benzimidazole (Compound 5)
and 1-benzyl-2-phenyl-1H-benzimidazole (Compound 3) as
they were demonstrated most inhibitory effect on Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus
faecalis and Bacillus cereus. Additionally, all compounds were
predominantly more effective against gram positive than
gram negative bacteria. On the other hand, 1,2-diphenyl-1Hbenzimidazole (Compound 1) was shown moderately antifungal activity against Candida albicans, Candida tropicalis,
Candida parapsilosis, Candida glabrata and Candida krusei.
We have concluded that substitution at N-1 and C-2 positions of the benzimidazole ring on antimicrobial activity was
important and our next studies will be focused on effect of
these substitutions on antimicrobial activity.
N
R
2
N
R
1
R1: C6H5, p-Cl C6H5, CH2C6H5 R2: C6H5, p-Cl C6H5, p-CH3 C6H5,
p-OCH3C6H5, p-N(CH3)2 C6H5, p-NO2C6H5, 2,6-Cl C6H5
Pharmacia Lettre 2(2): 27-34, 2010.
4. Kumar RV, Gopal KR, Sheshu Kumar KVSR. Facile synthesis and antimicrobial properties of 2-(substitutedbenzylsulfanyl)-1h-benzimidazoles. J Heterocycl Chem
42: 1405-1408, 2005.
5. Starcevic K, Kralj M, Ester K, Sabol I, Grce M, Pavelic K,
Karminski-Zamola G. Synthesis, antiviral and antitu-
mor activity of 2-substituted-5-amidino-benzimidazoles. Bioorg Med Chem 15: 4419-4426, 2007.
International Symposium on Drug Research & Development 2011
85
POSTER PRESENTATIONS
P-031
POSTER PRESENTATIONS
DRD 2011
P-032
SYNTHESIS AND CYTOTOXIC ACTIVITY OF HYDRAZIDE HYDRAZONES
AND THEIR CORRESPONDING 3-ACETYL-2,5-DISUBSTITUTED-1,3,4Oxadiazolines
Kadriye Akdağ1, Sevgi Karakuş1, Bedia Koçyİğİt Kaymakçıoğlu1, Sevim Rollas1,
Suna ÖZBAŞ Turan 2, Jülide Akbuğa2
Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34668 İstanbul, Türkiye
2
Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Biotechnology,
34668 İstanbul, Türkiye
1
I
n recent years, the five membered 1,3,4-oxadiazole
rings have gained importance due to their application in pharmaceutical chemistry. Therefore several
1,3,4-oxadiazole derivatives exhibited broad spectrum of
biological activities such as antimicrobial, antituberculosis, analgesic, antiinflammatory and anticancer activities.1-2
Many synthesis methods are reported about the cyclization of 1,3,4-oxadiazole derivatives. One of these concepts
includes the cyclodehydration of 1,2-diacyl or 1,2-diaroylhydrazines with a different reagents such as phosphorous
pentoxide, phosphorous oxychloride, thionyl chloride, triflic
anhydride, triphenylphosphine, polyphosphoric acid and
sulfuric acid. Another synthesis method of 1,3,4-oxadiazole
is that the acid hydrazides are cyclization with acid chlorides,
aromatic acids or aromatic aldehydes by using a dehydrating
reagent like sulfuric acid, phosphorous oxychloride.3-4 In this
research, 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazolines (2) were synthesized by cyclization of hydrazide-hydrazones (1) with acetic anhydrides. Hydrazide-hydrazones
were known to be exhibit various pharmacological activities such as antimicrobial, antiviral, anti-HIV, anticancer and
antiinflammatory.5-7 Cytotoxicity of the synthesized compounds have been evaluated by using HEK293 cell line of
MTT [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium
bromide] assay.
O
Ar
NH N
N
NH
H3CO
NH
O
H
O
H3CO
O
CH3
N
Ar
O
2
1
REFERENCES
1. S. Rollas, N. Gulerman, H. Erdeniz. Farmaco 57: 171, 2002.
2. F. Macaev, G. Rusu, S. Pogrebnoi, A. Gudima, E. Stingaci, L.
Vlad, N. Shvets, F. Kandemirli, A. Dimoglo, R. Reynoldsd.
Bioorg Med Chem 13: 4842, 2005.
3. P. Brown, DJ. Best, NJP. Broom, R. Cassels, PJ. Bhanlon, TJ.
Mitchell, NF. Osborne, JM. Wilson. J Med Chem 40: 2563,
1997.
4. S. Liras, MP. Allen, BE. Segelstein. Synth Commun 30: 437,
2000.
5. MT. Abdel-Aal, WA. El-Sayed, EH. El-Ashry. Arch Pharm
Chem Life Sci 339: 656, 2006.
6. SAF. Rostom, MA. Shalaby, MA. El-Demellawy. Eur J Med
Chem 38: 959, 2003.
7. B. Koçyigit-Kaymakcıoglu, E. Oruc, S. Unsalan, F. Kandemirli, N. Shvets, S. Rollas, A. Dimoglo. Eur J Med Chem 41:
1253, 2006.
International Symposium on Drug Research & Development 2011
86
DRD 2011
DETERMINATION OF pKa VALUES OF FOUR ANTIPSYCHOTIC DRUGS By
Hplc
Senem ŞANLI1, *, Bediha YALÇIN1, 2, Yüksel ALTUN3
1
Department of Chemistry, Faculty of Science and Arts, Hitit University, Çorum, Türkiye
Department of Analytical Chemistry, Faculty of Science and Arts, Ondokuz Mayıs University, Kurupelit, Samsun, Türkiye
3
Gazi University, Gazi Faculty of Education, Department of Chemistry, 06500 Teknikokullar, Ankara, Türkiye
*[email protected]
2
A
ntipsychotic agents are used in psychiatric patients for the management of psychotic episodes
as well as for other behavioral symptoms such as
agitation. Second generation antipsychotics (SGAs) (such
as sertindole, olanzapine, ziprasidone and risperidone) are
popular for the treatment of schizophrenia and other psychoses in the clinic [1].
In this study, pKa values of four antipsychotic drugs,
namely; sertindole, olanzapine, clozapine and risperidone
were determined in 42.5% (v/v) acetonitrile-water mixtures
using LC-UV method. X-Terra RP-18 column (250x4.60 mm
IDx5m) was used and the column temperature was 25 oC.
REFERENCES
1. Zhang G, Terry Jr AV, Bartlett MG. Simultaneous determination of five antipsychotic drugs in rat plasma by high
performance liquid chromatography with ultraviolet de-
The pKa values of studied compounds were determined
from k/pH data pairs by means of the non-linear regression
program NLREG [2]. As an example, NLREG graphic of sertindole (pKa 8.180±0.135) was given in Figure 1.
Figure 1. NLREG graphic of sertindole in 42.5% (v/v) acetonitrile-water mixtures.
tection. J Chromatogr B 856: 20-28, 2007.
2. Sherrod PH, NLREG, Nonlinear Regression Analysis and
Curve Fitting Program, 2007, (http://www.nlreg.com).
International Symposium on Drug Research & Development 2011
87
POSTER PRESENTATIONS
P-033
POSTER PRESENTATIONS
DRD 2011
P-034
CYTOTOXIC AND APOPTOTIC EFFECTS OF NEW 5-TRIFLUOROMETHOXY1H-INDOLE-2,3-DIONE THIOSEMICARBAZONES ON LYMPHOMA AND
LEUKEMIA CELL LINES
Serap ERDEM KURUCA1,*, Nilgün KARALI2, Kadriye AKGÜN DAR3, Ebru GÜREL3,
Zeynep KARAKAŞ 4
Department of Physiology, Istanbul Faculty of Medicine, İstanbul University, Çapa-İstanbul, Türkiye
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İstanbul University, Beyazıt-İstanbul, Türkiye
3
Department of Biology, Faculty of Science, İstanbul University, Beyazıt-İstanbul, Turkey
4
Department of Pediatric Hematology and Oncology, İstanbul Faculty of Medicine, İstanbul University, Çapa-İstanbul,
Türkiye
*[email protected]
1
2
T
hiosemicarbazones have drawn great interests
for their high potential biological activity especially their anticancer activity. The discovery of
numerous biologically active 1H-indole-2,3-dione thiosemicarbazones led in the past decade to extensive synthesis of
related compounds and as a result, anticancer agents were
developed. In particular, among the 5-substituted analogs
developed in as growth inhibitors against several human
cancer cell lines, 5-halide, methoxy and trifluoromethoxy
groups containing derivatives show high antiproliferative
effects. In this study, we investigated anticancer potential
of new 5-trifluoromethoxy-1H-indole-2,3-dione 3-(N-substituted thiosemicarbazone) derivatives that are first synthesized by Istanbul University, Faculty of Pharmacy (figure 1).
The cytotoxic effects of these compounds were evaluated
by colorimetric MTT method in chronic leukemia cell lines
(K562, HL60), B-lymphoma cell lines (P3HR1) and mononuclear cells of acute lymphoblastic leukemia patients (ALL-MC).
The IC50 values (IC50 is a concentration that kills 50% of cells)
were calculated from dose-response curve according to cytotoxicity index. Effectiveness of thiosemicarbazone derivatives were evaluated by comparing IC50 values in leukemic
cell lines. Also, to investigate apoptotic mechanism of these
compounds, caspase3 immunohistochemical staining was
performed on P3HR1 cells. All of compounds were found cytotoxic in little different ranges (<5ug) in P3HR1 cell line and
in ALL-MC. It is thinkable, effect mechanism may be occurs
through caspase3 apoptotic pathway. It was interesting finding that 5-trifluoromethoxy-1H-indole-2,3-dione-3-(N-allyl
thiosemicarbazone) was effective in all tested cancer cell
lines. As a result, 5-trifluoromethoxy-1H-indole-2,3-dione3-thiosemicarbazones might have chemotherapeutic drug
potential in B-lymphoma and chronic leukemia.
OCF3
R
NH
N
NH
NH
S
O
Fig 1: 5-Trifluoromethoxy-1H-indole-2,3-dione 3-(N-substituted thiosemicarbazones)
R= CH3, C2H5, CH2-CH=CH2, cyclo-C6H11, C6H5CH2,
C6H5, 4-CH3C6H4, 4-CH3OC6H4, 4-BrC6H4, 4-ClC6H4,
4-FC6H4, 4-NO2C6H4
International Symposium on Drug Research & Development 2011
88
DRD 2011
Quorum Sensing Inhibitor Activities of Essential Oils
Seyhan ULUSOY* , Rümeysa ERİŞ
Department of Biology, Süleyman Demirel University, 32260 Isparta, Türkiye
*[email protected]
B
acterial cell to cell communication or quorum
sensing (QS), N-acyl-L-homoserine lactone based
signalling system, coordinates a wide variety of
functions in Gram-negative bacteria, including antibiotic
and exoenzyme production, biofilm formation, violacein
production1-2. Thus, manipulating this communication system could provide an opportunity to modulate bacterial QS
dependent traits such as pathogenity. Various properties of
plant based products most studied; antibacterial3, anticancer4, and anti-QS properties5-6.
REFERENCES
1. Whitehead NA, Barnard AM, Slater H, Simpson NJ, Salmond GP. Quorum-sensing in Gram-negative bacteria.
FEMS Microbiology Reviews 25: 365-404, 2001.
2. McClean KH, Winson MK, Fish L, Taylor A, Chhabra SR, Camara M, Daykin M, Lamb J.H, Swift S, Bycroft BW, Stewart
GS, Williams P. Quorum sensing and Chromobacterium
violaceum: Exploitation of violacein production and inhibition for the detection of N-acylhomoserine lactones.
Microbiology 143: 3703-3711, 1997.
3. Cowan MM. Plant Products as Antimicrobial Agents. Clinical Microbiology Reviews 12: 564-582, 1999.
In this study, quorum sensing inhibitor (QSI) potential of
twenty essential oils was investigated to find natural and nontoxic QS inhibitor candidate ompounds may reveal in modulating QS using this communication system in pathogenic
bacteria. QS inhitor activities of natural oils were screened
using four kinds of biomonitor organisms; Quorum Sensing
Inhibitor Selector strain1 (QSIS1) and Chromobacterium violaceum strain CV026, C. violaceum strain VIR07 and C. violaceum strain ATCC 12472. Rose, clove, pinus and chamomile
essential oils were showed significant inhibitor activities for
all biomonitor strains tested at very low concentrations.
4. Srivastava V, Singh NA, Kumar JK, Gupta MM and Khanuja
SPS. Plant-based anticancer molecules: A chemical and
biological profile of some important leads. Bioorganic &
Medicinal Chemistry 13:5892-5908, 2005.
5. Bjarnsholt T, Jensen PO, Rasmussen TB, Christophersen
L, Calum H, Hentzer M, Hougen HP, Rygaard J, Moser C,
Eberl L, Hoiby N and Givskov M. Garlic blocks quorum
sensing and promotes rapid clearing of pulmonary Pseudomonas aeruginosa infections. Microbiology 151: 38733880, 2005.
6. Choo JH, Rukayadi Y, Hwang JK. Inhibition of bacterial
QS by vanilla extract. Letters in Applied Microbiology 42:
637-641, 2006.
International Symposium on Drug Research & Development 2011
89
POSTER PRESENTATIONS
P-035
POSTER PRESENTATIONS
DRD 2011
P-036
Profens Interferes with Cell-Cell Communication in
Pseudomonas aeruginosa
Seyhan ULUSOY1,*, Gülgün BOŞGELMEZ TINAZ1,2
2
1
Department of Biology, Süleyman Demirel University, 32260 Isparta, Türkiye
Department of Clinical Microbiology, Faculty of Medicine, Marmara University, İstanbul, Türkiye
*[email protected]
D
ensity dependent cell-cell communication or
quorum sensing (QS) has been shown to regulate
an array of phenotypes in a variety of Gram-positive and Gram-negative bacterial species, including biofilm
formation, antibiotic synthesis, swarming, conjugation and
the production of virulence determinants[1,2]. QS depends
on the production of signal molecules which enable a bacterium to monitor its own cell population density. The discovery that many pathogenic bacteria employ QS to regulate
their pathogenicity and virulence factor production makes
the QS system an attractive target for antimicrobial therapy
[3,4]. Inhibition of bacterial QS systems may offer new hope
in combat with multi antibiotic-resistant bacteria and find
application in many different fields, such as medicine, agriculture and food technology.
REFERENCES
1. Pesci EC, Pearson JP, Seed PC and Iglewski BH. Regulation
of las and rhl quorum sensing in Pseudomonas aeruginosa. Journal of Bacteriology 179: 3127-3132, 1997.
2. Whitehead NA, Barnard AM, Slater H, Simpson NJ, Salmond GP. Quorum-sensing in Gram-negative bacteria.
FEMS Microbiology Reviews 25: 365-404, 2001.
3. Hentzer M, Wu H, Andersen JB, Riedel K, Rasmussen TB,
Bagge N, Kumar N, Schembri MA, Song Z, Kristoffersen P,
In this study, anti-QS potentials of nonsterodial anti-inflammatory drugs (NSAIDs) such as diclofenac sodium salt,
flurbiprofen, ibuprofen, indomethacin, ketoprofen, naproxen sodium, fenoprofen calcium salt hydrate were investigated using biomonitor strains. And further examined the effects of these drugs on swarming motility, biofilm formation,
elastase and pyociyanin production of P. aeruginosa PAO1
strain. NSAIDs showed to significant inhibition on elastase
production and swarming motility.
Our findings suggest that diclofenac and ketoprofen
have elastase and swarming inhibitory activity in vitro and
could be a choice to the treatment of pseudomonal bacterial
infections in combination with conventional antimicrobials.
Manefield M, Costerton JW, Molin S, Eber L, Steinberg P,
Kjelleberg S, Hoiby N, Givskov M. Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors. The EMBO Journal 22: 3803-3815, 2003.
4. Wu H, Song Z, Hentzer M, Andersen JB, Molin S, Givskov
M and Hoiby N. Synthetic furanones inhibit quorumsensing and enhance bacterial clearance in Pseudomonas aeruginosa lung infection in mice. Journal of Antimicrobial Chemotherapy 53: 1054-1061, 2004.
International Symposium on Drug Research & Development 2011
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DIABETIC PATIENTS’ SATISFACTION WITH INSULIN INJECTION
Kutay DEMİRKAN*, Hasan KACAMER, Emine TAŞHAN, Özlem ÇOBAN,
Zeynep LÜLECİ, Nuray KARATAŞ, Aygin BAYRAKTAR
Hacettepe University, Faculty of Pharmacy, Ankara, Türkiye
* [email protected]
T
he accuracy and convenience of pen devices for
insulin injection have improved patient’s quality of
life in diabetes mellitus (DM) treatment1. An intensive insulin therapy for a better glycemic control in diabetic
patients requires multiple daily insulin injections2. However,
patient compliance has really been a major concern for this
route of administration of insulin. Several alternative routes of
administration are under consideration for an effective glycemic control, including oral, inhaled, buccal, nasal, and patch
routes. Despite the advances in recent years, attempts for new
formulations have been faced with certain limitations3. The
aim of this study was to assess patient’s preferences and satisfaction on insulin injection and its administration technique
amongst the patients with DM. The patients were assessed for
their preferences on the route of administration, use and handling of insulin injections and sources for information about
diabetes and insulin therapy by using the 15-items questionnaire. Questionnaires were distributed to the patients when
they visited the retail pharmacies. Four pharmacies were selected according to location of externship of the pharmacy
students in Ankara. The questionnaires were read and filled by
senior pharmacy students in one month (March 2011) during
their community pharmacy externship period.
A total of 26 patients (77% female) with average age of 54
years old (range 9-71) completed the questionnaire. Seventy-seven percent of the patients had type II diabetes and the average
duration of diabetes was 11.1 years (range 1-30 years). Despite
REFERENCES
1. Hornquist JO, Wikby A, Andersson PO, Dufva AM. Insulin-pen treatment, quality of life and metabolic control:
Retrospective intra-group evaluations. Diabetes Res Clin
Pract. 10:221–230, 1990.
2. Diabetes Control and Complications Trial (DCCT) Re-
19 patients were prescribed with only one insulin brand, only 5
patients were injecting insulin once a day. Other patients were
administering 2, 3 or 4 injections a day (n=19, n=1, n=1, respectively). Fifty four percent of the patients were unsatisfied with
administering insulin as injection and 42.3% of the patients were
feeling discomfort while injecting insulin in public. Insulin injection is stated as easy by 73% of the patients, however most popular preferred route of insulin administration was transdermal
patch (42.3%) and oral route (30.7%). Painful injection (46.2%),
carrying/handling problems (38.5%) and administration frequency (26.9%) were the major complains of patients with insulin
injection. A majority of the patients injecting insulin with 90 degrees angle (73.1%), squeezing skin while injecting (65.4%) and
cleaning administration site with alcohol swap (57.7%). Patients
were knowledgeable about insulin storage (carrying on, ice cube,
refrigerator). 26.9% of the patients were tapering insulin dose on
their own according to home blood sugar monitoring. Majority
of the patients gather their knowledge about insulin injection
from physicians (53.8%) and nurses (26.9%). In addition, 53.8% of
the patients (n=14) were informed about insulin (primarily about
storage [71.4%], injection technique [57.1%] and dosing [57.1%])
by their pharmacists in further visits. 38.5% of the patients (n=10)
were also informed about diabetes (primarily about drug treatment [70%], hyperglycemia [50%], complications of diabetes
[40%] and foot-care [40%]) by their pharmacists. Convenience
and ease of use are the main concerns that the patients were
looking for insulin administration. Pharmacists should take more
active role in patient education especially for insulin injection
technique in diabetes care.
search Group: The effect of intensive treatment of diabetes on the development and progression of long-term
complications in insulin-dependent diabetes mellitus. N
Engl J Med 329:977–986, 1993.
3. Strack T. The pharmacokinetics of alternative insulin delivery systems. Curr Opin Investig Drugs. 11(4):394-401, 2010.
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P-038
The genotoxIc potentIals of some atypIc anthIpsychotIc drugs
on human lymphocytes
Hasan TÜrkez2, Başak Togar2, Abdulgani Tatar3, Ebubekir DİRİCAN1, İsmet Kırkpınar4,
Ahmet HacımÜftÜoĞlu5, Fatime GeyİkoĞlu2, M.Sait KeleŞ6
Kahramanmaraş Sütçü İmam University, Medical Faculty, Department of Microbiology, 46100 Kahramanmaraş, Türkiye
2
Atatürk University, Faculty of Science, Biology Department, 25240 Erzurum, Türkiye
3
Atatürk University, Medical Faculty, Medical Genetics Department, 25240 Erzurum, Türkiye
4
Atatürk University, Medical Faculty, Psychiatry Department, 25240 Erzurum, Türkiye
5
Atatürk University, Medical Faculty, Medical Pharmacology Department, 25240 Erzurum, Türkiye
6
Atatürk University, Medical Faculty, Biochemistry Department, 25240 Erzurum, Türkiye
1
O
lanzapine (OLZ), risperidone (RPD) and quetiapine (QTP) are atypical antipsychotic drugs
and are commonly used for the treatments of
schizophrenia and bipolar disorders (BD). However, recent
reports indicated that these drugs could exhibit toxic effects
on nervous and cardiovascular systems. To our best knowledge, there is scarce data considering the genotoxic damage
potentials of OLZ, RPD and QTP on human lymphocyte culture system. Therefore, in this study, the genotoxic potentials
of OLZ, RPD and QTP (0 to 400 mg/L) have been evaluated
in human whole blood cultures (WBCs) (n=4). The single cell
gel electhrophoresis (SCGE) and micronucleus (MN) assays
were applied to estimate the DNA damage. The results of the
present study indicated that the tested antipsychotic drug
did not induce genotoxicity. In fact, the mean values of the
total scores of cells showing DNA damage (for SCGE assay)
and MN/1000 cell were not found significantly different from
the control values (P>0.05). However, the application of the
highest drug concentrations (250 mg/L and above) caused
to sterility of lymphocyte cultures. It is concluded that the
tested three different atypical antipsychotic drugs can be
used safely, but it is necessary to consider the cyototoxic effects that are likely to appear depending on the doses exposured.
International Symposium on Drug Research & Development 2011
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DRD 2011
A Modulator AgaInst Mercury ChlorIde Induced GenotoxIc
Damage: Dermatocarpon IntestInIforme (L.)
Hasan TÜrkez2, Ebubekir DİRİCAN11
Kahramanmaraş Sütçü İmam University, Medical Faculty, Department of Microbiology, 46100 Kahramanmaraş, Türkiye
2
Department of Biology, Faculty of Sciences, Atatürk University, 25240 Erzurum, Türkiye
1
M
ercury has been used in many domains of human activities for many years, although in any
form of mercury is reported to be toxic. On the
other hand, lichens have been used in the treatment of several diseases such as tuberculosis, hemorrhoids, ulcer, dysentery and cancer. Animal investigations on some common
lichen species have demonstrated their antioxidant and antimutagenic activity. However, there is very scarce data on the
medical or biologic effects of specific lichen species. Therefore, in the present study, we assessed the cyotogenetic effects of mercuric chloride (HgCl2) and the role of aqueous
Dermatocarpon intestiniforme lichen extracts in mercurytreated human blood cultures (n=3). The sister chromatid exchange (SCE) and micronucleus (MN) assays were performed
to assess DNA damages in lymphocytes. Our results clearly
revealed that, the SCE and MN rates induced by HgCl2 were
alleviated by the presence of D. intestiniforme. As conclusion,
the results of present study revealed for the first time that
the lichen D. intestiniforme provided increased resistance of
DNA against HgCl2 induced genetic damage on human lymphocytes.
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P-040
The Evaluation of the Genotoxic and Oxidative Damage
Potentials of UlothrIx tenuIssIma (KUtz.) In VItro
Hasan Türkez2, Hasan Gürbüz3, Elanur Aydın2, Ali Aslan3, Ebubekir DİRİcan1
Kahramanmaraş Sütçü İmam University, Medical Faculty, Department of Microbiology,
46100 Kahramanmaraş, Türkiye
2
Department of Biology, Faculty of Sciences, Atatürk University, 25240 Erzurum, Türkiye
3
Atatürk University, Kazım Karabekir Education Faculty, Department of Biology, 25240 Erzurum, Türkiye
1
S
everal alga species are known to produce a variety
of toxic metabolites that pose a threat to aquatic
organisms, animals and humans but some of them
have also pharmacological properties. But, this toxic and
pharmacological properties don’t explain exactly. Moreover,
these metabolites have been thought to cause serious diseases including certain cancers and neurodegenerative disorders. On the other hand, Ulothrix is a genus of filamentous
green algae, generally found in fresh water and marine and
abundantly available in some lakes and rivers of Turkey. To
our best knowledge, no study was performed to assess the
genotoxic and biochemical effects of U. tenuissima on cultured human blood cells. Therefore, in order to determine
clastogenic or aneugenic effects of aqueous alga extracts
the micronucleus (MN) assay was carried out. Nuclear divisi-
on index (NDI) in peripheral lymphocytes was also analyzed
for cytotoxicity evaluations. In addition, biochemical parameters (total antioxidant capacity [TAC] and total oxidative
stress [TOS]) were examined to determine oxidative effects.
For this aim we obtained heparinized blood samples from
three healthy persons. The alga samples were collected from
Porsuk Pond in Hasankale (Erzurum, Turkey) in summer period of the year 2010. The aqueous extracts of this species
were added to cultures at different concentrations (0 to 5000
ppm) for 72h. Our results showed that this alga did not cause
any statistically important changes in the rates of studied genotoxicity endpoint. But dose-dependent alterations were
observed in TAC and TOS levels and NDI rates. In conclusion,
U. tenuissima was found to be non-genotoxic but caused to
sterility at higher concentrations due to oxidative stress.
International Symposium on Drug Research & Development 2011
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DRD 2011
DERMATOCARPON INTESTINIFORME (A LICHEN) MODULATES AFLATOXIN
B1 INDUCED GENETIC AND OXIDATIVE DAMAGE IN VITRO
Ebubekir DİRİCAN1, Hasan Türkez2
Kahramanmaraş Sütçü İmam University, Medical Faculty, Department of Microbiology, 46100 Kahramanmaraş, Türkiye
2
Atatürk University, Faculty of Science, Department of Biology, 25240 Erzurum, Türkiye
1
R
ecent reports suggest that aflatoxin B1 (AFB1), a
worldwide toxic contaminant of foods produced by
Aspergillus flavus and Aspergillus parasiticus, exhibits an oxidative stress mediated genotoxicity although, the
mechanism of cellular damage caused by AFB1 has not been
fully elucidated. Several antioxidant molecules such as ascorbic acid, beta-carotene and tocopherol have been shown to
possess anti-carcinogenic and anti-mutagenic properties
against AFB1 toxicity. On the other hand, lichens have long
been investigated popularly for biological roles; mainly antimicrobial and antioxidant activities. Also, the influence of
lichenic substances on DNA binding of AFB1, in mammalian
cells, is still unknown. Therefore, in this study, we aimed to
determine whether D. intestiniforme extracts conferred a
protection against AFB1-induced genotoxic and oxidative
damage in vitro in the presence or absence of mixed function
oxidases (S9 mix). For this aim, we determined sister chro-
matid exchange (SCE) rates and main antioxidant enzyme
activities including superoxide dismutase (SOD), catalase
(CAT) and glucose-6-phosphate dehydrogenase (G-6-PDH) in
AFB1 (10 µM) and lichen (1, 5, 10, 25, 50 and 100 µM) treated
human whole blood cultures (n=3) for 72h. The lichen extracts at tested concentrations did not exhibite any negative
effects on above studied parameters in culture tubes with
or without adding S9 mix. Moreover, the results of the present study indicated that the increases of SCE frequencies and
the decreases of antioxidant enzyme activities by AFB1 were
minimized by the application of the lichen extracts (at 25 and
50 µM). Our results firstly suggest that D. intestiniforme augments the antioxidants defense against AFB1 induced toxicity. Again, these results demonstrate that dose controlled
D.intestiniforme lichen diet may play a protective role in the
process of AFB1 mutagenesis and/or carcinogenesis.
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P-042
THE EFFECTS OF ASCORBIC ACID ON LISTERINE TOXICITY IN VITRO
Abdulgani Tatar2, Hasan Türkez3, Taner Arabacı4, Ebubekir DİRİCAN1
Kahramanmaraş Sütçü İmam University, Medical Faculty, Department of Microbiology, 46100 Kahramanmaraş, Türkiye
2
Atatürk University, Medical Faculty, Department of Medical Genetics, 25240 Erzurum, Türkiye
3
Atatürk University, Faculty of Science, Department of Biology, 25240 Erzurum, Türkiye
4
Atatürk University, Faculty of Dentistry, Department of Periodontology, 25240 Erzurum, Türkiye
1
L
isterine (LN), a commonly used mouth rinse, has
anti-fungal and anti-bacterial properties although
scarce data is available in the literature. Moreover,
the biologic safety profile of oral health care products is frequently assumed on the basis of simplistic test models. In
other view, ascorbic acid (AA) has several nonenzymatic actions and is a powerful water-soluble antioxidant. To our best
knowledge, no study was performed to examine the role of
AA on LN toxicity in vitro. Therefore, the present study was
undertaken to investigate the in vitro protective effect of AA
against LN toxicity using micronucleus (MN) test and nuclear
division index (NDI) analysis Different concentrations of LN
(0 to 100% of ml/culture v/v) and AA (5 and 10 µM) were applied to whole human blood cultures for 72h. The results of
the present study showed that, LN did not induce MN formations but caused statistically significant decreases of NDI.
However, co-treatment of AA and LN resulted in increases of
NDI rates as compared to the group treated with LN alone.
In conclusion, the ameliorating role of AA in minimizing LNinduced toxicity was indicated for the first time in the present study.
International Symposium on Drug Research & Development 2011
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DRD 2011
DEVELOPMENT OF VALIDATED RP-HPLC METHOD FOR THE ESTIMATION
OF GEMIFLOXACIN FROM TABLET DOSAGE FORM
Mehmet GÜMÜŞTAŞ1,2, Sibel A. ÖZKAN1,*
1
Ankara University, Faculty of Pharmacy, Department of Analytical Chemistry, 06100 Ankara, Türkiye
2
Hitit University, Science and Literature Faculty, Department of Chemistry, 19040 Çorum, Türkiye
*
[email protected]
G
emifloxacin (GEM) 7-[(4Z)-3-(aminomethyl)4-methoxyimino-pyrrolidin-1-yl]- 1-cyclopropyl6-fluoro-4-oxo- 1,8-naphthyridine-3-carboxylic
acid is a new fluroquinolone antibacterial compound with
enhanced affinity for bacterial topoisomerase IV and it is
used for the treatment of respiratory and urinary tract infection. The compound has broad spectrum of activity against
gram-positive and gram-negative bacteria.
The aim of this work presenting a HPLC study which purposes a rapid, simple, sufficiently precise and accurate method for the determination of GEM, in raw material and pharmaceutical formulations. For this reason HPLC-DAD method
is developed. In this method; a reversed-phase (X-Select RP18 (250 x 4.6 mm ID x 5m) with a mobile phase of methanol–
water (50:50 ;v/v), containing 15 mM phosphoric acid (pH
2.50 ) at 1.0 ml/min flow rate was used to separate GEM and
internal standard (IS) with a detection of 272 nm. The chromatographic separation was performed at 25 oC. Granisetron
was chosen as the internal standard (IS). The proposed HPLC
method gives a good resolution 11.48 between GEM and internal standard within a short analysis time. Using these conditions, the retention times were obtained as 3.20 min for IS,
4.25 min for GEM.
All necessary validation parameters and system suitability
test results were obtained as details. Linearity was obtained
in the concentration range between 0.25 and 20 mg mL-1. The
LOD and LOQ values are 0.004, 0.013 mg mL-1, respectively.
Also interday and intraday studies realized and 0.069 % and
0.101 % RSD values, respectively, show the precision of this
method. Also this validated method applied for pharmaceutical formulations and the results of recovery tests are found
99.96 %. High percentage recovery shows that the method is
free from the interferences of the commonly used excipients
and additives in the formulations of drugs. The proposed
method is suitable for quality control laboratories, where
economy and time are essential.
International Symposium on Drug Research & Development 2011
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DRD 2011
P-044
DETERMINATION OF GRANISETRON BY HPLC-DAD TECHNIQUE IN
PHARMACEUTICAL DOSAGE FORMS
Mehmet GÜMÜŞTAŞ1,2*, Sibel A. ÖZKAN1
1
Ankara University, Faculty of Pharmacy, Department of Analytical Chemistry, 06100 Ankara, Türkiye
2
Hitit University, Science and Literature Faculty, Department of Chemistry, 19040 Çorum, Türkiye
*[email protected]
G
ranisetron (GRA), 1-methyl-N-((1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-1H-indazole-3carboxamide is a serotonin 5-HT3 receptor antagonist used as an antiemetic to treat nausea and vomiting
following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the
vomiting center in the medulla oblongata. It does not have
much effect on vomiting due to motion sickness. This drug
does not have any effect on dopamine receptors or muscarinic receptors.
An HPLC-DAD method is presented for the determination
of GRA. In this method; a reversed-phase column (X-Select
RP-18 (250 x 4.6 mm ID x 5m) with the mobile phase assayed
were methanol–water (45:55 ;v/v), containing 15 mM phosphoric acid. The pH of the mobile phase was adjusted at 2.50
by addition of sodium hydroxide. 1.0 ml/min flow rate was
used to separate both compounds with a detection of 215
nm for GRA and IS, respectively. The chromatographic separation was performed at 25 oC. Hydrochlorothiazide (HCT)
was chosen as the internal standard (IS) because it showed
a shorter retention time with better peak shapes and better
resolution, compared to other potential internal standards.
Using these conditions, the retention times were obtained as
3.30 min for HCT, 4.19 min for GRA.
The proposed method has been extensively validated.
System suitability tests were also carried out. Resolution of
GRA is 10.03; theoretical plate number 28572; selectivity (α)
1,77; tailing factor 1.080. Linearity was obtained in the concentration range of 0.25-15 mg mL-1. In order to demonstrate
the validity and applicability of the proposed HPLC method,
recovery tests were carried. The results of recovery tests are
applied two different pharmaceutical products and found
100.16 % for BRAND1 and 100.19 % for BARND2. High percentage recovery shows that the method is free from the interferences of the commonly used excipients and additives in
the formulations of drugs.The present HPLC study purposes
a rapid, simple, sufficiently precise and accurate method for
the determination of GRA in raw material and pharmaceutical formulations. The proposed method is suitable for quality
control laboratories, where economy and time are essential.
International Symposium on Drug Research & Development 2011
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DRD 2011
Electrocatalytic Response of Lidocaine Using Chemically
Modified Electrodes For Construction of Drug Biosensors
Gamze TAN1,*, Gülçin BOLAT2, Mehmet Ali ONUR3
1
Hacettepe University, Institut of Science, Dept. of Biology, 06800 Ankara, Türkiye
Hacettepe University, Faculty of Science, Dept. of Chemistry, 06800 Ankara, Türkiye
3
Hacettepe University, Faculty of Science, Dept. of Biology, 06800 Ankara, Türkiye
*
[email protected]
2
L
sophisticated and costly instruments and special training10.
For these reasons, the method with high sensitivity enjoying
rapid, simple and accurate simultaneously is expected to be
established. Amperometric enzyme biosensors have considerable potential for continuous monitoring of drugs or metabolites in biological fluids11.
ocal anesthetics are drugs that block reversibly
nerve conduction, when they are applied locally to
nerve tissue at appropriate concentrations1. However the toxicity from an excessively high concentration of the
local anesthetics in the blood seems as main obstacle standing in front of their medical uses. Toxicity degree of anesthetics are modulated by several factors including distribution/
plasma concentrations, overdosing, systemic absorption,
relative vascularity of the injection site even the speed of
the injection. In the case of increasing the toxicity there may
occur many side effects particularly cardiovascular and neurological complications. This is because the quantitative determination of local anesthetics in blood and other biological materials are obviously around the considerable point in
assessment of toxicity, metabolism and distribution of these
drugs following various routes of administration2,3. Various
methods for the determination of local anesthetic drugs have
been developed like spectrophotometry4, gas or liquid chromatography5,6, fluorimetric detection7, chemiluminescence8,
flow-injection analysis9. Many of these methods mentioned
above, require several time-consuming manipulation steps,
In this work, potential application of electrochemical activity of a chemically modified electrode to the lidocaine, the
most commonly used local anesthetic for a wide range of
procedures particularly dental surgery, was investigated for
the construction of drug biosensors. The electrocatalytic response of the drugs were examined by a biosensor based on
direct electrochemistry of hemoglobin (Hb) immobilized on
self-assembled monolayer (SAM) modified gold electrodes
(Au/MPA/Hb electrode). Hb showed enzymatic behavior on
drug binding to the surface of the electrode. In this research,
Amperometric and voltammetric studies showed that the
modified electrode (Au/MPA/Hb) exhibited good electrocatalytic activity for the reduction of lidocaine and showed high
sensitivity which leads to construction of a drug biosensor.
REFERENCES
1. Tsirlis A, Karanikola T, Dabarakis N, Liverdos K, Charisi M.
Comparative in vitro Study of Relative Anesthetic Potency of Ropivacaine and Lidocaine. Research Journal of
Pharmacology 4(1):1-4, 2010.
2. Keenaghan JB. The Determination of Lidocaine and Prilocaine in Whole Blood by Gas Chromatography. Anesthesiology 29(1): 110-12, 1968.
3. Ruzafa A, Pastor MC, Aguilar JL, Galimany R. Determination of Plasma Levels of Bupivacaine by High-Performance Liquid Chromatography. Journal of Liquid Chromatography 14(15): 2937 – 49, 1991.
4. Salch GA, Askal HF, Spectrophotometric determination
of certain local anaesthetics in pharmaceutical prepara-
tions. Anal. Lett 28(15): 2663-2671, 1995.
5. Ohshima T, Takayasu T. Simultaneous determination of
local anesthetics including ester-type anesthetics in human plasma and urine by gas chromatography-mass
spectrometry with solid-phase extraction. J Chromatogr
B Biomed Sci Appl 726 (1-2):185-94, 1999.
6. Luo Y, McNamara B, Fennell MA, Teleis DC, May L, Rudy
J, Watson AO, Uboh CE, Soma LR. Quantification of penicillin-G and procaine in equine urine and plasma using
high-performance liquid chromatography. J Chromatogr
B Biomed Sci Appl 714(2): 269-76, 1998.
7. Shuang S, Choi MMF. Retention behaviour and fluorimetric detection of procaine hydrochloride using carboxy-
International Symposium on Drug Research & Development 2011
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methyl-cyclodextrin as an additive in reversed-phase
liquid chromatography. J. Chromatogr A 919(2): 321-9,
2001.
8. Paseková H, Miroslav P. Determination of procaine, benzocaine and tetracaine by sequential injection analysis
with permanganate-induced chemiluminescence detection. Talanta 52(1): 67-75, 2000.
9. Mo ZH, Lou J, Long XH, Xia ZL. Determination of procaine
hydrochloride by ion-pairing flow-injection analysis. Fresenius’ J Anal Chem 358(4): 556-558, 1997.
10.Wang CY, Hu XY, Jin GD, Leng ZZ. Differential pulse adsorption voltammetry for determination of procaine
hydrochloride at a pumice modified carbon paste electrode in pharmaceutical preparations and urine. J Pharm
Biomed Anal 30(1): 131-39, 2002.
11.Harwood GWJ, Pouton CW. Amperometric enzyme biosensors for the analysis of drugs and metabolites. Advanced Drug Delivery Reviews 18(2): 163-91, 1996.
International Symposium on Drug Research & Development 2011
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Constructing catalytic organophospate scavenger based on
D134H, a naturally occurring human acetylcholinesterase
variant
Tuba Küçükkilinç1,*, Rory Cochran2, Anne Valle2, Zoran Radić2, Palmer Taylor2
1Hacettepe University, Faculty of Pharmacy, Dept. of Biochemistry 06100 Ankara, Türkiye
2Dept. of Pharmacology, Skaggs School of Pharmacy & Pharmaceutical Sciences,University of California at San
Diego, La Jolla, CA 92093-0636, USA
*[email protected]
O
rganophosphates (OPs) are very poisonous
chemicals that are widely used in agriculture
and are found in nerve agents. OPs inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by
forming covalent chemical bonds through a process called
phosphorylation. Use of human cholinesterase-oxime couples of varying structure serving as catalytic bioscavengers
is a new therapeutic approach in treatment of OP poisoning.
Our goal was to generate site specific mutations in AChE protein sequence in order to convert human AChE into catalytic
scavenger that will inactivate multiple OP molecules per one
molecule of scavenger.
D134H is a naturally occurring single nucleotide polymorphism (SNP) in humans. Paraoxon and Cyclosarin (analogue)
inhibition of D134H by 2PAM was 3-8 times slower than wt
while reactivation of Paraoxon inhibited enzyme was 7 times
faster1. At the same time catalytic parameters for acetylthiocholine hydrolysis were not affected by the mutation suggesting that acceleration in inhibition and reactivation could
be related to different transition state geometries in those
three reactions. Results of this study points that residues outside the active center influence inhibition, reactivation and
catalysis rates.
REFERENCES
1. Kucukkilinc T, Cochran R, Kalisiak J, Garcia E, Valle A, Amitai
G, Radić Z, Taylor P. Investigating the structural influence
of surface mutations on acetylcholinesterase inhibition
by organophosphorus compounds and oxime reactivation. Chemico-Biologico Interactions 187: 238-240, 2010. International Symposium on Drug Research & Development 2011
101
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P-047
DETERMINATION OF NATEGLINIDE IN HUMAN PLASMA BY LIQUID
CHROMATOGRAPHY TANDEM MASS SPECTROMETRY
Ezgi UĞURLU1,*, Berrak GÜNEY1, Suna TOPTAN1, Sami EREN1, Erkin ALKAN1, Tuncel ÖZDEN2
1Novagenix Bioanalytical Drug R&D Centre, Ankara, Türkiye
2Gazi University Faculty of Pharmacy, Ankara, Türkiye
*[email protected]
A
sensitive and selective liquid chromatographic
tandem mass spectrometric (LC-MS/MS) method
has been developed originally and validated for
the determination of nateglinide in human plasma.
Nateglinide is a novel oral glucose regulator for the treatment of type II diabetes mellitus. It is an amino-acid derivative that lowers blood glucose levels by stimulating insulin
secretion from the pancreas1,2.
Nateglinide and nateglinide-phenyl d5 (internal standard) were extracted from plasma by liquid–liquid extrac-
REFERENCES
1. Physicians’ Desk Reference (PDR). 63rd edition. Montvale,
NJ, 2009, p. 2314-2316.
tion using ethyl acetate with 0.5 mL plasma. Chromatographic seperation was performed on a Waters Sunfire C18
(2.1x50mm,3.5µm ID) analytical column at 30°C with using
acetonitrile:water:formic acid (700:300:0.9, v/v/v) as mobile
phase and 0.3 mL/min flow rate. The method was validated
with the limit of quantitation 50 ng/mL and the calibration
was linear in the range of 50 – 20000 ng/mL for nateglinide. The method fulfills the accuracy, precision, selectivity
and linearity. Stability analyses were showed that all plasma
samples are stable for 3.5 months when stored at -70°C. Furthermore, this method was successfully applied to the bioequivalence study of nateglinide tablets in 36 healthy volunteers.
2. Bauer S, Störmer E, Kirchheiner J et al. Rapid and simple
method for the analysis of nateglinide in human plasma
using HPLC analysis with UV detection. J Pharm Biomed
Anal 31: 551 – 555, 2003.
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DRD 2011
PRODUCTION OF ISCHEMIA MODIFIED ALBUMIN BY PHOTOCATALYSIS
Onur DUMANLI*, Rukiye DUMANLI, A. Nur ONAR
Ondokuz Mayıs University, Faculty of Science, Department of Chemistry, 55139 Samsun, Türkiye
*[email protected]
H
uman serum albumin is the most abundant protein in human blood plasma. It is produced in the
liver. Albumin comprises about half of the blood
serum protein.
is known as albumin cobalt bonding (ACB) test recently accepted by FDA [2-4]. ACB test is based on the determination
of a reduction in cobalt binding in the human serum albumin N-terminal region during myocardial ischemia.
Several markers of ischemia have been proposed. The research and development studies are underway to adequately validate their clinical usefulness or lack of evidence [1].
The observation of serum albumin in patients with myocardial ischemia produced a lower metal binding capacity
for cobalt than the nonischemic normal serum albumin. This
In this study, albumin solution was treated with UV
light in the presence of titanium dioxide at different periods to produce ischemia modified albumin in vitro. Then
cobalt chloride solution (2.32 mM) was incubated with UV
light treated and untreated albumin solutions for 10 min.
Unbound cobalt to albumin was determined using voltammetric method. In phosphate buffer (100mM, pH 7.2), cobalt
reduction peak was observed at -300 mV (vs Ag/AgCl) and
at the reverse scanning the oxidation peak appeared at 540
mV (vs Ag/AgCl) potential while using cyclic voltammetry
and mercury drop working electrode.
REFERENCES
1. Wu AHB, editor. Clinical Markers: Pathology and Laboratory Medicine, second ed. Totowa, NJ: Humana, 2003.
2. ACB Test Reagent Pack, COBAS MIRA Plus. Package insert.
Denver, CO: Ischemia Technologies, August 2002.
3. Bar-Or D, Curtis G, Rao N, Bampos N, Lau E. Characterization of the Co2+ and Ni2+ binding amino-acid residues
of the N-terminus of human albumin. Eur J Biochem
268:42–47, 2001.
4. Bar-Or D, Lau E, Winkler JV. Novel assay for cobalt-albumin binding and its potential as a marker for myocardial
ischemia—a preliminary report. J Emerg Med 19: 311–
315, 2000.
Ischemia-modified albumin (IMA) is another biomarker
with known clinical value in the assessment of patients presenting with a suspected acute coronary syndrome (ACS).
International Symposium on Drug Research & Development 2011
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POSTER PRESENTATIONS
P-048
POSTER PRESENTATIONS
DRD 2011
P-049
SPECTROPHOTOMETRIC DETERMINATION OF MEMANTINE
HYDROCHLORIDE IN BULK FORM USING 4-CHLORO-7NITROBENZOFURAZAN DERIVATIZATION
Neva ALASAĞ1 , Dilek DOĞRUKOL AK2
Anadolu University, Health Science Institute, Department of Analytical Chemistry, 26470 Eskişehir, Türkiye
2
Anadolu University, Faculty of Pharmacy, Department of Analytical Chemistry, 26470 Eskişehir, Türkiye
1
M
emantine hydrochloride (1-amino-3,5-dimethyladamantane hydrochloride) is a tricyclic
amine chemically and pharmacologically related to the antiviral prototype amantadine and its α-methyl
derivative rimantadine. Memantine is used in Parkinson’s disease and movement disorders. Recently, it has been demonstrated to be useful in dementia syndrome.
Memantine free base, which is both highly basic (pKa
10.42) and lipophilic (log P 3.28), suggests that it may show
binding to various derivatization agent like FMOC, dansyl
chloride etc., due to ionic interaction of its basic primary
amine group. Since memantine lacks useful chromophores,
it can not be readily assayed by UV-spectrophotometric
techniques.
In this study, proposed method is based on the derivatization of memantine hydrochloride with 4-chloro-7-nitrobenzofurazan (NBD-Cl) in borate buffer of pH 11.25 to yield a
yellow product. Determination of memantine hydrochloride
was performed by UV-vis spectrophotometry having maximum absorbance at 467 nm wavelength. The optimum experimental conditions such as buffer pH, derivatization time
and temperature, the amounts of derivatization agent and
hydrochloric acid, and dilution solvent have been investigated. Memantine hydrochloride was succesfully derivatized
with 0.025M 4-chloro-7-nitrobenzofurazan (NBD-Cl) and
0.05 M borate buffer solution by keeping it at 70oC about
100 minutes. The method was linear over the concentration
range of 11.3 – 55.7 µg/mL of memantine hydrochloride.
International Symposium on Drug Research & Development 2011
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DRD 2011
SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF NOVEL
N-ACYLSULFONAMIDE
Radia Bouasla, Malika Berredjem*, Nour-Eddine Aouf
Applied Organic Chemistry laboratory, Bioorganic Chemistry Group, University of Annaba, BP 12. Annaba. Algeria
*[email protected]
S
In our previous work, we have reported the synthesis
of news series of modified N-acylsulfonamides 1, 2, 3 (Fig.
1), starting from Chlorosulfonyl Isocyanate (CSI). We have
established that CSI is a suitable reagent allowing the introduction a sulfonamides moiety in bioactive molecules.
The acylsulfonamides were prepared in four steps carbamoylation, sulfamoylation, deprotection and acylation.
ubstituted acylsulfonamides have been widely
used as carboxylic acid bioisosteres in medicinal
chemistry due to their comparable acidity1.
They have received considerable attention due to
their diverse biological activities, with several types of
pharmacological agents possessing antibacterial inhibitors or tRNA synthetases2, antagonists for Angiotensin
II3, leukotriene D4, receptors4, and antithyroid5 or prote-
O
O
F
O
O
O
O
N
N
S
O
N
H
N
S
C H3
CH 3
O
2
1
N
H
S
3
N
H
CH3
O
Figure 1
ase inhibitory6 activity among others. Another research
line that progressed much in the last time regards different N-acylsulfonamides with remarkable antiviral activity. Some clinically used HIV protease inhibitors possess
a sulfonamide moiety in their structure.
REFERENCES
1. (a) Yuan H, Silverman R B. Bioorg Med Chem 14: 1331,
2006. (b) Connor E E. Sulfonamide Antibiotics Prim. Care
Update Ob. Gyn 532, 1998. (c) Chambers, M S, Hobbs SC,
Graham MI, Watt AP, Fletcher SR, Baker R, Fredman SB,
Patel S, Smith AJ, Matassa VG. Bioorg Med Chem Lett 5:
2303, 1995.
2. Banwell MG, Crasto CF, Easton CJ, Forrest AK, Karoli T,
March DR, Mensah L, Nairn MR, O’Hanlon PJ, Oldham MD,
Yue W. Bioorg Med Chem Lett 10: 2263, 2000.
The effects of these substitutions on biological activity in vitro are herein reported. Antibacterial activity
of these tree molecules was tested on Pseudomonas
aeruginosa, Escherichia Coli and Staphylococcus aureus.
3. Chang LL, Ashton WT, Flanagan KL, Chen TB, OMalley SS,
Zingaro GJ, Siegel PKS, Kivlighn SD, Lotti VJ, Chang RSL,
Greenless WJ. J Med Chem 37: 2263, 1994.
4. Musser JH, Kreft AF, Bender RHW, Kubrak DM, Grimes D,
Carlson R. P, Hand JM, Chang J. J Med Chem 33: 240, 1990.
5. Thornber CW, Chem Soc Rev 8: 563, 1979.
6. Supuran CT, Scozzafava A, Clare, B. W. Med Res 22: 329,
2002.
International Symposium on Drug Research & Development 2011
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P-050
POSTER PRESENTATIONS
DRD 2011
P-051
SYNTHESIS AND ANTICANDIDAL ACTIVITY OF NEW
TRIAZOLOTHIADIAZINE DERIVATIVES
Zafer Asım KAPLANCIKLI1, Mehlika Dilek ALTINTOP1,*, Gülhan TURAN ZITOUNI1,
Ahmet ÖZDEMİR1, Gökalp İŞCAN2
Anadolu University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 26470 Eskişehir, Türkiye
2
Anadolu University, Faculty of Pharmacy, Department of Pharmacognosy, 26470 Eskişehir, Türkiye
*[email protected]
1
T
he greatly increased incidence of life-threatening
fungal infections due mainly to Candida species has resulted in a corresponding increase in
demand for new agents to treat these infections1. Azoles,
especially triazole antifungal agents, play a leading role in
the treatment of systemic fungal infections owing to their
broad spectrum ana improved safety profile2.
In this study, new triazolothiadiazine derivatives were
synthesized via the ring closure reaction of 4-amino-5-substituted-2,4-dihydro-3H-1,2,4-triazol-3-thiones with phenacylbromides3. The compounds were tested in vitro against
various Candida species ana compared with ketoconazole
[4]. Among these compounds, the compound bearing cyclohexyl moiety and p-chlorophenyl substituent on triazoloREFERENCES
1. Pfaller MA, Diekema DJ. Epidemiology of Invasive Candidiasis: a Persistent Public Health Problem. Clin Microbiol
Rev 20 (1): 133-163, 2007.
2. Sheehan DJ, Hitchcock CA, Sibley CM. Current and emerging azole antifungal agents. Clin Microbiol Rev 12 (1): 4079, 1999.
thiadiazine ring was found to be the most potent derivative
against C. albicans (ATCC 90028). It is clear that there is a
positive correlation between anti candidal activity ana two
functional moieties, namely cycloaliphatic groupand p-chlorophenyl substituent on triazolothiadiazine ring.
N
R
N
S
N
N
R: 4-(OH)C6H5, C6H11
R': H, NO2, F, Cl, CH3
R'
3. Kaplancıklı ZA, Turan-Zitouni G, Özdemir A, Revial G. New
triazole ana triazolothiadiazine derivatives as possible
antimicrobial agents. Eur J Med Chem 43: 155-159, 2008.
4. Koneman EW, Allen SD, Janda WM, Schreckenberger PC,
Winn WC. Color Atlas and Textbook of Diagnostic Microbiology. USA: Lippincott-Raven Pub, 1997, p. 785-856.
International Symposium on Drug Research & Development 2011
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DRD 2011
SYNTHESIS AND ANTI-PROLIFERATIVE ACTIVITY OF SOME HYDRAZONE
DERIVATIVES
Gülhan Turan ZITOUNI1, Mehlika Dilek ALTINTOP1,*, Ahmet ÖZDEMİR1, Zafer Asım KAPLANCIKLI1,
Miriş DİKMEN2
Anadolu University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 26470 Eskişehir, Türkiye
2
Anadolu University, Faculty of Pharmacy, Department of Pharmacology, 26470 Eskişehir, Türkiye
*
[email protected]
1
H
ydrazone derivatives have attracted a great deal
of interest in medicinal chemistry and considerable research on them in relation to their anti-proliferative activity has been accomplished [1]. The structures
of obtained compounds were confirmed by the spectroscopic data of infrared (IR), nuclear magnetic resonance (NMR)
and FAB+-MS spectroscopy. Anti-proliferative activity tests
were performed on A549 (human lung cancer) cell lines.
Some compounds were effective against A549 (human lung
cancer) cell lines among these compounds. They exhibited
time and dose dependent antiproliferative activity against
A549 cancer cell line.
R
H
N N
N
N
N
N
O
HO
OH
OH
R= NO2, CH3, OCH3, CN, OH, CH(CH3)2, N(CH3)2, Cl, Br, F
REFERENCES
1. Rollas S, Küçükgüzel SG. Biological activities of hydrazone
derivatives. Molecules 12: 1910-1939, 2007.
International Symposium on Drug Research & Development 2011
107
POSTER PRESENTATIONS
P-052
POSTER PRESENTATIONS
DRD 2011
P-053
ALGINATE/CHITOSAN NANOPARTICLES ACT AS A PROMISING SUSTAINED
RELEASE CARRIER FOR OCULAR DELIVERY
Sankar RAJAVEL1,*,**, Nagasamy VENKATESH2, K. GOWTHAMARAJAN2, M. P. NARMADHA3,
B. A. VISWANATH1
1
Faculty of Pharmacy, Dept. of Pharmaceutics, ABIPER, Bangalore-64, Karnataka, India
Faculty of Pharmacy, Dept. of Pharmaceutics, JSS College of Pharmacy, Ooty, Tamil Nadu, India
3
Faculty of Pharmacy, Dept. of Pharmacy Practice, SVCP, Thiruchengode, Tamil Nadu, India
*
Permanent address: 2/185 Periyamanali Post. Namakkal District. Tamil Nadu, India
**
[email protected]
2
T
o overcome the poor ocular bioavailability and
rapid precorneal elimination of the ocular drug by
the use of nanoparticle forming systems with the
help of natural carriers those are instilled into the eye as an
eye drops. The present work describes the formulation and
in vitro characterization of ophthalmic delivery system of
antibacterial drug Ofloxacin, using mucoadhesive biopolymers, Chitosan and Sodium alginate1. Because of the polyelectrolyte complex formation between carboxyl groups of
alginate and the amine groups of chitosan, nanoparticles
were prepared by Ionotropic polyelectrolyte pre gelation
technique2,3. Nanoparticles were characterized by FTIR, SEM,
REFERENCES
1. Annick Ludwig. The use of mucoadhesive polymers in
ocular drug delivery. Advanced Drug Delivery Reviews
57: 1595– 1639, 2005.
2. Bruno S, Domingos F, Francisco V, Antonio R. Probing
insulin’s secondary structure after entrapment into alginate/chitosan nanoparticles. European Journal of Pharmaceutics and Biopharmaceutics 65: 10-17, 2007.
and Drug loading. The designed nanoparticles have particle
size from 140-240 nm with an average size of 184.4nm. In
vitro release studies showed that chitosan/ sodium alginate
nanoparticles showed burst release at first hour then retained
a gradual sustained release over a period of 24 hours than
conventional ophthalmic eye drops4. In vitro release studies
showed that it follows first order release and fickian diffusion
process. The optimized nanoparticles were more sterile and
stable and the developed work was an viable alternative to
conventional eye drops, more economical, reduced dosing
frequency resulting better patient compliance.
3. Heidi VS, Hilde KH, Gjertrud M, Olav S,Bjorn TS. Polyelectrolyte complex formation using alginate and chitosan.
Carbohydrate Polymers 74: 813-821, 2008.
4. Sanjay KM, Shruti C, Sushma T, Kanchan K, Farhan JA, Roop
KK. Chitosan–sodium alginate nanoparticles as submicroscopic reservoirs for ocular delivery: Formulation, optimization and in vitro characterization. European Journal of
Pharmaceutics and Biopharmaceutics 68: 513–525, 2008.
International Symposium on Drug Research & Development 2011
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DRD 2011
COMBINATION EFFECTS OF CIS-PLATINUM AND VINIFERIN FOR GLIOMA
IN VITRO
Gülşen AKALIN ÇİFTÇİ*, Filiz ÖZDEMİR, Mesut ŞEN, Zerrin İNCESU
Anadolu University, Faculty of Pharmacy, Department of Biochemistry, 26470 Eskişehir, Türkiye
*[email protected]
C
is-platinum is a widely used chemotherapeutic
agent to treat malignant disease. Unfortunately,
ototoxicity occurs in a large percentage of patients treated with higher dose regimens. The mechanisms
appear to involve the production of reactive oxygen species (ROS), which can trigger cell death1. In this regard, we
aimed to investigate combination effects of cis-platinum
and viniferin, which is an antioxidant,2 on glioma (C6) cells.
Here, cytotoxic activities of both drugs against the C6 cells
were assessed using MTT assay3. The IC50 values were determined. Apoptotic cell ratio was investigated by annexin-V/
propidium iodide by flow cytometer (Becton-Dickinson) afREFERENCES
1. Leonard PR, Craig AW, Debashree M, Vickram R. Mechanisms of cisplatin-induced ototoxicity and prevention.
Hearing Research 226: 157–167, 2007.
2. Privat C, Telo JP, Bernardes-Genisson V, Vieira A, Souchard
JP, Nepveu F. Antioxidant properties of trans-E-viniferin as
ter combine drug treatment. The IC50 values of cis-platinum,
viniferin and combination of drugs were 35 µM, 130 µM and
16,25 mM (cis-platinum)-127,5 µM (viniferin), respectively.
After the cells were treated with either IC50 doses or 80% viability doses of cis-platinum, viniferin and combined drugs,
the early apoptotic rates of the combined drugs was determined higher than uses of drugs alone. These results showed
that antioxidant reagent, viniferin would be able to reduce
the cytotoxic dose of cis-platinum synergistically but this reagent showed antagonistic effect on lower doses that were
evaluated by isobologram test.
compared to stilbene derivatives in aqueous and nonaqueous media. J Agric Food Chem 50: 1213-1217, 2002.
3. Mosmann, T. Rapid colorimetric assay for cellular growth
and survival: Application to proliferation and cytotoxicity
assays. J Immunol Methods 65: 55–63, 1983.
International Symposium on Drug Research & Development 2011
109
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P-054
POSTER PRESENTATIONS
DRD 2011
P-055
SYNTHESIS AND BIOLOGICAL EVALUATION OF SIMPLE AROMATIC ESTERS
AND AMIDES OF SOME HYDROXYCINNAMIC ACIDS
Şeyma CANKARA PİROL1, *, Burcu ÇALIŞKAN1, Fatma KAYNAK2, Erden BANOĞLU1
1Departments of Pharmaceutical Chemistry
2Pharmaceutical Microbiology, Faculty of Pharmacy,
Gazi University, 06330 Etiler, Ankara, Türkiye
*[email protected]
T
he antioxidant activity of ferulic acid (FA) and its
alkyl ester derivatives in plants is well establisted.
Therefore, a series of aromatic ester derivatives of
FA in which the phenolic hydroxyl of FA was free or acetylated have been synthesized in our laboratory. These molecules are tested their antioxidant, radical scavenging potential and antimicrobial activities in in vitro test systems. The
superoxide radical scavenging capacity of all aromatic ester
derivatives of FA showed equally or better activity than that
of α-tocopherol. DPPH radical scavenging capacity was only
found in compounds bearing free phenolic hydroxyl group
on FA side. Some compounds were found to inhibit the
growth of Gram positive bacteria, yeasts and mold. Majority
of the synthetic aromatic esters showed higher antioxidant
and some demonstrated antimicrobial as well as biofilm
REFERENCES
1. Çalışkan, B. et al., Synthesis, antioxidant and antimicrobial
evaluation of simple aromatic esters of ferulic acid. Archiv
Pharm Res 2010, in publication.
2. Padinchare, R. Synthesis and evaluation of caffeic acid
amides as antioxidants. Bioorg&Med Chem Lett 11: 215217, 2001.
eradication activity than that of FA1. Meanwhile, some amide derivatives of caffeic acid have been reported to have
antimicrobial, antioxidant and anticancer activity2-4. Based
on above information, we have prepared various ester and
piperazine amide derivatives of FA to investigate their antimicrobial activities.
General structure of synthesized ester and amide derivatives
of FA.
3. Hongbin, Z. Synthesis, biological evaluation and structure-activity relationship study of novel cytotoxic azacaffeic acid derivatives. Bioorg&Med Chem 18: 63516359, 2010.
4. Jie, F. Synthesis, structure and structure-activity relationship analysis of caffeic acid amides as potential antimicrobials. Eur J Med Chem 45: 2638-2643, 2010.
International Symposium on Drug Research & Development 2011
110
DRD 2011
SYNTHESIS OF SOME NOVEL MANNICH BASES OF KOJIC ACID
Gülşah KARAKAYA, Mutlu D. AYTEMİR*
Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06100 Sıhhiye, Ankara, Türkiye
*[email protected]
K
ojic acid (5-hydroxy-2-hydroxymethyl-4H-pyran4-one) is a natural fungal metabolite produced
by many species of Aspergillus and Penicillium
moulds1. Due to its tyrosinase inhibitor activity, it has been
studied as a skin-whitening agent in cosmetic and a food additive to prevent enzymatic browning. Kojic acid has been
added to food as an antioxidant. In addition, it has been used
as an antibiotic, pesticide, and analytical chemical2.
Since the physicochemical properties of kojic acid is
suitable, a reasonable number of derivatives of kojic acid
has been prepared so far. Halogen derivatives of kojic acid
including chlorokojic acid (5-hydroxy-2-chloromethyl-4Hpyran-4-one) which is synthesized by chlorination of kojic
acid has significant antibacterial and antifungal activities3.
Previously, Mannich bases of kojic acid, chlorokojic acid and
REFERENCES
1. Bentley R. From miso, sak´e and shoyu to cosmetics: A
century of science for kojic acid. Nat Prod Rep 23: 10461062, 2006.
2. Burdock GA, Soni MG, Carabin IG. Evaluation of health aspects of kojic acid in food. Regul Toxic Pharm 33: 80-101,
2001.
3. Brtko J, Rondahl L, Fickova M, Hudecova D, Eybl V, Uher M.
Kojic acid and its derivatives: History and present state of
art. Cent Eur J Publ Health 12: 16–18, 2004.
4. Aytemir MD, Çalış Ü, Özalp M. Synthesis and evaluation of
anticonvulsant and antimicrobial activities of 3-hydroxy6-methyl-2-substituted 4H-pyran-4-one derivatives. Arch
allomaltol (5-hydroxy-2-methyl-4H-pyran-4-one) were synthesized in our laboratory and their biological activities were
evaluated. These compounds found to have remarkable antimicrobial, antiviral and anticonvulsant effects4-7.
In the effort to get those agents, herein, we have reported several new 6-hydroxymethyl-3-hydroxy-2-substituted
4H-pyran-4-one derivatives including benzyl and halogen
substituted derivatives such as 3-chloro, 4-chloro, 3,4-dichloro and 2,6-dichloro. The structures of the compounds were
identified by using IR and ESI-MS data.
Pharm Pharm Med Chem 337: 281- 288, 2004.
5. Aytemir MD, Septioğlu E, Çalış Ü. Synthesis and anticonvulsant activity of new kojic acid derivatives. Arzneimittel
Forschung 60(1): 22–29, 2010.
6. Aytemir MD, Özçelik B. A study of cytotoxicity of novel
chlorokojic acid derivatives with their antimicrobial and
antiviral activities. Eur J Med Chem 45: 4089-4095, 2010.
7. Aytemir MD, Özçelik B. Synthesis and biological activities of new Mannich bases of chlorokojic acid derivatives. Med Chem Res (accepted manuscript DOI: 10.1007/
s00044-010-9338-x).
International Symposium on Drug Research & Development 2011
111
POSTER PRESENTATIONS
P-056
POSTER PRESENTATIONS
DRD 2011
P-057
THE EFFECTS OF SOME BENZOTHIAZOLE/PIPERAZINE DERIVATIVES ON
LEARNING AND MEMORY PARAMETERS OF STREPTOZOTOCIN MODEL OF
ALZHEIMER’S DISEASE IN ACTIVE AVOIDANCE TEST
Ümide DEMİR ÖZKAY1, Yusuf ÖZKAY2,*, Yusuf ÖZTÜRK1, İlhan IŞIKDAĞ2
Anadolu University, Faculty of Pharmacy, Department of Pharmacology, 26470 Eskişehir, Türkiye
Anadolu University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 26470 Eskişehir, Türkiye
*
[email protected]
1
2
I
n this study, effects of five benzothiazole/piperazine
derivatives on learning and memory parameters were
investigated using streptozotocin (STZ) model of Alzheimer’s disease (SMAD) in rats. Syntheses of test compounds were based on functional groups of anti-Alzheimer
agents, donepezil, FK960 and sabeluzol [1-3]. Structures of
the synthesized compounds were elucidated by IR, 1H-NMR
and Mass spectral analyses. SMAD was generated by intracerebroventricular injection of STZ (3 mg/kg) at first and
third days, bilaterally. Active avoidance test was performed
in order to examine the effects of test compounds (1 mg/kg,
5 mg/kg and 10 mg/kg) on learning and memory parameters
of SMAD in rats. Effects of test compounds on spontaneous
locomotor activities of rats were examined with the application of activity cage tests. Donepezil (1 mg/kg and 3 mg/
kg) was used as a standard drug. The experimental protocols
have been approved by the Local Ethical Committee on Animal Experimentation of the Eskişehir Osmangazi University,
Turkey. Compounds B2-B3 at 10 mg/kg and B4-B5 at 5 and 10
REFERENCES
1. Murray A, Raskind MD, Elaine R, Peskind MD. Alzheimer’s
disease and related disorders. Med Clin North Am 85:
803-817, 2001.
2. Mohr E, Nair NP, Sampson M, Murtha S, Belanger G, Pappas B, Mendis T. Treatment of Alzheimer’s disease with sa-
mg/kg doses significantly decreased the latency periods and
increased the number of avoidance responses of rats. Compound B1 was found to be ineffective. Compounds B2-B3
at 10 mg/kg doses, B4-B5 at 5 and 10 mg/kg doses were as
effective as 1 mg/kg and 3 mg/kg doses of donepezil. Any
of the test compounds were not significantly changed the
spontaneous locomotor activities of rats. Experimental studies revealed that, four of the compounds repaired the parameters related to the learning and memory deficits of SMAD
in rats.
N
S
N
H
N
O
N
R
R: B1; Phenyl, B2; Benzyl, B3; 4-Methoxybenzyl, B4; 4-Methylbenzyl, B5; 4-Chlorobenzyl
beluzole: Functional and structural correlates. Clin Neuropharmacol 20: 338-345, 1997
3. Doggrell SA. The potential of activation of somatostatinergic neurotransmission with FK960 in Alzheimer’s disease. Expert Opin Investig Drugs 13: 69-72, 2004. International Symposium on Drug Research & Development 2011
112
DRD 2011
ANTICANCER ACTIVITY OF SOME ISOXAZOLE DERIVATIVES
Yusuf ÖZKAY1,*, Zerrin İNCESU2, Nur İpek ÖNDER2, İlhan IŞIKDAĞ2
Anadolu University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 26470 Eskişehir, Türkiye
2
Anadolu University, Faculty of Pharmacy, Department of Biochemistry, 26470 Eskişehir, Türkiye
*
[email protected]
1
A
s we reported previously, azole and benzazole
derivatives possess chemotherapeutic importance1. Hence, in the present study some isoxazole derivatives bearing azoles and benzazoles as imidazole,
triazole, tetrazole, thiadiazole, benzimidazole and benzothiazole were synthesized in order to investigate their cytotoxic
activity on C6 (glioma) and HT-29 (colon cancer) cell lines.
Target compounds were synthesized in accordance with
our reported method2. Reaction of various mercapto-(benz)
azoles and 3-(2-chloroacetamino)-5-methylisoxazole gave
the 3-[2-substitutedsulfanylacetamino)-5-methylisoxazole
derivatives. Structures of the compounds were elucidated by
REFERENCES
1. Özkay, Y, Işıkdağ İ, İncesu Z, Akalın G. Synthesis of 2-substituted-N-[4-(1-methyl-4,5- diphenyl-1H-imidazole-2-yl)
phenyl]acetamide derivatives and evaluation of their
anticancer activity. Eur J Med Chem 45: 3320-3328, 2010.
spectral analyses. MTT assay was applied for determination
of cytotoxicity levels of the compounds. The compounds 7
and 9 found to be most cytotoxic on HT-29 and C6 cell lines,
respectively.
O
N
O
S
(Benz)azole
N
2. Özkay-Demir Ü, Özkay Y, Can ÖD, Synthesis and analgesic
effects of 2-(2-carboxyphenylsulfanyl)-N-(4-substituted
phenyl)acetamide derivatives. Med Chem Res 20: 152157, 2011.
International Symposium on Drug Research & Development 2011
113
POSTER PRESENTATIONS
P-058
POSTER PRESENTATIONS
DRD 2011
P-059
ANALGESIC AND ANTIINFLAMATORY ACTIVITY OF SOME THIAZOLE
DERIVATIVES
Yusuf ÖZKAY1,*, Özgür Devrim CAN2, Ümide DEMİR ÖZKAY2, Leyla YURTTAŞ1
Anadolu University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 26470 Eskişehir, Türkiye
2
Anadolu University, Faculty of Pharmacy, Department of Pharmacology, 26470 Eskişehir, Türkiye
*
[email protected]
1
T
hiazole is an important hetorocylic ring which is
often subjected to new drug development studies. There are some reports including analgesic
and anti-inflammatory effects of thiazole based compounds
[1-3]. Aryl acetic acid derivatives such as indomethacin, sulindac, etodolac, ketorolac, and diclofenac constitute a class
of nonsteroidal anti-inflammatory agents. Thus, in this study,
some novel thiazole based phenyl acetic acid derivatives
were synthesized so as to investigate their possible analgesic and anti-inflammatory activities. Synthesis of compounds
were performed in ethanol by reacting 4-thioureido-phenylacetic acid with 2-chloro-1,2-diaryl-ethanone derivatives.
Structures of the compounds were elucidated by spectral
REFERENCES
1. Sharma RN, Xavier FP, Vasu KK, Chaturvedi SC, Pancholi
SS. Synthesis of 4-benzyl-1,3-thiazole derivatives as
potential anti-inflammatory agents: an analogue-based
drug design approach. J Enzyme Inhib Med Chem 24:
890-897, 2009.
2. Franklin PX, Pillai AD, Rathod PD, Yerande S, Nivsarkar
M, Padh H, Vasu KK, Sudarsanam V. 2-Amino-5-thiazolyl
analyses. Acetic acid-induced writhing test and carrageenaninduced paw edema tests were carried out to observe analgesic and anti-inflammatory activities, respectively. Pharmacological tests revealed that synthesized compounds
exhibited analgesic and anti-inflammatory activities to different extents.
R
R
N
S
N
H
COOH
R: Various substituents
motif: A novel scaffold for designing anti-inflammatory
agents of diverse structures. Eur J Med Chem 43: 129134, 2008.
3. Nagatomi H, Ando K. Studies on the anti-inflammatory
activity and ulcerogenic adverse effect of thiazole derivatives, especially 2-amino-thiazoleacetic acid derivatives. Arzneimittelforschung 34: 599-603, 1984.
International Symposium on Drug Research & Development 2011
114
DRD 2011
PHARMACOPHORE AND FUNCTIONAL GROUP IDENTIFICATION OF
4-ANILINO QUINAZOLINE DERIVATES AS TYROSINE KINASE (EGFR)
INHIBITORS
Hayriye YILMAZ1, *, Yahya GÜZEL2, Gökçe ALTIPARMAK2, Mükerrem Betül YERER1
Erciyes University, Faculty of Pharmacy, 38039 Kayseri, Türkiye
Erciyes University, Faculty of Science, Department of Chemistry, 38039 Kayseri, Türkiye
*
[email protected]
1
2
Q
SAR (Quantitative-Structure Activity RelationShips) is one of the various cheminformatic approaches possible for efficient model building.
Concisely, QSAR is a mathematical equation relating molecular descriptors to biological activity for known series of compounds so that this model can be used to evaluate activity
of new chemical entities1,2. We attempt to find consistent relationships between the values of molecular properties and
the biological activity, and try to rationalize the structureactivity relationship using Molecular Comparative Electron
Topologic (MCET) method. In four dimensional quantitative
structure activity relationship (4D QSAR) analyses, the activity can be calculated much more accurately via atoms which
are located at the defined positions of the align conformers.
It was found that the -log (IC50) values of the compounds
were highly dependent on the topology, size and electrostatic character of the substituents at seven positions of the
4-Anilino Quinazoline scaffold. Depending on the negative
or positive charge of the groups correctly embedded in these
substituents, the 3D bio-structure to increase or decrease
-log (IC50) values in the training set was predicted. A test set
of fourteen compounds was used to evaluate the predictivity of the model. Although only atomic properties defined
through topological descriptors were used in the calculation of activity, the resulting 4D-QSAR model from the MCET
method was of sufficient statistical quality (R2= 0.73 and Q2=
0.68).
A 4D QSAR analysis was applied to a series of 61 4-Anilino
Quinazoline inhibitors Epidermal Growth Factor Receptor
(EGFR) by the MCET method.
Acknowledgement: This work was financially supported by Erciyes University Scientific Research Projects (BAP) of Turkey (Grant No; FBD-10-2983).
Figure 1. Structure of 4-(X-bromoanilino)-Y-quinazolines.
REFERENCES
1. Kurup A. Garg R. Hansch C. Comparative QSAR study of
tyrosine kinase inhibitors. Chem. Rev 101: 2573-2600,
2001.
2. Malleshappa NN, Harun MP, Varun B. 2D QSAR studies on
a series of 4-anilino quinazoline derivatives as tyrosine
kinase (EGFR) inhibitor: An approach to design anticancer agents. Digest Journal of Nanomaterials and Biostructures 2: 387-40, 2010.
International Symposium on Drug Research & Development 2011
115
POSTER PRESENTATIONS
P-060
POSTER PRESENTATIONS
DRD 2011
P-061
LIGAND BASED RESEARCH OF 82 N-BENZYLPIPERIDINE DERIVATIVES TO
MOUSE ACETYLCHOLINESTERASE AND 4D QSAR ANALYSIS
Hayriye YILMAZ1,*, Gökçe ALTIPARMAK2, Yahya GÜZEL2, Burçin KILIÇ2, Zülbiye ÖNAL2
1
Erciyes University, Faculty of Pharmacy, 38039 Kayseri, Türkiye
Erciyes University, Faculty of Science, Department of Chemistry, 38039 Kayseri, Türkiye
*
[email protected]
2
A
lzheimer’s disease (AD) is a progressive neurodegenerative disease affecting an increasingly
important part of the elderly population. This
pathology manifests itself clinically by a memory loss and
biochemically by the deregulation of neurotransmission,
e.g. serotoninergic, dopaminergic and cholinergic systems1.
N-benzylpiperidine derivates are competitive, reversible, potent and selective inhibitors of acetylcholinesterase(AChE).
A combination of a high AChE inhibitory activity with a low
toxicity level makes them appropriate candidates for application to the treatment of AD. The strategy of QSAR (Quantitative Structure Activity Relationship) modeling is to condense the relationship between the structure of molecules
and their properties into a mathematical expression. In this
study four dimensional quantitative structure activity relationship (4D QSAR) analyses is performed comparing the
matrix of the conformers. So in order to understand structural requirements and predict inhibitory activity of AChE,
we have used a computational method called molecular
conformer electron topological (MCET) method, which is
newly developed by us, and have applied it for a series of
82 molecules of N-benzylpiperidine derivates. In order to
find the more convenient set of descriptors, the partial leastsquares (PLS) and genetic algorithm (GA) in MCET method
are used. The method is described in detail for identification
of pharmacophore (Pha), auxiliary group (AG) and anti-pharmacophore shielding (APS) group. This analysis including Nbenzylpiperidine molecules is used to obtain information on
ligand-receptor interactions that lead to either an increase
or decrease in AChE inhibitory activity for the molecules of
similar or different skeleton.
Figure 1. N-Benzylpiperidine derivatives.
Acknowledgement: This study was financially supported by the Scientific Technical Research Council of Turkey (TUBITAK) (Grant No: TBAG-108t148).
REFERENCES
1. Bernard P, Kireev DB, Chrétien JR, Fortier PL, Coppet L,.
Automated docking of 82 N-benzylpiperidine derivatives
to Mouse acetylcholinesterase and comparative molecu-
lar field analysis with ‘natural’ alignment. Journal of Computer-Aided Molecular Design 13: 355-371, 1999.
International Symposium on Drug Research & Development 2011
116
DRD 2011
4D QSAR STUDYING WITH MCET METHOD ON
PHENYLTHIAZOLYLHYDRAZIDE (PTH) DERIVATIVES
Hayriye YILMAZ1,*, Yahya GÜZEL2, Zülbiye ÖNAL2, Sefa AKSAKAL2
1
Erciyes University, Faculty of Pharmacy, 38039 Kayseri, Türkiye
Erciyes University, Faculty of Science, Department of Chemistry, 38039 Kayseri, Türkiye
*
[email protected]
2
T
he pathological hallmarks of Alzheimer’s disease
(AD) are two types of aggregates in brain: extracellular amyloid plaques consisting of the Aβ
peptide[1] and intracellular neurofibrillary tangles (NFTs).
[2] Abnormal filaments called paired helical filaments (PHFs)
are major components of NFTs, and a microtubule- associated protein tau consists of its core protein. Even though
the primary cause of these aggregation processes in not
well-understood, there is a general consensus that protein
aggregates are toxic for neurons and a pathological series of
neurotoxic events lead to neurodegeneration and finally AD.
In this study, we report a 4D-QSAR study on the PTH derivatives in anticipation of getting a model that would account for the quantitative differences in bioactivity seen in
this series and provide insights into designing of novel tau
aggregation inhibitors with improved activity.
In respect to the molecular conformations, quantum
chemical calculations are obtained via “Spartan’08” software
program. In the first step, Spartan’s molecular mechanics
forcefield (MMFF) is used, because it presently provides the
calculation of equilibrium geometries, strain energies and
normal-mode vibrational frequencies, as well as for search-
ing of conformation space for both cyclic and acyclic molecules. After energy minimizations and molecular dynamics calculations are performed the acceptable state conformers of the
lowest energy for each molecule are selected. The most crucial
step in performing 4D-QSAR is to determine the bio-structure
formed by pharmacophere (Pha), auxiliary group (AG) and antipharmacophere shielding (APS) so that all compounds could
be aligned together via Pha. By using molecular conformers in
MCET method, we attempted 4D-QSAR study.As biological
activities are generally skewed, the reported IC50 values were
converted into the corresponding logIC50. As usual, PLS (partial least squares) method was used to establish and validate
4D-QSAR, and LOO (leave-one-out) cross-validation method
was used to evaluate the initial model. The cross-validated coefficient q2 was calculated, the optimum number of components was then given, and the 3D model, consist of Pha, AG
and APS was finally derived corresponding to the optimum
number.The results are listed, and the graphic results for the
experimental versus predicted activities of both training set
and test set are displayed. The good agreement between actual
and predicted logIC50 values for the test set compounds suggests that the constructed 4D QSAR models are reliable and
can be used for the design of novel tau aggregation inhibitors.v
REFERENCES
1. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s
disease: progress and problems on the road to therapeutics. Science 297: 353-6, 2002.
2. Vieira MN, Forny-Germano L, Saraiva LM, Sebollela A,
Martinez A M, Houzel J C, De Felice F G, Ferreira STJ.
Soluble oligomers from a non-disease related protein
mimic Abeta-induced tau hyperphosphorylation and
neurodegeneration. Neurochem 2: 736-748, 2007.
International Symposium on Drug Research & Development 2011
117
POSTER PRESENTATIONS
P-062
POSTER PRESENTATIONS
DRD 2011
P-063
CINNAMALDEHYDE INHIBITS BIOFILM FORMATION ON CONTACT LENSES
Ebru ÖNEM1, *, Seyhan ULUSOY1, Gülgün BOŞGELMEZ TINAZ1,2
Department of Biology, Suleyman Demirel University, 32260 Isparta, Türkiye
Department of Clinical Microbiology, Faculty of Medicine, Marmara University, İstanbul, Türkiye
*
[email protected]
1
2
M
any Gram negative bacteria use N-acyl homoserine lactone signal molecules to monitor
their own population density and coordinate
gene regulation in a process called quorum sensing (QS).
Pseudomonas aeruginosa controls production of virulence
factors (elastase, protease) and biofilm formation via QS1.
Moreover P. aeruginosa is one of the most common bacteria
associated with contact lenses related eye infections2,3. The
plant based coumpounds has long been a source of mediciREFERENCES
1. Al-Mutairi D, Kilty JS. Bacterial biofilms and the pathophysiology of chronic rhinosinusitis. Current Opinion in
Allergy and Clinical Immunology 11:18-23, 2011.
2. Szczotka-Flynn LB, Pearlman E, Ghannoum M. Microbial
contamination of contact lenses, lens care solutions, and
their accessories: A Literature Rewiev. Eye & Contact Lens
2:116-129, 2010.
nes4. As much as their antibacterial effect, anti-QS properties
of natural compounds has been great interest in the treatment of bacterial infections.
In this study, the inhibition of biofilm formation was investigated against P. aeruginosa PAO1 in the presence of
cinnamaldehyde on contact lenses with crystal violet assay.
Cinnamaldehyde was showed significant inhibitor activity
on biofilm formation at very low concentration.
3. Rändler C, Matthes R, McBain AJ, Giese B, Fraunholz
M, Sietmann R , Kohlmann T, Hübner No and Kramer A.
A three-phase in-vitro system for studying Pseudomonas
aeruginosa adhesion and biofilm formation upon hydrogel contact lenses. BMC Microbiology 10: 282, 2010.
4. Cragg GM, Newman DJ, Snader KM. Natural products
in drug discovery and development. J Nat Prod 60: 52-60,
1997.
International Symposium on Drug Research & Development 2011
118
DRD 2011
SYNTHESIS AND ANTICONVULSANT EVALUATION OF SOME NEW
PHENYLSEMICARBAZONE DERIVATIVES OF ARYLALKYLIMIDAZOLES
1, 2
3, *
Ebubekir SEPTİOĞLU , Ünsal ÇALIŞ
On Leave from Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100
Sıhhiye-Ankara, Türkiye
2
Kavacık Pharmacy, Kavacıksubayevleri Mah. Sandalcı Sok. No: 20/B-C 06120 Keçiören-Ankara/Türkiye
3
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye-Ankara, Türkiye
*
[email protected]
1
P
reparing new antiepileptic agents which is more
active and has less toxicity is one of the current
studies on development of biologically active
drugs1. Recently, the anticonvulsant activities of semicarbazone derivatives were reported by various studies2,3. Also
techniques such as IR, NMR, ESI-MS and HRMS. Anticonvulsant
activities were examined against reference standarts by maximal electroshock (MES) and subcutaneous pentylenetetrazol
(scPTZ) induced seizure tests. Neurotoxicity was determined
by the rotorod toxicity test. All these tests were performed in
O
O
H N
O
Ar
C CH2 Br
N
(a)
NH C NH NH2
O
Ar
C CH2 N
NH C NH
N
N
Ar
C CH2 N
N
(c)
Ar = 2-Naphthyl, 1,1'-(4-Bipheny-1-yl) Reagents: (a) DMF, 4 °C to r.t., (b) conc. H2SO4, reflux
Scheme: Schematic representation and structures of synthesized compounds.
arylalkylimidazoles have anticonvulsive effects too4. In hope
of getting synergistic response by gathering semicarbazone
and arylakylimidazole functions at the same structure, in this
study we prepared two new compounds and evaluate their
anticonvulsant activities.
A series of some novel 2-(1H-imidazole-1-yl)-1-aryl ethane-1-one N-phenylsemicarbazones were synthesized and
prepared by the reaction of phenylsemicarbazides with 1-aryl-2-imidazol-1-yl-ethanone to evaluate their anticonvulsant
activities. The structures of the synthesized compounds were
confirmed by elemental analysis results and the spectroscopic
REFERENCES
1. Brodie MJ. Do we need any more new antiepileptic drugs?
Epilepsy Res 45(1-3): 3-6, 2001.
2. Shafiee A, Rineh A, Kebriaeezadeh A, Foroumadi A, Sheibani V, Afarinesh M. Synthesis and anticonvulsant activity of
4-(2-phenoxyphenyl)semicarbazones. Med Chem Res 18(9):
758-769, 2009.
3. Rajak H, Veerasamy R, Singour P, Kharya MD, Mishra P. Anticonvulsant activity of a novel series of 2,5-disubstituted
1,3,4-oxadiazoles: Semicarbazones based pharmacoph-
accordance with the procedures of the Antiepileptic Drug Development (ADD) program which was developed by National
Institute of Neurological Disorders and Stroke (NINDS)5.
As a result of activity studies; while napthtyl derivative of
semicarbazones showed protection against all tested doses
except 0.5 h at MES test, biphenyl derivative not showed any
activity. Both two structures have not shown any neurotoxicity at all tested doses.
This project is supported by Hacettepe University Scientific Research Unit. Project No: 07 01 301 002.
oric model studies. Lett Drug Des Discov 6(6): 456-463,
2009.
4. Karakurt A, Dalkara S, Özalp M, Özbey S, Kendi E, Stables
JP. Synthesis of some 1-(2-naphthyl)-2-(imidazole-1-yl)
ethanone oxime and oxime ether derivatives and their anticonvulsant and antimicrobial activities. Eur J Med Chem
36(5): 421-433, May 2001.
5. Krall RL, Penry JK, White BG, Kupferberg HJ, Swinyard EA.
Antiepileptic Drug Development. 2. Anticonvulsant Drug
Screening. Epilepsia 19(4): 409-428, 1978.
International Symposium on Drug Research & Development 2011
119
POSTER PRESENTATIONS
P-064
POSTER PRESENTATIONS
DRD 2011
P-065
DEVELOPMENT AND VALIDATION OF UPLC METHOD FOR DETERMINATION
OF AZITHROMYCIN AND ITS IMPURITIES IN PHARMACEUTICAL
PREPARATIONS AND STRESS TESTING FOR DETERMINATION OF
DEGRADATION PRODUCTS
Şeyda İLTER1, Sedef KIR2,*
Deva Holding A.Ş. 34303, Küçükçekmece - İstanbul, Türkiye
Hacettepe University, Faculty of Pharmacy, Department of Analytical Chemistry, 06100 Sıhhiye,Ankara, Türkiye
*
[email protected]
1
2
A
zithromycin is a semisynthetic macrolide antibiotic with a 15-membered azalactone ring. It binds
to the 50 S ribosomal subunits of susceptible bacteria and suppresses protein synthesis1. These drugs may be
bactericidal or bacteriostatic. It is also used to treat bacterial
upper and lower respiratory tract infections, skin and skin
structure infections, and sexually transmitted diseases2.
Ultra Performance Liquid Chromatography (UPLC) is
a new technique giving new possibilities in liquid chromatography, especially concerning with decrease of time
and solvent consumption. UPLC chromatographic system
is designed in a special way to withstand against high sysREFERENCES
1. Lee HW, Hand DL. Characteristics and mechanisms
of azithromycin accumulation and efflux in human
polymorphonuclear leukocytes. Int J Antimicrobial
Agents 18: 419-425, 2001.
2. Petropoulos AD, Kouvela EC, Starosta AL, Wilson DN,
Dinos GP, Kalpaxis DL. Time-resolved binding of azithromycin to Escherichia coli ribosomes. J Molecular
tem back-pressures3. The aim of this study is to determine
Azithromycin and its impurities by UPLC from the pharmaceutical preparation and the validation of the method according to the ICH guidelines 4.
This study describes a fast, selective and highly sensitive
approach, which enables the determination of azithromycin
with good accuracy using UPLC. This method was fully validated and applied to the pharmaceutical preparation. The
amounts of degradation products formed by the exposure
of drug to the stress conditions analysed by the developed
chromatographic method. Optimization of the conditions
for the analysis of Azithromycin and its impurities were done
with Acquity BEH C18, 50 x 2.1 mm column with 1.7 µm partical size. The UPLC anaysis of Azithromycin and its impurities
were performed using 5 mM phospate buffer / acetonitrile
(65 : 35, v/v) pH = 6.0 mobile phase with 0.4 mL/min flow rate
and UV detector (240 nm).
The selective, precise, accurate, sensitive, rubbest and
rugged UPLC method with high resolution, short retention
time and low analysis cost was compared with HPLC method.
Pharmaceutical preparations exposed to stress conditions and the degradation products occurred with temperature, photolysis, acid hydrolysis, base hydrolysis, oxidation
and reduction were determined by validated UPLC method.
Biology 385: 1179-1192, 2009.
3. Novakova L, Matysova L, Solich P. Advantages of
application of UPLC in pharmaceutical analysis. Talanta
68: 908-918, 2006.
4. International Conferences on Harmonization, Guidance
on Impurities in New Drug Products. Q3B(R). Federal
Register. 65: 44791-44797, 2000.
International Symposium on Drug Research & Development 2011
120
DRD 2011
WHAT CAN YEAST HYBRID TECHNOLOGY TELL US IN DRUG SENSITIVITY
IN DRUG SCREENING; ITS IMPLICATIONS AND LIMITATIONS
Sevil ZENCİR1, Pakize CANTÜRK2, Zeki TOPÇU2
1
Department of Biochemistry, Faculty of Science, Ege University, 35100 İzmir, Türkiye
Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Ege University, 35100 İzmir, Türkiye
2
Y
east hybrid is a powerful technique in determining molecular interactions. Variations of this technology such as yeast-2- hybrid, yeast-1-hybrid and
yeast-3-hybrid provides us an extended tool in identifying
protein-protein, DNA-protein and receptor-ligand interactions, respectively. Considering the fact that most of the
pathological outcomes in mammalian cells arise as a result
of inappropriate molecular interactions, determination of
these interactions is an essential step in contemprorary drug
design. The synthetic compounds of pharmaceutical significance can be tested for their ability to interfere the interac-
tions of pathological consequence using a derivative of the
method, termed as reverse hybrid. Our laboratory employs
yeast hybrid technology in a number of research with pharmaceutical implications. We are currently verifiying a number of interactions that we pulled up on cDNA library screen
for selected bait constractions. Our results are discussed in
terms of implications and limitations of this technology in
drug screening.
Acknowledgement: This study is supported by grants
from TUBITAK, TBAG108T945.
International Symposium on Drug Research & Development 2011
121
POSTER PRESENTATIONS
P-066
POSTER PRESENTATIONS
DRD 2011
P-067
DETERMINATION OF DISSOCIATION CONSTANTS OF GLICLAZIDE
AND GLIBENCLAMIDE WITH POTENTIOMETRİC METHOD IN
TETRAHYDROFURAN-WATER BINARY MIXTURES
Dilara BAŞAT1, *, Nurullah ŞANLI2, Sibel A. ÖZKAN3
Bitlis Eren University , Science & Literature Faculty, Department of Chemistry,13000 Bitlis, Türkiye
2
Hitit University, Science & Literature Faculty, Department of Chemistry, Çorum, Türkiye
3
Ankara University, Faculty of Pharmacy, Department of Analytical Chemistry, 06100 Ankara, Türkiye
*
[email protected]
1
T
ype-2 diabetes is a long-term metabolic disorder
where in the body becomes resistant to the effects
of insulin, a hormone that regulates sugar absorption. Treatment of type-2 diabetes (non-insulin dependent) is
now possible with orally administered hypoglycemic agents
that help reduce blood sugar levels. Currently the most commonly prescribed medications for Type 2 diabetes are metformin and the second generation sulfonylureas which include glipizide, gliclazide, glibenclamide and glimepride [1].
amide group of gliclazide and glibenclamide (Figure 1) have
been determined in tetrahydrofuran–water binary mixtures
at five different percentages (40, 45, 50, 55, and 60% (v/v)) by
potentiometrically.
The relationships between pKa values and different bulk
properties were examined and the linear solvation energy
relationships (LSER) method was used to correlate pKa values
with solvent dipolarity/polarizability (п*), solvent hydrogen-
Figure 1. Structure of gliclazide and glibenclamide.
Glibenclamide and gliclazide are practically insoluble in
water. A common approach for the pKa measurements of
aqueous insoluble compounds involves the use of hydro-organic mixtures. Typically, at least three and up to six different
percentages of co-solvent are recommended. In this study,
the dissociation constant of 4-substitue benzene sulfonREFERENCES
1. Sweetman SC (2009) Ed., Martindale, The Extra Pharmacopoeia, 36th Ed., Pharmaceutical Press, London.
2. Barbosa J, Barron D, Buti S. Chromatographic behaviour
of ionizable compounds in Liquid Chromatography. Part
bond –donating acidity (a) and solvent hydrogen- bondaccepting basicity (β) [2].The equations obtained allowed
calculation of the pKa values of the substances in any tetrahydrofuran–water mixture. The pKa values obtained in aqueous
medium have been compared with the values predicted by
the SPARC on-line pKa calculator [3].
1. pH scale, pKa and pHs values for standard buffers in
tetrahydrofuran-water. Anal Chim Acta 389: 31-42, 1999.
3. SPARC On-line Calculator, University of Georgia, USA,
http://ibmlc2.chem.uga.edu/sparc/index.cfm
International Symposium on Drug Research & Development 2011
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DRD 2011
POTENTIOMETRIC DETERMINATION OF DISSOCIATION CONSTANTS FOR
PIOGLITAZONE AND ROSIGLITAZONE IN TETRAHYDROFURAN-WATER
BINARY MIXTURES
Dilara BAŞAT1,*, Ebru ÇUBUK DEMİRALAY 2, Güleren ALSANCAK 2
Bitlis Eren University, Science & Literature Faculty, Department of Chemistry, 13000 Bitlis, Türkiye
Süleyman Demirel University, Science & Literature Faculty, Department of Chemistry, 32260 Isparta, Türkiye
*
[email protected]
1
2
H
uman diabetes is currently classified into two
general categories: Type I, or insulin-dependent diabetes mellitus, and Type II, or noninsulin-dependent diabetes mellitus1. Many patients
with type II diabetes require treatment with more than
one antihyperglycaemic drugs to achieve optimal glycaemic control. The thiazolidinediones are novel oral
antihyperglycaemic drugs that improve glycaemic control primarily by decreasing insulin resistance by sensitizing the skeletal muscle, liver and adipose tissue to
the actions of insulin2. Rosiglitazone and pioglitazone
are in a class of drugs called thiazolidinediones. Rosiglitazone contains a thiazolidinedione core, but differs
from pioglitazone in the presence of an aminopyridyl
side chain3 (Figure 1).
The major drawback in the determination of pKa values of these drugs are their very low aqueous solubility because of their hyrophobic nature. Very often, the
main difficiulty in the determination of aqueous pKa of
drug candidates is their aqueous insolubility that forces the use of a hydroorganic solvent.
In the study tetrahydrofuran–water binary mixture
was selected as hydroorganic solvent and the dissociation constants of rosiglitazone and pioglitazone have
been determined in these mixtures (40- 60% (v/v)) in
accordance with IUPAC procedures by potentiometrically. Potentiometry has been the most useful techniques for the determination of equilibrium constants
in hydroorganic mixture, because of their accuracy and
reproducibility. The relationships between pKa values
and relative permittivity were examined and the linear
solvation energy relationships (LSER) method was used
to correlate pKa values with solvent properties (п*,a, β)
[4]. The aqueous pKa values have been calculated from
the pKa values determined in tetrahydrofuran–water
mixtures. These values have been compared with the
values predicted by the SPARC on-line pKa calculator,
ACD Lab, Marvin Sketch.
Figure 1. pKa values of rosiglitazone and pioglitazone (ACD
Lab).
REFERENCES
1. DeFronzo RA, Ferrannini E, Koivisto V. New concepts in
the pathogenesis and treatment of noninsulin-dependent diabetes mellitus. Am J Med 74 (Suppl 1A): 52-81,
1983.
2. Cox, S.L. Rosiglitazone maleate/metformin hydrochloride: A new formulation therapy for type 2 diabetes.
Drugs Today 40(7): 633, 2004.
3. R.R. Henry, Thiazolidinediones. Endocrinol Metab Clin
North Am 26: 553, 1997.
4. Baron D, Buti S, Ruiz M, Barbosa J. Evaluation of acidity
constants and preferential solvation in tetrahydrofuranwater mixtures. Polyhedron 18: 3281-3288, 1999.
International Symposium on Drug Research & Development 2011
123
POSTER PRESENTATIONS
P-068
POSTER PRESENTATIONS
DRD 2011
P-069
EFFECT OF FOOD ON THE PHARMACOKINETICS OF TRIMETAZIDINE
Emel D. KURTOĞLU 1,*, Onursal SAĞLAM 1, Sami EREN1, Erkin ALKAN1, Tuncel ÖZDEN 2
Novagenix Bioanalytical Drug R&D Centre, Ankara, Türkiye
2
Gazi University, Faculty of Pharmacy, Ankara, Türkiye
*
[email protected]
1
A
randomised, open-label, four period, crossover
bioequivalence study has been conducted in
fasting and fed conditions in 36 healthy volunteers who have been given two different branded trimetazidine products. Treatments were separated by washout
periods of 10 days. To investigate the influence of food on
the pharmacokinetics of trimatezidine, some pharmacokinetic parameters (tmax, Cmax and AUC0-tlast) were evaluated as
REFERENCES
1. Guidance for Industry. Food-Effect Bioavailability and Fed
Bioequivalence Studies. FDA, CDER, December 2002.
a paralel design. The 90% confidence intervals of difference
between pharmacokinetic parameters of trimetazidine in
fasting and fed conditions were evaluated, in both test and
reference products.
Our results showed that the bioavailability of trimetazidine is not effected by food.
2. Guideline on the Investigation of Bioequivalence. CPMP/
QWP/EWP/1401/98 Rev.1, Draft, London, EMEA, July
2008.
International Symposium on Drug Research & Development 2011
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DRD 2011
AN ELECTROCHEMICALLY ACTIVE OXIDATIVE STRESS MARKER:
3-NITROTYROSINE
Muharrem ÖZTÜRK1,*, Ebru TÜRKÖZ ACAR2, A. Nur ONAR1
Department of Chemistry, Art and Sciences Faculty, Ondokuz Mayıs University, 55139 Samsun, Türkiye
2
Faculty of Pharmacy, Yeditepe University, 26 Ağustos Campus, 34755 Ataşehir, İstanbul, Türkiye
*
[email protected]
1
T
yrosine residues in proteins including enzymes are
chemically converted to 3-nitrotyrosine by peroxynitrite. 3-Nitrotyrosine is currently being used
as a marker for oxidative stress damage1.
Adsorptive stripping square wave voltammetric determination of 3-nitrotyrosine was developed by Acar and Onar
using phosphate buffer at pH 9 with a very low LOD (»10-10 M)
and LOQ (»10-9 M) values. The method was applied 3-nitrotyrosine determination in cerebrospinal fluid after precipitation of proteins. However the analysis of cerebrospinal fluid
for nitrotyrosine gave false positive results, possibly due to
the precipitation reactions of proteins2.
In this work we tried to improve this strong method. It
is preferred to prepare the calibration curve in the presence
of synthetic cerebrospinal fluid as recommended in the
analysis of biological fluids. The irreversible reduction peak
of 3-NT was observed at -774 mV and -750 mV (vs. Ag/AgCl,
3M KCl) in phosphate buffers at pH 9.0 and pH 7.2 respectively. There is a peak at the reduction potential of 3-nitrotyrosine arising from both synthetic and natural cerebrospinal
fluid. This peak moved to more negative potentials while
pH of supporting electrolyte was increased and emerged at
more positive potentials when pH was decreased in parallel
to 3-nitrotyrosine peak. This behaviour leads to higher LOD
and LOQ values. Comparison of calibration curves were performed, those were prepared in the presence and absence of
synthetic cerebrospinal fluid at pH 9.0 and pH 7.2 in order to
quantify 3-nitrotyrosine in real cerebrospinal fluids.
REFERENCES
1. Hurst SK. Whence nitrotyrosine? J Clin Invest 109: 12871289, 2002.
2. Türköz Acar E. Development of quantitative determina-
tion method for 3-nitrotyrosine [Dissertation], Samsun
(Türkiye), Ondokuz Mayıs University Institute of Natural
Sciences, 2008.
International Symposium on Drug Research & Development 2011
125
POSTER PRESENTATIONS
P-070
POSTER PRESENTATIONS
DRD 2011
P-071
SYNTHESIS AND Antimicrobial Activity of New 1H-Benzimidazole
Derivatives
Görkem SARIKAYA1, *, A. Selcen ALPAN1, Hüseyin TAŞLI2, H. Semih GÜNEŞ1
1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ege University, 35100 Bornova, İzmir, Türkiye
Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Ege University, 35100 Bornova, Izmir, Türkiye
*
[email protected]
2
1
H-Benzimidazoles have been associated with various types of biological effects such as antioxidan,
antiparasitic, antiproliferative, antiviral activities1-4.
In this study, three 2-substitutedphenyl-1H-benzimidazoles and their six novel benzimidazole analogues were
synthesized and evaluated for in vitro antibacterial and antifungal activities by the micro dilution method. The structures of the compounds were confirmed by UV, IR, 1H NMR,
HRMS data.
REFERENCES
1. Ayhan-Kılcgil G, Kuş C, Özdamar ED, Can-Eke B, İşcan M.
Synthesis and antioxidant capacities of some new benzimidazole derivatives. Arch Pharm Chem Life Sci 34: 607–
1, 2007.
2. Navarrete-VaÂzquez G, Cedillo R, HernaÂndez-Campos
A, YeÂpez L, HernaÂndez-Luis, F, Valdez J, Morales R,
CorteÂs R, HernaÂndez M, Castillo R. Synthesis and antiparasitic activity of 2-(trifuoromethyl)-benzimidazole
All of the compounds were tested for antibacterial activity against ATCC strains of Escherichia coli ATCC 25922,
Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus
ATCC 29213 and for antifungal activity against Candida albicans ATCC 90028. The synthesized compounds did not show
any significant antifungal activitiy on Candida albicans ATCC
90028. It is found that all of the compounds are more effective to gram (+) bacteria than gram (-) bacteria. Furthermore,
2-(1H-benzimidazole-2-yl)phenyl intermediates bearing ohydroxyphenyl substituent on 1H-benzimidazole ring possess equal or similar results compared to the standart compound, Ceftazidime.
derivatives. Bioorg Med Chem Lett 11: 187-90, 2001.
3. Garuti, L., Roberti, M., Malagoli, M., Rossi, T, Castelli, M.
Synthesis and antiproliferative activity of some benzimidazole-4,7-dione derivatives. Bioorg Med Chem Lett
10: 2193-5, 2000.
4. [4] Luo X, Zhang Z, Yang Y, Xue F, Xiu N, She Y. Design,
synthesis, and antiviral properties of 2-aryl-1H-benzimidazole-4-carboxamide derivatives. Front Chem Eng China
3(3): 305–9, 2009.
International Symposium on Drug Research & Development 2011
126
DRD 2011
ANTIMICROBIAL METABOLITES FROM A MARINE DERIVED FUNGUS
Aspergillus Flavus
Ş.Orçun KALKAN1, *, Ataç UZEL1, Funda N. YALÇIN2, Erdal BEDİR3
Ege University, Faculty of Science, Department of Biology, Basic and Industrial Microbiology Section,
35100 Bornova, İzmir, Türkiye
2
Hacettepe University, Faculty of Pharmacy, Department of Pharmacognosy, 06100 Ankara, Türkiye
3
Ege University, Faculty of Engineering, Department of Bioengineering, 35100 Bornova, İzmir, Türkiye
*
[email protected]
1
N
ew antimicrobial molecules have attracted great
interest due to emergence of antibiotic resistance
in pathogenic bacteria. Since the terrestrial sources were extremely exploited for natural antibiotic producer
microorganisms, studies were shifted to marine sources
recently1. The marine microorganisms can produce quite
potent metabolites different than the terrestrials because
of the different conditions in marine environments such as
pressure, salinity, temperature and nutrient compositions2.
In our study, we isolated 42 fungal strains from different sponge and marine sediment samples and
screened their activity against a panel of antibiotic resistant test microorganisms. An Aspergillus flavus strain
showed potent activity against test microorganisms,
and bioactivity guided isolation studies were carried
out. Three molecules were isolated (1-3) from fermentation broth of the strain, and one of them was identified
as 4-(hydroxymethyl)-5-hydroxy-2H-pyran-2-one (1) by
using NMR. 2-Pyrone is a six-membered cyclic unsaturated ester, and its derivatives are highly abundant in
1.
2.
3.
4.
REFERENCES
P. R. Jensen and W. Fenical, Marine microorganisms and
drug discovery: current status and future potential, in
Drugs from the Sea, Karger Publishers: Basel, 2000, 6.
J. Kohlmeyer and E. Kohlmeyer, Marine Mycology: The
Higher Fungi, Academic Press: New York, 1979.
McGlacken GP, Fairlamb IJS. 2-Pyrone natural products
and mimetics: isolation, characterization and biological
activity. Nat Prod Rep 22: 369-385, 2005.
Suzuki K, Kuwahara A, Yoshida H, Fujita S, Nishikiori T, Nishikiori T. NF00659A1, A2, A3, B1 and B2, novel antitumor
antibiotics produced by Aspergillus sp. NF 00659. I. Taxonomy, fermentation, isolation and biological activities. J
Antibiot 50: 314-317, 1997.
bacteria, fungus, plant, insect and animal systems, and
take part in many different types of biological processes
such as defense against other organisms, as key biosynthetic intermediates, and as metabolites3. A wide range
of bioactivities such as, antitumour4,5, antimicrobial and
antifungal activities6,7 have demonstrated the medicinal
importance of 2-pyrones. Although 1 has been reported
recently as a cytotoxic agent, there is no data for its antimicrobial activity [8]. Compound 1 produced 14mm,
11mm and 10 mm inhibition zones against Pseudomonas aeruginosa, Escherichia coli 0157:H7 RSSK 234 and
methicillin-resistant Staphylococcus aureus RSSK 95047
(MRSA) at 700 mg per disc in disc diffusion assay. The
structure elucidation and bioactivity studies for the remaining compounds (2-3) are in progress.
O
O
OH
OH
1
5. Kondoh M, Usui T, Kobayashi S, Tsuchiya K, Nishikawa K,
Nishikiori T, Mayumi T, Osada H. Cell cycle arrest and antitumor activity of pironetin and its derivatives. Cancer Lett
126: 29-32, 1998.
6. Barrero AF, Oltra JE, Herrador MM, Cabrera E, Sanchez JF,
Quílez JF, Rojas F, Reyes JF. Gibepyrones: a -pyrones from
Gibberella fujikuroi. Tetrahedron 49: 141-150, 1993.
7. Parker SR, Culter HG, Jacyno JM, Hillf RA. Biological activity of 6-pentyl-2H-pyran-2-one and its analogs. J Agric
Food Chem 45: 2774-2776, 1997.
8. Lin A, Lu X, Fang Y, Zhu T, Gu Q, Zhu W. Two New 5-hydroxy2-pyrone derivatives isolated from a marine-derived fungus Aspergillus flavus. J Antibiot 61(4): 245-249, 2008.
International Symposium on Drug Research & Development 2011
127
POSTER PRESENTATIONS
P-072
POSTER PRESENTATIONS
DRD 2011
P-073
SYNTHESIS OF DOXORUBICIN INCORPORATED MAGNETIC ALBUMIN
NANOSPHERES WITH A SIMPLE METHOD AND IN VITRO DOXORUBICIN
RELEASE STUDIES
Güliz AK*, Habibe YILMAZ, Şenay ŞANLIER
Ege University, Faculty of Science, Biochemistry Department, 35100 İzmir, Türkiye
*[email protected]
D
oxorubicin is the best known and most widely
used member of the anthracycline antibiotic
group of anticancer agent. The therapy-limiting
toxicity for this drug is cardiomyopathy, which may lead to
congestive heart failure and death. A different approach to
ameliorating doxorubicin-related toxicity is to use drug carriers, which engender a change in the pharmacodistribution
of the drug, resulting in reduced drug concentrations in the
heart [1]. Albumin is playing an increasing role as a drug
carrier in the clinical setting. These properties as well as its
preferential uptake in tumor, ready availability, biodegradability and lack of toxicity and immunogenicity make it an
ideal candidate for drug delivery [2]. Magnetic drug delivery
by particulate carriers is a very efficient method of delivering a drug to a localized disease site. In magnetic targeting,
a drug or therapeutic radioisotope is bound to a magnetic
compound, injected into a patient’s blood stream, and then
stopped with a powerful magnetic field in the target area [3].
For this aim, we synthesized doxorubicin loaded magnetic
albumin nanoparticles in order to obtain targeted drug de-
REFERENCES
1. Waterhouse DN, Tardi PG, Mayer LD, Bally MB. A comparison of liposomal formulations of doxorubicin with drug
administered in free form. Drug Safety 24 (12): 903-920,
2001.
2. Kratz F. Albumin as a drug carrier: Design of prodrugs,
drug conjugates and nanoparticles. Journal of Controlled
Release 132: 171-183, 2008.
livery and controlled release. Albumin nanoparticles were
prepared by a desolvation technique followed by glutaraldehyde crosslinking with a minor modification [4]. Fe3O4
was synthesized by co-precipitation method as previously
described [5]. 25 mg albumin, 1 mg doxorubicin and Fe3O4
were dissolved in 1 ml distilled water, then desolvating
agent, ethanol was added with 4 ml/min of flow rate by a
pump system under continious stirring (480 rpm) at room
temperature. After desolvation process glutaraldehyde was
added to induce particle crosslinking. At the end of 24 h, resulting solution was centrifuged and purified. The effect of
albumin, doxorubicin and magnetic agent concentration, pH
and glutaraldehyde amount were researched and optimum
conditions were determined based on size of nanoparticles,
desolvation effiency and drug loading capacity. Doxorubicin incorporated magnetic albumin nanoparticles and free
doxorubicin were used for in vitro release studies at pH 5,
6, 7,4. At predetermined intervals samples were taken and
doxorubicin amount was analyzed spectrophotometrically.
Then, obtained results were compared according to cumulative release.
3. Hafeli UO. Magnetically modulated therapeutic systems.
International Journal of Pharmaceutics 277: 19-24, 2004.
4. Langer K, Balthasar S, Vogel V, Dinauer N, von Briesen H,
Schubert D. Optimization of the preparation process for
human serum albumin (HSA) nanoparticles. International
Journal of Pharmaceutics 257: 169-180, 2003.
5. The study of novel Fe3O4@γ--Fe2O3 core/shell nanomaterials with improved properties. Journal of Magnetism
and Magnetic Materials 321: 1052-1057, 2009.
International Symposium on Drug Research & Development 2011
128
DRD 2011
SPECTROPHOTOMETRIC METHOD FOR THE DETERMINATION OF
ETODOLAC IN PHARMACEUTICAL FORMULATIONS
Alptuğ ATİLA, Atakan TURAN, Yücel KADIOĞLU
Department of Analytical Chemistry, Faculty of Pharmacy, Atatürk University, 25240, Erzurum, Türkiye
H
umans and domestic animals are used non-steroidal anti-inflammatory drugs (NSAIDs) due to their
anti-inflammatory, analgesic and anti-pyretic effects1. Etodolac (1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid) is an effective and well-tolerated NSAID,
and is indicated for the treatment of analgesia and for the
signs and symptoms of rheumatoid arthritis and osteoarthritis2.
Etodolac was kindly supplied from Novagenix Pharmaceutical Industry (Ankara, Turkey). Acetaminophen as internal standard (IS) was obtained from Sigma-Aldrich (product
of USA). Thermospectronic double beam UV-Vis spectrophotometer (HEλIOSβ) with a fixed slid width (2 nm) connected
to a computer loaded with vision 32 software was used. Validation parameters such as limit of detection (LOD), limit of
quantification (LOQ), linearity, precision, accuracy, recovery,
specificity are studied as reported in the International Conference on Harmonization Guidelines. Standard stock solution
of etodolac (100 μg/mL) was prepared in methanol. Spectrophotometrically, etodolac were determined by means of
UV absorbance values (A) at 272 nm. Linearity range Beer’s
law was found as 3-20.0 μg/mL. The calibration curve have
linearity with correlation coefficient r=0.999. Mean recoveries and the relative standard deviations of the method were
fond as 98.21 % and 2.51%, respectively. Developed method
was successfully applied to etodolac in pharmaceutical formulations.
International Symposium on Drug Research & Development 2011
129
POSTER PRESENTATIONS
P-074
POSTER PRESENTATIONS
DRD 2011
P-075
PREPARATION AND IN VITRO RELEASE STUDIES OF CISPLATIN LOADED
MAGNETIC GELATIN NANOPARTICLES
Habibe YILMAZ*, Güliz AK, Şenay ŞANLIER
Ege University, Faculty of Science, Biochemistry Department, 35100 İzmir, Türkiye
*[email protected]
G
elatin, a natural macromolecule, is widely used in
biotechnological and biomedical applications. It
has a number of advantages in comparison with
the other synthetic polymers, which make it suitable for drugcarrying: for example, it is biodegradable, non-toxic and easy
to crosslink. Moreover, it is inexpensive, can be sterilized, is
not usually contaminated with pyrogens and possesses relatively low antigenicity1. Cisplatin (cis-dichlorodiamminoplatinum) is an anticancer agent that widely used to treat ovarian and lung cancer etc. However, its clinical use is limited
due to its severe side effects such as neurotoxicity, gastrointestinal disturbance, and acute nephrotoxicity thus because
of its low molecular weight, cisplatin is rapidly passed into
the blood circulating and the time period of retention in the
tumor is very short, no significantly high and prolonged antitumor effects have been expected2. The structure of cisplatin was shown in Figure 1. Magnetic nanoparticles such as
Fe3O4 can be coated with polymers and allows to control the
localization of drug in the targeted area3. In this study, gelatin type B was chosen to prepare cisplatin loaded magnetic
gelatin nanoparticles. Gelatin nanoparticles were syntheREFERENCES
1. Gaihre B, Aryal S, Khil MS, Kim HY. Encapsulation of Fe3O4
in gelatin nanoparticles: Effect of different paramaters on
size and stability of the colloidal dispersion. Journal of
Microencapsulation 25(1): 21-30, 2008.
2. Ding D, Zhu Z, Liu Q, Wang J, Hu Y, Jiang X, Liu B. Cisplatinloaded gelatin-poly(acrylic acid) nanoparticles: Synthesis,
antitumor efficiency in vivo and penetration in tumors.
European Journal of Pharmaceutics and Biopharmaceutics EJPB 10857, 2011.
3. Mederios SF, Santos AM, Fessi H, Ellaissari A. Stimuli-responsive magnetic particles for biomedical applications.
sized by two-step desolvation method as described in the
earliest studies. In the first step, 5% gelatin solution precipitated with 1 ml aceton and high molecular weight gelatin
discarded. In the second step, precipitate redissolved in 1 ml
pure water and 2 ml aceton added dropwise to prepare gelatin nanoparticles4. Synthesis of magnetic agent, Fe3O4, was
performed by co-precipitation method and used to form
magnetic gelatin nanoparticles5. The effect of the matrix
concentration, Fe3O4 (magnetite) amount, pH, cross-linking
agent glutaraldehyde concentration, flow ratio of desolvating agent, acetone determined. Moreover, in vitro cisplatin
release from magnetic gelatin nanoparticles studies were
carried out.
Figure 1. The structure of cisplatin.
Int Jour of Pharmaceutics 403: 139-161, 2011.
4. Zwiorek K., Bourquin C, Battiany J, Winter G, Endres S, Endres S, Hartmann G, Coester C. Delivery by cationic gelatin nanoparticles strongly increases the immunostimulatory effects of CpG oligonucleotides. Pharmaceutical
Research 25 (3): 551-562, 2008.
5. Gao Q, Chen F, Zhang J, Hong G, Ni J, Wei X, Wang D. The
study of novel Fe3O4@g-Fe2O3 core/shell nanomaterials with improved properties. Journal of Magnetizm and
Magnetic Materials 321: 1052-1057, 2008.
International Symposium on Drug Research & Development 2011
130
DRD 2011
STUDY OF RESVERATROL-COPPER COMPLEXES BY CAPILLARY
ELECTROPHORESIS
Behice YAVUZ ERDOĞAN1,*, A. Nur ONAR2
Department of Food Technology Programmes, Technical Vocational School of Higher Education, Ondokuz Mayıs
University, Terme, 55600 Samsun, Türkiye
2
Department of Chemistry, Art and Sciences Faculty, Ondokuz Mayıs University, 55139 Samsun, Türkiye
*
[email protected]
1
I
n biological systems redox active free metals (e.g. copper,
iron and manganese) catalyze free radical producing reactions that are slow in their absence1,2,3. On the other hand
several copper, iron and manganese complexes have been reported to exhibit the ability of catalyzing the dismutation of superoxide radicals. It is claimed that the presence of the reduced
forms of metal ions in solutions of complexes may be responsible for this superoxide dismutase (SOD) like activity4.
There exists the possibility of reduction of metal ions by
phenols. The presence of a different oxidation state of Cu in
complex with a phenolic antioxidant ligand may have important implications in the biological reactions and therefore
has to be studied in detail5.
REFERENCES
1. Guo Q, Zahao B, Li M, Shen S,Xin W. Studies on protective
mechanism of four components of green tea polyphenols againts lipid peroxidation in synaptosomes. Biochim
Biophys Acta 1304: 210-222, 1996.
2. Brown KE, Kinter MT, Oberley TD, Freeman ML, Frierson
HL,Ridnour LA,Tao Y,Oberlet LW, Spitz DR. Enhanced
gamma-glutamyl transpeptidase expression and selective loss of CuZn superoxide dismutase in hepatic iron
overload. Free Radic Biol Med 24: 545-555, 1998.
3. Morel I, Abelea V, Sergent O, Cillard J. Involvement of phenoxyl radical intermediates in lipid antioxidant action of
myricetin in iron-treated rat hepatocyte culture. Biochem
Resveratrol (3, 4´, 5 trihydroxy-trans-stilbene) is a naturally occurring phytoalexin, a secondary plant metabolite6. This
polyphenol is supposed to be responsible for beneficiary
health effects of red wine.
It is aimed to show the presence of Cu (I) in the Cu (II) resveratrol complex by capillary electrophoresis. Borate buffer (0.05M), was chosen as running electrolyte. Copper (II)
and copper (I) - resveratrol complexes were prepared with
different ligand-metal ratios at various pHs. Capillary electrophoretic experimental conditions were selected as: +23kV
applied potential, 20°C temperature while using fused silica
column with 50μm inner diameter and 50cm length.
Pharmacol 55: 1399-1404, 1998.
4. Barik A, Mishra B, Shen L, Mohan H, Kadam RM, Dutta S,
Zhang HY, Priyadarsini KI. Evaluation of new copper(II)
curcumin complex as superoxide dismutase mimic and
its free radical reactions. Free Radic Biol Med 39: 811-822,
2005.
5. Harbir SM, Sudhir K, Ashis KS, Tulsi M. Radical scavenging
and cataltic actvity of metal-phenolic complexes. J Phys
Chem B 109: 24197-24202, 2005.
6. Langcake P, Cornford CA, Pryce RJ. Identification of pterostilbene as a phytoalexin from Vitis vinifera leaves. Phytochemistry 18: 1025-1027, 1979.
International Symposium on Drug Research & Development 2011
131
POSTER PRESENTATIONS
P-076
P-077
ELECTROCHEMICAL DETERMINATION OF DOXYCYCLINE
Berrin GÜRLER*, Sabriye PERÇİN ÖZKORUCUKLU, Esengül KIR
Süleyman Demirel University, Faculty of Science and Art, Dept. of Chemistry, Isparta, Türkiye
*
[email protected]
T
he tetracycline antibiotics are active against a wide
range of Gram-positive and Gram-negative bacteria, being widely used in human and veterinary
medicines as well as feed additives1. At the same time, because of their adverse effects on public health, concerns are
raised over the residues of antibiotics in biological products
and environment samples2. Even more important, consumed
foodstuffs containing low level doses of antibiotic, can lead
to bacterial resistance in humans3. Several methods for the
determination of tetracyclines in pure form and in veterinary
drugs have been used4. Electrochemical detection is also
used due to the well-known advantages like sample pretreatment and sensitivity.
In this work, preparation of a molecularly imprinted polymer (MIP) film and its recognition properties for doxycyline
were investigated. The overoxidized polypyrrole (OPPy) was
prepared by incorporation of a template molecule (doxycyline) during the electropolymerization of pyrrole onto
a pencil graphite electrode. The voltammetric behavior of
doxycyline on imprinted and non-imprinted (NIP) films was
investigated by differential pulse voltammetry in BrittonRobinson buffer solutions prepared in 20% and 30% acetoREFERENCES
1. Kazemifard A.G., Moore D.E. Evaluation of amperometric
detection for the liquid-chromatographic determination
of tetracycline antibiotics and their common contaminants in pharmaceutical formulations. Journal of Pharmaceutical and Biomedical Analysis 16: 689-696, 1997.
2. Cai Y, Cai Y, Shi Y, Mou S, Lu Y. Optimizing the integrated pulsed
amperometric multicycle step waveform fort he determination of tetracyclines. J Chromatogr A 1118: 35-40, 2006.
nitrile-water binary mixtures between the pH 1.5 and 4.0.
The MIP electrode exhibited a high selectivity and sensitivity
toward doxycyline. The highest anodic signal of doxycycline
with MIP electrode was obtained in Britton-Robinson buffer
solution prepared in 30% acetonitrile-water at pH 2. The calibration curve for doxycyline at MIP electrode has linear region for a concentration range of 0.05 to 0.5 mM (R2=0.9997).
The detection limit was determined as 4.24 x 10-5 M (S/N=3).
The same method was also applied to determination of doxycyline in commercial pharmaceutical sample. The recovery
factor in tablet was found as 99.99% with the relative standard deviation of 0.46.
i/A
POSTER PRESENTATIONS
DRD 2011
0.35x10-3
0.30x10-3
0.25x10-3
0.20x10-3
0.15x10-3
0.10x10-3
0.05x10-3
0
-0.05x10-3
-3
-0.10x10
0.250
DPV
0.500
0.750
1.000
1.250
E/V
Figure.1. Differential pulse voltammogram for 1mM doxycycline in tablet at MIP electrode.
3. Masawat P., Mark Slater J. The determination of tetracycline residues in food using a disposable screen-printed
gold electrode (SPGE). Sensors and Actuators B 124: 127132, 2007.
4. Kurzawa M., Kowalczyk-Marzec A. Electrochemical determination of oxytetracycline in veterinary drugs. Journal
of Pharmaceutical and Biomedical Analysis 34: 95-102,
2004.
International Symposium on Drug Research & Development 2011
132
DRD 2011
SYNTHESIS AND ANTIMICROBIAL EVALUATION OF 6-SUBSTITUTED3(2H)-PYRIDAZINONE-2-ACETYL-2-(P-SUBSTITUTED BENZAL)
HYDRAZONE DERIVATIVES
Zeynep ÖZDEMİR1, Mehtap GÖKÇE2, Berrin ÖZÇELİK3
İnönü University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 33169 Malatya, Türkiye
2
Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06330 Ankara, Türkiye
3
Gazi University, Faculty of Pharmacy, Department of Microbiology, 06330 Ankara, Türkiye
1
T
he pyridazinone nucleus has been incorporated
into a wide variety of therapeutically interesting
molecules to transform them into better drugs.
Some of the present day drugs such as emorfazone (analgesic), pimobendan (positive inotropic, vasodilator), levosimendan (calcium sensitizer), imazodan (cardiotonic), zardaverin (cardiotonic) medazonamide (antitussive) are the best
examples for potent molecules possessing pyridazinone
nucleus. Due to favorable presence a pyridazinone moiety in
known active structures, pyridazinone derivatives provoked
a special interest in the search for new antibacterial agents
Also, it is well known that the hydrazone group plays an important for the antimicrobial activity a number of hydrazone
derivatives have been claimed to possess interesting antibacterial and antifungal activities Considering above, we report synthesis of eleven 6-substituted-3(2H)-pyridazinone-2acetyl-2-(p-substitutedbenzaldehyde)hydrazone derivatives
by the condensation reaction of 6-substituted-3(2H)-pyridazinone-2-acetohydrazides with substituted benzaldehyde derivatives. The structures of these new pyridazinone
derivatives were confirmed by their IR, 1H-NMR spectra and
elementary analysis. Antimicrobial activities of the synthesized compounds were investigated against Escherichia coli
(ATCC 25922/isolated strain), Pseudomonas aeroginosa (ATCC
10145/ isolated strain), Proteus mirabilis (ATCC 7002/ isolated
strain), Klepsiella pneumoniae (RSKK 574/ isolated strain), Acinetobacer baumannii (RSKK 02026/ isolated strain), Staphylococcus aureus (ATCC 25923/ isolated strain), Enterococcus
faecalis (ATCC 29212/ isolated strain) ve Bacillus subtilis (ATCC
6633/ isolated strain), Candida albicans (ATCC 10231) and
Candida krusei (ATCC 6258).
R
CH2
N
CO
NH
N
N
O
N
Com.
CH2
R1
Com.
R1
Va
H
Vg
3-OCH3
Vb
4-F
Vh
4-OCH3
Vc
4-Cl
Vi
4-NO2
Vd
4-Br
Vj
3-OCH3, 4-OH
Ve
2-Cl
Vm
4-N(CH3)2
Vf
4-CH3
International Symposium on Drug Research & Development 2011
133
CH
POSTER PRESENTATIONS
P-078
POSTER PRESENTATIONS
DRD 2011
P-079
ELECTROCHEMICAL BEHAVIOR AND QUANTIFICATION OF
CIPROFLOXACIN IN THE ACETONITRILE-WATER BINARY MIXTURE
Berrin GÜRLER*, Sabriye PERÇİN ÖZKORUCUKLU, Esengül KIR
Süleyman Demirel University, Faculty of Science and Art, Dept. of Chemistry, Isparta, Türkiye
*
[email protected]
I
n recent years, molecularly imprinted polymers (MIPs)
have gained and increasing interest in the research into
new analytical techniques. In analytical seperation science, MIPs have been applied in several analytical methods,
such as liquid chromatography, capillary electrophoresis,
solid phase extraction, and as a selective sorbent in chemical
sensors [1]. Owing to the high affinities, selectivities and mechanical stabilities, imprinted polymers have been used for
the determination of drugs [2]. Quinolones comprise a most
interesting group of antibiotics and these drugs are suitable
for the treatment of systematic infections [3]. It is necessary
to define any risk to public health from the use of quinolones
in food animals [4]. To make detection of a member of quinolones ciprofloxacin easy and fast we developed a sensor
based on molecularly imprinted polymer electrodes [5].
cin on NIP and MIP electrodes was investigated in BrittonRobinson buffer solution prepared in 40% acetonitrile-water
binary mixture at pH 7.5 by differential puls voltammetry
(DPV). The DPV peak currents of ciprofloxacin are higher for
MIP electrodes than for NIP electrodes. Calibration curve
was obtained in the range of 0.5-2 mM of ciprofloxacin with
a correlation coefficient of 0.991 at MIP electrode. The limit
of detection of ciprofloxacin was calculated to be 4.61 x 10-2
M (S/N=3). MIP electrode also was used for determination of
ciprofloxacin in commercial tablet. The recovery factor was
obtained as 70% (RSD 0.052).
In this study, molecularly imprinted (MIP) and non-imprinted (NIP) polypyrrole electrodes were prepared by cyclic
voltammetric deposition of conducting polymer (pyrrole) in
the presence of supporting electrolyte with and without a
template molecule (ciprofloxacin) on a pencil graphite electrode, respectively. Electrochemical behavior of ciprofloxaREFERENCES
1. Anderson LI. Molecular imprinting: Developments and
applications in the analytical chemistry field. J Chromatogr B 745: 3-13, 2000.
2. Özcan L, Şahin M, Şahin Y. Electrochemical preparation
of a molecularly imprinted polypyrrole-modified pencil
graphite electrode for determination of ascorbic acid.
Sensors 8: 5792-5805, 2008.
3. Barbosa J, Barrón D, Cano J, Jiménez-Lozano E, Sanz-Nebot V, Toro I. Evaluation of electrophoretic method versus
chromatographic, potentiometric and absorptiometric
methodologies for determing pKa values of quinolones
Figure. 1: Chemical structure of ciprofloxacin.
in hydroorganic mixtres. Journal of Pharmaceutical and
Biomedical Analysis 24: 1087-1098, 2001.
4. Perçin Özkorucuklu S, Şahin Y, Alsancak G. Voltammetric
behaviour of sulfamethoxazole on electropolymerizedmolecularly imprinted overoxidized polypyrrole. Sensors
8: 8463-8478, 2008.
5. Özcan L, ŞahinY. Determination of paracetamol based on
electropolymerized-molecularly imprinted polypyrrole
modified pencil graphite electrode. Sensors and Actuators B 127: 362-369, 2007.
International Symposium on Drug Research & Development 2011
134
DRD 2011
INVESTIGATING THE INFLUENCE OF CLEANSING FORMULATIONS IN
TURKISH MARKET ON SEBUM & MOISTURE LEVELS OF THE SKIN
Leman ÇELİK*, Özge ŞAHİN, Atlan YÜKSEL, Nefise Özlen ŞAHİN
Mersin University, Faculty of Pharmacy, Department of Biopharmaceutics, Yenişehir Campus, 33169 Mersin, Türkiye
*
[email protected]
C
leaning products used for skin care belong to the
group of frequently consumed cosmetic preparations with the least known structure. Among
them, facial cleansing tissues, gels, milks, and single or multiple phase cleaning solutions are the most widely used
cleansing products1.
The purpose of use of these products is to intensively
clean the skin without interfering its properties. In literature,
it’s suggested that this type of products usually moisturize
the skin as well as remove the sebum layer without causing dryness and loss of moisture unlike traditional cleansing soaps2. However, it seems difficult to support this claim
for the marketed products. Taken this into consideration, in
this study, the marketed cleansing products in the forms of
creams and solutions were tested for their influence on the
skin moisture and sebum levels.
Initially, the cleansing products of leading cosmetic companies were selected and collected from the market to be
tested. Next, the salon tests required for cream and solution type cosmetics were carried out on these products. The
test products were applied onto forehead and cheek of the
healthy volunteers (n= 40) in the age range of 25 to 50 after obtaining their written consent for participation to this
study. Sebum and moisture levels were measured before
and after applying cleansing formulations [Figure 1].
REFERENCES
1. Rieger MM. [ed]. Harry’s Cosmetology. 8th ed: MA, USA:
Chemical Publishing company, 2000.
Figure 1a. Effect of solution type cleansing product.
Figure 1b. Effect of cream type cleansing product.
The data were compared statistically using Student t-test.
In the end of the study, it was found out that cream type products raised sebum levels slightly and increased the moisture
levels from 237 microsiemens to 522 microsiemens. On the
other hand, use of solution type cleansing products reduced
sebum level significantly. The moisture level of the skin decreased to 142 siemens due to enhanced dryness. This is in
contrast to the claim of the product.
2. Suzuki T, Nakamura M, Sumida H, Shigeta A. Liquid crystal
make-up remover: conditions of formation and its cleansing mechanisms. J Soc Cosm Chem 43: 21-36, 1992.
International Symposium on Drug Research & Development 2011
135
POSTER PRESENTATIONS
P-080
POSTER PRESENTATIONS
DRD 2011
P-081
DETERMINATION OF DISSOCIATION CONSTANTS OF VALSARTAN IN
ACETONITRILE-WATER BINARY MIXTURES BY POTENTIOMETRIC METHOD
Ebru ÇUBUK DEMİRALAY
Department of Chemistry, Faculty of Science and Literature, Süleyman Demirel University, 32260 Isparta, Türkiye
[email protected]
S
artans are an important class of drugs acting as selective antagonists of angiotensin II (ARA-IIs) at the
AT1 receptors. This antagonism is commonly used
to treat hypertension, but additional therapeutic indications
are emerging for these drugs such as the management of
congestive heart failure, myocardial infarction, and diabetic
nephropathy1.
The knowledge of acid–base equilibria of this antihypertensive drug has a great pharmacological importance. Moreover, knowing the structure and the
different acid–base species, the best way of drug administration, the absorption rate, the distribution profile
and the excretion percentage can be established2. But,
there are a limited number study for determination of
the pKa values of valsartan2-4.
The aim of this work is the application of potentiometric method to the determination of dissociation
constants of valsartan. Valsartan ((S)-N-valeryl-N-{[2_(1H-tetrazol-5-yl)biphenyl- 4-yl]methyl}-valine) contains two acidic centers, the carboxylic acid group and
the tetrazole ring. Dissociation pathways of valsartan
are given in Figure. The pKa values obtained in aqueous medium for valsartan have been compared with the
values predicted by ACD Lab, Marvin Sketch.
Dissociation constants of valsartan are determined
in acetonitrile-water mixtures in the interval (R(v/v),
40-60%) by using potentiometric method. Dissociation
constants of valsartan obtained by the potentiometric
method using the PKPOT program5. The aqueous pKa
values of valsartan obtained from this study are in good
agreement with ACD Lab, Marvin Sketch programs.
pKa1
pKa2
Macro-equilibria of valsartan ionization
REFERENCES
1. Jackson EK, in Goodman and GilmanLs. The Pharmacological Basis of TherapeuticsL, Eds. J. G. Hardman, L. E.
Limbird, McGraw-Hill, 2001, New York.
2. Cagigal E, González L, Alonso RM, Jiménez RM. pKa determination of angiotensin II receptor antagonists (ARA II)
by spectrofluorimetry. J Pharm Biomed Anal 26: 477-486,
2001.
3. Toscoa P, Rolando B, Fruttero R Henchoz Y, Martel S, Carrupt PA, Gasco A. Physicochemical profiling of sartans: A
detailed study of ionization constants and distribution
coefficients. Helv Chim Acta 91: 468-482, 2008.
4. Demiralay EÇ, Çubuk B, Alsancak G, Özkan SA. Combined
effect of polarity and pH on the chromatographic behaviour of some angiotensin II receptor antagonists and optimization of their determination in pharmaceutical dosage forms. J Pharm Biomed Anal 53: 475-482, 2010.
5. Barbosa J, Barron D, Beltran JL, Sanz-Nebot V. PKPOT A
program for the potentiometric study of ionic equilibria
in aqueous and non-aqueous media. Anal Chim Acta 317:
75-81, 1995.
International Symposium on Drug Research & Development 2011
136
DRD 2011
SPECTROSCOPIC pKa VALUES OF PROTON PUMP INHIBITORS IN
ACETONITRILE WATER BINARY MIXTURES
Merve GÜRKAYNAK1, Ebru ÇUBUK DEMİRALAY1,*, Hale CANBAY2, Sibel A. ÖZKAN3
2
1
Süleyman Demirel University, Science & Literature Faculty, Department of Chemistry, 32260 Isparta,Türkiye
Süleyman Demirel University, Experimental and Observational Student Practice and Research Centre, Isparta,
Türkiye
3
Ankara University, Faculty of Pharmacy, Department of Analytical Chemistry, 06100 Ankara, Türkiye
*
[email protected]
P
roton pump inhibitors (PPI) are used for the
treatment of conditions such as ulcers and
gastroesophageal reflux disease which are all
caused by stomach acid. Omeprazole, lansoprazole,
pantoprazole, and rabeprazole are the member of PPI.
They have a smaller anti-secretory potency on a milligram basis.
The PPI pharmacophore is 2-pyridylmethylsulfinylbenzimidazole1]. The PPI products contain this basic
structural framework and differ only in the nature of
substituents placed on the pyridine and benzimidazole
rings.
General structures of PPI.
The benzimidazoles possess characteristic absorption spectra in the UV region. In order to determine the
pKa values of these compounds by spectroscopic metREFERENCES
1. Victoria F. The chemically elegant proton pump inhibitors. Am J Pharm Educ A 70(5): 1-11, 2006.
2. Jerez G, Kaufman G, Prystai M, Schenkeveld S, Donkor KK.
Determination of thermodynamic pKa values of benzimi-
hod, spectral data at different pH values were recorded
over the wavelength region 198 - 346 nm at 25oC. The
method used for calculating the pKa is based on the
equilibrium reaction of protonated benzimidazole and
Beer’s Law2. Benzimidazole and its derivates have limited solubility in water. In this work, acetonitrile water
binary mixtures used to facilitate solubility of the benzimidazoles.
Benzimidazoles are considered weak base. Two protonation contants related to the protonations at the
pyridine nitrogen and 3-position benzimidazole nitrogen atom and dissociation constant related to the
deprotonation at the 1-position of the benzimidazole
ring have been determined3. The effect of the electron
donating or withdrawing nature of these substituents
were investigated. The aqueous pKa values have been
calculated from the pKa values determined in acetonitrile water mixtures. The results obtained have been
compared with the values predicted by the SPARC online pKa calculator, ACD Lab, Marvin Sketch. pKa values
of these compounds were also determined potentiometrically. It is satisfying to note that pKa values obtained by the two methods are in close agreement.
dazole derivatives by capillary electrophoresis. J Sep Sci
32: 1087-1095, 2009.
3. Yang R, Schulman GS, Zavala JP. Acid-base chemistry of
omeprazole in aqueous solutions. Anal Chim Acta 481:
155-164, 2003.
International Symposium on Drug Research & Development 2011
137
POSTER PRESENTATIONS
P-082
POSTER PRESENTATIONS
DRD 2011
P-083
DETERMINATION OF pKa VALUES OF BENZIMIDAZOLE DERIVATIVES WITH
POTENTIOMETRIC METHOD IN METHANOL-WATER BINARY MIXTURES
İsmail ÇELİK1, Güleren ALSANCAK1,*, Ebru ÇUBUK DEMİRALAY1, Hale CANBAY2
2
1
Süleyman Demirel University, Science & Literature Faculty, Department of Chemistry, 32260 Isparta, Türkiye
Süleyman Demirel University Experimental and Observational Student Practice and Research Centre, Isparta,
Türkiye
*
[email protected]
P
roton pump inhibitors (PPI) have shown to be
an effective inhibitor of gastric acid secretion and for treatment of peptic ulcers1. They are
α-pyridylmethylsulfinyl benzimidazoles with different substitutions on the pyridine or the benzimidazole groups, their
pharmacological properties are similar. Their activity is initiated by a series of ionic reactions that lead to the reduction
of protonic activity in the parietal cells. The pharmacological
characteristics of PPI are related to their protolytic behavior estimated by their pKa values. Benzimidazole is a slightly
non-polar molecule, therefore, it is very difficult to dissolve
in water. Very often, the main difficulty in the determination
of aqueous pKa of drug candidates is their aqueous insolubility that forces the use of a hydro-organic solvent. Methanolwater binary mixtures have been widely recommended
because, among the organic solvents, methanol shows the
closest properties to water2.
In this study, pKa values of PPI have been determined
potentiometrically in methanol–water binary mixtures (3045%). Potentiometry has been the most useful techniques
REFERENCES
1. Jerez G, Kaufman G, Prystai M, Schenkeveld S, Donkor
KK. Determination of thermodynamic pKa values of benzimidazole derivatives by capillary electrophoresis. J Sep
Sci 32: 1087-1095, 2009.
2. Ruiz R, Rosés M, Ràfols C, Bosch E. Critical validation of
a new simpler approach to estimate
aqueous pKa
for the determination of equilibrium constants in hydroorganic mixture, because of their accuracy and reproducibility. Moreover, the use of computer program for the refinement of equilibrium constants allows the different pKa values
in polyprotic substances3.
The pKa values determined for the involved equilibria for
the four PPI studied in methanol-water mixtures were correlated with the Kamlet and Taft solvatochromic parameter
(π*, α, β). The pKa values of PPI in any methanol-water mixture can be calculated from the relationships found and the
most important solvent properties that affect electrolyte dissociation can also be evaluated.
A completely different approachs to evaluate the aqueous pKa of organic compounds are the one based on the
analysis of the chemical structure. The pKa values obtained
in aqueous medium for pantoprazole have been compared
with the values predicted by the SPARC on-line pKa calculator, ACD Lab, Marvin Sketch.
of drugs sparingly soluble in water. Anal Chim Acta 550:
210-221, 2005.
3. Barbosa J, Barron D, Beltran JL, Sanz-Nebot V. PKPOT A
program for the potentiometric study of ionic equilibria
in aqueous and non-aqueous media. Anal Chim Acta 317:
75-81, 1995.
International Symposium on Drug Research & Development 2011
138
DRD 2011
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME
2/3-(BENZOYLAMINO)PROPIONANILIDE DERIVATIVES
Şirin UYSAL1, *, Bayri ERAÇ2, Zeynep SOYER1
1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ege Unıversity, 35100 Bornova, İzmir, Türkiye
Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Ege Unıversity, 35100 Bornova, İzmir, Türkiye
*[email protected]
2
T
he usage of most antimicrobial agents is limited
not only by the rapidly developing drug resistance
but also the increasing resistance of pathogene
organisms and side effects. Therefore, there is still need to
develop new antimicrobial compounds which enhances activity profile. Literature data shows that substituted anilides
have a wide range of bioactivities such as antimicrobial, antifungal, anticonvulsant, anaesthetic, antiproliferative, antiplaque, antiplatelet-aggregation, antioxidant and potassium
channel activating potentials1-3. In this study, based on the
REFERENCES
1. Koehn FE. J Med Chem 51: 2613-2617, 2008.
2. Black MT, Hodgson J. Adv Drug Delivery Rev 57: 15281538, 2005.
3. Narasimhan B, Narang R, Judge V, Ohlan R, Ohlan S.
literature reviews, we aimed to synthesize ten 2/3-(benzoylamino)propionanilide derivatives bearing substituents with
different liphophilic and electronic nature on N-phenyl ring
and the structure of compounds were confirmed by spectral
and elemental analysis. The target compounds were tested
for their antimicrobial activity in vitro against two Gram positive bacteria (Staphylococcus aureus, Enterococcus faecalis)
and two Gram negative bacteria (Escherichia coli, Pseudomonas aeruginosa) by using microdilution method (CLSI)4.
(2007). ARKİVOC XV : 112-126
4. CLSI (Formerly NCCLS) Methods for dilution antimicrobial
susceptibility tests for bacteria that grow aerobically approved standard M7-A6, 6th ed., Vol 23, Wayne, PA: NCCLS,
2003.
International Symposium on Drug Research & Development 2011
139
POSTER PRESENTATIONS
P-084
POSTER PRESENTATIONS
DRD 2011
P-085
SYNTHESIS AND CHARACTERIZATION OF PLATINUM(II) COMPLEXES WITH
IMIDAZOLE AND 2-PHENYLIMIDAZOLE LIGANDS
Semra UTKU1, Çağla BOĞATARKAN1, *, Fatma GÜMÜŞ2
Mersin University, Faculty of Pharmacy, Dept. of Pharmaceutical Chemistry, 33169 Mersin, Türkiye
2
Gazi University, Faculty of Pharmacy, Dept. of Pharmaceutical Chemistry, 06330 Ankara, Türkiye
*
[email protected]
1
Since Rosenberg discovered the antitumor activity of
cisplatin in 1967, cisplatin is the mainstay of treatment for
testicular ovarian, bladder, cervical, small-cell and non-smallcell lung cancer1.
Despite its wide application as a chemotherapeutic
agent, cisplatin exhibits two main disadvantages: intrinsic or
acquired resistance and toxicity. These side effects limit the
use of cisplatin in some cancers. So far, tremendous efforts
have been devoted to developing cisplatin analogues with
broader spectra of activity, improved clinical efficacy, and
reduced toxicity.
The replacement of ammine groups can result in different structural and formational alterations in target DNA,
which may affect the character of biological effects of the
anologues. It has been shown that increasing cytotoxicity of
cisplatin analogues, in which NH3 groups were replaced by
more hydrophobic amine ligands, correlated with growing
hydrophobicity of these analogues2.
REFERENCES
1. Rosenberg B, Van Camp L, Krigas T. Inhibition of cell division in Escherichia coli by electrolysis product from a
platinum electrode. Nature 205: 698-699, 1965.
2. Tallen G, Mock C, Gangopadhyay SB, Kangarloo B, Krebs
B, Wolff JEA. Overcoming cisplatin resistance: Design of
One noteworthy approach in the design of new platinum anticancer drugs is to use physiologically active compounds as ligands. The imidazole ring is a physiologically active ligand, as a histidine moiety, function as ligands toward
transition metal ions in a variety of biologically important
molecules including iron-heme systems, vitamin B12 and its
derivatives and several metalloproteins3.
In this study, four platinum(II) complexes with the structures cis-[PtL2Cl2] and cis-[PtL2I2] (L=imidazole or 2-phenylimidazole as “non-leaving groups) were synthesized and
characterized by their elemental analyses, IR, 1H NMR and
ESI-LC/MS.
novel hydrophobic platinum compounds. Anticancer Res
20: 445-450, 2000.
3. Sundberg R, Martin RB. Interactions of histidine and other
imidazole derivatives with transition metal ions in chemical and biological systems. Chem Rev 74: 471-517, 1974.
International Symposium on Drug Research & Development 2011
140
DRD 2011
QUANTIFICATION OF TRIMETAZIDINE IN HUMAN PLASMA BY LIQUID
CHROMATOGRAPHY-ELECTROSPRAY IONIZATION MASS SPECTROMETRY
Nesrin YÜZÜAK1,*, Sami EREN1, Suna TOPTAN1, Berrak GÜNEY1, Emel D. KURTOĞLU1
, Tuncel ÖZDEN2
1
Novagenix Bioanalytical Drug R&D Centre, Ankara, Türkiye
Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara, Türkiye
*
[email protected]
2
A
rapid liquid chromatography electrospray ionization mass spectrometry (LC/ESI-MS) method with
good sensitivity and specificity has been developed and validated for the quantification of trimetazidine in
human plasma.
Trimetazidine is a anti-ischaemic drug, which protects
the myocardial cell from the harmful effects of ischaemia1,2.
Trimetazidine was used for the treatment of angina pectoris, ischemia in the neurosensorial tissues and Meniere’s disease3.
The sample preparation based on liquid-liquid extraction
with ethyl acetate using 0.2 mL human plasma. Tizanidine
was used as the internal standard. The analytes were chromatographically separated on a Waters Sunfire C18 column,
(2.1 x 50 mm, 3.5µm) with the mobile phase consisting of
methanol, water and formic acid (500:500:1, v/v/v) at a flow
rate of 0.2 mL/min. The calibration curves were linear within
the range of 2.5-250 ng/mL. The limit of quantification (LOQ)
was 2.5 ng/mL. This method was successfully aplied to the
pharmacokinetic study of trimetazidine in healthy volunteers.
REFERENCES
1. Beşikçi OA, Özkan SA. Trimetazidine revisited: A comprehensive review of the pharmacological effects and analytical techniques for the determination of trimetazidine.
Cardiovasc Ther 26(2): 147-165, 2008.
2. Medvedovici A, Albu F, Georgia C, David V. Non-extractive procedure followed by LC/APCI MS/MS analysis of
trimetazidine in plasma samples for assessing bioequivalence of immediate/modified release formulations.
Biomed Chromatogr 19: 549-555, 2005.
3. Zhang T, Meng P, Kou W et al. Rapid and sensitive UPLCMS–MS for the determination of trimetazidine in human
plasma. Chromatogr 71: 1101-1105, 2010.
International Symposium on Drug Research & Development 2011
141
POSTER PRESENTATIONS
P-086
POSTER PRESENTATIONS
DRD 2011
P-087
VOLTAMMETRIC AND IMPEDIMETRIC DETECTION OF INTERACTION
BETWEEN ANTICANCER DRUG DAUNORUBICIN AND DNA
Gülşah ÇONGUR, Ayfer ÇALIŞKAN, Arzum ERDEM*
Ege University, Faculty of Pharmacy, Department of Analytical Chemistry, İzmir, Türkiye
*
[email protected]
T
he investigation on drug–DNA interactions has a
great importance for understanding the mechanism of action of antitumor, antiviral drugs and
some carcinogenic compounds. Therefore, the interactions
of some anticancer drugs with DNA have been studied by a
variety of techniques1-3 including electrochemistry.
Daunorubicin (DNR) is an anthracycline anticancer antibiotic, that it is used for leukemia treatment as chemotherapy
agent. It can destroy Guanine (G) base structure, intercalate
between G and Cytosine (C) bases and damage hydrogen
bonds; therofore it can inhibite nucleic acids synthesis2.
There have been numerous instrumental methods for DNR
determination: such as, high-performance liquid chromatography4, capillary electrophoresis5, optical6 and electrochemical methods8,9.
1.
2.
3.
4.
5.
REFERENCES
Palecek E., Fojta M. Detecting DNA hybridization and
damage. Analytical Chemistry 73: 74A-83A, 2001.
Duan, S, Bleibel WK, Huang RS, Shukla SJ, Wu X, Badner
JA, Dolan ME. Mapping genes that contribute to daunorubicin-induced cytotoxicity. Cancer Res 67: 5425–5433,
2007.
Erdem A. Nanomaterial based electrochemical sensing
strategies. Talanta 74: 318-325, 2007.
Emara S, Morita I.. Simultaneous determination of free
and bound adriamycin, adriamycinol, adriamycinone
and duanorubicin in plasma using column-switching
technique and protein-coated pre-columns. Talanta 41:
1973–1979, 1994.
[5] Simeon N, Chatelut E, Canal P, Nertz M, Couderc F. Anthracycline analysis by capillary electrophoresis: Application to the analysis of daunorubicine in Kaposi sarcoma
tumor. J Chromatogr A 853: 449-455, 1999.
In this study, differential pulse voltammetry (DPV) and
electrochemical impedance spectoscopy (EIS) methods
were used for monitoring of interaction between DNR and
double stranded DNA both electrode surface and also in the
solution phase. The interaction of DNR with DNA was investigated voltammetrically by monitoring the changes at the
oxidation signals of DNR and guanine. Effect of experimental
parameters such as DNR concentration, DNA concentration
and DNR-DNA interaction time were studied based on the
sensor response by using DPV technique. Before and after
interaction process, the charge transfer resistance (Rct) obtained at the electrode surface was measured by EIS technique
under these optimum conditions.
Acknowledgements: A.E would like to express her gratitude to the Turkish Academy of Sciences (TUBA) as the associate member of TUBA for their support.
6. Gavenda A, Sevcik J, Psotova J, Bednar P, Bartak P, Adamovsky P, Simanek V. Determination of anthracycline
antibiotics doxorubicin and daunorubicin by capillary
electrophoresis with UV absorption detection. Electrophoresis 22: 2782-2785, 2001.
7. Hu Q, Zhang L, Zhou, T, Fang Y. Determination of daunorubicin in human urine by capillary zone electrophoresis
with amperometric detection. Anal. Chim. Acta 416: 1519, 2000.
8. Erdem A, Karadeniz H, Çalışkan A. Single-walled carbon
nanotubes modified graphite electrodes for electrochemical monitoring of nucleic acids and biomolecular
interactions. Electroanalysis 21: 464-471, 2009.
9. Erdem A, Karadeniz H, Çalışkan A. Dendrimer modified
graphite sensors for detection of anticancer drug daunorubicin by voltammetry and electrochemical impedance
spectroscopy. Analyst 136: 1041-1045, 2011.
International Symposium on Drug Research & Development 2011
142
DRD 2011
CARBON NANOTUBE-BIOPOLYMER COMPOSITE MODIFIED ELECTRODES
FOR ELECTROCHEMICAL MONITORING OF INTERACTION BETWEEN
MITOMYCIN C AND DNA
Pembe Ece CANAVAR, Arzum ERDEM*
Ege University, Faculty of Pharmacy, Analytical Chemistry Department, İzmir, Türkiye
*
[email protected]
D
NA biosensors play an important role in the new
generation sensor technology with a wide range
of application areas. These biosensors has recognition surfaces which are formed of nucleic acid sequences,
detect target based on nucleic acid hybridization which allows high selectivity in the analysis. Recently, in nucleic acid
analysis, electrochemical DNA biosensors have become
popular with their practicality, reliability, high sensitivity,
fastness and economy1-4.
In our study, carbon nanotube-biopolymer composite
electrode was developed for electrochemical monitoring of
interaction between MC and DNA by using differential pulse
voltammetry (DPV) and electrochemical impedance spectroscopy (EIS) techniques.
Today nanomaterials in different properties have been
still under development4-8, can be combined with classic
sensor technology. Especially composite structure formed
by carbon nanotubes and various polymers can be used for
the modification of the sensor surface4.
Mitomycin C
Mitomycin C (MC) an antitumor agent and anticancer antibiotic drug, which was isolated from Streptomyces caespitosus
used in the anticancer chemotherapy against a broad spectrum of solid tumors, especially for gastrointestinal cancers.
1.
2.
3.
4.
5.
REFERENCES
Palecek E, Fojta M. Detecting DNA hybridization and
damage. Analytical Chemistry 73: 74A-83A, 2001.
Jelen F, Erdem A, Palecek E. Cyclic voltammetry of echinomycin and its interaction with double-stranded and
single-stranded DNA adsorbed at the electrode. Bioelectrochemistry 55: 165-167, 2002.
Erdem A. Nanometarial based electrochemical DNA sensing strategies. Talanta 74: 318-325, 2007.
Wang J. Carbon-nanotube based electrochemical biosensors. Electroanalysis 17: 7-14, 2005.
Erdem A, Papakonstantinou P, Murphy H. Direct DNA Hybridization at Disposable Graphite Electrodes Modified
with Carbon Nanotubes. Analytical Chemistry 78: 66566659, 2006.
Acknowledgements: A.E would like to express her gratitude to the Turkish Academy of Sciences (TUBA) as the associate member of TUBA for their support.
6. Erdem A, Karadeniz H, Çalışkan A. Single walled carbon
nanotubes modified graphite electrodes for electrochemical monitoring of nucleic acids and biomoleculer
interactions. Electroanalysis 21: 464-471, 2009.
7. Çalışkan A, Karadeniz H, Erdem A. Direct DNA hybridization on the single-walled carbon nanotubes modified
sensors detected by voltammetry and electrochemical
impedance spectroscopy. Electroanalysis 21: 2116-2124,
2009.
8. Erdem A, Papakonstantinou P, Murphy H, Mcmullan M,
Karadeniz H. Streptavidin modified carbon nanotube
based graphite electrode for label-free sequence specific
DNA detection. Electroanalysis 22: 611-617, 2010.
International Symposium on Drug Research & Development 2011
143
POSTER PRESENTATIONS
P-088
POSTER PRESENTATIONS
DRD 2011
P-089
MAGNETIC-BEAD ASSAY FOR MONITORING OF DNA HYBRIDIZATION
USING ANTITUMOR DRUG ECHINOMYCIN AS AN ELECTROCHEMICAL
INDICATOR
Hakan KARADENİZ, Arzum ERDEM*
Ege University, Faculty of Pharmacy, Analytical Chemistry Department, 35100 Bornova, İzmir, Türkiye
*[email protected]
D
NA hybridization biosensors can be employed for
determining early diagnoses of infectious agents
in various environments1,2 and these devices can
be exploited for monitoring sequence-specific hybridization
events directly3-4 based on the oxidation signal of guanine/
adenine or using DNA intercalators (some antibiotics, metal
coordination complexes, etc.) which form complexes with
the nitrogenous bases of DNA5,6.
The electrochemical nucleic acid sensor system based
on magnetic particles4,6-10 as labeling with an enzyme7 or using label free system4,9-10 or combining with metal nanoparticles8, brings the sequence spesific detection of DNA hybridization observed in exceedingly low detection limits as
resulting in efficient magnetic separation.
Echinomycin (ECHI) represents one of the quinoxaline
antibiotics which has antitumor activity11. The mechanism of
ECHI interaction with dsDNA was described as bisintercalation. It can bind to the minor groove of DNA duplex showing
strong preference for the CpG sequence11.
In our study, an indicator-based and indicator-free magnetic assays connected with a disposable graphite sensor,
were successfully developed for the electrochemical detection of DNA hybridization. The changes at the oxidation
signals of indicator, ECHI and electroactive DNA bases; guanine and adenine were monitored in the presence of DNA
hybridization by using differential pulse voltammetry (DPV)
technique. The selectivity of these magnetic assays for DNA
hybridization was also investigated in the presence of single
base mismatch and noncomplementary DNA sequences.
Acknowledgements: A.E would like to express her gratitude to the Turkish Academy of Sciences (TUBA) as the associate member of TUBA for their support.
REFERENCES
1. Wang J. Survey and summary: From DNA biosensors to
gene chips. Nucl Acids Res 28: 3011-3016 , 2000.
2. Palecek E, Fojta M. DNA hybridization and damage. Anal.
Chem 73: 75A-83A, 2000.
3. Erdem A, Pividori MI, Del Vale M, Alegret S. Rigid carbon composites: A new transducing material for label-free electrochemical genosensing. J Electroanal Chem 567: 29-37, 2004.
4. Wang J, Kawde AN, Erdem A, Salazar M. Magnetic-beads
based label-free electrochemical detection of DNA hybridization. Analyst 126: 2020-2024, 2001.
5. Jelen F, Erdem A, Palecek E. Cyclic voltammetry of Echinomycin and its interacion with double-stranded and
single-stranded DNA adsorbed at the electrode. Bioelectrochem 55: 165-167, 2002.
6. Karadeniz H, Erdem A, Kuralay F, Jelen F. Indicator-based
and indicator-free magnetic assays connected with disposable electrochemical nucleic acid sensor system. Talanta 78: 187-192, 2009.
7. Wang J, Xu DK, Erdem A, Polsky R, Salazar MA. Genomagnetic electrochemical assays of DNA hybridization. Talanta 56: 931-938, 2002.
8. Wang J, Liu GD, Merkoci A. Particle-based detection of DNA
hybridization using electrochemical stripping measurements of an iron tracer. Anal Chim Acta 482: 149-155, 2003.
9. Erdem A, Ariksoysal, Karadeniz H, Kara P, Şengönül A, Sayıner AA, Özsöz M. Electrochemical genomagnetic assay
for the detection of Hepatitis B virus DNA in polymerase
chain amplicons by using disposable sensor technology.
Electrochem Commun 7: 815-820, 2005.
10.Erdem A, Pividori MI, Lermo A, Bonanni A, Del Valle M, Alegret S. Genomagnetic assay based on label-free electrochemical detection using magneto-composite electrodes.
Sensors and Actuators B-Chemistry 114: 591-598, 2006.
11.Waring MJ, Wakelin LP. Echinomycin: A bifunctional intercalating antibiotic. Nature 252: 653-657, 1974.
International Symposium on Drug Research & Development 2011
144
DRD 2011
TAMOXIFEN SUPPRESS FOLLICULAR DEVELOPMENT AND
DIFFERENTIATION IN FETAL MICE OVARY
R. PIRI1, M. KARIMI SHOAR1,*, H. MAZUOCHIAN1, L. ROUSHANGAR2, J. SOLEIMANI RAD2,
K. AFSORDEH2
1
Medical student, Student Research Committee, Faculty of Medicine, Tabriz University of Medical Sciences, Iran
Neuroscience Research Center and Department of Histology and Embryology, Faculty of Medicine, Tabriz University
of Medical Sciences, Iran
*
[email protected]
2
F
ollicular nests is an early stage of follicular development which is not hormone dependent. Mechanisms regulating the development of primordial
follicles and their transition to primary follicles are not well
established. The aim of this study is to investigate if maternal
treatment with tamoxifen, a drug which binds to estrogen
receptors and is used for induction of ovulation and cancer
treatment, has any effect on fetal follicular development.
In this study 30 adult female and 15 adult male mice are
used. The female mice are divided into two groups of control and experimental. Two female mice at their estrous cycle
were put with one male mouse in a cage for mating. Observation of vaginal plaque was considered as the first day of
pregnancy and the mice on 13th day of pregnancy received
100µgr Tamoxifen as ip injection. After delivery, 2, 3, 6 and
7 days old new borns were sacrificed and their ovaries were
fixed and prepared for light microscopic studies. In the secREFERENCES
1. Text sources: EBSCO, Ingenta plc, OhioLINK Electronic Journal Center
tions, the number of follicular nests, primordial and primary
follicles were counted and compared with control values using t-test. Morphometry and microscopy revealed that on
2nd and 3rd days, the follicular nests appeared as clusters
of somatic or pre-granulosa cells surrounding oocytes. The
number of follicular nests was significantly (p< 0.001) higher in experimental group in comparison to control group
(20±1.49 vs 28.8±1.25) indicating suppression of follicular
development in tamoxifen treated group. On the 6th and
7th days old infants, the number of primary multilayered follicles were significantly (p<0.01) lower than those in control
group 50.85±3.07 vs 62.88±3.33. However, most of the follicles were in monolayer primary follicle state.
It is concluded that tamoxifen suppresses follicular differentiation and development at early stages of folliculogenesis which could result in depletion of ovarian reserve in
adulthood1,2.
2. Medical sources: Health Problems in PregnancyMedlineplus Health Information
International Symposium on Drug Research & Development 2011
145
POSTER PRESENTATIONS
P-090
POSTER PRESENTATIONS
DRD 2011
P-091
SYNTHESIS OF SOME NEW NAFIMIDONE OXIME ESTER DERIVATIVES AND
THEIR ANTICONVULSANT ACTIVITIES
Mehmet Abdullah ALAGÖZ1, Arzu KARAKURT1, Ünsal ÇALIŞ2, Sevim DALKARA2
1
İnönü University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 44280 Malatya, Türkiye
Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06100 Ankara, Türkiye
2
E
pilepsy is one of the most common neurological
diseases and affects a large number of the world’s
population. Antiepileptic drug therapy is symptomatic and none of the antiepileptic drugs in the market is ideal
since most of them have many undesirable side effects and
moreover some type of the seizures cannot be controlled by
these drugs1. Therefore to develop new anticonvulsant agents
is still popular. (Arylalkyl)imidazoles is a group of anticonvulsant drugs and nafimidone is one of the representatives of this
O
O
CH3
O
HN
CH2Br
Br2
For this purpose three new oxime ester derivatives of nafimidone were synthesized by esterification of nafimidone
oxime. Structures of these compounds were confirmed by
IR, 1H-NMR MASS and elementary analysis data. Their anticonvulsant activities were determined by maximal electroshock seizure (MES) and subcutaneous metrazole seizure
(ScM) tests in mice ip and neurotoxicity of the compounds
was evaluated by rotord test according to ASP4.
CH2
N
N
NH2OH.HCl
N
O
R= -CH2CH3 (1a)
R
O
OH
N
N
N
N
N
N
R= -CH(CH2CH2CH3)2 (1b)
DCC/DMAP
R=
R-COOH
group2. There are many articles in the literature about the SARs
of this group and the structural requirements for the activity.
In the recent years, it has been reported that nafimidon oxime
ethers also showed remarkable anticonvulsant activity3.
(1c )
We found that all of the oxime ester derivatives of nafimidone have anticonvulsant activities aganist MES and/or ScM
seizures and none of the compounds showed neurotoxicity
in rotorod test. These activities were found to be comparable
to the oxime ethers3.
Therefore, in this study, we aimed to prepare some oxime
esters and to test their anticonvulsant activities to establish
new SARs and to obtain new anticonvulsant compounds.
Acknowledgement: This Project was supported by TUBITAK (Project No: 11S270).
REFERENCES
1. Malawska B. New anticonvulsant agents. Curr Top Med
Chem 5: 69-85, 2005
2. Walker KAM, Wallach MB, Hirschfeld DR. 1-(Naphthylalkyl)1H-imidazole derivatives, a new class of anticonvulsant
agents. J Med Chem 24: 67-74, 1981.
3. Karakurt A, Dalkara S, Özalp M, Kendi E, Stables JP. Synthesis of some 1-(2-naphyl)-2-(imidazole-1yl)etanon oxime and oxime ether derivatives and their anticonvulsant
and antimicrobial activities. Eur J Med Chem. 36: 421-433,
2001.
4. Stables JP, Kupferberg HJ. The NIH anticonvulsant drug
development (ADD) program: preclinical anticonvulsant
screening project, in: molecular and cellular targets for
antiepileptic drugs, Avanzini G, Tanganelli P, Avoli M.
(Eds.), London, England: John Libbey & Company Ltd;
1997.
International Symposium on Drug Research & Development 2011
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DRD 2011
SYNTHESIS AND CHARACTERIZATION OF SOME NOVEL
3,6-DISUBSTITUTED 1,2,4-TRIAZOLO[3,4-b]-1,3,4-THIADIAZINES
S. Peri AYTAÇ, Birsen TOZKOPARAN*
Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06100 Sıhhiye, Ankara, Türkiye
*[email protected]
F
or treatment of inflammatory and rheumatic diseases, nonsteroidal anti-inflammatory drugs
(NSAIDs) are still considered as the first choice
among the various pharmacological groups. However, their gastrointestinal-focused adverse effects and renal toxicity
risks are limiting their therapeutic usefulness. In this regard,
development of safer agents are still a necessity.
Almost twenty years, on the purpose of developing novel
compounds carrying analgesic/anti-inflammatory activity, we
have focused on mercaptotriazoles and their condensed heterocyclic derivatives. On the basis of our preliminary studies
showing that some 3,6-disubstituted-7H-1,2,4-triazolo[3,4-b]1,3,4-thiadiazine derivatives had potent anti-inflammatory/
analgesic activities besides negligible ulcer risk in the stomach, we have planned some further structural modifications.
Herein we describe the synthesis of novel 3,6-disubstituted7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine derivatives with possible anti-inflammatory/analgesic activity.
Titled compounds have been synthesized by reacting
4-amino-1,2,4-triazole-5-thiones with appropriate phenacyl
bromides (or chlorides) in anhydrous ethanol under reflux
and chemical structures of the compounds were confirmed
by spectral data.
N
CH 3
O(CH 2) n
N N
NH
N
S
CH 3
1,2
R : -H, -F, -Cl
n: 1, 2
N
S
N
NH 2
International Symposium on Drug Research & Development 2011
147
O(CH 2) n
1a-2c
R
POSTER PRESENTATIONS
P-092
POSTER PRESENTATIONS
DRD 2011
P-093
ANTIPROLIFERATIVE AND APOPTOTIC EFFECTS OF HYPERICUM
PERFORATUM ON PEDIATRIC SARCOMA CELLS
Mehtap KILIÇ EREN1, Özlem ÖZ2,*, Leyla Didem KOZACI3, Mustafa BİRİNCİOĞLU2
1Adnan Menderes University, Faculty of Medicine, 1Department of Medical Biology,
2Department of Medical Pharmacology,
3 Department of Medical Biochemistry, 09100 Aytepe Campus, Aydın, Türkiye
*[email protected]
S
t. John’s wort (Hypericum perforatum L.) is a medicinal plant that has been used to treat respiratory and
inflammatory diseases, peptic ulcers, skin wounds
and psychiatric disorders for centuries1. In recent years the
effects of H. perforatum on various cancer types have been
the centre of interest. H. perforatum contains a number of
constituents such as naphthodianthrones (hypericin), phloroglucinols (hyperforin), proanthocyanidins, xanthones and
hypericin (HY) and flavonoids (quercetin) with a broad range
of anti-tumour activities1.
lyze the inhibitory effects of Hypericum perforatum L. extract
on the growth of pediatric sarcoma cell lines such as A204
(rhabdomyosarcoma) and A673 (Ewing’s sarcoma), which are
wild type and p53 deficient, respectively2.
Cell viability was determined by trypan blue test. Cell
proliferation/ metabolic activity was measured using the
tetrazolium-based assay WST-1, while cytotoxicity was assessed with the LDH (lactate dehydrogenase) release test.
Apoptosis was measured by TUNEL (terminal deoxynucleotidyl transferase-mediated dUDP nick-end labeling) assay.
Sarcomas represent 20% of pediatric malignancies and
5% of all neoplasms in adults. Rhabdomyosarcoma (RMS)
is among the most common malignancies of the childhood
and adolescence and accounts for 5% of all malignant tumors in patients under 15 years of age. Ewing’s sarcoma (ES),
the second most common primary bone malignancy is the
most lethal form of bone cancer observed in children. Both
in RMS and ES, despite aggressive approaches incorporating surgery, dose intensive combination chemotherapy, and
radiation therapy, the outcome for patients with metastatic
disease remains still poor. Therefore, novel therapeutic strategies are in require for improving the treatment efficiency
in both RMS and ES. Hence, in this work we aimed to ana-
Here, we report for the first time that H. perforatum
showed cytotoxicity on both A204 and A673 cells in a time
and dose dependent manner. H. perforatum inhibited the
growth of A204 cells with IC50 value (half-maximal inhibitory concentrations) of 10±2,5 µg/ml. Whereas it showed less
inhibitory effect on A673 cell line with IC50 value of 50±16
µg/ml. Apoptosis, as an underlying mechanism of this cytoxocity was shown in both cell lines that have been tested
after incubation with IC50 dose of H. perforatum. Our results
suggest H. perforatum as a potential anticancer agent which
might be utilized for the development of future treatment
strategies in RMS and ES.
REFERENCES
1. Medina MA, Martínez-Poveda B, Amores-Sánchez MI,
Quesada AR. Hyperforin: More than an antidepressant
bioactive compound? Life Sciences 79: 105–111, 2006.
2. Kılıç M, Kasperczyk H, Fulda S, Debatin K-M. Role of hypoxia inducible factor-1a in modulation of apoptosis resistance. Oncogene 26 (14): 2027-2038, 2007.
International Symposium on Drug Research & Development 2011
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DRD 2011
MONOAMINE OXIDASE INHIBITORY EFFECT OF NEWLY SYNTHESIZED
PYRAZOLOTHIAZOLES DERİVATİVES
Umut SALGIN GÖKŞEN1, Nesrin GÖKHAN KELEKÇİ1, *, Gülberk UÇAR2
Department of Pharmaceutical Chemistry, 2Department of Biochemistry, Faculty of Pharmacy, Hacettepe University,
06100 Sıhhiye, Ankara, Türkiye
*
[email protected]
1
P
yrazolines are well known and important nitrogen containing five membered heterocyclic compounds. Several pyrazoline derivatives have been
found to possess considerable biological activities which
stimulated research activities in this field1. Their prominent
effects are e.g., antibacterial, antifungal, antiinflamatory, analgesic, hypotensive and antidepressant activities2-4.
Therefore, it is tempting to develop new MAO inhibitor
agents, a hybrid molecules containing both pyrazole and thiazole moieties. 1-[4-(4-Substituted)phenyl-2-thiazolyl]-3-(4-substituted)phenyl-5-(2-furyl)-4,5-dihydro-(1H)-pyrazole derivatives were cyclized using phenacyl bromides to afford the novel
pyrazolothiazoles. The structures of the compounds were indicated by IR, 1H-NMR, mass and elementary analysis. In order to
obtain information about the stereochemistry of the molecules
and to confirm the assigned structure, X-ray analyses were undertaken9. All the synthesized compounds were investigated
for their ability to selectively inhibit MAO isoforms by in-vitro
tests. All the compounds were found to inhibit rat liver MAO-B
selectively and reversibly in a competitive manner.
On the other hand, the nitrogen and sulfur heterocyclic
systems are very interesting because of their physicochemical properties with relevance to the design of new drugs and
new materials. In that respect, compounds containing the
thiazole ring system are known to possess pharmacological properties such as tuberculostatic, antimicrobial, antiinAcknowledgment
flamatory, analgesic and antibacterial activities5-7. Literature
*
This study was supported by the
survey reveals 2-aminothiazole derivatives as the potential
Hacettepe University Research Fund
inhibitors of cdk5/p25 for the treatment of Alzheimer’s dis(Project Number: 010D03301003).
ease and other neurodegenerative disorders8. REFERENCES
1. Levai A. Synthesis of chlorinated 3,5-diaryl-2-pyrazolines 6. Kaplancıklı ZA, Turan-Zitouni G, Özdemir A, Revial G,
by the reaction of chlorochalcones with hydrazines.
Güven K. Synthesis and antimicrobial activity of some
Arkivoc IX: 344-352, 2005.
thiazolyl-pyrazoline derivatives. Phosphorus, Sulfur, Sili2. Kini S, Gandhi AM. Novel 2-pyrazoline derivatives as potencon Relat Elem 182: 749-764, 2007.
tial antibacterial and antifungal agents. Indian J Pharm Sci 7. Nasr MNA, Said SA. Novel 3,3a,4,5,6,7-hexahydroindazole
70: 102-105, 2008.
and arylthiazolylpyrazoline derivatives as anti-inflammatory
3. Gökhan-Kelekçi N, Yabanoğlu S, Küpeli E, Salgın U, et al. A new
agents. Arch Pharm Pharm Med Chem 336: 551-559, 2003.
therapeutic approach in Alzheimer disease: Some novel pyr- 8. Shiradkar MR, Akula KC, et al. Clubbed thiazoles by MAOS:
azole derivatives as dual MAO-B inhibitors and antiinflammaA novel approach to cyclin-dependent kinase 5/p25 intory analgesics. Bioorg Med Chem 15: 5775-5786, 2007.
hibitors as a potential treatment for Alzheimer’s disease.
4. Turan-Zitounia G, Chevallet P, Kiliç FS, Erol K. Synthesis of some
Bioorg Med Chem 15: 2601-2610, 2007.
thiazolyl-pyrazoline derivatives and preliminary investigation 9. Şahin ZS, Işık Ş, Salgın-Gökşen U, Gökhan-Kelekçi N.
of their hypotensive activity. Eur J Med Chem 35: 635-641, 2000.
Syntheses and structural characterization of 1-(4-phe5. Nosova EV, Kravchenko MA, Lipunova GN, et al. Synthenyl-2-thiazolyl)-3-(4-methylphenyl)-5-(2-furyl)-4,5-disis and antituberculous activity of fluorinated 3-R-hydrahydro-(1H)-pyrazole and 1-(4-(4-fluoro)phenyl-2-thiazolyl)zino-2-benzoylacrylates and their cyclization products.
3-(4-methylphenyl)-5-(2-furyl)-4,5-dihydro-(1H)-pyrazole.
Pharm Chem J 36: 585-587, 2002.
Chinese J Struct Chem 29(5): 700-705, 2010.
International Symposium on Drug Research & Development 2011
149
POSTER PRESENTATIONS
P-094
POSTER PRESENTATIONS
DRD 2011
P-095
EVALUATION OF A NEW ANTHELMENTIC COMBINATION EFFICACY ON
PREVALENT GASTROINTESTINAL/PULMONARY NEMATODES OF SMALL
RUMINANTS IN URMIA, IRAN
Mohammad SADAGHIAN1,*, Sohrab RASOULI2
1
Department of Pathobiology, Faculty of Veterinary Medicine, Shabestar Branch, Islamic Azad University , Shabestar, Iran
2
Department of Pathobiology, Faculty of Veterinary Medicine, Urmia Branch, Islamic Azad University , Urmia, Iran
*
[email protected]
S
mall ruminants make a significant contribution to
food security and income of many resource-poor
families in most developing countries. However,
the main constraint to production of small ruminants in the
developing countries is gastrointestinal/ pulmonary parasites, particularly nematodes1.From some decades ago; anthelmintic (AH) drugs have represented the cornerstone of
control for these parasites. However, considering the phenomenon of AH resistance has shown a constant development, it is necessary to formulate new combination in efficient doses to minimize AH resistance in different areas’
parasitic populations2. The present study was conducted to
evaluate the effects of Felonil® (37.5 mg Levamisole HCl and
50 mg Triclabendazole/ml) against gastrointestinal/ pulmonary (GIN/P) nematodes of small ruminants in Urmia surroundings, northwest of Iran.
One thousand free grazing sheep and goats of both
sexes aged above 4 month were primarily subjected to
faecal egg/ larva count using Mc master and Baerman
technique3 then 100 naturally heavily infected sheep
and goats were selected for the study and were divided
into two equal groups. Then group A were drenched
1ml/5 kg BW of Felonil® whereas group B received equal
amounts of normal saline as placebo. Faecal samples
were taken directly from rectum at 1st, 3rd, 7th and
14th day post-treatment from each group subjects.
Nematodes egg/larva per gram of faeces (EPG/LPG)
was examined using mentioned techniques. Also, at
the end of period, 5 animals from each group were necropsied to investigate GIN/P nematodes.
The effect of treatment on GIN/ P nematodes EPG/ LPG
was observed from first day and there was significant decrease in EPG/ LPG levels of different sampling sessions up
to the end of study (P<0/05). The results showed that administration of the dose recommended by manufacturer
company, has 100% efficacy against pulmonary nematodes whereas 97% about GIN nematodes and it is necessary to elevate the dose to cover 100% efficacy against
all economic important nematodes and avoid low dose
administration AH resistance rule.
REFERENCES
1. Max RA. Effect of repeated wattle tannin drenches 2. Torres-Acosta JFJ. and Hoste H. Alternative or improved methods to limit gastro-intestinal parasiton worm burdens, faecal egg counts and egg hatchism
in grazing sheep and goats. Small Ruminants
ability during naturally acquired nematode infecResearch 77:159-173, 2008.
tions in sheep and goats. Vet Parasitology 169: 1383. Urquhart GM. and others. Veterinary Parasitology.
143, 2010.
2nd ed., United Kingdom: Blackwell Publishing, 2003,
p. 276-281.
International Symposium on Drug Research & Development 2011
150
DRD 2011
HPLC Method development and valIdatIon: Sımultaneous
determınatıon of phenolıc acıds ın fruıt juıcES
Tuğba İDUĞ, Ebru BÜYÜKTUNCEL*
İnönü University, Faculty of Pharmacy, Department of Analytical Chemistry, 44280 Malatya, Türkiye
*
[email protected]
perature. 5mM KH2PO4 adjusted to pH 3.5 with orthophosphoric acid. Analysis was run at a flow rate of 1
mL.min-1 with a 33 min run time at ambient temperature
(Figure 1). The injection volume was 20 µL. The dedector was
set at 215, 254, 280 and 323 nm. The resolution values
for separation of phenolic acids were higher than 1.5.
DAD1 A, Sig=280,4 Ref=360,100 (TEST\17031100.D)
The separation was achieved on a C18 column with
a mobile phase of 5 mM KH2PO4 solution (pH 3.5) - acetonitrile (92:8) under isocratic conditions at room temREFERENCES
1. Amakura Y, et al. Determination of phenolic acids in
fruit juices by isocratic column liquid chromatography. Journal of Chromatography A 891(1): 183-188,
2000.
2. Saraji M, Mousavi F. Use of hollow fibre-based liquidliquid-liquid microextraction and high-performance
liquid chromatography-diode array detection for
the determination of phenolic acids in fruit juices.
Food Chemistry 123(4): 1310-1317, 2010.
3. Halliwell B. Dietary polyphenols: Good, bad, or indifferent for your health? Cardiovascular Research
73(2): 341-347, 2007.
40
20
0
0
5
10
15
20
25
ferulic acid acid
60
p-coumaric acid
acid
A reversed-phase high performance liquid chromatographic method was improved for simultaneous determination of phenolic acids (gallic acid, 3,4-dihydroxy benzoic
acid, p-hydroxy benzoic acid, chlorogenic acid, vanillic acid,
caffeic acid, syringic acid, p-coumaric acid and ferulic acid)
in fruit juices. 2,5-dihydroxy benzaldehyde was used as an
internal standard.
vanillic acid
caffeic acid
syringic acid
acid
80
p-hydroxy benzoic acid
Gallic acid
100
chlorogenic acid
mAU
3,4-dihydroxy benzoic acid
P
henolic acids are widely distrubuted in the plant
kingdom and are present in, e.g. tea, red wine,
fruits, beverages and various medicinal plants1.
Phenolic acids include hydroxycinnamic acids and hydroxybenzoic acids2. They are bioactive compounds participate in
diary diet and influence health. They are antioxidant, antitumor, antimutagenic, and antibacterial3-5. Moreover, phenolic
acids can inhibit DNA damage6.
30
min
Figure 1. HPLC chromatogram of phenolic acids at 280
nm.
The optimized chromatographic method was carefully validated for precision and accuracy. Consequently, the described method will be employed to determine phenolic compounds in fruit juices.
4. Küpeli E, et al. Phenolic compounds of Sideritis ozturkii and their in vivo anti-inflammatory and antinociceptive activities. Journal of Ethnopharmacology 112(2): 356-360, 2007.
5. Vaquero MJR, Alberto MR, Manca de Nadra MC. Influence of phenolic compounds from wines on the
growth of Listeria monocytogenes. Food Control
18(5): 587-593, 2007.
6. Kasai H, et al. Action of chlorogenic acid in vegetables and fruits as an inhibitor of 8-hydroxydeoxyguanosine formation in vitro and in a rat carcinogenesis model. Food and Chemical Toxicology 38(5):
467-471, 2000.
International Symposium on Drug Research & Development 2011
151
POSTER PRESENTATIONS
P-096
POSTER PRESENTATIONS
DRD 2011
P-097
CHARACTERIZATION OF FENOFIBRATE NANOPARTICLES FOR ORAL DRUG
DELIVERY
Emre TÜRELİ1,2,*, Bernd BAUMSTÜMMLER1, Peter LANGGUTH2
1
MJR PharmJet GmbH, 66424 Homburg, Germany
Johannes Gutenberg University, Faculty of Pharmacy, Dept. of Biopharmaceutics and Pharmaceutical Technology 55099 Mainz,
Germany
*
[email protected]
2
P
article size is the parameter that determines behaviour and bio-distribution of nanoparticles in physiological conditions. Thus, the use of classified particles is a prerequisite for drug delivery to a specific target[1-2].
Production of such nanoparticles for drug targeting requires
simple and efficient methods yielding narrow size distributions within specified limits. In this study a novel method
MicroJet reactor technology was used for the preparation of
nanoparticles[4].
The objective of the study was to compare dissolution
profiles, in-vitro mucoadhesiveness and caco-2 permeability
profiles of different nanoparticle formulations of fenofibrate.
Three different formulations were prepared including fenofibrate nanoparticles (FN) with poloxamer 407 as stabilizer,
HPMCP/Fenofibrate nanoparticles (FHN) and HPMCP/Chito-
san/Fenofibrate nanoparticles (FHCN). Dissolution profiles of
nanoparticle formulations were compared in different dissolution media such as SIF, SGF, Fessif, Fassif. Although the presence of chitosan in FHCN formulation slowed the release of
fenofibrate from nanoparticles, dissolution was completed
for every formulation within first 10 minutes regardless of the
buffer used. Furthermore for nanoparticle formulations there
was no significant difference between fessif and fassif dissolution profiles whereas in the case of fenofibrate powder, the
amount released was approximately 4 times higher in fessif.
According to the in-vitro mucoadhesiveness studies, the only
formulation that was attached to mucin was the FHCN due to
the high chitosan content and positive ZETA potential. This
was also reflected to the Caco-2 permeation studies where the
amount of fenofibrate absorbed for FHCN was significantly
higher than the other nanoparticle formulations.
REFERENCES
1. Lipinski CA. Drug-like properties and the causes of poor
solubility and poor permeability. Journal of Pharmacological and Toxicological Methods 44(1): 235-249, 2000.
2. Merisko-Liversidge, E.M. and G.G. Liversidge. Drug
nanoparticles: Formulating poorly water-soluble compounds. Toxicologic Pathology 36(1): 43-48, 2008.
3. Türeli AE, Penth B, Langguth P, Baumstümmler B, inventors; MJR PharmJet GmbH assignee. Device and method
for producing pharmaceutically highly refined particles
and for coating said particles in microjet reactors. PCT/
DE2010/075015 2010 Feb. 11
International Symposium on Drug Research & Development 2011
152
DRD 2011
PYRAZOLINE-BASED MYCOBACTIN ANALOGUES AS DUAL INHIBITORS OF
MAO/CHOLINESTERASE
Samiye YABANOĞLU ÇİFTÇİ1, Bercis İmge UÇAR2, Venkatesan JAYAPRAKASH3, Barij N. SINHA3,
Gülberk UÇAR1,*
Hacettepe University, Faculty of Pharmacy, Dept. of Biochemistry, 06100 Ankara, Türkiye
2
Başkent University, Faculty of Medicine, 16. Sok No:11, Bahçelievler, Ankara, Türkiye
3
Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, 835215, India
*
[email protected]
1
S
ince design strategy and advantages of dual inhibitors in neurodegenerative disorders have been reviewed1,2, in the present work the acetylcholine esterase (AChE) and butrylcholine esterase (BuChE) inhibitory
activities of the thirty two 3,5-diaryl-2-pyrazoline-1-thiocarbamoyl derivatives which were synthesized as analogues of
Mycobactin and evaluated as potent MAO inhibitors3 were
determined. Each compound was evaluated for its ability to
REFERENCES
1. Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti
V,Recanatini M, Melchiorre C. (2008) Multi-target-directed ligands to combat neurodegenerative diseases. J Med
Chem 51(3): 347-72, 2008.
2. Uçar G, Gökhan N, Yeşilada A, Bilgin AA. 1-N-Substituted
thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazolines: a novel
cholinesterase and selective monoamine oxidase B inhibitors for the treatment of Parkinson’s and Alzheimer’s
inhibit human AChE and BuChE using Ellman’s spectrophotometric method [4]. All the compounds inhibited AChE and
BuChE at nM to low μM concentration. Compounds c1-c7
were highly selective towards AChE, c3, c5-7 being mixedtype reversible and the rest being non-competitive irreversible. Compounds c12-17 were highly selective towards BuChE, c12, c14-17 being mixed-type reversible and c13 being
noncompetitive irreversible.
diseases. Neurosci Lett 382(3): 327-31, 2005.
3. Jayaprakash V, Sinha BN, Ucar G, Ercan A. Pyrazolinebased
mycobactin analogues as MAO-inhibitors. Bioorg Med
Chem Lett 18(24): 6362-68, 2008.
4. Ellman GL, Courtney KD, Andres Jr. V, Featherstone RM. A
new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7(2): 88-95, 1961.
International Symposium on Drug Research & Development 2011
153
POSTER PRESENTATIONS
P-098
POSTER PRESENTATIONS
DRD 2011
P-099
INVESTIGATION OF THE PROTECTIVE EFFECT OF SODIUM NITRITE ON
INFLAMMATORY PROCESSES ACTIVATED DURING HEPATIC ISCHEMIAREPERFUSION (I/R) INJURY IN MOUSE HEPATIC I/R MODEL
Bercis İmge UÇAR1, Açelya YALOVAÇ ASLAN2, Samiye YABANOĞLU ÇİFTÇİ2, Bülent GÜMÜŞEL3,
Gülberk UÇAR2,*
Başkent University, Faculty of Medicine, 16. Sok No:11, Bahçelievler, Ankara, Türkiye
Hacettepe University, Faculty of Pharmacy, Dept. of Biochemistry, 06100 Ankara, Türkiye
3
Hacettepe University, Faculty of Pharmacy, Dept. of Pharmacology, 06100 Ankara, Türkiye
*
[email protected]
1
2
H
epatic ischemia-reperfusion (I/R) injury is a major
complication associated with liver transplantation and resectional surgery. The purpose of the
present study was to investigate the possible protective effects of nitrite administrated in different concentrations and
time periods on the inflammatory processes activated during I/R in mouse hepatic I/R model. After 45 minutes ischemia and 5 hours reperfusion period performed on 8-10 week
and 25-30 g mice, blood and tissue samples were collected.
Groups were arranged consist of 6 mice as control, sham, I/R
protocol (45 minutes ischemia and 5 hours reperfusion) and
study groups administrated with 4 different concentrations
(1.65, 16.5, 165, 1650 µg/kg) of sodium nitrite given 12 and
24 hours prior to I/R protocol. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and lactate
dehydrogenase (LDH) enzyme activities were determined as
quantitative indices of liver damage. These enzyme activities
were found to be increased in I/R group compared to control
group. Malondialdehyde (MDA), reduced (GSH) and oxidized
(GSSG) glutathione levels, and antioxidant enzyme activities
(glutathione-S-transferase, glutathione reductase, glutathione peroxidase, superoxide dismutase, catalase) were de-
termined in liver tissue samples of control, sham and study
groups. GSH content and GSH/GSSG ratio were found to be
significantly decreased; GSSG and MDA content significantly
increased in the I/R group. All antioxidant enzyme activities
were found to be significantly lowered in I/R group. Myeloperoxidase (MPO) activity was measured as the indicator of
leukocyte infiltration in liver tissue of study groups and it was
demonstrated that liver MPO activity was markedly elevated
in I/R group. Plasma levels of proinflammatory cytokines
(TNF-α, IL-1β, IL-6, IL-8 and IL-12) were significantly increased
in I/R group compared to control group. In all study groups
which were administrated with sodium nitrite, all parameters determined to change with I/R protocol, were decreased
to control levels depending on the concentration of nitrite
administered. Moreover, the cytoprotective effect of nitrite
were determined to be more effective when administred 24
hours before compared to 12 hours before administration.
Based on these findings, nitrite administration were found
to have significant protective effect on I/R injury. This study
is unique in terms of performing on mice, and examining all
these parameters in the same study groups.
International Symposium on Drug Research & Development 2011
154
DRD 2011
5-ARYLIDENE-4-THIAZOLIDINONES AS INHIBITORS OF HCV NS5B
POLYMERASE
Gökhan SATILMIŞ1,*, İlkay KÜÇÜKGÜZEL1, Esra TATAR1, Neerja KAUSHİK-BASU2,
Guru Kumar Kollongod RAMANATHAN2, Tanaji T. TALELE3
1Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Haydarpaşa 34668 İstanbul,
Türkiye
2New Jersey Medical School, Department of Biochemistry & Molecular Biology, NJ 07103, USA.
3St. John’s University, Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions,
New York 11439
*[email protected]
H
epatitis C virus (HCV) is an important human pathogen of global public health significance with
an estimated prevalence of 200 million people
world-wide and a predicted 100,000 new-cases each year. Persistent HCV infection is the leading cause of severe hepatitis
that often progresses to cirrhosis, steatosis, and hepatocellular carcinoma. There are no vaccines against HCV and current
therapeutic options are limited in efficacy against various
HCV genotypes and in addition are associated with drawbacks of specificity and toxicity. Therefore the development
of new antiviral agents against HCV is an area of high priority.
HCV NS5B RNA-dependent RNA polymerase is a pivotal viral
genome replicating protein with no functional equivalent in
the host and therefore represents an attractive therapeutic
target. Previously, we had reported on the identification of
2-Aryl-3-heteroaryl-1,3-thiazolidin-4-ones1 and 5-arylidene
analogues of these scaffold as HCV NS5B inhibitors. We evaluated eigtheen derivatives of this scaffold and identifed four
derivatives which exhibited greater than 50% NS5B RdRp activity inhibition at 100 micromolar compound concetration.
Further evaluation of their inhibitory activities resulted in
the identification of 2-{[5-(4-chlorophenyl)-1,3,4-thiadiazol2-yl]imino}-5-(2,6-dichlorobenzylidene)-1,3-thiazolidin-4one (KUC100309) which exhibited an IC50 value of 5.6 mM.
Molecular docking of this derivative within the allosteric
pockets of NS5B suggested its binding at the allosteric pocket (AP)-2 on NS5B and provided clues towards further optimization and synthesis of new derivatives with improved
anti-NS5B activity. In the light of modeling experiments of
KUC100309, four new derivatives were then designed and
synthesized in order to be evaluated as inhibitors of HCV
NS5B. Results will be discussed in detail.
derivatives of 4-oxo-2-thionothiazolidines2 as novel HCV
NS5B inhibitors. 2’,4’-Difluoro-N-[2-(2-fluorophenyl)-4-oxo1,3-thiazolidin-3-yl]-4-hydroxybiphenyl-3-carboxamide,
which was designed and synthesized3 by Ş.G.Küçükgüzel
et.al., have been reported to inhibit NS5B polymerase noncompetetively4. Here we report on the identification of novel
REFERENCES
1. Rawal RK, Katti SB, Kaushik-Basu N, Arora P, Pan Z. Bioorg
Med Chem Lett 18, 6114, 2008.
2. Talele TT, Arora P, Kulkarni SS, Patel MR, Singh S, Chudayeu M, Kaushik-Basu N. Bioorg Med Chem 18, 4630, 2010.
N
Cl
S
O
N
HN
N
S
Cl
Cl
KUC100309
3. Küçükgüzel ŞG, Kocatepe A, De Clercq E, Şahin F, Güllüce
M. Eur J Med Chem 41, 353, 2006.
4. Kaushik-Basu N, Bopda-Waffo A, Basu A, Chen Y, Talele TT,
Küçükgüzel ŞG. Frontiers in Bioscience 13, 3857, 2008.
International Symposium on Drug Research & Development 2011
155
POSTER PRESENTATIONS
P-100
POSTER PRESENTATIONS
DRD 2011
P-101
SYNTHESIS OF NEW PYRAZOLE DERIVATIVES AS ANTIMICROBIAL
AGENTS
Bünyamin ŞIK1, Arzu KARAKURT2,*, Selami GÜNAL3
1Undergraduate student of İnönü University, Faculty of Pharmacy, 44280 Malatya, Türkiye
2İnönü University, Faculty of Pharmacy Department of Pharmaceutical Chemistry, 44280 Malatya, Türkiye
3İnönü University, Faculty of Pharmacy, Department of Pharmaceutical Microbiology, 44280 Malatya, Türkiye
*[email protected]
A
ntifungal agents are an important part of antiinfective drugs and have been using in clinical
practice for a long time. The azole antifungals are
a rapidly expanding family of antifungal drugs. The synthesis of new systemic antifungal medications has been getting
mandatory because of the resistant fungal infections and
side effects of current antifungal drugs. For these reasons,
synthesis of new better antifungal agents are needed for
the patients who have AIDS, organ transplants and immune
compromise conditions such as prolong corticosteroid or
antineoplastic therapy1.
The compounds have been prepared according to the
synthesis scheme is given below and the structure of compounds was confirmed by IR, 1H-NMR and Mass spectral data.
Previously, we prepared some new 1-(2-naphtyl)-2-(1Hpyrazol-1-yl) oxime ether derivatives and found that most
of these compounds showed antifungal activity at low concentration (12.5 mg/ml)2. Therefore, in this study two new
1-(naphtalene-2-yl)-2-(1H-pyrazol-1-yl) etanon oxime ester
derivatives have been synthesized and their antimicrobial
evaluation were determined by to show antifungal activity.
The compounds were evaluated against the following
microorganisms: Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Candida albicans and C. tropicalis by using modified agar dilution methods for antibacterial and antifungal activities3,4.
REFERENCES
1. Kidwai M, Venkataramanan R, Rastogiand S, Sapra P. Discovery and development of antifungal compounds antiınfective agents, Curr Med Chem 2: 27-71, 2003.
2. Özdemir Z. Yeni (arilalkil)pirazol türevi oksim eterlerin sentezleri, antikonvülsan ve antimikrobiyal aktiviteleri, İnönü
Üniversitesi, Sağlık Bilimleri, Yüksek lisans Tezi, Malatya.
O
O
O
N
Br
Br2
N
HN
N
O
O
(CH3CH2CH2CO)2O
N
N
OH
N
N
NH2OH . HCl
N
O 2N
N
Na
O
NO2
COCl
O
N
N
N
Acknowledgement: This study is a part of final project of
undergraduate student.
3. Clinical and Laboratory Standards Institute, Approved
Standard-Seventh Edition, CLSI Document M7-A7, Pennsylvania, 2003.
4. Clinical and Laboratory Standards Institute, Approved
Standard-Second Edition. NCCLS document M27-A2,
Pennsylvania, 2002.
International Symposium on Drug Research & Development 2011
156
DRD 2011
POSTER PRESENTATIONS
P-102
STUDIES ON THE NEW OXIME ETHERS OF 1-(2-NAPHTYL)-2-(1,2,4TRIAZOL-1-YL)ETHANONE AND THEIR ANTIMICROBIAL ACTIVITIES
Fatime BEYTÜT1, Mehmet Abdullah ALAGÖZ2, Arzu KARAKURT2,*, Selami GÜNAL3
1
Undergraduate student of İnönü University, Faculty of Pharmacy, 44280 Malatya, Türkiye
İnönü University, Faculty of Pharmacy Department of Pharmaceutical Chemistry, 44280 Malatya, Türkiye
3
İnönü University, Faculty of Pharmacy, Department of Pharmaceutical Microbiology, 44280 Malatya, Türkiye
*
[email protected]
2
I
n the past decades, incidence of antimicrobial resistance in microbial infections has increased in the world
especially for patient with HIV, cancer and organ transplantation. For this reason development of new and more effective antimicrobial agents are urgent needs for treatment
of resistance infections1.
Azole antifungals are important for the treatment of
invasive fungal infections which have a growing importance. In this study we prepared three new oxime ether
derivatives with triazole ring as a continuation of our
interest in azole derivatives2.
These compounds have been synthesized starting
from 2-acetylnaphthalene as given below:
REFERENCES
1. Razonable RR. Antifungal Therapy. Expert Rev Anti Infect
Ther 8(6): 639-41, 2010.
2. Karakurt A, Aytemir MD, Stables JP, Özalp M, Kaynak, FB,
Özbey S, Dalkara S. Synthesis of some oxime ether derivatives of 1-(2-naphthyl)-2-(1,2,4-triazol-1-yl)ethanone and
their anticonvulsant and antimicrobial activities. Arch
Pharm 339: 513-520. 2006.
O
O
HN
N
N
OR
OH
NH2OH . HCl
N
N
Na
RX / DMF
N
R= -(CH2)5CH3
N
N
N
O
N
Br
Br2
N
N
-(CH2)4CH3
CH3
CCH2CH3
CH3
IR, 1H-NMR and Mass spectroscopic methods were
used for elicitation of their structure. Evaluation of their
antibacterial and antifungal activities was realised by
using modified agar dilution methods against Staphylococcus aureus, Enterococcus faecalis, Escherichia coli,
Pseudomonas aeruginosa Candida albicans and C. tropicalis3,4.
3. Clinical and Laboratory Standards Institute, Approved
Standard-Seventh Edition, CLSI Document M7-A7, Pennsylvania, 2003.
4. Clinical and Laboratory Standards Institute, Approved
Standard-Second Edition. NCCLS document M27-A2,
Pennsylvania, 2002.
International Symposium on Drug Research & Development 2011
157
POSTER PRESENTATIONS
DRD 2011
P-103
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME NOVEL OXIME
ETHER DERIVATIVES OF 1-(2-NAPHTYL)-2-(1,2,4-TRIAZOL-1-YL)
ETHANONE
Nagihan KAYA1, Mehmet Abdullah ALAGÖZ2, Arzu KARAKURT2,*, Selami GÜNAL3
Undergraduate student of İnönü University, Faculty of Pharmacy, 44280 Malatya, Türkiye
İnönü University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 44280 Malatya, Türkiye
3
İnönü University, Faculty of Pharmacy, Department of Pharmaceutical Microbiology, 44280 Malatya, Türkiye
*
[email protected]
1
2
F
ungal infections occur more seriously in immune
compromised patients than the others and it is necessary to treat these them with systemically effective antifungal agents due to the increase in the probability
of recurrence1. Therefore development of new antifungal
agents with better activity profile is an attractive area for
medicinal chemists.
tivitity at low concentration (16 mg/ml)2. Therefore in this
study we aimed to design new oxime ether derivatives
with triazole ring and to evaluate their antifungal/antibacterial activities. The structure of the compounds and
their synthesis scheme are given below.
O
O
Br2
Azole antifungals have maintained a key role in the
treatment of immune compromised patients who need
oral therapy. Triazole derivatives have a special importance among the other azole derivatives. Fluconazole,
itraconazole, terconazole are the examples of rhe antifungal drugs in the market which has triazole ring in
their structure.
HN
N N
N
NH2OH . HCl
R=
OR
OH
N
N
N N
Na
RX / Acetone
N
O
N
Br
CH2CH2CH2CH3
CHCH2CH3
N N
CH3
CH2CH2CH CH2
Previously, we prepared some new 1-(2-naphtyl)-2(1,2,4-triazol-1-yl)oxime ether derivatives and found that
most of the these compounds showed antimicrobial ac-
Their structures of the have been confirmed by IR, 1H-NMR
and Mass spectral data. Antimicrobial activity of the compounds has been tested agains two Gr (+) (Staphylococcus aureus, Enterococcus faecalis) and two Gr (-) bacteria (Pseudomonas
aeruginosa, Escherichia coli) and two yeasts like fungi (Candida
albicans, C. tropicalis) by modified agar dilution method3,4.
REFERENCES
1. Kuş C, Alp M. Sistemik mantar enfeksiyonlarının tedavisinde yeni hedefler ve yeni bileşikler. Ankara Ecz Fak
Derg 31(2): 91-131, 2002.
2. Karakurt A, Aytemir MD, Stables JP, Özalp M, Kaynak, FB,
Özbey S, Dalkara S. Synthesis of some oxime ether derivatives of 1-(2-naphthyl)-2-(1,2,4-triazol-1-yl)ethanone and
their anticonvulsant and antimicrobial activities. Arch
Pharm 339: 513-520. 2006.
3. Clinical and Laboratory Standards Institute, Approved
Standard-Seventh Edition, CLSI Document M7-A7, Pennsylvania, 2003.
4. Clinical and Laboratory Standards Institute, Approved
Standard-Second Edition. NCCLS document M27-A2,
Pennsylvania, 2002.
International Symposium on Drug Research & Development 2011
158
DRD 2011
DEVELOPMENT OF RP-HPLC METHOD FOR THE DETERMINATION OF
AMLODIPINE IN COMMERCIALLY AVAILABLE TABLET DOSAGE FORMS
Fevziye Ö. ŞİMŞEK1, Kamile Zümrüt DİRİCAN2,*, Mustafa Sinan KAYNAK3, Nurullah ŞANLI4,
Selma ŞAHİN5
Süleyman Demirel University, Faculty of Science and Arts, Dept. of Chemistry, 32100 Isparta, Türkiye
2
İnönü University, Faculty of Pharmacy, Undergraduate Student, 44280 Malatya, Türkiye
3
İnönü University, Faculty of Pharmacy, Dept. of Pharmaceutical Technology, 44280 Malatya, Türkiye
4
Hitit University, Faculty of Science and Arts, Dept. of Chemistry, 19040 Çorum, Türkiye
5
Hacettepe University, Faculty of Pharmacy, Dept. of Pharmaceutical Technology, 06100 Ankara, Türkiye
*
[email protected]
1
A
mlodipine (AML) (as besylate, mesylate or maleate) is a long-acting calcium channel blocker (dihydropyridine) used as an anti-hypertensive and
in the treatment of angina. AML acts by relaxing the smooth
muscle in the arterial wall, decreasing peripheral resistance
and hence reducing blood pressure; in angina it increases
blood flow to the heart muscle [1]. Currently, more than ten
different AML (as besylate) containing tablets (5 and 10 mg)
are commercially available in the Turkish drug market.
The aim of this study was to develop a new, fast, reliable
and validated HPLC method for the determination of AML
in tablet dosage forms. A C18 column (Fortis™ 250x4.60 mm
5µm) which was heated at 45oC during the analysis, was used
for the separation and quantification of AML. The mobile
phase consisted of water (15 mM o-phosphoric acid, pH 5.0)
and acetonitrile (50:50 v/v). Analyses were run at a flow rate
1.0 mL/min and UV detector was set at 238 nm. The injec-
tion volume was 20 µL and total run time for an assay was
approximately 5 min. A loop diuretic furosemide (FSM) was
used as the internal standard. The developed method was
validated according to the ICH guideline [2]. For application
of the proposed HPLC method, commercially available four
different AML containing tablets (one reference and three
generic tablets) were obtained from the market and analysed for their drug content.
Under the given chromatographic conditions, AML and
FSM were eluted at 4.28 and 3.68 minutes, respectively. The
method was linear in the concentration range of 1.0 to 16.0
µg/mL, and limit of quantitation was 2.139 µg/mL (Table 1).
Under the conditions used, the analysis completely fulfilled
the system suitability test limits suggested by FDA for the
quantitative chromatographic methods. The method was
successfully applied for the analysis of AML in commercially
available tablets.
Table 1. Statistical evaluation of the calibration data
Compound
Linearity
range (μg/mL)
Slope
Intercept
SE of
slope
SE of
intercept
Correl.
coeff.
Detection
limit (μg/mL)
Quantitation
limit (μg/mL)
AML
1.0-16.0 n=6
0.176
-0.040
0.003
0.025
0.9995
0.6417
2.1390
REFERENCES
1. Levine CB, Fahrbach KR, Frame D, Connelly JE, Estok RP,
Stone LR, et al. Clinical Therapeutics 25: 35-57, 2003.
2. ICH Steering Committee (2005). Harmonized Tripartite
Guideline.
International Symposium on Drug Research & Development 2011
159
POSTER PRESENTATIONS
P-104
POSTER PRESENTATIONS
DRD 2011
P-105
DETERMINATION OF PERMEABILITY OF DICLOFENAC SODIUM IN THE
IN-SITU INTESTINAL PERFUSION PREPARATION
Mustafa Sinan KAYNAK1, Hatice ÇAĞLAR2,*, Ebru BÜYÜKTUNCEL2, Selma ŞAHİN3
İnönü University, Faculty of Pharmacy, Dept. of Pharmaceutical Technology, 44280 Malatya, Türkiye
2
İnönü University, Faculty of Pharmacy, Dept. of Analytical Chemistry, 44280 Malatya, Türkiye
3
Hacettepe University, Faculty of Pharmacy, Dept. of Pharmaceutical Technology, 06100 Ankara, Türkiye
*
[email protected]
1
D
iclofenac is a non-steroidal anti-inflammatory
drug (NSAID) with analgesic, anti-inflammatory
and antipyretic properties. Compared to other
NSAIDs, diclofenac is well tolerated and rarely produces gastrointestinal ulcerations or other serious side-effects1. This
study was designed to investigate the intestinal permeability of diclofenac sodium in the single pass in situ-intestinal
perfusion preparation. To compare jejunal permeability of
diclofenac, Phenol red which is not absorbed across the intestinal membrane was used as the low permeability marker
(2), whereas metoprolol, a highly permeable drug, was selected as the reference standard.
red) and high (0.4 mg/mL metoprolol tartarate) permeability
markers were perfused for 60 min. At predetermined time
intervals, perfusate samples were collected from the outlet
tubing and then analyzed with a reversed phase HPLC method developed by Çağlar et al. [3]. Permeability values (Peff ) of
diclofenac sodium and metoprolol tartarate were calculated
using inlet (Cin) and outlet (Cout) concentrations, flow rate of
perfusion medium (Qin), length (L) and diameter (r) of the
perfused intestinal segment.
⎡
⎛ C
⎢− Qin . ln⎜⎜ out
⎢⎣
⎝ C in
Peff =
2.π .r.l
⎞
⎟⎟
⎠
l
⎤
⎥
⎥⎦
Jejunal permeability of diclofenac sodium was investigated in the rat using single-pass in-situ intestinal perfusion
method (n=7). Briefly, abdomen of the rats was opened by
a midline longitudinal incision; a segment of the jejunum
(10 cm) was cannulated with plastic tubing. Golytely solution containing 25 mmol/L NaCl, 10 mmol/L KCl, 40 mmol/L
Na2SO4, 20 mmol/L NaHCO3 and 80 mmol/L mannitol was
chosen as the perfusion medium. The isolated intestinal
segment was then perfused with this perfusion medium at
a flow rate of 0.2 mL/min. The perfusion medium containing diclofenac sodium (0.4 mg/mL), zero (0.7 mM phenol
Peff values estimated for metoprolol and diclofenac were
0.43 (± 0.19x10-4) and 1.44 (±0.52x10-4) cm/s, respectively.
Metoprolol is widely used as the high permeability marker.
If a compound’s permeability is higher than that of metoprolol, it is considered as a high permeability compound. Based
on our results, diclofenac can be classified as a high permeability compound.
REFERENCES
1. Roškar R, Kmetec V. Liquid chromatographic determination of diclofenac in human synovial fluid, J Chromatogr
B 788: 57-64, 2003
2. Milani PZ, Valizadeh H, Azarmi Y, Jalali MB, Tajerzadeh H.
Simultaneous determination of metoprolol, propranolol
and phenol red in samples from rat in situ intestinal per-
fusion studies, DARU 14(2): 102-108, 2006.
3. Çağlar H, Kaynak MS, Sahin S, Büyüktuncel E. HPLC Method development and validation: Simultaneous determination of diclofenac, metoprolol and phenol red in biological matrix for intestinal perfusion studies, Eur J Pharm
Sci 38(Suppl 1): 179-181, 2009.
International Symposium on Drug Research & Development 2011
160
DRD 2011
DEVELOPMENT AND VALIDATION OF A RP-HPLC METHOD FOR
DETERMINATION OF FUROSEMIDE IN TABLET DOSAGE FORMS
Fevziye Ö. ŞİMŞEK1, Songül ERDOĞDU2,*, Mustafa Sinan KAYNAK3, Nurullah ŞANLI4,
Selma ŞAHİN5
Süleyman Demirel University, Faculty of Science and Arts, Dept. of Chemistry, 32100 Isparta, Türkiye
2
İnönü University, Faculty of Pharmacy, Undergraduate Student, 44280 Malatya, Türkiye
3
İnönü University, Faculty of Pharmacy, Dept. of Pharmaceutical Technology, 44280 Malatya, Türkiye
4
Hitit University, Faculty of Science and Arts, Dept. of Chemistry, 19040 Çorum, Türkiye
5
Hacettepe University, Faculty of Pharmacy, Dept. of Pharmaceutical Technology, 06100 Ankara, Türkiye
*
[email protected]
1
F
urosemide (FSM) is a loop diuretic commonly used
in adults, infants and children for the treatment of
edematous states associated with congestive heart
failure, cirrhosis of the liver and renal disease. Oral furosemide may be used in adults for the treatment of hypertension alone or in combination with other antihypertensive
agents1. Currently, two different FSM containing tablets are
commercially available in the Turkish drug market.
tion volume was 20 µL and total run time for an assay was
approximately 5 min. A calcium channel blocker Amlodipine (AML) was used as the internal standard. The proposed
HPLC method was validated according to the ICH guideline2.
For application of the method, commercially available two
different FSM containing tablets (one reference and one generic tablet) were obtained from the market and analyzed
for their drug content.
The aim of our study was to develop a new, fast, reliable
and validated HPLC method for the determination of FSM in
tablet dosage forms. Chromatographic separation of FSM
was achieved on a C18 column (Fortis™ 250x4.60 mm 5µm)
Under the given chromatographic conditions, FSM and
AML were eluted at 3.68 and 4.28 minutes, respectively. The
method was linear in the concentration range of 0.1 to 12.0
µg/mL, and limit of quantitation was 0.0311 µg/mL (Table 1).
Under the conditions used, the analysis completely fulfilled
the system suitability test limits suggested by FDA for the
quantitative chromatographic methods. The method was
successfully applied for the analysis of FSM in commercially
available tablets.
with a mobile phase consisted of water (15 mM o-phosphoric acid) and acetonitrile (50:50 v/v). The pH of the mobile
phase was adjusted to 5.0. The column was heated at 45oC
during the analysis. Analyses were run at a flow rate 1 mL/
min and UV detection was performed at 238 nm. The injec-
Table 1. Statistical evaluation of the calibration data of FSM by RP-HPLC
Compound
Linearity range
(μg/mL)
Slope
Intercept
SE of
slope
SE of intercept
Correl
coeff.
Detection limit
(μg/mL)
Quantitation
limit (μg/mL)
FSM
0.1-12.0 n=7
1.610
0.052
0.023
0.130
0.9995
0.0102
0.0311
REFERENCES
1. D.C. Brater, Pharmacology of diuretics, Am. J. Med. Sci.,
319 (2000) 38-50.
2. ICH Steering Committee (2005). Harmonized Tripartite
Guideline.
International Symposium on Drug Research & Development 2011
161
POSTER PRESENTATIONS
P-106
POSTER PRESENTATIONS
DRD 2011
P-107
COMPARISON OF DISSOLUTION PROFILES OF TWO COMMERCIALLY
AVAILABLE FUROSEMIDE TABLETS
Müge GENEŞ1, Naile ÖZTÜRK2,*, Mustafa Sinan KAYNAK1, Selma ŞAHİN3
İnönü University, Faculty of Pharmacy, Department of Pharmaceutical Technology, 44280 Malatya, Türkiye
2
İnönü University, Faculty of Pharmacy, Undergraduate Student, 44280 Malatya, Türkiye
3
Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Technology, 06100 Ankara,Türkiye
*
[email protected]
1
D
rug absorption from a solid dosage form after oral
administration depends on the release of drug
substance from the drug product, the dissolution
or solubilization of the drug under physiological conditions
and the permeability across the gastrointestinal tract. Because of the critical nature of the first two of these steps, in vitro
dissolution may be relevant to the prediction of in vivo performance. Based on this general consideration, in vitro dissolution test for immediate release solid oral dosage forms
(i.e. tablets, capsules) is used to assess the batch-to-batch
quality control of a drug product; guide the development of
new formulations; and ensure the sustainability of the product quality and performance after certain changes, such as
those in the formulation, the manufacturing process, the site
of manufacture, and the scale-up of the manufacturing process1,2. Furosemide (FSM) is a loop diuretic commonly used
in adults, infants and children for the treatment of edematous states associated with congestive heart failure, cirrhosis
of the liver and renal disease. Oral furosemide may be used
in adults for the treatment of hypertension alone or in combination with other antihypertensive agents3. Currently, two
different FSM containing tablets are commercially available
in the Turkish drug market. The objective of this study was to
compare the in-vitro release profiles of Furosemide (40 mg)
from two commercially available Furosemide tablets.
REFERENCES
1. Guidance for Industry: Dissolution testing of immediate
release solid dosage forms. Food and Drug Administration, CDER, 1997. Retrieved from www.fda.gov/cder/
guidance/index.htm
Dissolution studies on the test (T) and reference (Lasix®
40mg) tablets were conducted using USP Apparatus II (paddle method) with six replicates at 37 ± 0.5°C. pH 5.8 phosphate were used as the dissolution medium (900 mL) and
the paddle rotation speed was kept at 50 rpm. The buffer was
prepared freshly according to USP 29. In all experiments, at
predetermined time intervals (5, 10, 20, 30, 40, 50 and 60
min), sample (2 mL) was withdrawn and replaced with an
equal volume of fresh medium to maintain a constant total
volume. After filtration and dilution of the samples with the
dissolution medium, the concentrations of Furosemide were
determined by spectrophotometer at 339.5 nm. Drug release profiles of the tablets were compared by using similarity (f2) and difference (f1) factors equations were given below.
⎡ n
⎢ Σ Rt − Tt
f1 = ⎢ t =1 n
⎢⎣ tΣ=1 Rt
⎤
⎥
⎥ x100
⎥⎦
⎧⎪⎡ 1 n
⎤
f 2 = 50 x log ⎨⎢1 + ∑ Rt − Tt ⎥
⎪⎩⎣ n t =1
⎦
−0.5
⎫⎪
x100⎬
⎪⎭
If a f1 value is between 0-15 or f2 value is between 50-100
it is considered that the formulations are similar. Based on
our results, dissolution profiles of furosemide obtained for
the test and reference products were condidered similar (f1
< 5 and f2 >50).
2. EMEA: CPMP Note for guidance on the investigation of
bioavailability and bioequivalence, CPMP, July 2001.
3. Brater DC. Pharmacology of diuretics, Am J Med Sci 319:
38-50, 2000
International Symposium on Drug Research & Development 2011
162
DRD 2011
SYNTHESIS OF OXAZOLES AS A MUSHROOM TYROSINASE INHIBITORS
Neslihan ŞAKİ, Mustafa AKIN, Sevgi NALBANTOĞLU
Kocaeli University, Faculty of Sciences and Arts, Department of Chemistry, 41380 Kocaeli, Türkiye
O
xazoles are an important class of heterocycles
that exhibit diverse biological activities. Natural
products containing the oxazole substructure
have been shown to exhibit potent enzyme properties1.
Oxazoles that are monosubstituted at C-2 have been used as
synthetic intermediates in the synthesis of natural products
and pharmaceuticals2.
Tyrosinase is a multifunctional copper-containing enzyme, that is, key in melanin biosynthesis, melanisation in
animals and browning in plants. Melanin plays an important
role in protecting human skin from the harmful effects of UV
radiation from the sun. Tyrosinase inhibitors can therefore
be clinically useful fort the treatment of some dermatological disorders associated with melanin hyperpigmentation. In
addition, these inhibitors are also known tobe useful in cosmetics for whitening and depigmentation after sunburn3-5.
REFERENCES
1. Taylor EC, Wipf P. Oxazoles: Synthesis, Reactions, and
Spectroscopy; John Wiley & Sons: Hoboken, 2003.
2. Anderson BA, Becke LM, Booher RN, Flaugh ME, Harn NK,
Kress TJ, Varie DL, Wepsiec JP. J Org Chem 62: 8634, 1997.
3. Kai Bao, Yi Dai, Zhi-Bin Zhu, Feng-Juan Tu, Wei-Ge Zhang,
Xin-Seng Yao, Design and synthesis of biphenyl deriva-
In this study, we synthesized new oxazole derivatives. The
synthesis of oxazoles is achieved via nickel-catalyzed crosscoupling reaction of 2-methylthio-oxazole and various organo-zinc reagents. Inhibiton abilities of our synthetic oxazoles
were initialy investigated in vitro on mushroom tyrosinase
using arbutin as the positive control. In conclusion, new series of oxazoles were prepared and their activity as tyrosinase
inhibitors was examined. It was found that R groups which
are on the phenolic rings shows better inhibitor activity than
R groups with methyl and methoxy groups.
O
S-Me
+
O
RZnX
N
THF
R
N
Metal catalyzed synthesis of 2-substitued oxazoles
R: Various substituents
tives as mushroom tyrosinase inhibitors. Bioorganic &
Medicinal Chemistry 18: 6708-6714, 2010.
4. Kima YJ, Uyamab H. Cell Mol Life Sci 62: 1707, 2005.
5. Te-Shang C. An updated rewiev of tyrosinase inhibitors.
Int J Mol Sci 10: 2440-2475, 2009.
International Symposium on Drug Research & Development 2011
163
POSTER PRESENTATIONS
P-108
POSTER PRESENTATIONS
DRD 2011
 P-109
SIMULTANEOUS DETERMINATION OF AMLODIPINE, METOPROLOL AND
PHENOL RED IN BIOLOGICAL MATRIX FOR INTESTINAL PERFUSION STUDIES
Agata BOGACZ1,*,**, Michał STELMASİŃSKİ1,*, Ebru BÜYÜTUNCEL2, Mustafa Sinan KAYNAK3,
Selma ŞAHİN4
İnönü University, Faculty of Pharmacy, Undergraduate ERASMUS Exchange Student, 44280 Malatya, Türkiye
2
İnönü University, Faculty of Pharmacy, Department of Analytical Chemistry, 44280 Malatya, Türkiye
3
İnönü University, Faculty of Pharmacy, Department of Pharmaceutical Technology,
44280 Malatya, Türkiye
4
Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Technology, 06100 Ankara, Türkiye
*
Permenant address: Jagiellonian University, Faculty of Pharmacy, Undergraduate Student,
30-690 Krakow, Poland
**
[email protected]
1
A
mlodipine (AML) (as besylate, mesylate or maleate) is a long-acting calcium channel blocker
used as an anti-hypertensive and in the treatment of angina. AML acts by relaxing the smooth muscle in
the arterial wall, decreasing peripheral resistance and hence
reducing blood pressure; in angina it increases blood flow to
the heart muscle1. In intestinal perfusion studies, reference
compounds are usually added to the perfusion medium for
comparison of the test compound. For this purpose, phenol
red (PHR) is used as a zero permeability marker and metoprolol (MTP) as a high permeability marker2. In this study,
reversed-phase liquid chromatographic method, optimized
for the simultaneous determination of amlodipine (test
compound), metoprolol and phenol red in biological matrix
(blank perfusion medium), was reported.
A C18 column (Phenomenex™ Luna 150x4.60 mm 5µm)
was used for the separation and quantification of AML. The
mobile phase consisted of methanol and phosphate buffer
(12.5 mM) (60:40 v/v). pH of mobile phase was adjusted at
7.0 with triethylamine. Analyses were run at a flow rate 1.0
mL/min and UV detector was set at 238 nm, 430 nm and 227
nm wavelengths for AML, PHR and MTP respectively. The injection volume was 20 µL and total run time for the assay
was approximately 8 min. An antiepileptic drug carbamazeREFERENCES
1. Levine CB, Fahrbach KR, Frame D, Connelly JE, Estok RP,
Stone LR, et al. Clinical Therapeutics 25: 35-57, 2003.
2. Milani PZ, Valizadeh H, Azarmi Y, Jalali MB, Tajerzadeh H.
Simultaneous determination of metoprolol, propranolol
pine (CBZ) was used as the internal standard. The developed
method was validated according to the ICH guideline3. For
the application of the proposed HPLC method, test and reference compounds were spiked into Golytely solution (25 mM
NaCl, 10 mM KCl, 40 mM Na2SO4, 20 mM NaHCO3 and 80 mM
mannitol) at concentrations of 60 µg/mL for AML, PHR, MTP
and 10µg/mL for CBZ.
Under these conditions, MTP, PHR, CBZ and AML were
eluted at 2.1, 2.9, 5.4 and 7.5 minutes, respectively (Figure
1). The method was linear in the concentration range of
10.0 to 80.0 µg/mL. Under the chromatographic conditions
used, the analysis completely fulfilled the system suitability
test limits suggested by FDA for the quantitative chromatographic methods. The method was successfully applied for
the analysis of AML in samples of spiked Golytely solution.
Figure 1. HPLC chromatogram of MTP, PHR, CBZ and AML.
and phenol red in samples from rat in situ intestinal perfusion studies, DARU 14(2): 102-108, 2006.
3. ICH Steering Committee (2005). Harmonized Tripartite
Guideline.
International Symposium on Drug Research & Development 2011
164
DRD 2011
ANTIOXIDANT PROPERTIES OF SOME PLANTS FROM TURKISH FLORA
Kağan ATİKELER1,*, Duygu KAYA2, Funda N. YALÇIN2
Hacettepe University, Faculty of Pharmacy, 5th year student 06100 Ankara, TURKEY
Hacettepe University, Faculty of Pharmacy, Department of Pharmacognosy, 06100 Ankara, TURKEY,
*[email protected]
1
2
M
any diseases and degenerative processes can
be associated with the overproduction of reactive oxygen species including inflammation,
brain ischemia, mutagenesis, dementia and physiological
aging. In addition, it is well known the increased amount
of free radicals in wounded and inflammated tissues, cancerous cells and organs. For these reasons, several methods
have been developed to measure antioxidant activity of the
herbal extracts in vitro and here we have tested free radical
scavenging activity of the MeOH extract of selected species from Turkish Flora (Aethionema dumanii, Trigonella spec,
Minuartia hamata, Hypcoum imberbe, Ziziphora capitata,
Ajuga chamaepitys and Cruciata articulate). The spectrophotometric 2,2-diphenyl-1-picrylhydrazil (DPPH) method were
used to test the free radical scavenging activity1. Aethionema
dumanii MeOH extract was exhibited the most antioxidant
activity with results.
REFERENCES
1. Harput US, Genç Y, Khan N, Saracoglu İ, Rec. Nat. Prod., 5,
100-107 (2011).
International Symposium on Drug Research & Development 2011
165
POSTER PRESENTATIONS
P-110
INDEX
DRD 2011
A
BASU, Arijit
ACAR, Mustafa Fahir
61
ADIYAMAN, Mustafa
50
AFSORDEH, K.
145
AKALIN ÇİFTÇİ, Gülşen
109
AKBUĞA, Jülide
86
AKDAĞ, Kadriye
86
AK, Güliz
44, 128, 130
AKGÜN DAR, Kadriye
AKHTAR, Naveed
88
45, 48
AKIN, Mustafa
163
AKSAKAL, Sefa
117
ALAGÖZ, Mehmet Abdullah146,
157, 158
ALASAĞ, Neva
104
ALFARANO, Chiara
32
ALGÜL, Öztekin
85
ALİ, Atif
48
ALKAN, Erkin
102, 124
ALPAN, A. Selcen
126
ALSANCAK, Güleren
123, 138
ALTINTOP, Mehlika Dilek 80, 106, 107
ALTIPARMAK, Gökçe
ALTUN, Yüksel
115, 116
87
AOUF, Nour-Eddine
105
ındex
60
ÇELİK, Venhar
62, 63
BAUMSTÜMMLER, Bernd
152
ÇINAR, Ebru
80
BAYRAKTAR, Aygin
91
ÇOBAN, Özlem
91
BEDİR, Erdal
127
ÇONGUR, Gülşah
142
BEE, Tim
16
BEHERA, Jagannath
60
ÇUBUK DEMİRALAY, Ebru123, 136, 137,
138
BEKSAÇ, M. Sinan
59
D
BELLUR ATICI, Esen
50
BERBER, İsmet
77
BERREDJEM, Malika
105
BEYTÜT, Fatime
157
BİBEROĞLU, Kevser
66
BİLGİNER, Sinan
55
27
159
DİZMAN, Cemil
35
BOPPANA, Kiran
60
DOĞAN, Ayşegül
59
BORA, Aykut
28
DOĞAN, İnci Selin
79
BOŞGELMEZ TINAZ, Gülgün 90,
118
DOĞAN, Zümrüt
68
BOUASIA, Radia
105
BOURIN, Philippe
32
BULANT, Steeve
41
BÜYÜKTUNCEL, Ebru151, 160, 164
C
CAN, Özgür Devrim
80, 114
CANAVAR, Pembe Ece
CANBAY, Hale
143
137, 138
CANTÜRK, Pakize
121
ATİLA, Alptuğ
82, 129
AYDIN, Elanur
94
COCHRAN, Rory
101
73, 77
CUSSAC, Daniel
32
CHENG, Woei Ping
DOĞRUKOL AK, Dilek
DUBEY, P.K.
104
60
DUMANLI, Onur
103
DUMANLI, Rukiye
103
DURAN, Nizami
85
E
56, 57
B
DİLBAZ, Nesrin
99
110
111
112, 114
BOLAT, Gülçin
CANKARA PİROL, Şeyma
AYTEMİR, Mutlu D.
DEMİR ÖZKAY, Ümide
DİRİCAN, Kamile Zümrüt
94
147
91
140
ASLAN, Ali
AYTAÇ, S. Peri
DEMİRKAN, Kutay
BOĞATARKAN, Çağla
83, 84
81
64
DİRİCAN, Ebubekir92, 93, 94, 95,
96
ASAN, Adem
AYDIN, Sevil
DEĞİM, Zelihagül
164
47
AYDINÖZ, Bilal
61, 79, 146
BOGACZ, Agata
ARAIN, Rafee
165
DALKARA, Sevim
148
96
ATİKELER, Kağan
69, 70
BİRİNCİOĞLU, Mustafa
ARABACI, Taner
ATALAY, Rengül-Çetin
DAĞDEVİREN, İnci Nejla
15, 23
Ç
ÇAĞLAR, Hatice
160
ÇALIŞKAN, Ayfer
142
ÇALIŞKAN, Burcu
110
BALCI, Metin
34
ÇALIŞ, Pınar
59
BALZARINI, Jan
78
ÇALIŞ, Sema
21
BANOĞLU, Erden
110
ÇALIŞ, Ünsal
119, 146
EL-SALEH, Firas
16
ERAÇ, Bayri
139
ERDEM, Arzum
19, 142, 143, 144
ERDEM KURUCA, Serap
88
ERDOĞDU, Songül
161
EREN, Sami
102, 124, 141
ERGAN, Erdem
75
ERİŞ, Rümeysa
89
EROĞLU, Hakan
59
ERTÜRK, Ali Serol
35
F
FABIAN, Walter M. F.
42
FARSHI, Farhad
17
G
GENEŞ, Müge
162
BAŞAK, Neşe
58
ÇANDAR, Dürdane
BAŞARAN, Eyüp
76
ÇELİK, İsmail
138
GESKOVSKI, Nikola
21
122, 123
ÇELİK, Leman
135
GEYİKOĞLU, Fatime
92
BAŞAT, Dilara
65
International Symposium on Drug Research & Development 2011
166
DRD 2011
KADIOĞLU, Yücel
82, 129
GÖKÇE, Mehtap
133
KALKAN, Ş.Orçun
127
GÖKHAN KELEKÇİ, Nesrin
149
KAPLANCIKLI, Zafer Asım 80, 106, 107
GORAČINOVA, Katerina
21
GOWTHAMARAJAN, K.
108
KARADENİZ, Hakan
144
45
KARAKAŞ, Zeynep
88
55, 56, 57, 58
KARAKAYA, Gülşah
111
GULFISHAN
GÜL, Halise İnci
KARADAŞ, Nurgül
83
LATIF, M.
43
LÜLECİ, Zeynep
91
M
MADNİ, Asadullah
48
MAMOOD, Tariq
45
MAZUOCHIAN, H.
145
MERCAN, Zeliha
71
MERT, Adem
65
MIAS, Céline
32
MUHAMMAD, Haji
43
GÜMÜŞEL, Bülent
154
KARAKÜÇÜK İYİDOĞAN, Ayşegül 69,
70, 71, 72, 73, 74, 75, 76, 77, 78
GÜMÜŞ, Fatma
140
KARAKURT, Arzu
146, 156, 157, 158
97, 98
KARAKUŞ, Sevgi
86
156, 157, 158
KARALI, Nilgün
88
73
KARATAŞ, Nuray
91
126
KARLIĞA, Bekir
49
NALBANTOĞLU, Sevgi
163
KART, Didem
61
NARMADHA, M. P.
108
81, 155
GÜL, Mustafa
58
GÜMÜŞTAŞ, Mehmet
GÜNAL, Selami
GÜNER, Özgül
GÜNEŞ, H. Semih
GÜNEY, Berrak
102, 141
GÜRBÜZ, Hasan
GÜREL, Ebru
GÜRKAYNAK, Merve
GÜRLER, Berrin
GÜRSOY, Şule
NEMUTLU, Emirhan
59
88
KAYA, Duygu
165
NITISS, John L.
30
137
KAYA, Nagihan
158
NITISS, Karin C.
30
132, 134
KAYNAK, Fatma
110
115, 116, 117
H
ONAR, A. Nur
KELEŞ, M. Sait
92
ONUR, Mehmet Ali
KHALIQ, Obaid
43
KHAN, Barkat Ali
45, 48
ORUÇ EMRE, Emine Elçin69, 70, 71, 72,
73, 75, 77, 78
92
HAQUE, Qamarul
47
KHAN, Haji Muhammad Shoaib 45,
48
HASSAN, Fahad
43
KILIÇ, Burçin
116
HINCAL, A. Atilla
29
KILIÇ EREN, Mehtap
148
KILIÇ, İbrahim Halil
71, 75
KIRCHHAUSEN, Tomas
41
I
112, 113
İ
KIR, Esengül
132, 134
KIRKPINAR, İsmet
KIR, Sedef
92
59, 120
İÇEN, Irmak
62, 63
İDUĞ, Tuğba
151
KOÇAK, Ö. Faruk
İLTER, Şeyda
120
KOÇYİĞİT KAYMAKÇIOĞLU, Bedia 69,
72, 86
82
İNCESU, Zerrin
109, 113
İŞCAN, Gökalp
106
KOZACI, Leyla Didem
148
71, 75
KÜÇÜKGÜZEL, İlkay
155
KÜÇÜKGÜZEL, Ş.Güniz
81
KÜÇÜKKILINÇ, Tuba
101
KÜÇÜKOĞLU, Kaan
56, 57
J
JAHANGIR, Sajid
42, 47
JAYAPRAKASH, Venkatesan 60,
153
K
KACAMER, Hasan
91
O
KAYNAK, Mustafa Sinan159, 160, 161,
162, 164
HACIMÜFTÜOĞLU, Ahmet
İŞLER, Derya
N
94
GÜVENER DEMİRAĞ, Nilgün 25
IŞIKDAĞ, İlhan
62, 63
KAUSHİK-BASU, Neerja
68
GÜZEL, Yahya
MUNZUROĞLU, Ömer
KURAL, Cömert
41
KURTOĞLU, Emel D.
124, 141
ÖNAL, Zülbiye
116, 117
ÖNDER, Nur İpek
113
ÖNEM, Ebru
118
ÖZASLAN, Mehmet
71, 75
ÖZBAŞ TURAN, Suna
86
ÖZÇELİK, Berrin
133
ÖZDEMİR, Ahmet
80, 106, 107
ÖZDEMİR, Filiz
109
ÖZDEMİR, Zeynep
133
ÖZDEN, Tuncel
102, 124, 141
ÖZEK, M. Aykut
59
ÖZKAN, Sibel A.
97, 98, 122, 137
ÖZKAY, Yusuf
112, 113, 114
ÖZ, Özlem
148
ÖZTÜRK, Muharrem
125
ÖZTÜRK, Naile
162
ÖZTÜRK, Yusuf
112
152
International Symposium on Drug Research & Development 2011
167
99
Ö
L
LANGGUTH, Peter
103, 125, 131
INDEX
21
GLAVAŠ-DODOV, Marija
INDEX
DRD 2011
P
Ş
U
PARALI, Tezcan
35
ŞAHİN, Fikrettin
PARINI, Angelo
32
ŞAHİN, Nefise Özlen
135
UÇAR, Gülberk
PERÇİN ÖZKORUCUKLU, Sabriye132,
134
ŞAHİN, Özge
135
UĞURLU, Ezgi
ŞAHİN, Selma
159, 160, 161, 162, 164
PIRI, R.
145
ŞAKİ, Neslihan
163
33
ŞANLIER, Şenay
44, 128, 130
UTKU, Semra
140
ŞANLI, Nurullah 83, 84, 122, 159, 161
UYSAL, Şirin
139
ŞANLI, Senem
83, 84, 87
UZEL, Ataç
127
ŞEN, Mesut
109
ŞIK, Bünyamin
156
PIZZINAT, Nathalie
Q
QADRI, M. Samiuddin
43
R
RADIĆ, Zoran
101
RAD, J. SOLEIMANI
145
RAHMAN, Mohammed
16
RAJAVEL, Sankar
108
RAMANATHAN, Guru Kumar Kollongod
81, 155
58
ŞİMŞEK, Fevziye Ö.
159, 161
T
TACAL, Özden
66
TAHIRI, Iftikhar Ahmed
TALELE, Tanaji T.
155
48
TAN, Gamze
99
RASOULI, Sohrab
46, 150
TARI, Özden
85
ROGOJINA, Anna
ROLLAS, Sevim
RONCALLI, Jérôme
ROTTMANN, Nils Wilhelm
ROUSHANGAR, L.
59
TAŞDEMİR, Demet
30
TAŞHAN, Emine
91
86
TAŞLI, Hüseyin
126
32
TATAR, Abdulgani
92, 96
20
TATAR, Esra
155
TAYLOR, Palmer
101
145
RUBIO, Jose Miguel
62
S
SADAGHIAN, Mohammad
46, 150
SAĞLAM, Onursal
124
SALGIN GÖKŞEN, Umut
149
SANKARAN, Vadivelan
60
SARAÇ, Selma
79
SARIKAYA, Görkem
126
SATILMIŞ, Gökhan
155
SEPTİOĞLU, Ebubekir
119
SHANMUGANATHAM, Karthik 30
SHOAR, M. KARIMI
145
SICAK, Yusuf
72
SIMONOSKA, Maja
21
SINHA, Barij N.
60, 153
SÖNMEZ, Mehmet
77, 78
TEKE, Şenel
74
TEMEL, İsmail
68
TOGAR, Başak
92
TOPÇU, Zeki
121
TOPTAN, Suna
102, 141
TOZKOPARAN, Birsen
147
TUĞRAK, Mehtap
58
TÜLÜ, Metin
35
TUNCEL, Ercan
24
TURAN, Atakan
129
152
TÜRKEZ, Hasan
92, 93, 94, 95, 96
TÜRKÖZ ACAR, Ebru
TÜRKÖZ, Yusuf
125
139
STELMASİŃSKİ, Michał
164
89, 90, 118
VALLE, Anne
101
VENKATESH, Nagasamy
108
VERSIANI, Mohammad Ali
43, 47
VISWANATH, B. A.
108
Y
YABANOĞLU ÇİFTÇİ, Samiye 60,
153, 154
YALÇIN, Bediha
83, 84, 87
YALÇIN, Funda N.
127, 165
YALOVAÇ ASLAN, Açelya
60, 154
YASMEEN, Kousar
47
YAVUZ ERDOĞAN, Behice
131
YELEKÇİ, Kemal
18
YERER, Mükerrem Betül
115
YILDIZ, Bülent Okan
26
YILMAZ, Habibe
128, 130
YILMAZ, Hayriye
115, 116, 117
YILMAZ, İsmet
67, 68
YILMAZ, Şükran
64
YÜCEL, Çiğdem
64
YÜKSEL, Atlan
135
YURTTAŞ, Leyla
114
YÜZÜAK, Nesrin
141
Z
ZENCİR, Sevil
121
ZENGİN, Gülay
65
ZENGİN, Hüseyin
65
68
International Symposium on Drug Research & Development 2011
168
48
V
77
SOYER, Zeynep
102
ULUSOY, Seyhan
TURAN ZITOUNI, Gülhan 80, 106, 107
TÜRELİ, Emre
153, 154
60, 149, 153, 154
UL-HASSAN, Shams
43, 47
RASOOL, Fatima
REÇBER, Tuba
UÇAR, Bercis İmge
Türkiye’ye değer katıyoruz
Sanofi - aventis Grubu olarak 2000’e yakın çalıºanımızla aºı ve ilaçlarımızın yaklaºık
%70’ini Türkiye’de üreterek ekonomimize katkı sağlıyoruz. İnsanların yaºamını
iyileºtirmek için Türkiye’ye Ar-Ge yatırımı yapıyor, sağlık profesyonellerimize eğitim ve
bilimsel destek sunuyoruz.