Download Significant contribution of Ram Sagar towards Organic Chemistry

Significant contribution of Ram Sagar towards Organic Chemistry
I contributed towards the area of synthetic carbohydrate chemistry, medicinal
chemistry as well as natural product chemistry during my PhD. I have designed and
synthesized a new series of C-3-branched 2,3-dideoxy glucopyranosides on the concept of
structure based drug design for anti-tubercular activity (Tetrahedron 2004, 60, 1139911406; Indian Pat. Appl. (2007), 37pp. IN 2006DE00533 (Ref. No. 0210NF2005); J. Med.
Chem. 2007, 50, 2942-2950). Many of the synthesised compounds have shown good in vitro
activity. Two among them have also shown promising anti-TB activity in vivo. Further lead
optimization of these compounds is in progress at CDRI Lucknow.
Apart from synthesizing medicinally important molecules, I have also developed
several novel synthetic transformation reactions on carbohydrate templates such as:
(a) Ring annulation reaction of 4-hydroxypyrones with glycals derived Perlin aldehydes
towards the formation of pyrano-pyrones (Carbohydr. Res. 2005, 340, 1287-1300) (b)
Synthesis of epoxyalcohols, precursor of amino alcohols, through asymmetric epoxidation on
sugar derived allylic alcohols. (Tetrahedron: Asymmetry 2006, 17, 1189-1198); (c) We have
developed several methodologies, one of them was consecutive approach for the synthesis
of highly functionalised chirally pure tetrahydrofuran motifs. (Tetrahedron: Asymmetry 2006,
17, 3294-3299).
I have worked as a research associate, at Indian Institute of Technology Kanpur
(IITK). My work was focused on the metal-catalyzed synthesis of conformationally restricted
aza-sugars (J. Org. Chem. 2011, in communication) and stereoselective synthesis of Safigol
and its natural isomer (Tetrahedron Lett. 2008, 73, 3270).
During my first independent post-doc abroad at the department of chemistry, Seoul
National University, South Korea, I designed and synthesised carbohybrids, a new class of
compounds, on Diversity Oriented Synthesis (DOS) pathways starting from carbohydrate
precursor, and evaluated their bio-activity (J. Org. Chem. 2009, 74, 2171; J. Org. Chem.
2008, 73, 3270 and Tetrahedron Lett. 2008, 49, 5080).
Here in the University of Oxford, UK, I successfully finished two projects investigating
the sugar signalling in plants in particular on trehalose pathways towards more biomass
production, these finding can be considered as alternative of GM crops. These findings has
been filed for UK patent (UK Patent 2011 (No. 01107031.5) 26.04.2011). Currently I am
developing new chemistries for Native Chemical Ligation (NCL) and also working on HIV
vaccine development projects. I have made significant progress on these lines, but details
can’t be discussed due to unpublished results and intellectual property right (IPR).
15 international papers published and 2 patents filed from my pre- and post- doctoral
research. Some papers are in communications from my current work.
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Research Plan
Ram Sagar
I did my pre-doctoral research in the area of structure based drug design and
synthesis, in particular anti-tuberculosis drugs, starting from carbohydrate precursors as the
chiral pool. I also obtained expertise in the isolation and characterisation of bioactive
molecules from Indian medicinal plants.
My first post doctoral research experience at Seoul National University, South Korea,
was synthesis of Carbohybrids starting from carbohydrates on the concept of Diversity
Oriented Synthesis. During this time I also learned how to utilise such diversified molecules,
fulfilling different 3D chemical space, as chemical probe to investigate various biological
process in living system.
Currently I am working in many broad spectrum projects at the interface of chemistry
and biology. In one project I am focusing to investigate the sugar singling process and
interfere it in plant by organic molecules in order to enhance the biomass production in plant.
I am also working in the area of HIV vaccine development project.
Based on my pre-doctoral and post-doctoral research experience I will
undertake/initiate following research projects during my independent academic carrier.
1. Carbohydrates and proteins: The biological roles of carbohydrates have until
recently been viewed as simple ones: as sources of energy, e.g., glucose, or as
polymeric building materials, e.g., chitin in crab shells, cellulose in wood.
However, it is becoming increasingly clear that oligosaccharides (carbohydrates in
small clusters) and alterations in proteins (modifications)
1,2
are examples of
chemically complex biological markers that can act in important recognition
processes such as microbial infection, cancer metastasis and cellular adhesion in
inflammation, in addition to many intracellular communication events. Their
remarkable structural diversity means that they can often mediate highly specific
and therefore complex processes. The application of an understanding of such
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systems on a fundamental level leads to the design, synthesis and modification of
potential therapeutic and biotechnologically applicable systems.
Thus, my future research focus in this area will be the synthesis, manipulation
and redesign of naturally occurring carbohydrate-containing and peptidecontaining structures (bioconjugates) which allows the probing of key
biochemical mechanisms. Through the understanding of these processes potential
therapeutic strategies would be developed. My work will involve experimental
techniques and novel synthetic methodology, target synthesis using both
biotransformations and conventional synthetic methods on proteins (Scheme 1).
Scheme 1.
I will also undertake the synthesis of high mannose glycans present on the cell surface
of various pathogens in order to find some vaccine candidate. The modified sugars will also
be synthesised and linked to get new glycans which may possess totally different function.
The coupling of these glycans with different carrier proteins (BSA and Q-beta etc) will be
undertaken in order to get new glycoconjugates (Scheme 2). These new glycans will be
explored towards vaccine development.
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Scheme 2.
2. Diversity Oriented Synthesis and Chemical Biology: A collection of “naturalproduct-like” small molecules that specifically perturb the individual functions of
gene products are facilitating the exploration of biological pathways.3 Therefore,
the development of an efficient route for the synthesis of drug like small
molecules, that specifically perturb the individual function of gene products, has
been the focus of research for medicinal chemists and chemical biologists.4
Diversity-oriented synthesis (DOS) that aims to populate the chemical space with
skeletally and stereochemically diverse small molecules with high appending
potentials has been proven to be an essential tool for the discovery of bioactive
small molecules.5 The incorporation of privileged substructural motifs has become
an essential element in DOS pathways.
Thus, my future research in this area will be to investigate potential privileged
substructural motif and modify them to generate diverse library of Carbohybrid
with different 3D chemical space. The novel stereospecific organic molecules thus
obtained will be explored for their specific interactions with biopolymers and
develop microarrays methods to understand many complex processes in the
biological system (e.g. plant and animals) and utilised the knowledge thus
obtained for the benefit of mankind. The commercially available glycal (e.g.
Glucal, galactal, arabinal, xylal etc, Figure 1) will be explored as starting material
to prepare suitable chiral synthone (Scheme 3) which can be modified further in
order to get diversified molecules.
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Figure 1.
Scheme 3.
3. Efficient synthesis of Iminosugars: The iminosugars are very important class of
naturally occurring molecules which posses various biological activities. They are
inhibitors of glycosyltransferases and glycosidases and have therapeutic
application against cancer, AIDS and diabetes. 6 The new and simple route for the
synthesis of various iminosugar as shown in scheme 4 will also be undertaken.
Scheme 4.
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4. Asymmetric Methodology: Carbohydrates are an unrivalled source of
contiguous, stereogenic centres - chirality that grows on trees. It is therefore all
the more surprising that their use to induce asymmetry has been more limited than
the use of other sources. I will undertake to change this by developing ligands and
organocatalysts based on sugar scaffolds and by exploring the role of sugars in
prebiotic emergence of chirality.
References:
1. a) van Kasteren, S. I.; Kramer, H. B.; Jensen, H. H.; Campbell, S. J.; Kirkpatrick, J.;
Oldham, N. J.; Anthony, D. C. and Davis, B. G. Nature 2007, 446, 1105. b) Davis, B. G.
Science 2004, 303, 480.
2. van Kasteren, S. I.; Kramer, H. B.; Gamblin, D. P.; and Davis, B. G. Nature protocols 2007,
2, 3186.
3. Bruke, M. D. and Schreiber, S. L. Angew. Chem. Int. Ed. 2004, 43, 46.
4. Schreiber, S. L. Nature 2009, 457, 153.
5. Schreiber, S. L. Science 2000, 287, 1964.
6. a) Doddi, V. R.; Vankar, Y. D.; Eur. J. Org. Chem. 2007, 5583. b) Carmona, A. T.; Fuentes,
J.; Robina, I.; García, E. R.; Demange, R.; Vogel, P.; Winters, A. L. J. Org. Chem. 2003, 68,
3874.
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My approach to teaching will be reflection of my approach to chemistry research. I
will take a great deal of pleasure in attacking complex problems, not because they are
complex, but because by breaking them down and systematically unraveling the mysteries
they hold I can hope to gain insight into the fundamental chemical principles at their core.
Sometimes it becomes much easier to learn, the 3D structures of chiral molecules and
their interactions with biopolymers, while sitting in front of a computer than from a live
instructor. Therefore, when feasible, I would use computer based tutorials and exercises that
require the active participation of the student. I would similarly encourage the use of online
data sources for term papers and group projects.
With my experience (outlined in my CV), as well as my interests and research
expertise, I am confident that, I could teach courses that would fall within the organic
chemistry in the departments. However, my greatest strengths lie within the following topics
of chemical sciences.
(i)
Fundamental of organic reactions.
(ii)
Reactions and their mechanism.
(iii)
Organic synthesis reagents and reactions.
(iv)
Stereochemistry and conformations.
(v)
Carbohydrate chemistry.
(vi)
Medicinal chemistry.
(vii)
Chemical biology.
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