Download copper complexes of non-steroidal anti

COPPER COMPLEXES OF NON-STEROIDAL ANTIINFLAMMATORY DRUGS
Andrea Čongrádyová, Klaudia Jomová
Department of Chemistry, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, Tr. A.
Hlinku 1, 949 74 Nitra, Slovakia
Correspondig author: [email protected]
Abstract
Plasma concentrations of low molecular weight copper-containing components are known to increase in
response to various diseases such as arthritis, epilepsy, and cancer. Each of these diseases is recognized as
having inflammatory components. Experiments on animals have shown that administration of low molecular
weight copper complexes produced anti-inflammatory effects. Based on these results it was confirmed that the
elevation of plasma copper-containing components represents a physiologic response which may lead to
remission. Promotion of this physiologic response is a valid approach to the treatment of the diseases with
inflammatory components. It was thus confirmed that copper complexes, a unique class of potentially more
therapeutically useful anti-arthritic agents have both anti-inflammatory and antiulcer activitie. However, the use
of discrete coordination complexes in drug delivery is at a very early stage of development mainly because of the
chronic ingestion of NSAIDs which in turn increases the risk for gastrointestinal complications, ranging from
dyspepsia to gastrointestinal bleeding, obstruction, and perforation. On the other hand, there has been
significant progress in the use of coordination copper complexes in drug delivery revealing their unique
advantages over many other drug delivery systems.
Key words: copper, NSAID, anti–inflammatory drugs, cyclooxygenase, prostaglandine (PG)
1 NSAIDs
Non-steroidal anti-inflammatory drugs (NSAIDs) are also known as non-steroidal antiinflammatory agents/analgesics (NSAIAs) or non-steroidal anti-inflammatory medicines
(NSAIMs). These drugs among a broad range of other effects have a similar eicosanoiddepressing and anti-inflammatory action as steroid drugs (Hawkey, 1999).Until recently, the
non-steroidal anti-inflammatory drugs included some of the most commonly used drugs
worldwide. These drugs have proved to be effective in the treatment of acute and chronic
painful and inflammatory musculoskeletal conditions (Simon et al., 2005).
In this contribution, we shortly summarise current knowledge about copper based nonsteroidal anti-inflammatory drugs (Cu-NSAIDs), their chemical composition, suggested mode
of action, the fields of medical applications as well as the possible adverse effects of their use.
2 NSAIDs - mechanism of action
NSAIDs act by preventing the conversion of arachidonic acid to intermediate and terminal
prostaglandins (PG) (Figure1). The terminal prostaglandins are extremely pro-inflammatory
and interface with other pain-producing mechanisms. Prostaglandin inhibition occurs because
the NSAIDs affect the converting enzyme cyclooxygenase (COX) (Polisson, 1996; Gasparini
et al., 2004). Different variants of COX have been described: COX-1, which is constitutively
expressed in nearly all tissues and it possesses mainly ‘housekeeping’ functions; COX-2,
which is induced at injury sites by inflammatory stimuli and play a key role during
inflammation; and finally the recently identified COX-3, whose function is still unknown.
Based on this general functional distinction, an effort was made to design drugs which
selectively inhibit COX-2 and thereby are devoid of the adverse effects associated with the
blockade of both COX-1 and COX-2, e.g. gastrointestinal lesions.
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Fig. 1 Schematic diagram for the conversion of arachidonic acid to eicosanoids (PGprostaglandins, TXA-thromboxane) by the cyclooxygenase (COX) and the major site of
action of the NSAIDs (non-steroidal anti-inflammatory drugs), (Dubois et al., 2005,
modified).
Polisson (1996) has divided NSAIDs according to their abilities to inhibit specific types of
COX-isoenzymes. Flurbiprofen, ibuprofen, and meclofenamate are the NSAIDs judged to be
equally potent against COX-1 and COX-2. Those NSAIDs that preferentially inhibited COX1 (10-30 times greater than COX-2) were piroxicam, indomethacin, and sulindac.
Methoxynaphthyl acetic acid, which is the active moiety of nabumetone, preferentially
inhibited COX-2 (about 7 times greater than COX-1).While non-selective NSAIDs inhibit
both COX-1 and COX-2 enzymes to a significant degree, selective NSAIDs inhibit COX-2
enzymes found at sites of inflammation (COX-2) more than the type that is normally found in
the stomach, blood platelets, and blood vessels (COX-1), (Mizushima, 2010).
Basha et al. (2011) have suggested the classification of NSAIDs based on chemical
structure to the six groups– salicylates, acetic acids, oxicams, propionic acids, fenamates,
pyrazoles, (Figure 2).
A
B
C
D
E
F
Fig. 2 Structural classes of NSAID: A – salicylates (e.g. Salicyl salicylate / Salsalate), B –
acetic acids (e.g. Indomethacin), C – oxicams (e.g. Ampiroxicam), D – propionic acids (e.g.
Ibuprofen), E – fenamates (e.g. Tolfenamic acid), F – pyrazoles (e.g. Phenylbutazone),
(Basha et al., 2011).
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3 Copper-based NSAIDs
Transition metals have been used as anti-inflammatory and anti-arthritic agents. Due to the
physiological importance of copper (Cu) and its unique redox activity, many different Cu
complexes and Cu chelators have been synthesized and investigated for their therapeutic and
diagnostic potential in human disease (Angelusiu et al., 2009; Duncan, White, 2012; Švorec et
al., 2009). Copper complexes of NSAIDs represent a large group of coordination compounds,
interesting from various perspectives that find their application in various fields, especially in
medicine, pharmacology, and the material industry. NSAID acids bind to the central atom Cu
(II) mainly due to the carboxyl group(s). The copper carboxylates drugs constitutes an
important element of anti-inflammatory and anticancer agents, some of which are a part of
several commercially available drugs (Weder et al., 2002).
Sorenson (1976) found out that Cu chelates were the intermediates responsible for the
observed anti-inflammatory activity of both cupric acetate and chelating compounds. The Cu
chelates were more active than Cu in the form of cupric acetate and the parent chelating
compounds, that´s why they were considered as the active forms of the anti-inflammatory
agents. The authors have confirmed that Cu chelates are active forms of anti-arthritic drugs. In
1984 Sorenson et al. affirmed hypothesis that the elevation of plasma copper-containing
components represents a physiologic response which may lead to remission. It was confirmed
as a valid approach to the treatment of arthritis, epilepsy, cancer, and other diseases with
inflammatory components.
Copper(II)-complexes, including Cu-NSAIDs, exhibit significant anti-inflammatory
activities as well as SOD mimetic activity. Some researchers propose that NSAIDs, in
addition to their inhibitory effects on the synthesis of PGs, may also inhibit the production, or
act as scavengers of free radicals in vivo. Whatever the mechanism of anti-inflammatory
action of Cu(II)-complexes in vivo, their beneficial function has long been recognized and
their clinical effect has been investigated extensively over the last 50 years (Weder, 2002).
Duncan and White (2012) have also confirmed the ability of copper complexes to increase
SOD activity, leading to relief of oxidative stress. It is obvious that the ability of Cu to
participate in redox reactions combined with the ability of the complex to allow enhanced Cu
delivery results in many efficacious compounds. Omoto et al. (2005) studied utilization of
tetrathiomolybdate (TM) in a rat model of adjuvant arthritis. TM administration resulted in
decreased severity, as demonstrated by a reduction of inflammatory cell invasion into joint
tissues. Ma and Moulton (2011) demonstrated that Cu - NSAIDs exhibited enhanced efficacy
and reduced side effects as their parent drugs. They first developed an approach to rationally
modify the lipophilicity and solubility of Cu-NSAIDs species by forming mixed-ligand
coordination complexes. By tuning the lipophilicity and solubility of a drug complex, its drug
delivery pattern should be modified accordingly. Bombardier et al. (2000) attested that in
patients with rheumatoid arthritis, treatment with rofecoxib, a selective inhibitor of COX-2, is
associated with significantly fewer clinically important upper gastrointestinal events than
treatment with naproxen, a nonselective inhibitor.
4 Applications in medicine
Inflammation is a protective response of the body to infection, injury, or a chronic medical
problem. Anti-inflammatory medicines are available in two categories, steroidal and nonsteroidal, and are prescribed to reduce inflammation. Steroid anti-inflammatories are powerful
medications, which are based on hormonal substances, like cortisone. These medications have
a stronger anti-inflammatory response than the non-steroidal medicines. The steroidal antiinflammatories can have these side effects: loss of bone, cataract, problems with the ability to
fight infection, swelling and weight gain, mood changes, high blood pressure and problems
with the bone marrow. Yajima et al. (2007) described the history of discovery NSAIDs when
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aspirin was synthesized as the first NSAID a century ago, and since then several types of
NSAID have been developed. They have excellent analgesic action with high safety;
therefore, they are used to treat pain associated with many diseases. In the area of orthopedics,
long-term therapy of these drugs is prescribed not only for patients with acute conditions,
such as trauma, but also for the treatment of chronic diseases, such as arthropathies, including
rheumatoid arthritis and low back pain. However, gastric mucosal lesions have long been
identified as a side effect of NSAIDs.
Most people tolerate NSAIDs without any difficulty. A major factor limiting their use is
gastrointestinal toxicity. Although endoscopic studies reveal that gastric or duodenal ulcers
develop in 15 to 30 percent of patients who regularly take NSAIDs, the chief concerns are
clinically important gastrointestinal problems, such as bleeding. It has been estimated that
more than 100,000 patients are hospitalized and 16,500 die each year in the United States as a
result of NSAID-associated gastrointestinal events (Bombardier et al., 2000). Huski and
Simon (2002) in their research also referred that from 5 to 7 percent of hospital admissions
are related to adverse effects of drugs, and of these hospitalizations, those that result from
gastrointestinal, nervous system, renal, or allergic effects of aspirin or the non-aspirin
NSAIDs (NS-NSAIDs) are responsible for approximately 30 percent.
Simon et al. (2005) observed that all drugs which inhibit COX-2 activity, both COX-2
selective inhibitors and NS-NSAIDs, may increase the risk for thromboembolic events thru
very complex physiologic and pathologic mechanisms, there remains the important clinical
decision making process which should reside with the patient and their health care provider in
deciding which therapies are most important for their unique problem. Kukanich et al. (2012)
confirmed that the newer veterinary approved NSAIDs have a lower frequency of
gastrointestinal adverse effects in dogs compared to drugs such as aspirin, ketoprofen and
flunixin, which may be due to differential effects on the COX isoforms. NSAIDs remain the
cornerstone of oral therapy for osteoarthritis unless contraindicated by intolerance, concurrent
therapies or underlying medical conditions. NSAIDs are also effective and frequently used for
the management of post-operative pain.
Dimiza et al. (2011) confirmed chemo-preventive and anti-tumourigenic activity of
NSAIDs by reducing the number and size of carcinogen-induced colon tumours and
exhibiting a synergistic role on the activity of certain antitumour drugs. Many studies have
also reported that NSAIDs induce the apoptosis of colon, breast, prostate, human myeloid
leukaemia and stomach cancer cell lines. Phospho-nonsteroidal anti-inflammatory drugs
(Phospho-NSAIDs) represent novel NSAID derivatives with improved anticancer activity and
reduced side effects in preclinical models. Wong et al. (2011) studied the metabolism of
phospho-NSAIDs by carboxylesterases, and assessed the impact of carboxylesterases on the
anticancer activity of phospho- NSAIDs in vitro and in vivo. Their results showed that
carboxylesterase mediates that metabolic inactivation of phospho-NSAIDs, and the inhibition
of carboxylesterases improves the efficacy of phospho-NSAIDs in vitro and in vivo.
5 Conclusion
The Cu complexes of NSAIDs appear to be promising for veterinary and medical use due
to the reduced gastrointestinal toxicity documented by the successful long term veterinary
applications and the anti-inflammatory activity. The mode of action of the NSAIDs is
primarily attributed to blockage of PG synthesis as a result of inhibition of COX-enzyme
system. However, a number of other potential sites of action are discussed as well. In view of
the presented current achievement in the field of NSAID drugs, it appears rational to prepare
less toxic and effective Cu-NSAIDs. The more complex approach to open new horisons in
this field including calculations on structure – activity relationships is awaited. In our work
we plan to prepare a series of copper (II) complex compounds with carboxylate ligands and to
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study their SOD-mimetic activity spectrophotometrically using Nitro-Blue tetrazolium (NBT)
assay with the xanthine-xanthine oxidase system. For the complexes where a suitable
monocrystal is obtained, X-ray structural analysis will be performed. Quantitative structureactivity relationship (QSAR) analysis will be employed to determine physico-chemical
properties of complexes relating to their biological activity.
6 References
Angelusiu, M. V. et al. 2009. Copper (II) and uranyl(II) complexes with
acylthiosemicarbazide: synthesis, characterization, antibacterial activity and effects on the
growth of promyelocytic leukemia cells HL-60. In J. Med. Chem. Vol. 44/8, 2009, p. 33233329.
Basha, R. et al. 2011. Therapeutic applications of NSAIDS in cancer: special emphasis on
tolfenamic acid. In Frontiers in Bioscience S3. 2011, p. 797 – 805.
Bombardier, C. et al. 2000.Comparison of upper gastrointestinal toxicity of rofecoxib and
naproxen in patients with rheumatoid arthhritis.In The New England Journal of Medicine.
2000, p. 1520 – 1528.
Dimiza, F. 2011. Interaction of copper (II) with the non – steroidal anti – inflammatory drugs
naproxen and diclofenac: Synthesis, structure, DNA – and albumin – binding. In Journal of
Inorganic Biochemistry. Vol. 105, 2011, p. 476 – 489.
Dubois, R.N. et al. 1998. Cyclooxygenase in biology and disease. In The FASEB Journal.
Vol. 12, 1998, p.1063-1073.
Gasparini, L. et al. 2004. Non – steroidal anti – inflammatory drugs (NSAIDs) in Alzheimer´s
disease: old and new mechanisms of action. In Journal of neurochemistry, Vol. 91, 2004,
p. 521 – 536.
Green, G. A. 2002. Understanding NSAIDS: from aspirin to COX-2. In Clin Cornerstone,
Vol.3, 2002, p. 50-59.
Halova-Lajoie B. et al. 2006. Copper(II) interactions with non steroidal anti-inflammatory
agents. III--3- Methoxyanthranilic acid as a potential *OH inactivating ligand: a
quantitative investigation of its copper handling role in vivo. In J. Inorg.Biochem.Vol.
100/3, 2006, p. 362-373.
Hawkey, C. J. 1999. New drug classes, COX – 2 inhibitors. In The Lancet.Vol. 353. 1999, p.
307 – 314.
Husni, M.E.; Simon, L.S. 2002.Additional considerations on the use of NSAIDs.Modern
Therapeutics in Rheumatic Diseases.In Humana Press. 2002,p. 47–65.
Kukanich, B. et al. 2012. Clinical pharmacology of nonsteroidal anti-inflammatory drugs in
dogs. In The Journal of Veterinary Anaesthesia.Vol. 39. 2012, p. 69 – 90.
Ma, Z.; Moulton, B. 2011. Recent advances of discrete coordination complexes and
coordination polymers. In Coordination chemistry reviews.Vol. 255. 2011, p. 1623 – 1641.
Mizushima, T. 2010. Molecular mechanism for various pharmacological activities of
NSAIDs.In Pharmaceuticals, Vol. 3/5, 2010, p. 1614 – 1636.
Omoto, A. et al. 2005. Copper chelation with tetrathiomolybdate suppresses adjuvant-induced
arthritis and inflammation associated cachexia in rats. In Arthritis Res. Ther.Vol. 7. 2005,
p. 1174 – 1182.
Pisetsky, D. S. 1991. NSAID/ Cox – 2; The Facts of NSAIDs, In New England Journal of
Medicine. Vol. 324/24, 1991, p. 1716 – 1725.
Polisson, R. 1996. Nonsteroidal Anti – inflammatory Drugs. Practical and Theoretical
Considerations in Their Selection, InThe American Journal of Medicine.Vol. 100, 1996,p.
31-36.
Rafique, S. et al. 2010.Transition metal complexes as potential therapeutic agents, In
Biotechnology and Molecular Biology Reviews. Vol. 5/2, 2010, p. 38-45.
110
Schoenlefd, P. et al. 1999. Nonsteroidal anti – inflammatory drug – associated gastrointestinal
complications – guidelines for prevention and treatment. In Aliment Pharmacol Ther.Vol.
13. 1999, p. 1273 – 1285.
Simon, L. S. 2005. The COX – 2 inhibitors: a reasoned review of the data, In Swiss Med
WKLY. Vol. 135, 2005. p. 419 – 424.
Smalley, W.E. et al. 1995. Nonsteroidal anti-inflammatory drugs and the incidence of
hospitalizations for peptic ulcer disease in elderly persons. In Am. J. Epidemiol.1995, p.
539-545.
Sorenson, J. R. J. 1976. Copper chelates as possible active forms of the antiarthritic agents. In
Journal of Medicinal Chemistry. Vol. 19/1, 1976, p. 135 – 148.
Sorenson, J. R. J. et al. 1984. Copper complexes: a physiological approach to the treatment of
´Inflammatory disease´. In Inorganica Chimica acta.Vol. 91. 1984, p. 285 – 294.
Švorec, J.; Valko, M.; Moncoľ, J.; Mazúr, M.; Melník, M.; Telser, J. 2009. Determination of
intermolecular copper-copper distances from the EPR half-field transitions and their
comparison with distances from X-ray structures: Applications to copper(II) complexes
with biologically important ligands. In Transition Metal Chemistry, Vol 34, 2009, p. 129134.
Ward, P. P. et al. 2005. Multifunctional roles of lactoferrin: a critical overview. In Cell Mol.
Life Sci. Vol. 62/22, 2005, p. 2540-2548.
Weder, J. E. et al. 2002. Copper complexes of non – steroidal anti – inflammatory drugs: an
opportunity yet to be realized. In Coordination chemistry reviews.Vol. 232/ 1 – 2, 2002. p.
95 – 126.
Wong, Ch. C. et al. 2011. Carboxylesterases 1 and 2 hydrolyze phospho – NSAIDs:
Relevance to their pharmacological activity. In The Journal of Pharamcology and
Experimental Therapeutics.2011, p. 28.
Yajima, H. et al. 2007. Up – to – date information on gastric mucosal lesions from long –
term NSAID therapy in orthopedic outpations: a study using logistic regression analysis. In
Journal of orthopaedic science.Vol. 12. 2007, p. 341 – 346.
111