ACS Medicinal Chemistry Letters
Letter
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the COX-1 (3KK6) active site and V-shaped docking pose of
these three COX-2 inhibitors as well as of celecoxib, rofecoxib,
and etoricoxib established their COX-2 selectivity. Thus, the
present work unfolds a new chemical class and next generation
selective COX-2 inhibitors as anti-inflammatory agents. In view
of the adverse side effect of some of the existing COX-2
selective anti-inflammatory drugs that led to the withdrawal of
some of them from the market, the present findings of new
anti-inflammatory scaffold should help finding more effective
therapeutics for the treatment of RA and OA. With the newer
clinical indication of NSAIDs with cancer risk reduction in
chronic dialysis patients, this new generation of COX-2
selective inhibitors may also provide newer and alternate
cancer therapeutics.
(9) Masferrer, J. L.; Zweifel, B. S.; Manning, P. T.; Hauser, S. D.;
Leahy, K. M.; Smith, W. G.; Isakson, P. C.; Seibert, K. Selevtive
inhibition of inducible cyclooxygenase 2 in vivo is anti-inflammatory
and nonulcerogenic. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 3228−3232.
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effects of the coxibs. J. Med. Chem. 2005, 48, 2251−2257.
(11) Cannon, C. P.; Cannon, P. J. COX-2 inhibitors and
cardiovascular risk. Science 2012, 336, 1386−1387.
(12) Shono, T.; Tofilon, P. J.; Bruner, J. M.; Owolabi, O.; Lang, F. F.
Cyclooxygenase-2 expression in human gliomas: prognostic signifi-
cance and molecular correlations. Cancer. Res. 2001, 61, 4375−4381.
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Anticancer Res. 2005, 25, 675−679.
(14) Bijnsdorp, I. V.; van den Berg, J.; Kuipers, G. K.; Wedekind, L.
E.; Slotman, B. J.; van Rijn, J.; Lafleur, M. V. M.; Sminia, P.
Radiosensitizing potential of the selective cyclooxygenase-2 (COX-2)
inhibitor meloxicam on human glioma cells. J. Neurooncol. 2007, 85,
25−31.
ASSOCIATED CONTENT
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S
* Supporting Information
Spectral data and scanned spectra (1H and 13C NMR, HPLC);
3D QSAR. This material is available free of charge via the
(15) Kang, K. B.; Wang, T. T.; Woon, C. T.; Cheah, E. S.; Moore, X.
L.; Zhu, C.; Wong, M. C. Enhancement of glioblastoma radioresponse
by a selective COX-2 inhibitor celecoxib: inhibition of tumor
angeiogenesis with extensive tumor necrosis. Int. Radiat. Oncol. Biol.
Phys. 2007, 67, 888−896.
AUTHOR INFORMATION
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Corresponding Author
*(A.K.C.) Tel: 91-(0)-172 2214683. Fax: 91-(0)-172 2214692.
(16) Hocherl, K.; Schmidt, C.; Bucher, M. COX-2 inhibition
̈
attenuates endotoxin-induced downregulation of organic anion
transporters in the rat renal cortex. Kidney Int. 2009, 75, 373−380.
(17) Schneider, F.; Meziani, F.; Chartier, C.; Alt, M.; Jaeger, A. Fatal
allergic vasculitis associated with celecoxib. Lancet 2002, 359, 852−
853.
Present Address
∥Department of Pharmacology, School of Pharmaceutical
Sciences, Shoolini University, Solan 173212, HP, India.
Author Contributions
(18) Woodcock, J. A difficult balance: pain management, drug safety,
and the FDA. N. Engl. J. Med. 2009, 361, 2105−2107.
(19) Dannenberg, A. J.; Altorki, N. K.; Boyle, J. O.; Dang, C.; Howe,
L. R.; Weksler, B. B.; Subbaramaiah, K. Cyclooxogenase 2: a
pharmacological target for prevention of cancer. Lancet Oncol. 2001,
2, 544−551.
(20) Thun, M. J.; Henley, S. J.; Patrono, C. Nonsteroidal anti-
inflammatory drugs as anticancer agents: mechanistic, pharmacologic,
and clinical issues. J. Natl. Cancer. Ist. 2002, 94, 252−266.
(21) Arber, N.; DuBois, R. N. Nonsteroidal anti-inflammatory drugs
and prevention of colorectal cancer. Curr. Gastroenterol. Rep. 1999, 1,
441−448.
A.K.C. conceived the project, designed the experiments,
analyzed the data, and wrote the paper. K.S., S.K.G., R.K.,
and P.P. performed the synthesis and enzyme assays. V.S.M.
and U.C.B. were associated with the enzyme inhibitory studies.
R.G. performed the in vivo experiments.
Funding
K.S. and S.K.G. thank CSIR and UGC (New Delhi, India),
respectively, for senior research fellowships. Financial support
from DST (New Delhi) (SR/S1/OC-33/2008) is also
gratefully acknowledged.
Notes
(22) Gupta, R. A.; DuBois, R. N. Colorectal cancer prevention and
treatment by inhibition of cyclooxygenase-2. Nat. Rev. Cancer. 2001, 1,
11−21.
The authors declare no competing financial interest.
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