In situ click chemistry generation of cyclooxygenase-2 inhibitors

Abstract

Cyclooxygenase-2 isozyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is also associated with several cancers and neurodegenerative diseases. The amino-acid sequence and structural similarity between inducible cyclooxygenase-2 and housekeeping cyclooxygenase-1 isoforms present a significant challenge to design selective cyclooxygenase-2 inhibitors. Herein, we describe the use of the cyclooxygenase-2 active site as a reaction vessel for the in situ generation of its own highly specific inhibitors. Multi-component competitive-binding studies confirmed that the cyclooxygenase-2 isozyme can judiciously select most appropriate chemical building blocks from a pool of chemicals to build its own highly potent inhibitor. Herein, with the use of kinetic target-guided synthesis, also termed as in situ click chemistry, we describe the discovery of two highly potent and selective cyclooxygenase-2 isozyme inhibitors. The in vivo anti-inflammatory activity of these two novel small molecules is significantly higher than that of widely used selective cyclooxygenase-2 inhibitors.

Effect of Sn Doping on Pd Electro-Catalysts for Enhanced Electro-Catalytic Activity towards Methanol and Ethanol Electro-Oxidation in Direct Alcohol Fuel Cells

“…Table 3 show the binding energies of the four components of C for CNO samples. The fit results with regards to binding energy (BE) are reported in Table 4 ; they show very good agreement amongst the spectra [ 41 , 42 , 43 ].…”

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