# In situ click chemistry generation of cyclooxygenase-2 inhibitors

“In situ click chemistry generation of cyclooxygenase-2 inhibitors” (2017), by Atul Bhardwaj et al. Chemistry research paper. Original abstract below, unchanged. A free PDF is available.

- Authors: Atul Bhardwaj, Jatinder Paul Kaur, Melinda Wuest, Frank R. Wuest
- Published: February 9, 2017
- Field: Chemistry
- DOI: https://doi.org/10.1038/s41467-016-0009-6
- Free PDF: https://www.nature.com/articles/s41467-016-0009-6.pdf

## 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.Traditional inflammation and pain relief drugs target both cyclooxygenase 1 and 2 (COX-1 and COX-2), causing severe side effects. Here, the authors use in situ click chemistry to develop COX-2 specific inhibitors with high in vivo anti-inflammatory activity.

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