In situ click chemistry generation of cyclooxygenase-2 inhibitors

TLDR

Cyclooxygenase‑2 is a key anti‑inflammatory target whose overexpression is linked to cancers and neurodegenerative diseases, yet its high structural similarity to cyclooxygenase‑1 hampers the design of selective inhibitors. The study aims to generate highly selective COX‑2 inhibitors by exploiting the enzyme’s active site as a reaction vessel for in situ click chemistry. Using kinetic target‑guided synthesis, the authors perform in situ click chemistry within the COX‑2 active site, allowing the enzyme to assemble potent.

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.