In situ click chemistry generation of cyclooxygenase-2 inhibitors
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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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The record
- Venue
- Nature Communications
- Topic
- Click Chemistry and Applications
- Field
- Chemistry
- Canadian institutions
- University of Alberta
- Funders
- Natural Sciences and Engineering Research Council of CanadaCanadian Institutes of Health ResearchAlberta Cancer Foundation
- Keywords
- CyclooxygenaseIsozymeIn vivoChemistryClick chemistryDrug discoveryGene isoformBiochemistryEnzymeComputational biologyCombinatorial chemistryBiologyBiotechnologyGene
- Has abstract in OpenAlex
- yes