In situ click chemistry generation of cyclooxygenase-2 inhibitors

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 isof...

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Vydané v:	Nature communications Ročník 8; číslo 1; s. 1 - 14
Hlavní autori:	Bhardwaj, Atul, Kaur, Jatinder, Wuest, Melinda, Wuest, Frank
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 23.02.2017 Nature Publishing Group Nature Portfolio
Predmet:	631/154/309/2144 631/92/96 639/638/309/2144 639/638/92/96 Animals Anti-inflammatory agents Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis Anti-Inflammatory Agents, Non-Steroidal - pharmacology Binding sites Biosynthesis Carrageenan Chemical synthesis Chemistry Click Chemistry - methods COX-2 inhibitors Cyclooxygenase 1 - chemistry Cyclooxygenase 1 - genetics Cyclooxygenase 1 - metabolism Cyclooxygenase 2 - chemistry Cyclooxygenase 2 - genetics Cyclooxygenase 2 - metabolism Cyclooxygenase 2 Inhibitors - chemical synthesis Cyclooxygenase 2 Inhibitors - pharmacology Cyclooxygenase-1 Cyclooxygenase-2 Drug Design Edema - chemically induced Edema - drug therapy Edema - enzymology Edema - pathology Enzymes Female Gene Expression Heart attacks Hindlimb Humanities and Social Sciences Humans Inflammation Inhibitors Kinetics Molecular Docking Simulation multidisciplinary Nonsteroidal anti-inflammatory drugs Pain Pharmaceuticals Protein Structure, Secondary Proteins Pyrazoles - chemical synthesis Pyrazoles - pharmacology Rats Science Science (multidisciplinary) Side effects Structure-Activity Relationship Thermodynamics Triazoles - chemical synthesis Triazoles - pharmacology
ISSN:	2041-1723, 2041-1723
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-016-0009-6