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.
Highlights
Cyclooxygenase-2 isozyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is associated with several cancers and neurodegenerative diseases
COXIBs are under scrutiny since several studies have demonstrated that chronic use of COXIBs can elevate the risk of myocardial infarction and other thrombotic events by stalling the biosynthesis of antipagrogr-ethgraotomryboptricostthacryocmlibno(xPaGneI2)Aw2 h(iTlexlAea2)vinugnatfhfeecbteiods2y6n–2t9h.esAiss of a result, COXIBs such as rofecoxib and valdecoxib were withdrawn from the market thereby leaving a demand for the synthesis and screening of novel COX-2 inhibitors
Based on the structural features of the COX-2 active site, we concluded that suitable clickable building blocks should meet two criteria: (i) at least one of the building blocks should possess a SO2Me COX-2 pharmacophore to facilitate its tight binding into the secondary-binding pocket of the COX-2 isozyme; (ii) the azide component should have a proper size and orientation that will not interfere with the entry of the alkyne component into the COX-2 active site, allowing the in situ click
Summary
Cyclooxygenase-2 isozyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is associated with several cancers and neurodegenerative diseases. COX-1 is a constitutively expressed house-keeping isozyme responsible for the basal production of essential PGs8 These PGs mediates homoeostatic functions in the gastrointestinal and cardiovascular system. There is accumulating evidence for the critical involvement of COX-2 in various pathologies that include inflammation, cancer, neurodegenerative diseases and multidrug resistance. There is accumulating evidence for the critical involvement of COX-2 in various pathologies that include inflammation, cancer, neurodegenerative diseases and multidrug resistance16 Beyond their traditional use as anti-inflammatory agents, COX-2 inhibitors have recently been used for molecular imaging and therapy of cancer. Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) (aspirin, ibuprofen, naproxen) inhibit both COX-1 and COX-2 isoforms; and their use is limited due to associated ulcerogenic and gastrointestinal side effects. COXIBs are under scrutiny since several studies have demonstrated that chronic use of COXIBs can elevate the risk of myocardial infarction and other thrombotic events by stalling the biosynthesis of antipagrogr-ethgraotomryboptricostthacryocmlibno(xPaGneI2)Aw2 h(iTlexlAea2)vinugnatfhfeecbteiods2y6n–2t9h.esAiss of a result, COXIBs such as rofecoxib and valdecoxib were withdrawn from the market thereby leaving a demand for the synthesis and screening of novel COX-2 inhibitors
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