Philip Kingsley
Last active: 3/12/2020

Cyclooxygenase-1-selective inhibitors based on the (E)-2'-des-methyl-sulindac sulfide scaffold.

Liedtke AJ, Crews BC, Daniel CM, Blobaum AL, Kingsley PJ, Ghebreselasie K, Marnett LJ
J Med Chem. 2012 55 (5): 2287-300

PMID: 22263894 · PMCID: PMC3297362 · DOI:10.1021/jm201528b

Prostaglandins (PGs) are powerful lipid mediators in many physiological and pathophysiological responses. They are produced by oxidation of arachidonic acid (AA) by cyclooxygenases (COX-1 and COX-2) followed by metabolism of endoperoxide intermediates by terminal PG synthases. PG biosynthesis is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). Specific inhibition of COX-2 has been extensively investigated, but relatively few COX-1-selective inhibitors have been described. Recent reports of a possible contribution of COX-1 in analgesia, neuroinflammation, or carcinogenesis suggest that COX-1 is a potential therapeutic target. We designed, synthesized, and evaluated a series of (E)-2'-des-methyl-sulindac sulfide (E-DMSS) analogues for inhibition of COX-1. Several potent and selective inhibitors were discovered, and the most promising compounds were active against COX-1 in intact ovarian carcinoma cells (OVCAR-3). The compounds inhibited tumor cell proliferation but only at concentrations >100-fold higher than the concentrations that inhibit COX-1 activity. E-DMSS analogues may be useful probes of COX-1 biology in vivo and promising leads for COX-1-targeted therapeutic agents.

MeSH Terms (16)

Animals Antineoplastic Agents Cell Line, Tumor Cell Proliferation Cyclooxygenase 1 Cyclooxygenase 2 Inhibitors Cyclooxygenase Inhibitors Drug Screening Assays, Antitumor Female Humans Hydrophobic and Hydrophilic Interactions Mice Sheep Stereoisomerism Structure-Activity Relationship Sulindac

Connections (2)

This publication is referenced by other Labnodes entities: