Philip Kingsley
Last active: 3/12/2020

The influence of double bond geometry in the inhibition of cyclooxygenases by sulindac derivatives.

Walters MJ, Blobaum AL, Kingsley PJ, Felts AS, Sulikowski GA, Marnett LJ
Bioorg Med Chem Lett. 2009 19 (12): 3271-4

PMID: 19427206 · PMCID: PMC2760071 · DOI:10.1016/j.bmcl.2009.04.078

Sulindac sulfide is a benzylidene-indene that is a potent, time-dependent inhibitor of cyclooxygenases-1 and -2. Removal of the 2'-methyl group from the indene ring dramatically reduces time-dependent inhibition of both enzymes but also changes the geometry of the benzylidene double bond from Z to E. Herein, we explore the importance of double bond geometry on cyclooxygenase inhibition. The Z-isomer of 2'-des-methyl sulindac sulfide was synthesized by reduction of a bromoindene precursor or by photoisomerization of the E-isomer. The Z-isomer inhibited both cyclooxygenases, but with diminished potency compared to sulindac sulfide. Thus, although the 2'-methyl group is a major determinant of time-dependent cyclooxygenase inhibition, the geometry of the benzylidene double bond plays a role as well.

MeSH Terms (11)

Animals Benzylidene Compounds Cyclooxygenase 1 Cyclooxygenase 2 Cyclooxygenase Inhibitors Indenes Mice Molecular Structure Sheep Structure-Activity Relationship Sulindac

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