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

ABSTRACT: 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.

SUBMITTER: Walters MJ

PROVIDER: S-EPMC2760071 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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

Walters Matthew J MJ Blobaum Anna L AL Kingsley Philip J PJ Felts Andrew S AS Sulikowski Gary A GA Marnett Lawrence J LJ

Bioorganic & medicinal chemistry letters 20090423 12

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 p ...[more]

PMID: 19427206

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