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

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.

Graphical abstractThe isomerization of (E)-2′-des-methyl sulindac sulfide to (Z)-2′-des-methyl sulindac sulfide results in differential COX inhibition.Figure optionsDownload full-size imageDownload as PowerPoint slide