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Sulikowski Lab

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

AUTHORS

Walters MJMatthew J , Blobaum AL Anna L , Kingsley PJ Philip J , Felts AS Andrew S , Sulikowski GA Gary A , Marnett LJ Lawrence J . Bioorganic & medicinal chemistry letters. 2009 6 15; 19(12). 3271-4

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.

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.