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

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Walters MJ, Blobaum AL, Kingsley PJ, Felts AS, Sulikowski GA, Marnett LJ

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

Bioorg Med Chem Lett. 2009 Jun 15;19(12):3271-4. doi: 10.1016/j.bmcl.2009.04.078. Epub 2009 Apr 23.

PubMed ID

19427206 [ View in PubMed

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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.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Indomethacin	Prostaglandin G/H synthase 2	IC 50 (nM)	40	N/A	N/A	Details