Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 19, Issue 12, Pages 3271-3274Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2009.04.078
Keywords
COX inhibition; Photoisomerization; NSAIDs; 2 '-des-Methyl sulindac sulfide
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Funding
- National Institutes of Health [CA89450]
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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. (C) 2009 Elsevier Ltd. All rights reserved.
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