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.
A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Matthew J
MJ
Walters
Anna L
AL
Blobaum
Philip J
PJ
Kingsley
Andrew S
AS
Felts
Gary A
GA
Sulikowski
Lawrence J
LJ
Marnett
D000818:Animals; D001597:Benzylidene Compounds; D051545:Cyclooxygenase 1 / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D007192:Indenes; D051379:Mice; D015394:Molecular Structure; D012756:Sheep; D013329:Structure-Activity Relationship; D013467:Sulindac / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D001597:Benzylidene Compounds; D016861:Cyclooxygenase Inhibitors; D007192:Indenes; D013467:Sulindac; C093581:indene; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2