Depside as potent inhibitor of prostaglandin biosynthesis: a new active site model for fatty acid cyclooxygenase.
Forty depsides and depsidones, the esters of phenolcarboxylic acids, were examined for their inhibitory effect against prostaglandin biosynthesis with rabbit renal microsomes. 4-0-Methylcryptochlorophaeic acid was the most active inhibitor so far tested and its IC50 value was 0.34 muM. Kinetic investigation has shown that this depside acts competitively with respect to arachidonic acid as most of the non - steroidal antiinflammatory drugs. X-Ray analysis has revealed that 4-0-methylcryptochlorophaeic acid maintains its rigid conformation by forming a strong hydrogen bond between the hydroxyl and methoxyl groups. Comparison of CPK models between 4-0-methylcryptochlorophaeic acid and non-steroidal antiinflammatory drugs revealed that the carboxyl group and the two rings of these drugs are almost superimposable to those of the depside. This finding led us to propose a new active site model based on the three dimentional structure of the depside.
D000818:Animals; D001665:Binding Sites; D055598:Chemical Phenomena; D002621:Chemistry; D003460:Crystallization; D053630:Depsides; D062385:Hydroxybenzoates / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology; D008861:Microsomes / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases; D011817:Rabbits; D014961:X-Ray Diffraction
D053630:Depsides; D062385:Hydroxybenzoates; D011451:Prostaglandin-Endoperoxide Synthases