Inhibition of Prostaglandin Biosynthesis by 4-O-Methylcryptochlorophaeic Acid; Synthesis of Monomeric Arylcarboxylic Acids for Inhibitory Activity Testing and X-Ray Analysis of 4-O-Methylcryptochlorophaeic Acid

Abstract

In order to clarify the structure-activity relationship of 4-O-methylcryptochlorophaeic acid (1), which is a lichen meta-depside and a potent inhibitor of prostaglandin (PG) biosynthesis found in our previous screening work, arylcarboxylic acids (5—8) corresponding to the monomeric moieties of 4-O-methylcryptochlorophaeic acid (1) were synthesized and tested for inhibitory effect against PG biosynthesis by an enzyme system prepared from rabbit renal medulla. They were a hundred times less active than 4-O-methylcryptochlorophaeic acid (1), indicating that the dimeric structure of the meta-depside is essential for inhibitory activity against PG biosynthesis. Kinetic studies on the mechanism of inhibition revealed that 4-O-methylcryptochlorophaeic acid (1) inhibits PG biosynthesis competitively with respect to the substrate, arachidonic acid. The three dimensional structure of 4-O-methylcryptochlorophaeic acid (1), which is expected to have a molecular structure able to fit into an active site that accommodates arachidonic acid, was determined by single crystal X-ray analysis with the direct approach. The obtained structure reveals that 4-O-methylcryptochlorophaeic acid (1) maintains a rigid conformation by forming a strong hydrogen bond between a hydroxy group and a methoxy group. Based on these findings, a new active site model of fatty acid cyclooxygenase is proposed in order to explain the inhibition by the meta-depside and acidic non-steroidal antiinflammatory drugs. © 1983, The Pharmaceutical Society of Japan. All rights reserved.