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

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 previous screening work, arylcarboxylic acids corresponding to the monomeric moieties of 1 were synthesized and tested for inhibitory effect against PG biosynthesis by an enzyme system prepared from rabbit renal medulla. They were 100 times less active than 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 1 inhibits PG biosynthesis competitively with respect to the substrate, arachidonic acid. The 3-dimensional structure of 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 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 to explain the inhibition by the meta-depside and acidic non-steroidal antiinflammatory drugs.