Synthesis and Antiinflammatory Effects of a New Tricyclic Diterpene and Its Analogues as Potent COX-2 Inhibitors

The cycloooxygenase enzymes catalyze the oxidative conversion of arachidonic acid into prostag1andin H$_2$Which mediates both benificial and pathological effects. The COX-1 is constitutively expressed in most tissues and in blood platelets wherease the expression of COX-2 isoform is induced in response to inflmmatory stimuli such as cyctokynes. Thus the identification of a novel COX-2 selective inhibitor should offer excellent antiinflammatory activity with minimal side effects such as gastrointestinal toxicity. Recently, a group of structurally unique and biologically active pimarane diterpenoids has been isolated from indigenous Korean medicinal plants. These new diterpenoids turned out to be potential analgesic and antiinflammatory agent due to their potent inhibitory activities of prostaglandin synthesis. We have also found that the inhibition of PGE$_2$synthesis is attributed to the potent COX inhibition by pimarane diterpenoid in arachidonic acid cascade. In conjunction with development of new analgesic and nonsteroidal antiinflammatory agent, a series of works on these diterpenoids have been extensively carried out in our laboratories. These efforts involve the structure-activity relationship of pimaradienoic acid, molecular modelings and COX inibitory activities as well as actiinflammatory effects of its structural analogues. In addition, the total syntheses of the new natural pimarane diterpenoids, their stereoisomers and other structural variants were intensively investigated.