Aggregation of platelets induced by novel synthetic secoprostaglandins

Two series of 8-acetly-12-hydroxyalkadienoic acids and 14-hydroxy-9-oxoalkadienoic acid which can be regarded as 11,12- and 8,12- secoprostaglandin E2 were synthesized and evaluated for their biological properties. Key members of each series, 11,12-(8Ac-HAD) and 8, 12-seco-11-norprostaglandin E2 (14H-OAD), were found to induce platelet aggregation which were inhibited by preincubation of platelet rich plasma with prostaglandin I2 but not inhibited by indomethacin, 8Ac-HAD produced dose-dependent potent contraction of rabbit aorta. Injection of 8Ac-HAD (1 mg/kg) into vein of rat induced sudden death of the animal. Both compounds were stable and platelet aggregating activity did not decrease at least for four hours at 0 degree C. Structure-activity relationship study of the series were carried out. Reduction of the acetyl carbonyl and methoxime formation of 8Ac-HAD lowered platelet aggregating activity, and 8-propionyl substituent and 12-deoxy derivative of 8Ac-HAD showed no activity. 12 (R)-Isomer and dl 12-methyl derivative of 8Ac-HAD retained the platelet aggregating activity. Modification of omega-chain did not cause any essential effect on the activity. Unlike 8Ac-HAD, several modification of 14H-OAD failed to maintain the aggregating activity.