Synthesis of dammarane-type triterpene derivatives and their ability to inhibit HIV and HCV proteases

Abstract

We synthesized dammarane-type triterpene derivatives and evaluated their ability to inhibit HIV-1 and HCV proteases to understand their structure–activity relationships. All of the mono- and di-succinyl derivatives ( 5a– 5f) were powerful inhibitors of HIV-1 protease (IC 50 < 10 μM). However, only di-succinyl ( 5e) and 2,3- seco-2,3-dioic acid ( 3b) derivatives similarly inhibited HCV protease (IC 50 < 10 μM). A-nor dammarane-type triterpenes ( 4a and 4b, IC 50 10.0 and 29.9 μM, respectively) inhibited HIV-1 protease moderately or strongly, but were inactive against HCV protease. All compounds that powerfully inhibited HIV-1 or HCV protease did not appreciably inhibit the general human proteases, renin and trypsin (IC 50 > 1000 μM). These findings indicated that the mono-succinyl dammarane type derivatives ( 5a– 5d) selectively inhibited HIV-1 protease and that the di-succinyl ( 5e, 5f) as well as 2,3- seco-2,3-dioic acid ( 3b) derivatives preferably inhibited both viral proteases.