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

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 (IC₅₀ < 10 μM). However, only di-succinyl (5e) and 2,3-seco-2,3-dioic acid (3b) derivatives similarly inhibited HCV protease (IC₅₀ < 10 μM). A-nor dammarane-type triterpenes (4a and 4b, IC₅₀ 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 (IC₅₀ > 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.