Anti-AIDS Agents. 34.† Synthesis and Structure−Activity Relationships of Betulin Derivatives as Anti-HIV Agents

Succinyl and 3‘-substituted glutaryl betulin derivatives showed stronger anti-HIV activity and higher therapeutic index (TI) values than their dihydrobetulin counterparts, with ratios of 1.2:1 to 15:1 (cf. 7 and 15, 9 and 17, 10 and 18, 11 and 19, and 12 and 20). For various 3‘-substituted glutaryl compounds, the order of anti-HIV effects, from strong to weak inhibition, was 3‘,3‘-dimethyl, 3‘-methyl, 3‘-ethyl-3‘-methyl, followed by 3‘,3‘-tetramethylene glutaryl derivatives (10 > 9 > 11 > 12, 18 > 17 > 19 > 20). The most potent compound, 10, has two 3‘,3‘-dimethylglutaryl groups and displays significant anti-HIV potency with an EC50 value of 0.000 66 μM and a TI of 21 515. Results for compounds (22 and 23) without a C-3 acyl group confirmed the importance of the C-3 acyl group to the anti-HIV effect. With 3‘,3‘-tetramethylene glutaryl derivatives, triacyl 29 showed stronger inhibition than diacyl 12; in contrast, 3‘,3‘-dimethylglutaryl compounds displayed opposite results. 3-Keto compounds (35 and 36) and...