Anti-AIDS agents. Part 61: Anti-HIV activity of new podophyllotoxin derivatives

A series of novel podophyllotoxin derivatives containing structural modifications at C-4 (7-14), C-4' (16-17), and the methylenedioxy A-ring (23-28) was synthesized and tested for inhibition of HIV replication. Four of these compounds (25-28) were previously reported to show EC50 values of <0.001 mug/mL and therapeutic index (TI) values >120. Three of the newly tested compounds (8.. 12, and 20) showed good activity with EC50 values of 0.012, <0.001, and 0.389 mug/ml and TI values of 19.1, >16, and 19.4, respectively. A comparison of the anti-HIV activity of these derivatives suggested that an opened A-ring with 6,7-dimethoxy substitution and a 4'-demethylated E ring enhanced anti-HIV activity. (C) 2004 Elsevier Ltd. All rights reserved.