Antitumor agents. Part 235: Novel 4′-ester etoposide analogues as potent DNA topoisomerase II inhibitors with improved therapeutic potential Original Research Article

Eight 4′-ester epipodophyllotoxin derivatives (9–16) were designed and synthesized with the aim to overcome drug-resistance and improve water-solubility simultaneously. These compounds were superior to etoposide (1) in causing cellular protein-linked DNA breaks and inhibiting KB and 1-resistant KB-7d cell replication. Compounds 9 and 10 showed significant inhibitory activity against DNA topoisomerase II in vitro. Compound 10 also exhibited an in vitro DNA cleavage pattern similar to that of GL-331 (5). A hypothetical model on the action mode of 1-analogues is proposed based on the results.