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

Abstract 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.