Antitumor agents. Part 227: Studies on novel 4′-O-demethyl- epipodophyllotoxins as antitumor agents targeting topoisomerase II

Abstract Eight novel epipodophyllotoxin derivatives ( 6 – 13 ), which were designed to overcome drug resistance and enhance topoisomerase II inhibition, were synthesized and evaluated. Two of these compounds ( 7 and 8 ) showed better preclinical activity profiles, including cell growth inhibition, cell killing, and in vitro topoisomerase II inhibition, as compared to the prototype molecule etoposide ( 1 ). They also retained the superior drug-resistance profile of GL-331 ( 4 ), an epipodophyllotoxin derivative currently in clinical evaluation.