Antitumor agents. 126. Novel 4 beta-substituted anilino derivatives of 3',4'-O,O-didemethylpodophyllotoxin as potent inhibitors of human DNA topoisomerase II.

A series of derivatives of 3',4'-O,O-didemethylpodophyllotoxin have been synthesized and evaluated for their inhibitor activity against neoplastic cell growth (KB) and against human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. The results show that the compounds possessing a 4 beta-anilino moiety either unsubstituted or substituted at the para (F, COOCH3, COCH3, CN, CH2CN, NO2) or meta (OH) positions or with an ethylenedioxy moiety showed the same or greater activity than etoposide in causing cellular protein-linked DNA breakage and in inhibiting DNA topoisomerase II. However, compared to the corresponding 4'-O-demethyl analogues, the 3',4'-O,O-didemethyl compounds have a similar potency in inhibition of DNA topoisomerase II but are less active in causing cellular protein-linked DNA breakage. Complete correlation between the three biological activities--cytotoxicity, inhibition of DNA topoisomerase II, and induction of protein-linked DNA breakage--was also not observed. This supports the possibility that the biological determinants of action among these compounds may be different.