SEQUENCE-SPECIFIC DNA INTERACTIONS BY NOVEL ALKYLATING ANTHRACYCLINE DERIVATIVES

New alkylating anthracycline derivatives with promising antitumor acti vity have been synthesized. We selected two of these compounds, 4-deme thoxy-N,N-bis (2 chloroethyl)-3'-methylsulfonyl-daunorubicin (FCE 2772 6) and demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulfon daunorubicin (FCE 28729), comparing their interaction with DNA and that of the non -alkylating derivative 4-demethoxy-4'-methylsulfonyl-daunorubicin (FCE 27894). The two alkylating derivatives were more cytotoxic than idaru bicin and presented low cross-resistance with doxorubicin. Both FCE 27 726 and FCE 28729 were found to alkylate guanines at the N-7 position in the major groove with roughly the same specificity, but at differen t concentrations. FCE 27726 was 10 times more potent than FCE 28729 in alkylating DNA. At higher concentrations, FCE 27726 was able to alkyl ate adenines, possibly at the N-3 position contained in a sequence 5'- PyA (A) under bar. FCE 27726, as expected, was able to form DNA inters trand cross-links either in vitro and in vivo in treated cells. FCE 28 729 did not form DNA interstrand cross-links in vivo. In vitro, at hig h concentrations, some DNA interstrand cross-links were evident. The n on-alkylating derivative FCE 27894 did not produce any alkylation or D NA interstrand cross-links either in vitro or in vivo.