Sequence-specific DNA interactions by novel alkylating anthracycline derivatives.
New alkylating anthracycline derivatives with promising antitumor activity have been synthesized. We selected two of these compounds, 4-demethoxy-N,N-bis(2 chloroethyl)-4'-methylsulfonyl-daunorubicin (FCE 27726) and 4-demethoxy-3'-deamino-3'aziridinyl-4'-methylsulfonyl 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 idarubicin and presented low cross-resistance with doxorubicin. Both FCE 27726 and FCE 28729 were found to alkylate guanines at the N7 position in the major groove with roughly the same specificity, but at different concentrations. FCE 27726 was 10 times more potent than FCE 28729 in alkylating DNA. At higher concentrations, FCE 27726 was able to alkylate adenines, possibly at the N3 position contained in a sequence 5'-PyAA. FCE 27726, as expected, was able to form DNA interstrand cross-links either in vitro and in vivo in treated cells. FCE 28729 did not form DNA interstrand cross-links in vivo. In vitro, at high concentrations, some DNA interstrand cross-links were evident. The non-alkylating derivative FCE 27894 did not produce any alkylation or DNA interstrand cross-links either in vitro or in vivo.
Marchini
S
S
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Gonzalez Paz
O
O
Ripamonti
M
M
Geroni
C
C
Bargiotti
A
A
Caruso
M
M
Todeschi
S
S
D'Incalci
M
M
Broggini
M
M
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism*; D001483:Base Sequence; D004247:DNA / Q000378:metabolism*; D051379:Mice; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D004247:DNA