Substituent position dictates the intercalative DNA-binding mode for anthracene-9,10-dione antitumor drugs

Molecular modeling studies [Islam, S.A., Neidle, S., Gandecha, B.M., Partridge, M., Patterson, L.H., & Brown, J.R. (1985) J. Med. Chem. 28, 857-864] have suggested that anthracene-9,10-dione (anthraquinone) derivatives substituted at the 1,4 and 1,8 positions with-NH(CH2)2NH(CH2CH3)2+ side chains intercalate with DNA with both substituents in the same groove (classical intercalation) while a similarly substituted 1,5 derivative intercalates in a threading mode with one side chain in each groove. Modeling studies also suggested that anthracene-9,10-dione (anthraquinone) derivatives substituted at the 2,6 positions with -NHCO(CH2)R (where R is a cationic group) should bind to DNA by the threading mode, and several such derivatives have been synthesized [Agbandjie, M., Jenkins, T.C., McKenna, R., Reszka, A., & Neidle, S. (1992) J. Med. Chem. 35, 1418-1429]. We have conducted stopped-flow kinetics association and dissociation experiments on the interaction of these anthraquinones with calf thymus DNA and with DNA polymers with alternating AT and GC base pairs to experimentally determine the binding mode and how the threading mode affects intercalation rates relative to similarly substituted classical intercalators. The binding modes, determined by analysis of relative rates, energies of activation, and effects of salt concentration on association and dissociation rate constants, agree completely with the modes predicted by molecular modeling methods. Association and dissociation rate constants for the threading mode are approximately a factor of 10 lower than constants for the classical intercalation mode, and the two modes, thus, have similar binding constants. Variations in rate constants for changes in cationic substituents at the 2 and 6 positions of the anthraquinone ring were surprisingly small.(ABSTRACT TRUNCATED AT 250 WORDS)