Characteristics of the binding of the anticancer agents mitoxantrone and ametantrone and related structures to deoxyribonucleic acids

The binding constants for interaction of the anticancer agents mitoxantrone and ametantrone and several congeners with calf thymus DNA and the effects of ionic strength changes have been determined spectrophotometrically. The agents show a preference for certain sequences, particularly those with GC base pairs, and the magnitude of the specificity depends on the specific substituents on the anthraquinone ring system. The binding constant for mitoxantrone with calf thymus DNA in 0.1 M Na+, pH 7, is approximately 6 X 10(6) M-1, and the rate constant for the sodium dodecyl sulfate driven dissociation of mitoxantrone from its calf thymus DNA complex under the same solution conditions and 20 degrees C was determined to be 1.3 s-1. The unwinding angle of mitoxantrone determined independently by viscosity measurements and by a novel assay employing calf thymus topoisomerase shows excellent agreement for a value of 17.5 degrees. The viscosity increase of sonicated calf thymus DNA varies considerably with the substituent on the anthraquinone ring system. Binding studies employing T4 and phi w-14 DNAs in which the major groove is occluded and the reverse experiment with anthramycin-treated calf thymus DNA indicate at least part of the mitoxantrone molecule may lie in the minor groove.