Circular dichroism study of the interaction of mitoxantrone, ametantrone and their Pd(II) complexes with deoxyribonucleic acid.

The interaction of mitoxantrone, ametantrone and their Pd(II) complexes with DNA have been studied using absorption and circular dichroism spectroscopy. We have shown that mitoxantrone forms with Pd(II) a complex in which two Pd(II) ions are bound to two molecules of drug (D1 and D2). One Pd(II) ion is bound to the two nitrogens of the side chain on C-5 of molecule D1 and to the two nitrogens of the side chain on C-5 of molecule D2, whereas the second Pd(II) ion is bound to the nitrogens of the side chain on C-8 of molecule D1 and of molecule D2. The same complex is formed between Pd(II) and ametantrone. The stability constants for these complexes are, respectively, beta M = (1.4 +/- 0.5).10(19) and beta A = (2.5 +/- 0.5).10(18). They display antitumor activity against P 388 leukemia which compares with that of the free drugs. Interactions of the free drugs with DNA have been studied. Mitoxantrone and ametantrone are not optically active by themselves. However, through interaction with DNA, there is an induction of optical activity within the electronic transitions of both drugs. At a nucleotide/drug molar ratio lower than about 5 a CD signal of the couplet type is observed, suggesting that there is a coupling between the pi----pi transitions of the molecules of drugs intercalated between the base pairs. This coupling disappears when the molar ratio is increased. The interactions of the Pd(II) complexes with DNA do not give rise to induction of optical activity within the electronic transition of the drugs, indicating that the presence of the metal ion prevents the intercalation of the drugs between the base pairs.