Studies on the interaction of altromycin B and its platinum(II) and palladium(II) metal complexes with calf thymus DNA and nucleotides

Abstract

The interaction of the anticancer antibiotic altromycin B and its isostructrural Pt(II) and Pd(II) metal complexes with native calf thymus (CT) DNA was studied using UV–thermal denaturation experiments, circular dichroism spectroscopy and temperature controlled spectrophotometric titrations. Altromycin B stabilizes the double helix by raising the T m, mainly by intercalation of its chromophore between the base pairs and interacting electrostatically via its sugar moieties with the edges of the DNA helix. Moreover, altromycin B induces a B→A structural transition of CT DNA. The effect on DNA stability and conformation depends on the metal ion. Pt(II) and Pd(II) complexes induce the B→A structural transition and stabilize the double helix similarly but they present lower final hyperchromicity due to premelting effects which were caused by intra- and interstrand crosslinking. Thus, a synergic effect of the metal ions to altromycin B–CT DNA interaction is observed in both cases. Altromycin B interacts with 5′-GMP, 5′-AMP and 5′-CMP by electrophilic attack of the opened epoxide ring to the N(7)G, N(1)/N(7)A and N(3)C. Thus, covalent binding between these nucleotides and altromycin B takes place and explain the multiple binding mode suggested by the studies of the interaction of altromycin B and its complexes with DNA. The [Pd(II)–altroB] complex dissociates in the presence of the nucleotides, and various species of Pd(II)–nucleotide complexes, especially with 5′-GMP, are formed. The [Pt(II)–altroB] complex dissociates too, but only one or two species of Pt(II)–nucleotide complexes are formed, and in the case of 5′-AMP interaction the formation of a tertiary altroB–Pt(II)–5′AMP complex is proposed. 5′-TMP reacts very weakly in comparison with the other three nucleotides. These interactions were followed by 1H-NMR.