The interaction of platinum and palladium complexes with closed and nicked circular and linear DNAs was investigated by a variety of methods. Cationic metal complexes containing flat, aromatic ligands, such as 2,2',2''-terpyridine, o-phenanthroline, and 2,2'-bipyridine, interfere with the usual fluorescence enhancement of ethidium bromide by competing for intercalation sites on calf-thymus DNA. Metal complexes having kinetically exchangable ligands, including the antitumor drugs cis-[(NH3)2PtCl2] and [(en)PtC12], inhibit noncompetitively the DNA-associated ethidium fluorescence enhancement by binding covalently to the bases and blocking potential intercalation sites. Only the metallointercalators were capable of altering the DNA duplex winding, as judged by the effects of these reagents upon the electrophoretic mobility and sedimentation behavior of PM-2 DNAs. Long-term (t greater than 120 h) interactions of metal complexes with PM-2 DNAs I, I0, and II, corresponding to superhelical, closed relaxed, and nicked circles, respectively, showed that covalent binding occurs the most readily to DNA I, possibly because of the presence of underwound duplex regions in this tightly wound superhelical DNA. The active antitumor drugs cis-[(NH3)2PtC12] and [(en)PtC12] bind covalently to DNA I under conditions where the inactive trans- [(NH3)2PtC12] does not. Most of the complexes studied were capable of producing chain scissions in PM-2DNA I. Exceptions are the kinetically inert complexes [(bipy)Pt(en)]2+ and (terpy)Pt(SCH2CH2OH)]+, suggesting that covalent binding might be a prerequisite for nicking.

The DNA binding of three platinum(II) intercalation reagents has been studied and found to depend upon base composition, the nature of the intercalator, and the ionic strength of the solvent medium. In 0.2 M NaCl, binding data for calf thymus DNA show the association constants to be approximately 10(4) M-1. The binding constants decrease in the order [(o-phen)Pt(en)]2+ greater than or equal to [(terpy)Pt(HET)]+ greater than [(bipy)Pt(en)]2+. The number of available intercalation sites for the doubly charged intercalators is only 70% of the number expected from the nearest-neighbor exclusion model. Binding of [(o-phen)Pt(en)]2+ and [(terpy)Pt(HET)]+ to various DNAs depends linearly on G.C content. Both reagents exhibit essentially the same degree of G.C specificity. Intercalative binding is a function of ionic strength. Increasing the salt concentration minimizes the importance of metallointercalator charge, and extrapolation to 1 M salt reveals the intercalative abilities, as reflected in binding constants, to be equivalent for [(terpy)Pt(HET)]+ and [o-phen)Pt(en)]2+ and about 1 order of magnitude less than that of ethidium.

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