Cisplatin-DNA cross-link models with an unusual type of chirality-neutral chelate amine carrier ligand, N,N '-dimethylpiperazine (Me(2)ppz): Me(2)ppzPt(guanosine monophosphate)(2) adducts that exhibit novel properties

Most simple cis-PtA(2)G(2) complexes that model the G-G cross-link DNA lesi ons caused by the clinically used anticancer drug cis-PtCl2(NH3)(2) undergo large fluxional motions at a rapid rats (A(2) = two amines or a diamine; G = guanine derivative). The carrier amine ligands in active compounds have NH groups, but the fundamental role of the NH groups has been obscured by t he dynamic motion. To assess carrier ligand effects. we examine retro model s, cis-PtA(2)G(2) complexes, in which dynamic motion has been reduced by th e incorporation of steric bulk into the carrier ligands. In this study we i ntroduce a new approach employing the chirality-neutral chelate (CNC) ligan d, Me(2)ppz (N,N'-dimethylpiperazine). Because they lie in the Pt coordinat ion plane, the methyl groups of Me(2)ppz do not clash with the O6 of the ba se of G ligands in the ground state, but such clashes sterically hinder dyn amic motion. NMR spectroscopy provided conclusive evidence that Me(2)ppzPt( GMP)(2) complexes (GMP = 5'- and 3'-GMP) exist as a slowly interconverting mixture of two dominant head-to-tail (HT) conformers and a head-to-head (HH ) conformer. Since the absence of carrier ligand chirality precluded using NMR methods to determine the absolute conformation of the two HT conformers , we used our recently developed CD pH jump method to establish chirality. The most abundant HT Me(2)ppzPt(5'-GMP)(2) form had Lambda chirality. Previ ously this chirality was shown to be favored by phosphate-cis G N1H hydroge n-bonding interligand interactions; such interactions also favor the Hr con formers over the HH conformer. For typical carrier ligands, G O6 and phosph ate interactions with the carrier ligand NH groups also favor the HT forms. These latter interactions are absent in Me(2)ppzPt(GMP)(2) complexes, but the HT forms are still dominant. Nevertheless, we do find the first evidenc e for an HH form of a simple cis-PtA(2)G(2) model with A(2) lacking any NH groups. In previous studies, the absence of the HH conformer in cis-PtA(2)G (2) complexes lacking carrier NH groups may be due to the presence of out-o f plane carrier ligand bull;. Such bulk fords both G O6-G O6 and G O6-carri er ligand clashes, thereby disfavoring the HH form. The major DNA cross-lin k adduct has the HH conformation. Thus, for anticancer activity, the small bulk of the NH group may be more important than the H-bonding interaction.