| Abstract
| - We employ retro models, cis-PtA2G2 (A2 = a diamine, G = guanine derivative), to assess the cross-linked head-to-head (HH) form of the cisplatin−DNA d(GpG) adduct widely postulated to be responsible for the anticanceractivity. Retro models are designed to have minimal dynamic motion to overcome problems recognized in modelsderived from cisplatin [A2 = (NH3)2]; the latter models are difficult to understand due to rapid rotation of Gbases about the Pt−N7 bond in solution and the dominance of the head-to-tail (HT) form in the solid. Observationof an HH form is unusual for cis-PtA2G2 models. Recently, we found the first HH forms for a cis-PtA2G2 modelwith A2 lacking NH groups in a study of new Me2ppzPtG2 models. (Me2ppz, N,N‘-dimethylpiperazine, has in-plane bulk which reduces dynamic motion by clashing with the G O6 as the base rotates into the coordinationplane from the ground state position approximately perpendicular to this plane. G = 5‘-GMP and 3‘-GMP.) Thefinding of an HH form (albeit in a mixture with HT forms) with both G H8 signals unusually downfield encouragedus to study additional Me2ppzPtG2 analogues in order to explain the unusual spectral features and to identifyfactors that influence the relative stability of HT and HH forms. Molecular modeling techniques suggest HHstructures with the H8's close to the deshielding region of the z axis of the magnetically anisotropic Pt atom,explaining the atypical shift pattern. When G = 1-Me-5‘-GMP, we obtained NMR evidence that the HH rotamerhas a high abundance (34%) and that the three rotamers have nearly equal abundance. These findings and theobservation that the relative HT distributions varied little or not at all as a function of pH when G = Guo,1-MeGuo, or 1-Me-5‘-GMP are consistent with two of our earlier proposals concerning phosphate groups in HTforms of cis-PtA2(GMP)2 complexes. We proposed that a G phosphate group can form hydrogen bonds with thecis G N1H (“second-sphere” communication) and (for 5‘-phosphate) A2 NH groups. The new results with 1-Me-5‘-GMP led us to propose a new role for a 5‘-phosphate group; it can also favor the HH form by counteractingthe natural preference for the G bases to adopt an HT orientation. Finally, the HH form was also sufficientlyabundant to allow observation of a distinct 195Pt NMR signal (downfield of the resonance observed for the HTforms) for several complexes. This is the first report of an HH 195Pt NMR signal for cis-PtA2G2 complexes.
- Me2ppzPtG2 (Me2ppz = N,N‘-dimethylpiperazine, G = guanine derivative) adducts differ from other cisplatin−DNA cross-link models since they have N-methyl groups in the coordination plane. When G = 1-Me-5‘-GMP, a large amount of the HH conformer was observed, demonstrating the influence of “second-sphere communication” on conformer distributions in cross-link models. The abundance of the HH form allowed the first observation of a 195Pt NMR signal for such a form.
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