A Rare Example of Three Abundant Conformers in One Retro Model of the Cisplatin−DNA d(GpG) Intrastrand Cross Link. Unambiguous Evidence That Guanine O6 to Carrier Amine Ligand Hydrogen Bonding Is Not Important. Possible Effect of the Lippard Base Pair Step Adjacent to the Lesion on Carrier Ligand Hydrogen Bonding in DNA Adducts

Guanine O6 to carrier ligand hydrogen bonding is a central feature of many hypotheses advanced to explain the anticancer activity of cis-type anticancer drugs, cis-PtA₂X₂ (A₂ = diamine or two amines). Early structural evidence suggested that cis-Pt(NH₃)₂(d(GpG)) (the cross-link model for the key cisplatin−DNA adduct) and other cis-PtA₂(d(GpG)) adducts exist exclusively or mainly as the HH1 conformer with head-to-head (HH) bases. The dynamic motion of the d(GpG) in these adducts is too rapid to permit definitive characterization of both the conformation and the H-bonding. Hence, we use retro models having A₂ ligands designed to slow the motion. Here, we employ Me₂ppz (N,N‘-dimethylpiperazine), which lacks NH groups. Me₂ppz is unique in having sp³ N-methyl groups directly in the coordination plane, allowing the coexistence of multiple conformers but hindering dynamic motion in Me₂ppzPt(d(GpG)) and Me₂ppzPt(GpG) retro models. Dynamic processes are decreased enough in Me₂ppzPt(d(GpG)) to permit HPLC separation of three abundant forms. After HPLC separation, the three re-equilibrate, proving that the three forms must be conformers and that Me₂ppz has little influence on conformer distribution. This marks the first reported characterization of three abundant conformers for one cis-PtA₂(d(GpG)) adduct. From NMR evidence, the Me₂ppzPt(d(GpG)) HH1 conformer has uncanted bases. Another conformer, one of two recently discovered conformer types, has head-to-tail (HT) bases with Δ chirality. For this ΔHT1 form, several lines of evidence establish that the dinucleotide moieties have essentially identical structures in d(GpG) (and GpG) adducts of Me₂ppzPt and other cis-PtA₂ complexes. For example, the shifts of the highly structure-sensitive G H8 NMR signals are almost identical for the ΔHT1 form of all adducts. In previous models, the stabilization of the ΔHT1 form could be attributed to G O6 H-bonding to A₂ NH groups. Such H-bonds are not possible for Me₂ppz. The unambiguous conclusions are that G O6 H-bonding is weak and that neither canting nor H-bonding is essential in HH forms. These two features are present in almost all other small models but are essentially absent in the cross-link base pair (bp) step in duplexes. We conclude from our work that the forces favoring canting and H-bonding are weak, and we hypothesize that steric effects within the Lippard bp step adjacent to this cross-link bp step easily overcome these forces.