Retro models of Pt anticancer drug DNA adducts: Chirality-controlling chelate ligand restriction of guanine dynamic motion in (2,2 '-Bipiperidine)PtG(2) complexes (G = guanine derivative)

Features of cisplatin-type anticancer drug adducts with nucleic acids and t heir constituents are clouded because they exist as a fluxional mixture of conformers. Retro-model adducts containing the specially designed chiral di amine ligand, Bip = 2,2'-bipiperidine, are dramatically less fluxional. Con formers of BipPtG(2) adducts with R,S,S,R and S,R,R,S asymmetric centers at the N, C, C, and N Pip chelate ring atoms and G = 5'-GMP, 5'-dGMP, 3'-GMP, or 9-ethylguanine are amenable to separate characterization. All possible BipPtG(2) atropisomers (one head-to-head (HH) and Delta and Lambda head-to- tail (HT) atropisomers) were observed by NMR spectroscopy. At equilibrium a t low pH, one HT atroprsomer dominates. CD spectra, G H8 chemical shifts, a nd low-pH equilibria of BipPtG(2) and Me(2)DABPtG(2) (Me(2)DAB = N,N'-dimet hyl-2,3-diaminobutane) are similar when the chelate ring atoms have the sam e stereochemistries; thus, Bip and Me(2)DAB Lire termed chirality-controlli ng chelates (CCC) since these ligands dictate the absolute conformation of die major HT rotamer. In each case, the HT conformer that cannot form G O6- NH(CCC) hydrogen bonds was dominant, and the G H8 chemical shift indicated that this conformer had less tilted bases, allowing favorable base-base dip ole-dipole interactions. For both the R,S,S,R and S,R,R,S Bip chiralities o f the BipPt(3'-GMP)(2) complexes, the percentage of Delta HT rotamer increa sed near pH 7, a probable consequence of phosphate-cis-G hydrogen bonds acc ompanied by favorable dipole interactions of less tilted bases. For the 5'- GMP complexes, these factors favor the Lambda HT rotamer near pH 7. When G has a 5'-phosphate group, rotamer distribution is also influenced by phosph ate-NH(Bip) hydrogen bonds. At high pH, the nature and/or strength of inter actions such as G dipole-G dipole interactions and G OS-NH(Bip) and phospha te-cis-G hydrogen bonding are altered by G N(1)H deprotonation. The feature s of the complexes at high pH can be largely explained as arising from the net result of these interactions. This information from retro models with a CCC ligand lays the foundation for understanding and evaluating the proper ties of the highly dynamic adducts of anticancer drugs.