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 their constituents are clouded because they exist as a fluxional mixture of conformers. Retro-model adducts containing the specially designed chiral diamine ligand, Bip = 2,2'-bipiperidine, are dramatically less fluxional. Conformers of BipPtG(2) adducts with R,S,S,R and S,R,R,S asymmetric centers at the N, C, C, and N Bip 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 at low pH, one HT atropisomer dominates. CD spectra, G H8 chemical shifts, and low-pH equilibria of BipPtG(2) and Me(2)()DABPtG(2) (Me(2)()DAB = N,N '-dimethyl-2,3-diaminobutane) are similar when the chelate ring atoms have the same stereochemistries; thus, Bip and Me(2)()DAB are termed chirality-controlling chelates (CCC) since these ligands dictate the absolute conformation of the 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 dipole-dipole interactions. For both the R,S,S,R and S,R,R,S Bip chiralities of the BipPt(3'-GMP)(2) complexes, the percentage of DeltaHT rotamer increased near pH 7, a probable consequence of phosphate-cis-G hydrogen bonds accompanied by favorable dipole interactions of less tilted bases. For the 5'-GMP complexes, these factors favor the LambdaHT rotamer near pH 7. When G has a 5'-phosphate group, rotamer distribution is also influenced by phosphate-NH(Bip) hydrogen bonds. At high pH, the nature and/or strength of interactions such as G dipole-G dipole interactions and G O6-NH(Bip) and phosphate-cis-G hydrogen bonding are altered by G N(1)H deprotonation. The features 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 properties of the highly dynamic adducts of anticancer drugs.
Ano
Susan O.
SO
Department of Chemistry, Emory University, Atlanta, Georgia 30322, and Dipartimento Farmaco-Chimico, Università degli Studi di Bari, 70125 Bari, Italy.
Intini
Francesco P.
FP
Natile
Giovanni
G
Marzilli
Luigi G.
LG