Retro Models of Pt Anticancer Drug DNA Adducts:  Chirality-Controlling Chelate Ligand Restriction of Guanine Dynamic Motion in (2,2‘-Bipiperidine)PtG₂ Complexes (G = Guanine Derivative)

Abstract

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.

A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance

“…1). The cisplatin-purine adducts exist as a fluxional mixture of conformers, as free rotation around the Pt-N 7 bond allows an equilibrium between the HH and HT atropisomers, 69 leading to a high degree of conformational freedom. This is responsible for the broadened features observed in the corresponding optical vibrational spectra, as well as for the complexity of the measured INS pattern.…”

The First Pure ΛHT Rotamer of a Complex with a cis‐[Metal(nucleotide)2] Unit: A cis‐[Pt(amine)2(nucleotide)2] ΛHT Rotamer with Unique Molecular Structural Features

“…Structural models with both 5'-GMP nucleo-A C H T U N G T R E N N U N G tides in the anti conformation suggested that the 5'-phosphates are directed toward the cis amines in the DHT conformer and toward the cis nucleotide in the LHT conformer. Therefore, phosphate interactions with the cis amine (hydrogen-bond interaction) and with the platinum core (electrostatic interactions) will favor the DHT conformer, whereas phosphate interactions with the cis guanine (hydrogen-bond interaction with cis-5'-GMP N1H) [55][56][57][58] will favor the LHT conformer. However, even for those cases in which our choice of carrier ligand restricted the rotation about the PtÀN7 bond, these adducts are rendered very dynamic by rapid motions involving rotation about the N9 À C1' and the C4' À C5' bonds, and interchange among a very broad range of sugar puckers.…”

“…We employed neutral pH because the phosphate group is fully deprotonated, favoring hydrogen bonding and the LHT conformer. [55][56][57][58] With this strategy we were able to obtain, for the first time, crystals of a pure LHT rotamer, [bis(guanosine-5'-monophosphate(-2))-…”

The Relation Between Stereochemistry and Biological Activity of Platinum(II) Complexes Chelated with Chiral Diamine Ligands: An Intricate Problem

“…Complexes (9d) and (17) have been used to investigate the dynamic behaviour of guanine residues and derivatives after platinum binding [22,70,71]. In the first place, these compounds have been tested only with guanines or their derivatives and not with nucleotides, providing only few information about their real effect on DNA conformation.…”