title: On the competition of the purine bases, functionalities of peptide side chains, and protecting agents for the coordination sites of dicationic cisplatin derivatives.
abstract: The Pt-L bond energies of simple triammineplatinum(II) complexes, [Pt(NH(3))(3)L](2+), with oxygen-, nitrogen-, and sulfur-containing donor ligands L have been predicted and rationalized using density functional theory. The ligands L have been chosen as models for functionalities of peptide side chains, for sulfur-containing protecting agents, and for adenine and guanine sites of the DNA as the ultimate target of platinum anticancer drugs. Calculation of the Pt-L bond energy in [Pt(NH(3))(3)L](2+) reveals that the soft metal center of triammineplatinum(II) prefers N ligands over S ligands. This remarkable result has been discussed in light of several interpretations of the hard and soft acids and bases principle. The concept of orbital-symmetry-based energy decomposition has been employed for the determination of the contributions from sigma and pi orbital interactions, electrostatics, and intramolecular hydrogen bonding to the Pt-L bond energy. The calculations show that considerable differences in the bond energies of the triammineplatinum(II) complexes with N-heterocycles such as 1-methylimidazole, 9-methyladenine, and 9-methylguanine arise from electrostatics rather than from orbital interactions. Surprisingly, the net stabilization by hydrogen bonding between the (Pt)N-H group and the oxygen of 9-methylguanine is as weak as the intramolecular hydrogen bond in the aqua complex [Pt(NH(3))(3)(H(2)O)](2+), challenging the common hypothesis that DNA-active anticancer drugs require carrier ligands with N-H functionalities because of their hydrogen-bonding ability. The influence of a polarizable environment on the stability of the complexes has been investigated systematically with the dependence of the dielectric constant epsilon. With increasing epsilon, the complexes with S-containing ligands are more strongly stabilized than the complexes of the N-containing heterocycles. At epsilon = 78.4, the dielectric constant of water, 9-methylguanine remains the only purine derivative investigated which is competitive to neutral sulfur ligands. These findings are particularly important for a rationalization of the results from recent experimental studies on the competition of biological donor ligands L for coordination with the metal center of [Pt(dien)L](2+) (dien = 1,5-diamino 3-azapentane).
authors: Swiss Center for Scientific Computing, SCSC, Swiss Federal Institute of Technology, ETH Zurich, CH-6728 Manno, Switzerland.
authors: Dirk V
authors: DV
authors: Deubel
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry* / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D007093:Imidazoles; D008024:Ligands; D010455:Peptides; C057270:cisplatin-DNA adduct; C116701:9-methylguanine; D006147:Guanine; C013115:9-methyladenine; D000225:Adenine; C018100:1-methylimidazole; D002945:Cisplatin