Deubel Dirk V
Swiss Center for Scientific Computing, SCSC, Swiss Federal Institute of Technology, ETH Zurich, CH-6728 Manno, Switzerland.
J Am Chem Soc. 2002 May 22;124(20):5834-42. doi: 10.1021/ja012221q.
The Pt-L bond energies of simple triammineplatinum(II) complexes, Pt(NH(3))(3)L, 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 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), 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 (dien = 1,5-diamino 3-azapentane).
利用密度泛函理论预测并合理解释了简单三氨合铂（II）配合物[Pt(NH₃)₃L]²⁺与含 氧、氮和硫的供体配体 L 之间的 Pt-L 键能。配体 L 被选作肽侧链功能基团、含硫保护剂以及作为铂类抗癌药物最终靶点的 DNA 中腺嘌呤和鸟嘌呤位点的模型。对[Pt(NH₃)₃L]²⁺中 Pt-L 键能的计算表明，三氨合铂（II）的软金属中心更倾向于与 N 配体而非 S 配体结合。基于软硬酸碱原理的几种解释对这一显著结果进行了讨论。基于轨道对称性的能量分解概念被用于确定σ和π轨道相互作用、静电作用以及分子内氢键对 Pt-L 键能的贡献。计算表明，三氨合铂（II）与 N-杂环如 1-甲基咪唑、9-甲基腺嘌呤和 9-甲基鸟嘌呤的配合物之间键能的显著差异源于静电作用而非轨道相互作用。令人惊讶的是，（Pt）N-H 基团与 9-甲基鸟嘌呤的氧之间通过氢键产生的净稳定作用与水合配合物[Pt(NH₃)₃(H₂O)]²⁺中的分子内氢键一样弱，这对常见的假设提出了挑战，即具有 DNA 活性的抗癌药物需要具有 N-H 功能基团的载体配体，因为它们具有氢键能力。利用介电常数ε的依赖性系统研究了可极化环境对配合物稳定性的影响。随着ε的增加，含 S 配体配合物的稳定性比含 N 杂环配合物的稳定性增强得更明显。在ε = 78.4（水的介电常数）时，9-甲基鸟嘌呤仍然是所研究的唯一一种能与中性硫配体竞争的嘌呤衍生物。这些发现对于合理解释近期关于生物供体配体 L 与[Pt(dien)L]²⁺（dien = 1,5-二氨基-3-氮杂戊烷）的金属中心配位竞争的实验研究结果尤为重要。
