Dipartimento di Chimica, Università della Calabria,Via P. Bucci, cubo 14c, 87036 Arcavacata di Rende (CS), Centro di Calcolo ad Alte Prestazioni per Elaborazioni Parallele e Distribuite-Centro d'Eccellenza MIUR, Italy.
J Phys Chem B. 2009 Oct 29;113(43):14473-9. doi: 10.1021/jp9056835.
The hydrolysis reaction processes of the second-generation platinum derivative Nedaplatin have been studied using density functional theory (DFT) combined with the conductor-like dielectric continuum model (CPCM) approach, in order to obtain detailed data on its mechanism of action. The first and the second hydrolysis of Nedaplatin, corresponding to the ring opening followed by the loss of the ligand, respectively, have been explored in neutral and acid conditions. The influence of an extra water molecule which could assist the degradation processes has also been considered including in our models an explicit water molecule other than the reactive one. The computed potential energy surfaces show that the rate limiting step in neutral conditions is the first hydrolysis process and, consequently, the double hydrated complex is suggested to be the species reacting with the DNA purine bases, while in acid conditions the trend is different, with the second hydrolysis process being the rate limiting step. The results obtained in this work allow us to make a comparison with the trends previously found for the other platinum anticancer drugs currently used in the medical protocols.
采用密度泛函理论（DFT）结合导体相似介电连续体模型（CPCM）方法研究了第二代铂衍生物奈达铂的水解反应过程，以获得其作用机制的详细数据。分别在中性和酸性条件下探索了奈达铂的第一次和第二次水解，分别对应于环的打开和配体的丢失。还考虑了一个额外水分子的影响，该水分子可以辅助降解过程，我们的模型中包括除了反应性水分子之外的显式水分子。计算的势能表面表明，中性条件下的速率限制步骤是第一次水解过程，因此，双水合配合物被认为是与 DNA 嘌呤碱基反应的物质，而在酸性条件下趋势不同，第二次水解过程是速率限制步骤。这项工作的结果使我们能够与目前在医疗方案中使用的其他铂类抗癌药物的先前发现的趋势进行比较。
