Comparative study of the hydrolysis of a third- and a first-generation platinum anticancer complexes

The hydrolysis of cis-[Pt(NH(3))(2)Cl(2)] (cisplatin) and of the third-generation platinum anticancer compound (cis-[PtCl(2)(NH(3))-(2-picoline)] (picoplatin) has been studied quantum-mechanically using density functional theory (mPW1PW91). Due to its asymmetry, picoplatin is an interesting case, since hydrolysis may proceed through two distinct reaction paths and with the entering water molecule sin or anti to the methyl group of 2-picoline. Solvent effects were taken into account either by applying the polarizable continuum model (PCM) solvent approach or by introducing a cluster of water molecules solvating the complex. With the PCM approach, it emerges that the steric hindrance of 2-picoline has a minimum impact on the activation barriers for picoplatin hydrolysis, since the water molecule approach is far from being axial and far from the methyl group. Accordingly, the TS state geometry with 5-coordinated platinum is not significantly more distorted than in the cisplatin case. Our results point out that the use of separated reactants as reference for energy barrier gives satisfactory results for each compound and produces correct relative magnitudes of first and second hydrolysis rate constants for each compound. However, this model is not able to predict the generally faster hydrolysis experimentally observed for cisplatin with respect to picoplatin. The study of the first hydrolysis step for the two compounds in the presence of explicit water molecules shows that the entering water molecule is strongly interacting with the others through a complex hydrogen bond network. The discrete solvation model is able to correctly predict a slightly slower hydrolysis of picoplatin highlighting the need of explicit solvation to predict small differences (within an order of magnitude) in the observed rate constants.