Hydrolysis of the Anticancer Drug Cisplatin: Pitfalls in the Interpretation of Quantum Chemical Calculations.

All three hydrolysis reactions of the anticancer drug cisplatin, cis-[Pt(NH3)2Cl2], including the acidity constants (pKa) of the aqua complexes have been compared using a combined density functional theory (DFT) and continuum dielectric model (CDM) approach. The calculations predict very similar activation barriers (25-27 kcal/mol) and reaction free energies (0-2 kcal/mol) for each of the three hydrolysis reactions. The predicted relative free energies of both Pt(II) and Ru(II) anticancer complexes agree well with available experimental values. However, our calculated data strongly disagree with several recent computational studies that predicted the second and third hydrolysis to be thermodynamically highly unfavorable and thus would have ruled out the involvement of cis-[Pt(NH3)2(OH2)2](2+) and cis-[Pt(NH3)2(OH2)(OH)](+) in the mode of action of the drug. This controversy can be resolved by the fact that former computational predictions of activation and reaction free energies in solution were based on second-shell reactant adducts and product adducts, which are the correct endpoints of the intrinsic reaction coordinate in vacuo but artifacts in aqueous solution.