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.

Four controversies on the mechanism of the olefin epoxidation with Mimoun-type complexes, [MoO(O2)2(OPR3)], Herrmann-type complexes, [ReO(O2)2Me], and related inorganic peroxides have inspired industrial and academic researchers in the last three decades. First, is the oxygen transfer from the peroxo complex to the olefin concerted or stepwise? Second, does the oxidant act as an electrophile or a nucleophile? Third, is the mechanism of the stoichiometric reaction also valid for catalytic protocols? Fourth, how can stereochemical information be transferred between oxidant and substrate? In this Account, we discuss answers to the long-standing questions, focusing on recent contributions from quantum chemical calculations.

Quantum-chemical calculations at the B3LYP level have been carried out to elucidate the reaction mechanism of the epoxidation of ethylene with the molybdenum diperoxo complex MoO(O2)2OPH3. All relevant transition states and intermediates which belong to the reaction pathways suggested by Mimoun and by Sharpless were optimized. The calculations show that there is no reaction channel from the ethylene complex to the putative metalla-2,3-dioxolane intermediate as suggested by Mimoun. There is a transition state for the direct formation of the five-membered cyclic intermediate from ethylene and the diperoxo complex. However, the subsequent extrusion of a C2H4O species from the metalla-2,3-dioxolane does not yield the epoxide but acetaldehyde. The calculations show that the reaction of MoO(O2)2OPH3 with ethylene can directly lead to the epoxide as suggested by Sharpless. The activation energy for the latter process is 15.2 kcal/mol, which is lower than the barrier for the formation of the metalla-2,3-dioxolane (23.7 kcal/mol). Calculations with the ligand OPMe3 instead of OPH3 show an even larger preference of the pathway leading to the epoxide than the formation of the five-membered ring. The calculations strongly support the mechanism suggested by Sharpless, while the Mimoun mechanism leads to carbonyl compounds as reaction products. Examination of the electronic structure of the transition state of the epoxide formation with the Charge Decomposition Analysis shows that the reaction should be considered as nucleophilic attack of the olefin toward the σ* orbital of the peroxo bond.

Potential consequences of the binding of the anticancer drug cisplatin to various biomolecules in the cell have been investigated by using a combined density functional theory and continuum dielectric model approach. Since the amine ligands remain coordinated at the metal upon formation of the most frequent DNA adducts, whereas they were found to be displaced from the metal upon formation of drug metabolites, we have analyzed the factors governing amine loss from platinum(II) complexes as a possible pathway of cisplatin inactivation. The calculations systematically show the effect of 1) the trans ligand, 2) the charge of complex, 3) the nucleophile, and 4) the environment on the thermodynamic instability and kinetic lability of the platinum-amine bonds. After initial binding of cisplatin hydrolysis products to thioethers or thiols, loss of the amine trans to this sulfur ligand rather than replacement of the sulfur ligand itself by other nucleophiles like guanine-N7 is predicted to be the predominant reaction. The results of this study contribute to an understanding of the modes of cisplatin inactivation prior to DNA binding, for example, by elevated glutathione levels in cisplatin-resistant cancer cells.

A comparative quantum chemical approach helps to clarify how the selectivity of anticancer metallopharmaceuticals towards potential biological targets can be controlled by metal and ligands.