Investigation of the Inertness to Hydrolysis of Platinum(IV) Prodrugs

Platinum(IV) complexes are an important class of compounds that can act as prodrugs, and due to their inertness, if correctly designed, they could have low toxicity outside the cancer cell and improve the pharmacological properties of the platinum(II) anticancer agents that are currently used in the clinic. Because of the efforts that are concentrated on the use of axial ligands able to control the reduction potentials, lipophilicity, charge, selectivity, targeting, and cell uptake of the Pt(IV) complexes, we considered to be of interest to probe the inertness of such complexes that is assumed to be a fulfilled prerequisite. To this aim, a density functional theory computational analysis of the hydrolysis mechanism and the corresponding energy profiles for a series of Pt(IV) derivatives of cisplatin, carboplatin, and oxaliplatin with acetato, haloacetato, and chlorido ligands was performed to probe their stability in biological fluids. The heights of the barriers calculated along the hydrolysis pathways for the associative displacement of ligands both in axial and equatorial positions confirm that Pt(IV) complexes are, in general, more inert than the corresponding Pt(II) drugs even if inertness is lower than expected. Some exceptions exist, such as derivatives of oxaliplatin for the hydrolysis in equatorial position. The nature of the axial ligands influences the course of the hydrolysis reaction even if a decisive role is played by the ligands in equatorial positions. The mechanism of the aquation in axial position of cisplatin Pt(IV) derivative with two chlorido axial ligands assisted by Pt(II) cisplatin was elucidated, and the calculated activation energy confirms the catalytic role played by the Pt(II) complex.