Quantum Chemical Investigations on the Hydrolysis of Gold(III)-Based Anticancer Drugs and Their Interaction with Amino Acid Residues.

A comprehensive hydrolysis mechanism of the promising class of Au(III) anticancer drugs [Au(DMDT)Cl] (DMDT = ,-dimethyldithiocarbamate) () and [Au(damp)Cl] (damp = 2-[(dimethylamino)methyl]phenyl) (') was done by means of density functional theory (DFT) in combination with the CPCM solvation model to explore the solution behavior and stability under physiological conditions. The activation free energies (Δ) for the second hydrolysis, (13.7 kcal/mol) and ' (10.0 kcal/mol) are found to be relatively lower in comparison to the first hydrolysis, and their rate constant values are computed to be 5.62 × 10 and 2.90 × 10 s, respectively. Besides these, the interaction mechanisms of aquated and ' with the potential protein-binding sites cysteine (Cys) and selenocysteine (Sec) were also investigated in detail. The kinetic study and activation Gibbs free energy profiles reveal that the aquated complexes of and ' bind more effectively to the Se site of Sec than to the S site of Cys. Intra- and intermolecular hydrogen bonding play a pivotal role in stabilizing the intermediates and transition states involved in the ligand substitution reactions of and '. Natural population analysis (NPA) was done to determine the charge distributions on important atoms during the hydrolysis and ligand substitution reactions.