Quantum Chemical Investigation on Hydrolysis of Orally Active Organometallic Ruthenium(II) and Osmium(II) Anticancer Drugs and Their Interaction with Histidine.

Influence of the metal center on hydrolysis of organometallic anticancer complexes containing an -phenyl-2-pyridinecarbothioamide (PCA) ligand, [M(η--cymene)(-phenyl-2-pyridinecarbothioamide)Cl] (M = Ru, , and Os, ), as well as their -fluorophenyl derivatives [M(η--cymene)(-fluorophenyl-2-pyridinecarbothioamide)Cl] (M = Ru, , and Os, ) have been investigated using the DFT method in aqueous medium. The activation energy barriers for the hydrolysis of (21.5 kcal/mol) and (20.7 kcal/mol) are found to be significantly lower than those of their corresponding osmium analogs (28.6 kcal/mol) and (27.5 kcal/mol). DFT evaluated results reveal the inertness of Os(II)-PCA complex toward the hydrolysis that rationalizes the experimental observations. However, the incorporation of fluoride substituent slightly decreases the activation energy for the hydrolysis of Ru(II)- and Os(II)-PCA. In addition, the interaction of hydrolyzed Ru(II)-PCAs ( and ) and Os(II)-PCAs ( and ) complexes with the histidine () have also been investigated. The aquated and show an enhanced propensity toward the interaction with histidine, and their activation Gibbs free energies are calculated to be 15.9 and 18.9 kcal/mol, respectively. ONIOM (QM/MM) study of the resulting aquated complexes inside histone protein shows the maximum stability of the complex having a binding energy of -43.6 kcal/mol.