Kinetics of Reactions of Dirhodium and Diruthenium Paddlewheel Tetraacetate Complexes with Nucleophilic Protein Sites: Computational Insights

Recently, dirhodium and diruthenium paddlewheel complexes have drawn attention as perspective anticancer drugs. In this study, the kinetics of reaction of typical paddlewheel scaffolds Rh2(μ-O2CCH3)4(H2O)2, Ru2(μ-O2CCH3)4(H2O)Cl, and [Ru2(μ-O2CCH3)4(HO)Cl]− with protein nucleophiles were investigated by means of the density functional theory. The substitution of axial ligandswater and chlorideby the models of protein residue side chains was analyzed, revealing the binding selectivity displayed by these paddlewheel metal scaffolds. The substitution of water is under a thermodynamic control, in which, although the Arg, Cys–, and Sec– residues are the most favorable, their binding is expected to be scarcely selective in a biological context. On the other hand, the replacement of the axial water with a more stable hydroxo ligand induces the chloride substitution in diRu complexes, which also targets Arg, Cys–, and Sec–, although with a moderately higher activation barrier for any examined protein residue. Additionally, the carried out characterization of the geometrical parameters of the transition states permitted determination of the impact of an increased steric hindrance of diRh and diRu complexes on their protein site selectivity. This study corroborates the idea of the substitution of the acetate ligands with biologically active, but more hindering, carboxylate ligands, in order to yield dual acting metallodrugs. This study allows us to assume that the delivery of diRu paddlewheel complexes in their monoanionic form [Ru2(μ-O2CR)4(OH)Cl]− decorated by the bulky substituents R may constitute an approach to augment the selectivity toward anticancer targets, such as TrxR in tumor cells, although under the condition that such a selectivity is operative only in high pH conditions