Quantum Chemical Studies of Ru(III) Anticancer Complexes

The success of platinum(II) anticancer drugs has stimulated the search for new metallopharmaceuticals. Two ruthenium(III) anticancer complexes, NAMI-A and KP1019, have reached clinical trials, but how these anticancer drugs work has not been fully understood. The objective of the proposed research is to explore using quantum chemical calculations key aspects in the chemistry of ruthenium(III) anticancer complexes to gain a deeper insight into their mode of action. In the first year, we will focus on two central themes: 1. Prediction and rationalization of redox potentials. Ru(III) anticancer complexes are believed to be activated upon reduction to their Ru(II) analogues. Because the redox potential is crucial to the pharmacological activity of these complexes, the computational prediction of redox potentials can contribute to a rational design of metallo-drugs. 2. Factors controlling the ruthenation of biomolecules. Hydrolysis of the Ru-chlorido bonds leads to aqua complexes that may react with a variety of biomolecules. The reactions are mainly controlled by the reactivity of the metal complexes to biologically relevant functional groups and the local concentrations of the reactants. We will investigate the transition states for possibly competing reactions and assess their importance. Emphasis will be placed on a systematic analysis of the effect of (i) the oxidation state, (ii) the hydrolysis state, (iii) the protonation state of the metal complex, and (iv) the axial ligands on the activation barriers. Our long-term goal is a contribution by quantum chemical calculations to a rational development of new drugs.