Electrophilic Activation of Oxidized Sulfur Ligands and Implications for the Biological Activity of Ruthenium(II) Arene Anticancer Complexes

Surprisingly, the anticancer activity of half-sandwich Ru arene complexes {[}(eta(6)-arene)Ru(en)Cl](+) appears to be promoted and not inhibited by binding to the intracellular thiol glutathione. Labilization of the Ru-S bond allowing DNA binding appeared to be initiated by oxygenation of the thiolate ligand, although oxidation by itself did not seem to weaken the Ru-S bond. In this study, we have investigated the solvation and acidic perturbations of mono (sulfenato) and bis (sulfinato) oxidized species of {[}(eta(6)-arene)Ru(en) (SR)]+ complex in the presence of Bronsted and Lewis acids. Sulfur K-edge X-ray absorption spectroscopy together with density functional theory calculations show that solvation and acidic perturbation of sulfenato species produce a significant decrease in the S-3p character of the Ru-S bond (Ru-4d sigma(sic) <- S-1s, charge donation). Also there is a drastic fall in the overall ligand charge donation to the metal center in both sulfenato and sulfinato species. Our investigation clearly shows that mono oxidized sulfenato species are most susceptible to ligand exchange, hence providing a possible pathway for in vivo activation and biological activity.