Biomolecule binding vs. anticancer activity: reactions of Ru(arene)[(thio)pyr-(id)one] compounds with amino acids and proteins

The interactions of the ruthenium(arene) complexes [chlorido(η(6)-p-cymene)(2-methyl-3-(oxo-κO)-4H-pyran-4-onato-κO)ruthenium(II)] 1, [chlorido(η(6)-p-cymene)(2-methyl-3-(oxo-κO)-4H-thiopyran-4-onato-κS)ruthenium(II)] 2 and [chlorido(η(6)-p-cymene){N-[(ethoxycarbonyl)methyl]-3-(oxo-κO)-1H-pyrid-2-onato-κO}ruthenium(II)] 3 with biomolecules such as l-methionine (Met) and ubiquitin (Ub) were investigated by electrospray ionization (ESI) ion trap mass spectrometry (MS). These Ru(II) compounds were shown to exhibit anticancer activity which varies depending on the (thio)pyr(id)onato ligands. Compounds 1 and 3 reacted readily with the model protein Ub to yield stable [Ub+Ru(p-cym)] adducts (p-cym=η(6)-p-cymene), whereas 2 was converted only to a minor degree. The protein adduct formation is reversible by incubation with N- and S-donor systems, the latter being more efficient. From these studies, an inverse correlation between metallodrug-protein interaction and cytotoxicity against human tumor cell lines was derived, where low protein binding ability is indicative of increased cytotoxic activity.