Understanding the interactions of diruthenium anticancer agents with amino acids

The dinuclear anticancer agents 1,n-bis{chlorido[3-(oxo-κO)-2-methyl-4-(1H)-pyridinonato-κO4](η⁶-p-cymene)-ruthenium(II)}alkane (PyRu ₂ⁿ ) exhibit high antiproliferative activity in human cancer cell. Reactivity studies with DNA and protein revealed uncommon protein-DNA and DNA-DNA crosslinking ability. We report here studies on the reactions of the diruthenium organometallics PyRu ₂⁶ and PyRu ₂⁸ in comparison with a mononuclear analogue PyRu³ with amino acids using mass spectrometry and NMR spectroscopy. The compounds behave very similarly, independent of the spacer length between the metal center and of the nuclearity of the complexes. Incubation with L-cysteine (Cys) results in fast release of the pyridone ligand, with the Ru complexes able to form Cys adducts. In contrast, L-methionine forms, initially, adducts with the metal centers, but over time, the adducts decompose. Similar behavior was observed for the reaction with L-histidine with [Ru(η⁶-p-cymene)(L-histidine)] species detected.