Stability of an organometallic ruthenium-ubiquitin adduct in the presence of glutathione: Relevance to antitumor activity

The interactions of the ruthenium(II) complex Ru(η6-p-cymene)(pta)Cl2 (RAPTA-C), an effective anticancer and antimetastatic agent, with biol. nucleophiles are important with respect to its mechanism of action, for example, the reaction with glutathione (GSH) potentially plays an important role in detoxification. RAPTA-C reacts rapidly with glutathione forming a series of adducts including Ru(η6-p-cymene)(pta)(GS), Ru(η6-p-cymene)(GS) and bis-GSH conjugates, which were characterized by Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). In addn., the ability of glutathione to cleave ruthenium-ubiquitin bonds was assayed and it was shown that GSH is capable of removing the Ru moiety from the protein, although no ternary adducts were identified.