Reactions of a cytotoxic hexanuclear arene ruthenium assembly with biological ligands

Reactions between the cytotoxic hexacationic arene ruthenium assembly [(p-cymene)6Ru6(oxa)3(tpt)2]6+ ([1]6+) (tpt = 2,4,6-tri(pyridin-4-yl)-1,3,5-triazine and oxa = oxalato) (IC50 = 0.96 ?M against A2780 human ovarian cancer cells) and a large range of amino acids (AA) as well as the tripeptide glutathione (GSH) were monitored in aq. soln. at 37 °C by NMR spectroscopy and ESI mass spectrometry. These reactions were undertaken in order to establish the nature of the species that are presumably transported into the cell, to det. possible mechanisms of detoxification, as well as to identify potential cellular targets that may be related to the cytotoxicity. Formation of degrdn. products with the general formula [(p-cymene)Ru(AA)]+ could be obsd. with all amino acids tested in which the amino acid acts as bidentate (N,N or N,O) or tridentate (N,N,O, N,O,O or N,S,O) chelating ligand. The kinetics of formation for the degrdn. product strongly varies as a function of the amino acid: the reaction occurred within hours with His but rather slowly with Pro and Ala. In addn., our results show that the metalla-assembly catalyzes the oxidn. of glutathione, which may also, at least partially, explain its high in vitro cytotoxicity. The results obtained for this metalla-assembly are in contrast to those previously obtained with other hexacationic arene ruthenium assemblies and indicate a higher reactivity of [1]6+ and a lower oxidn. potential compared to [(p-cymene)6Ru6(dhbq)3(tpt)2]6+ (dhbq = 2,5-dihydroxy-1,4-benzoquinonato) ([2]6+) and [(p-cymene)6Ru6(dhnq)3(tpt)2]6+ (dhnq = 5,8-dihydroxy-1,4-naphthoquinonato) ([3]6+). [on SciFinder(R)]