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The reactions of the dimeric complexes [RuX2(eta(6)-p-cymene)](2) (X = Br, I, SCN) with L-proline (ProH) and trans-4- hydroxy-L-proline (HypH), in methanol in the presence of NaOH, afforded [RuX(kappa N-2,O-Pro)(eta(6)-p-cymene)] (X = Br, 1b; I, 1c; SCN, 1d) and (RuX(kappa N-2,O-Hyp)(eta(6)-p-cymene)) (X = Br, 2b; I, 2c; SCN, 2d), respectively. Alternatively, the one-pot, sequential addition of the appropriate alpha-amino carboxylate and X- salt to [RuCl2(eta(6)-p-cymene)](2) led to [RuX(kappa N-2,O-Pro)(eta(6)-p-cymene)] (X = N-3, 1e; NO2, 1f; CN 1g) and [Ru(N-3)(kappa N-2,O-Hyp)(eta(6) -p-cymene)] (2e). Complexes [Ru(kappa N-3,O,O'-O2CCH(NH2)(R)O)(eta(6)-p-cymene)] (R = CH2, 3h; R = CHMe, 4h; R = CH2CH2, 5h) were prepared from the reaction of [RuCl2(eta(6)-p-cymene)](2) with the appropriate alpha-amino acid and NaOH in reftuxing isopropanol. Treatment of the L-serine (SerH(2)) derivative [RuCl(kappa N-2,O-SerH)(eta(6)-p-cymene)] (3a) with 1,3,5-triaza-7-phosphaadamantane (PTA) in water at reflux produced [Ru(kappa N-2,O-Ser)(kappa P-PTA)(eta(6)-p-cymene)]Cl ([3i]Cl). The products were isolated in good to excellent yields, and were characterized by elemental analysis, IR and multinuclear NMR spectroscopy. The structures of 1f and 2b-e were ascertained by X-ray diffraction studies. The behaviour of the complexes in water and cell culture medium was investigated by multinuclear NMR and UV-Vis spectroscopy, revealing a considerable influence of the monodentate ligand on the aqueous chemistry. Complexes 1d-e, 2d-e, 3h, 4h and [3i]Cl, showing substantial inertness in aqueous media, were assessed for their cyto-toxicity towards A2780 and A2780cisR cancer cell lines and the noncancerous HEK 293T cell line. A selection of compounds was also investigated for Ru uptake in A2780 cells and interactions with cyto-chrome c as a model protein. Combined, these studies provide insights into the previously debated role of the 'leaving' ligand on the biological activity of Ru(II) arene alpha-amino acid complexes.

Structural and electronic factors are crucial to rationalizethedifferent N,O or N,N chelating coordination of pyrazolones containinga pyridine ring. The reactivity of proligand 3-phenyl-1-(pyridin-2-yl)-5-pyrazolone(HLpy,ph) with the (arene)Ru(II) fragment was explored.Neutral and ionic (arene)Ru(II) complexes were obtained and fullycharacterized, also by X-ray diffraction, revealing the ligand tocoordinate in an unusual N,O-chelatingfashion. Other ruthenium complexes were also synthesized with 3-methyl-1-(pyridin-2-yl)-5-pyrazolone(HLpy,me) and 3-methyl-1-(pyridin-2-yl)-4-trifluoroacetyl-5-pyrazolone(HQ(py,CF3)). In these complexes the ligands adopt the preferred N,N-chelating mode. Ligands and complexeswere theoretically analyzed by density functional theory (DFT). Themost stable tautomer of HLpy,ph matched well with the experimentalbehavior of this proligand and the structures of Ru-complexes werewell described by calculations. The thermodynamic stability of the N,O- and N,N-coordination modes was analyzed and a proposal for the achievementof the N,O-coordination mode incomplexes 1-4 was proposed. Cytotoxicitytests were performed against human ovarian carcinoma (A2780 and Cisplatin-resistantA2780cis) and nontumorigenic human embryonic kidney (HEK293T) celllines, showing the free ligands to be more cytotoxic that the ensuing(arene)Ru(II) complexes.