The relative affinity of the cationic triangular metallaprism, [(pCH(3)C(6)H(4)Pr(i))(6)Ru(6)(tpt)(2)(dhbq)(3)](6+) ([1](6+)), for various amino acids, ascorbic acid, and glutathione (GSH) has been studied at 37 °C in aqueous solutions at pD 7, using NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS). The metallaprism [1](6+), which is constituted of six (pCH(3)C(6)H(4)Pr(i))Ru corners bridged by three 1,4-benzoquinonato (dhbq) ligands and connected by two 2,4,6tri(pyridin4yl)1,3,5-triazine (tpt) triangular panels, disassembled in the presence of Arg, His, and Lys, while it remains intact with Met. Coordination to the imidazole nitrogen atom in His or to the basic NH/NH(2) groups in Arg and Lys displaces the dhbq and tpt ligands from the (p-cymene)Ru units, and subsequent coordination to the amino and carboxylato groups forms stable N,N,O metallacycles. The binding to amino acids proceeds rapidly, as determined by NMR spectroscopy. Interestingly, solutions of [1](6+) are able to catalyze oxidation of the thiol group of Cys and GSH to give the corresponding disulfides and of ascorbic acid to give the corresponding dehydroascorbic acid. Competition experiments with Arg, Cys, His, and Lys show the simultaneous formation of one single adduct, the (p-cymene)Ru-His complex, and oxidation of Cys to cystine. Furthermore, the (p-cymene)Ru-His complex formed upon the addition of His to [1][CF(3)SO(3)](6) is able to oxidize Cys to cystine much more efficiently than [1](6+). These results provide evidence against interaction with proteins as process in the release of encapsulated guest molecules. Oxidation of Cys and GSH to give the corresponding disulfides may explain the in vitro anticancer activity of [1](6+).

A new series of cationic dinuclear p-cymene ruthenium complexes bridged by three thiophenolato ligands containing various substituents mainly in meta and ortho positions, [(Z 6 -p-MeC 6 H 4 Pr i ) 2 Ru 2 (m 2 -SR) 3 ] + (R = 3-C 6 H 4 Me: 1; R = 3-C 6 H 4 OMe: 2; R = 3-C 6 H 4 OEt: 3; R = 3-C 6 H 4 CF 3 : 4; R = 3-C 6 H 4 NH 2 : 5; R = 3-C 6 H 4 Cl: 6; R = 2-C 6 H 4 Me: 7; R = 2-C 6 H 4 OMe: 8; R = 2-C 6 H 4 Pr i : 9; R = 2-C 6 H 4 CF 3 : 10; R = npt: 11 (npt = 2-naphthyl); R = mco: 12 (mco = 4-methylcoumarinyl); R = 3,5-C 6 H 3 Me 2 : 13; R = 3,5-C 6 H 3 (CF 3 ) 2 : 14; R = 3,5-C 6 H 3 Cl 2 :15; R = 3,4-C 6 H 3 (OMe) 2 : 16), have been prepared from the reaction of the neutral p-cymene diruthenium dichloride dimer, [(Z 6 -p-MeC 6 H 4 Pr i ) 2 Ru 2 Cl 4 ], with the corresponding thiophenol RSH. All cationic complexes have been isolated as their chloride salts and fully characterized by spectroscopic and analytical methods.The molecular structures of 10 and 15 have been solved by a single-crystal X-ray structure analysis of [10]Cl and [15]Cl, which show that the two ruthenium atoms adopt a pseudo-octahedral geometry without a metal-metal bond in accordance with the noble gas rule. All complexes are highly cytotoxic towards human ovarian cancer cells, the IC 50 values being mostly in the nanomolar range. Complex 9 shows the highest cytotoxicity with an IC 50 value of 0.03 mM towards the A2780 cell line and the cisplatin-resistant mutant A2780cisR. The cytotoxicity of these complexes, which belong to the most active ruthenium anticancer compounds reported so far, can be correlated with the lipophilicity of the corresponding thiols. In comparison with the previous series, the results demonstrate that the positions of the substituents in the thiopenolato bridges are not as important as the nature of the substituents, alkyl substituents being the best ones in line with their lipophilic character.

1H high resolution magic angle spinning (HR-MAS) NMR spectroscopy was applied in combination with multivariate statistical analyses to study the metabolic response of whole cells to the treatment with a hexacationic ruthenium metallaprism [1]6+ as potential anticancer drug. Human ovarian cancer cells (A2780), the corresponding cisplatin resistant cells (A2780cisR), and human embryonic kidney cells (HEK-293) were each incubated for 24 h and 72 h with [1]6+ and compared to untreated cells. Different responses were obtained depending on the cell type and incubation time. Most pronounced changes were found for lipids, choline containing compounds, glutamate and glutathione, nucleotide sugars, lactate, and some amino acids. Possible contributions of these metabolites to physiologic processes are discussed. The time-dependent metabolic response patterns suggest that A2780 cells on one hand and HEK-293 cells and A2780cisR cells on the other hand may follow different cell death pathways and exist in different temporal stages thereof.

Reactions between the cationic triangular metallaprism [(p-cymene)(6)Ru(6)(tpt)(2)(dhnq)(3)](6+) ([1](6+)) [tpt is 2,4,6-tri(pyridine-4-yl)-1,3,5-triazine; dhnq is 5,8-dihydroxy-1,4-naphthoquinonato] and Arg, His, Lys, ascorbic acid, lactic acid and glutathione (GSH) have been studied at 37 °C in aqueous solution at pD 7 using NMR spectroscopy and electrospray ionisation mass spectrometry. Coordination to the imidazole nitrogen atom of His or to the basic NH/NH(2) groups in Arg and Lys slowly displaces the dhnq and tpt ligands from the (p-cymene)Ru units, and subsequently additional coordination to the amino and carboxylato groups forms stable N,N,O metallacycles. Compared with our previously reported study with the analogous metallaprism [(p-cymene)(6)Ru(6)(tpt)(2)(dhbq)(3)](6+) ([2](6+)) (dhbq is 2,5-dihydroxy-1,4-benzoquinonato), the larger metallaprism [1](6+) appears to be significantly more stable, and disassembled in the presence of Arg, His and Lys after only 12 h of incubation. Moreover, the reaction with His is not complete, since only 14 % of His reacted after more than 1 week of incubation. Solutions of [1](6+) are also able to catalyse oxidation of the thiol group of Cys and GSH to give the corresponding disulfides and of ascorbic acid to give the corresponding dehydroascorbic acid. However, the results are markedly different from those obtained with metallaprism [2](6+): the oxidation of Cys and ascorbic acid is not complete, and the formation of intermediate adducts could be evidenced. On the other hand, the oxidation of GSH remains fast and is completed after only 12 h. Oxidation of GSH to give the corresponding disulfide may explain its higher in vitro anticancer activity as compared with [2](6+). Our results suggest that metallaprism [1](6+) is more robust than [2](6+), may remain intact in the bloodstream and, therefore, may enter cancer cells undamaged, thus confirming the drug delivery potential for such water-soluble organometallic cages.

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Novel dinuclear arene ruthenium trithiolato complexes containing a water-soluble peptide moiety in one of the three thiolato bridges were designed and evaluated against A2780 human ovarian cancer cells and against their cisplatin-resistant mutant A2780cisR.

Interactions between three hexacationic arene ruthenium metallaprisms, [( p-cymene) 6+ , and a series of human proteins including human serum albumin, transferrin, cytochrome c, myoglobin and ubiquitin have been studied using NMR spectroscopy, mass spectrometry and circular dichroism spectroscopy. All data suggest that no covalent adducts are formed between the proteins and the metallaprisms. Indeed, in most cases electrostatic interactions, leading to precipitation of protein-metallaprism aggregates, have been observed. In addition, with the smallest proteins, ubiquitin, myoglobin and cytochrome c, the presence of the hexacationic arene ruthenium metallaprisms induces structural changes of the proteins, as emphasized by circular dichroism. The results suggest that proteins are certainly a biological target for these metalla-assemblies.