Therrien, Bruno

2014, Egbewande, Folake A., Paul, Lydia E. H., Therrien, Bruno, Furrer, Julien

Arene ruthenium complexes of ?-amino acids, obtained by mixing aq. solns. of [(?6-p-cymene)RuCl2]2 in the presence of AgCF3SO3 with various amino acids, have been studied at 37 °C using NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS). Small hydrophobic ?-amino acid anions were found to form bidentate N,O-chelate complexes, whereas ?-amino acids with coordinating side chains (e.g. serine, aspartic acid, histidine) acted as tridentate ligands. For many amino acids, more than two chelate complexes were formed. Presumably, complexes with the general formula [(?6-p-cymene)Ru(AA)2]n+ and bridged complexes with the general formula [{(?6-p-cymene)Ru}2(?-AA)2(?-OH)]+ were obsd. together with the expected bi- and tridentate chelate complexes. All complexes, isolated as triflate salts, were evaluated for their in vitro anticancer activity against the human ovarian cancer cell line A2780 and its cisplatin-resistant mutant A2780cisR. All complexes were found to be highly cytotoxic, with IC50 values ranging from 0.16-19.8 ?M. Interestingly, all complexes were selectivity active against A2780 cells relative to the A2780cisR variants, indicating a distinct mechanism of action that differs from that of many previously reported cytotoxic ruthenium complexes. No direct correlation between the kinetics of complex formation and cytotoxicity was apparent, suggesting that other physicochem. parameters such as complex stability and ligand exchange kinetics may play important roles in the biol. activity. [on SciFinder(R)]

2012, Paul, Lydia E. H., Therrien, Bruno, Furrer, Julien

Reactions between the cationic triangular metallaprism [(p-cymene)6Ru6(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 aq. soln. at pD 7 using NMR spectroscopy and electrospray ionization mass spectrometry. Coordination to the imidazole nitrogen atom of His or to the basic NH/NH2 groups in Arg and Lys slowly displaces the dhnq and tpt ligands from the (p-cymene)Ru units, and subsequently addnl. 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)6Ru6(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 wk of incubation. Solns. of [1]6+ are also able to catalyze oxidn. 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 oxidn. of Cys and ascorbic acid is not complete, and the formation of intermediate adducts could be evidenced. On the other hand, the oxidn. of GSH remains fast and is completed after only 12 h. Oxidn. 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-sol. organometallic cages. [on SciFinder(R)]

2013, Giannini, Federico, Paul, Lydia E. H., Furrer, Julien, Therrien, Bruno, Süss-Fink, Georg

Cationic dinuclear p-cymene Ru complexes bridged by three thiophenolato ligands contg. various substituents mainly in meta and ortho positions, [(?6-p-MeC6H4Pri)2Ru2(?2-SR)3]+ (R = 3-C6H4Me: 1; R = 3-C6H4OMe: 2; R = 3-C6H4OEt: 3; R = 3-C6H4CF3: 4; R = 3-C6H4NH2: 5; R = 3-C6H4Cl: 6; R = 2-C6H4Me: 7; R = 2-C6H4OMe: 8; R = 2-C6H4Pri: 9; R = 2-C6H4CF3: 10; R = npt: 11 (npt = 2-naphthyl); R = mco: 12 (mco = 4-methylcoumarinyl); R = 3,5-C6H3Me2: 13; R = 3,5-C6H3(CF3)2: 14; R = 3,5-C6H3Cl2: 15; R = 3,4-C6H3(OMe)2: 16), were prepd. from the reaction of the neutral p-cymene diruthenium dichloride dimer, [(?6-p-MeC6H4Pri)2Ru2Cl4], with the corresponding thiophenol RSH. All cationic complexes were isolated as their chloride salts and fully characterized by spectroscopic and anal. methods. The mol. structures of 10 and 15 were solved by a single-crystal x-ray structure anal. of [10]Cl and [15]Cl, which show that the two Ru 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 IC50 values being mostly in the nanomolar range. Complex 9 shows the highest cytotoxicity with an IC50 value of 0.03 ?M towards the A2780 cell line and the cisplatin-resistant mutant A2780cisR. The cytotoxicity of these complexes, which belong to the most active Ru anticancer compds. reported so far, can be correlated with the lipophilicity of the corresponding thiols. In comparison with the previous series, the positions of the substituents in the thiophenolato bridges are not as important as the nature of the substituents, alkyl substituents being the best ones in line with their lipophilic character. [on SciFinder(R)]

2012, Paul, Lydia E. H., Therrien, Bruno, Furrer, Julien

The relative affinity of the cationic triangular metallaprism, [(?6-p-cymene)6Ru6(?3-tpt)2(?-dhbq)3]6+ ([1]6+; tpt = 2,4,6-tri-4-pyridyl-1,3,5-triazine, H2dhbq = 2,5-dihydroxy-1,4-benzoquinone), for various amino acids, ascorbic acid, and glutathione (GSH) has been detd. at 37° in aq. solns. at pD 7, using NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS). The metallaprism [1]6+, which is constituted of six (1,4-MeC6H4iPr)Ru corners bridged by three 1,4-benzoquinonato (dhbq) ligands and connected by two 2,4,6-tri-4-pyridinyl-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/NH2 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 chelates. The binding to amino acids proceeds rapidly, as detd. by NMR spectroscopy. Interestingly, solns. of [1]6+ are able to catalyze oxidn. of the thiol group of Cys and GSH to give the corresponding disulfides and of ascorbic acid to give the corresponding dehydroascorbic acid. Competition expts. with Arg, Cys, His, and Lys show the simultaneous formation of one single adduct, the (p-cymene)Ru-His complex, and oxidn. of Cys to cystine. Furthermore, the (p-cymene)Ru-His complex formed upon the addn. of His to [1][CF3SO3]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 mols. Oxidn. of Cys and GSH to give the corresponding disulfides may explain the in vitro anticancer activity of [1]6+. [on SciFinder(R)]

2013, Paul, Lydia E. H., Furrer, Julien, Therrien, Bruno

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)]