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Therrien, Bruno
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Therrien, Bruno
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Professeur titulaire
Email
bruno.therrien@unine.ch
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Voici les éléments 1 - 10 sur 19
- PublicationMétadonnées seulementSynthesis, Characterization and Cytotoxicity of (?6-p-cymene)ruthenium(II) Complexes of ?-Amino Acids(2014)
; Furrer, JulienArene 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)] - PublicationMétadonnées seulementHighly cytotoxic diruthenium trithiolato complexes of the type [(?6-p-MeC6H4Pri)2Ru2(?2-SR)3]+: synthesis, characterization, molecular structure and in vitro anticancer activity(2013)
; 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)] - PublicationMétadonnées seulementSynthesis, characterisation and in vitro anticancer activity of hexanuclear thiolato-bridged arene ruthenium metalla-prisms(2013)
; ; Hexanuclear hexacationic thiolato-bridged arene ruthenium metalla-prisms of the general formula [[(?6-p-cymene)Ru]6(?-SR)6(?3-tpt)2][OTf]6 (R = CH2Ph, CH2C6H4-p-tBu, CH2CH2Ph; tpt = 2,4,6-tri-4-pyridyl-1,3,5-triazine), obtained from the self-assembly of dinuclear precursors [(p-cymene)2Ru2(?-SR)2Cl2] with tpt and AgCF3SO3, have been isolated and fully characterized as triflate salts. The metalla-prisms are highly cytotoxic against human ovarian cancer cells, esp. towards the cisplatin-resistant cell line A2780cisR (IC50 - PublicationMétadonnées seulementSynthesis, molecular structure, computational study and in vitro anticancer activity of dinuclear thiolato-bridged pentamethylcyclopentadienyl Rh(III) and Ir(III) complexes(2013)
; ; Neutral dinuclear dithiolato-bridged pentamethylcyclopentadienyl Rh(III) complexes (C5Me5)2Rh2(?-SR)2Cl2 (R = CH2Ph, 1; R = CH2CH2Ph, 2) and cationic dinuclear trithiolato-bridged pentamethylcyclopentadienyl Rh(III) and Ir(III) complexes [(C5Me5)2M2(?-SR)3]+ (M = Rh, R = CH2Ph, 3; M = Rh, R = CH2CH2Ph, 5; M = Rh, R = CH2C6H4-p-tBu, 7: M = Ir, R = CH2Ph, 4; M = Ir, R = CH2CH2Ph, 6; M = Ir, R = CH2C6H4-p-tBu, 8) were synthesized from the chloro-bridged pentamethylcyclopentadienyl Rh(III) and Ir(III) dimers (C5Me5)2M2(?-Cl)2Cl2 by reaction with the corresponding thiol deriv. (RSH). Complexes 3-8 were isolated as chloride salts. All complexes were obtained in good yield and were fully characterized by spectroscopic methods. The mol. structures of the neutral complexes (1 and 2) show interesting features: the two Rh atoms are bridged by two thiolato ligands with no metal-metal bonds and the pentamethylcyclopentadienyl and chlorido ligands are oriented syn to each other, an uncommon conformation for such dinuclear complexes. These structural features were rationalized using DFT calcns. Addnl., the antiproliferative activity of the complexes was evaluated against the cancerous A2780 (cisplatin sensitive) and A2780cisR (cisplatin resistant) human ovarian cell lines and on the noncancerous HEK293 human embryonic kidney cells. All complexes are active and the cationic Ir complexes 4, 6 and 8 are particularly cytotoxic, with IC50 values in the nanomolar range (IC50 < 0.1 ?M). The catalytic activity of the complexes for the oxidn. of glutathione (GSH) to GSSG was evaluated by NMR spectroscopy. [on SciFinder(R)] - PublicationMétadonnées seulementReactions of a cytotoxic hexanuclear arene ruthenium assembly with biological ligands(2013)
- PublicationMétadonnées seulementInteraction of a ruthenium hexacationic prism with amino acids and biological ligands: ESI mass spectrometry and NMR characterization of the reaction products(2012)
; Furrer, JulienReactions 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)] - PublicationMétadonnées seulementPhysical and physicochemical stimuli-responsive arene ruthenium metallaprism(2012)
- PublicationMétadonnées seulementHighly cytotoxic trithiophenolatodiruthenium complexes of the type [(?6-p-MeC6H4Pri)2Ru2(SC6H4-p-X)3]+: synthesis, molecular structure, electrochemistry, cytotoxicity, and glutathione oxidation potential(2012)
; ; - PublicationMétadonnées seulementInvestigation of the reactivity between a ruthenium hexacationic prism and biological ligands(2012)
; Furrer, JulienThe 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)] - PublicationAccès libreTemplate-Directed Synthesis of Hexanuclear Arene Ruthenium Complexes with Trigonal-Prismatic Architecture Based on 2,4,6-Tris(3-pyridyl)triazine Ligands(2011)
; ; Cationic arene ruthenium metalla-prisms of the general formula [Ru6(p-cymene)6(3-tpt)2(OO∩OO)3]6+ (3-tpt = 2,4,6-tris(3-pyridyl)-1,3,5-triazine; OO∩OO = 5,8-dioxido-1,4-naphthoquinonato [1]6+ or 6,11-dioxido-5,12-naphthacenedionato [2]6+) have been obtained from the corresponding dinuclear arene ruthenium complexes [Ru2(p-cymene)2(OO∩OO)Cl2] by reaction with 3-tpt, silver trifluoromethanesulfonate in the presence of an aromatic molecule (1,3,5-tribromobenzene, phenanthrene, pyrene, or triphenylene) that acts as a template. While the large template molecule triphenylene is permanently encapsulated in the metalla-prisms to give the complexes [triphenylene⊂1]6+ and [triphenylene⊂2]6+, 1,3,5-tribromobenzene can be removed in toluene, thus leaving the empty cages [1]6+ and [2]6+, which are isolated as their trifluoromethanesulfonate salts. In the case of the metalla-prism connected by the 5,8-dioxido-1,4-naphthoquinonato bridging ligands, the NMR spectrum reveals two isomers, 1a and 1b, the formation of which can be rationalized by means of multiple NMR experiments (one-dimensional, two-dimensional, ROESY, and DOSY). The empty and filled metalla-prisms, [1]6+, [2]6+, [template⊂1]6+, and [template⊂2]6+, have been characterized by NMR, UV−vis, and IR spectroscopy. The slow exchange processes of a guest molecule moving in and out of the cavity of cages [1]6+ and [2]6+ have been studied in solution with phenanthrene and pyrene. One-dimensional exchange spectroscopic (1D EXSY) measurements show that [phenanthrene⊂1]6+ is in a faster exchange regime than [phenanthrene⊂2]6+ and that phenanthrene is more easily exchanged than pyrene in cages [1]6+ and [2]6+, all observations being consistent with the portal size of the cages.