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  • Publication
    Accès libre
    Metallic Ruthenium nanoparticles intercalated in hectorite for highly selective catalytic hydrogenations
    (2015)
    Sun, Bing
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    The design of nanocomposites consisting of functional metals and proper matrices is a very active field of research for the development of recyclable catalysts. Highly active metallic nanoparticles must be stabilized by a suitable support in order to prevent aggregation to bulk metal. Hectorite, a representative smectite clay featured by its unique swelling properties and flexible intercalation capacity, provides an ideal platform for immobilizing metal nanoparticles.
    By intercalating organometallic benzene ruthenium complexes or Werner-type ruthenium(III) ions from RuCl3 ∙ xH2O as precursor, ruthenium nano¬particles intercalated in hectorite are successfully obtained via a reduction process with molecular hydrogen approach or sodium borohydride. Depending on the properties of solvents and the reduction conditions, a variety of ruthenium nanoparticles with different morphology are formed.
    In the catalytic hydrogenation of quinoline, hectorite-intercalated ruthenium nanoparticles show excellent reactivity and selectivity to the specific product. By using water or cyclohexane as reaction medium under a certain pressure of molecular H2, 1,2,3,4-tetrahydroquinoline and decahydroquinoline were exclusively obtained, respectively. Furthermore, by using sodium borohydride as reducing agent, the catalytic hydrogenation of quinoline proceeds in water under atmospheric pressure with the conversion and selectivity superior to 99%. Isotope labeling experiments combined with semi-empirical calculations reveal that both the sodium borohydride and water participate in the hydrogenation process by means of hydride transfer and proton transfer, respectively.
    Furthermore, hectorite-intercalated ruthenium nanoparticles can also be used for the hydrogenation of aromatic amino acids in aqueous media. By screening of the influencing factors, the pH of the solution was found to be critical for the complete conversion of aromatic amino acids. Critically, during the hydrogenation process, the chirality of the substrates remains unchanged.
  • Publication
    Accès libre
    Thiolato-bridged arene ruthenium complexes as anticancer agents
    (2015)
    Stíbal, David
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    Cancer is a major cause of morbidity and mortality in today’s world, affecting populations in all countries and all regions. Although no drug or treatment able to cure cancer in all of its forms and variations was found so far, the clinical advancements of 20th and 21st century provided a number of effective drugs for specific types of cancers and had a significant effect on the survival and the quality of life of patients. One of these drugs, the platinum-based complex cisplatin, achieved almost 100% cure rate of testicular cancer, not only saving lives of thousands of patients every year but also overturning a paradigm of medicinal chemistry – it was the first metal-based anticancer drug used in the clinic. The success of cisplatin encouraged the search for new metal-based anticancer agents, which soon expanded to other metals, such as ruthenium. During the last three decades, numerous ruthenium-based compounds with interesting anticancer properties were prepared and thoroughly investigated, two of which (NAMI-A and KP1019) were ultimately introduced into clinical trials, showing the potential of ruthenium complexes in cancer therapy.
    The goal of the presented thesis was to investigate the properties of dinuclear arene ruthenium thiolato-bridged complexes and to establish their potential as anticancer drugs. In the first part of the thesis, several monothiolato, dithiolato and trithiolato complexes were synthesized and evaluated for their stability and reactivity with biological substrates. The results were correlated with the in vitro anticancer activity of the three types of complexes and showed the most stable trithiolato complexes to be the most active against ovarian cancer cell lines. Subsequently, the most active trithiolato derivative, diruthenium-1, was thoroughly investigated in vitro and in vivo to establish the mode of action of this complex, showing its promising ability to influence the tumor growth and to prolong the survival of tumor-bearing mice.
    In the second part of this thesis, three series of conjugates of the mixed trithiolato complexes were synthesized to demonstrate the potential of the coupling of dinuclear arene ruthenium complexes with biologically active organic molecules. Thus, the thiolato-bridged complexes were coupled with propargyl bromide, the resulting conjugates being available for the 1,3-Huisgen addition with tumor targeting compounds. Conjugates with ibuprofen were synthesized to investigate the effect of the antiinflamatory agent on the activity and selectivity of the resulting complexes towards cancer cells. Finally, conjugates of dinuclear trithiolato arene ruthenium complexes with alkylating agent chlorambucil were synthesized to show the effect of the two different modes of action of the conjugates on their activity in vitro and in vivo.
    These results demonstrate the potential of the dinuclear thiolato-bridged arene ruthenium complexes as a versatile platform for the synthesis of anticancer agents with variable biological properties and modes of action.
  • Publication
    Métadonnées seulement
    Arene ruthenium and pentamethylcyclopentadienyl rhodium and iridium complexes containing N,O-chelating ligands derived from piroxicam: Synthesis, molecular structure and cytotoxicity
    (2014)
    Raja, Mathiyazhagan Ulaganatha
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    ; ; ;
    Riedel, Tina
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    Dyson, Paul J.
    The non-steroidal anti-inflammatory and anti-arthritic drug piroxicam (LH) reacts with arene ruthenium dichloride dimers in refluxing dichloromethane to give the complexes [(?6-arene)Ru(?2-N,O-L)Cl] (3: arene = C6H5Me, 4: arene = p-MeC6H4Pri, 5: arene = C6Me6). The reaction seems to proceed via the intermediates [(?6-arene)Ru(N-LH)Cl2], which can be obsd. for arene = C6H5Me (1) and isolated in the case of arene = p-MeC6H4Pri (2). The analogous reaction with pentamethylcyclopentadienyl rhodium and iridium gives the complexes [(?5-C5Me5)M(?2-N,O-L)Cl] (6: M = Rh, 7: M = Ir). The single-crystal x-ray structure analyses of the p-cymene ruthenium derivs. 4 and 2 show the metal atom in the archetypical piano stool geometry; in 4 the piroxicamato ligand is coordinated in a bidentate fashion through the pyridine nitrogen atom and the enolic oxygen atom, while in 2 the intact piroxicam ligand is coordinated in a monodentate fashion through the pyridine nitrogen atom. The piroxicamato complexes 3-5 are weakly cytotoxic towards human ovarian cancer cells. [on SciFinder(R)]
  • Publication
    Métadonnées seulement
    Synthesis, molecular structure, computational study and in vitro anticancer activity of dinuclear thiolato-bridged pentamethylcyclopentadienyl Rh(III) and Ir(III) complexes
    (2013)
    Gupta, Gajendra
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    Murray, Benjamin S.
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    Dyson, Paul J.
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    Fabre, Gabin
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    Trouillas, Patrick
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    Giannini, Federico
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    Furrer, Julien
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    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)]
  • Publication
    Métadonnées seulement
    Arene ruthenium dichloro complexes containing isonicotinic ester ligands: Synthesis, molecular structure and cytotoxicity
    (2013)
    Khan, Farooq-Ahmad
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    ; ;
    Zava, Olivier
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    Dyson, Paul J.
    A series of p-cymene ruthenium dichloro complexes contg. isonicotinic ester ligands, [(arene)RuCl2NC5H4-4-COO-C6H4-p-O-(CH2)n-CH3] (n = 1: 1, n = 3: 2, n = 5: 3, n = 7: 4, n = 9: 5, n = 11: 6, n = 13: 7, n = 15: 8), were prepd. from p-cymene ruthenium dichloro dimer and the corresponding isonicotinic ester ligand. The single-crystal x-ray anal. of 1 shows the mol. to adopt the usual pseudo-tetrahedral piano-stool geometry, the isonicotinic ester ligand being coordinated through the nitrogen atom. The cytotoxicity of all complexes and of the free ligands was studied towards human ovarian cancer cells; high activities were obsd. only for n = 9 (presenting a chain with ten carbon atoms), both as far as the free ligands and the complexes are concerned. Based on this result, a new isonicotinic ester ligand with a C10 substituent contg. a terminal alc. function, NC5H4-4-COO-C6H4-p-O-(CH2)10-OH, was synthesized by a four-step method, and arene ruthenium complexes thereof, [(arene)RuCl2NC5H4-4-COO-C6H4-p-O-(CH2)10-OH] (arene = C6H6: 9a, arene = p-MeC6H4Pri: 9b, arene = C6Me6: 9c) were prepd. The complexes 9a and 9b show indeed remarkable anticancer activities, the IC50 values for human ovarian cancer cells being in the submicromolar range. The highest cytotoxicity was obsd. for complex 9b, with IC50 values of 0.18 ?M for A2780 and 3.04 ?M for the cisplatin-resistant mutant A2780cisR. [on SciFinder(R)]
  • Publication
    Métadonnées seulement
    Nano
    (2013)
    Sun, Bing
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    Khan, Farooq-Ahmad
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    Vallat, Armelle
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  • Publication
    Accès libre
    Encapsulation of Photosensitizers in Hexa- and Octanuclear Organometallic Cages: Synthesis and Characterization of Carceplex and Host-Guest Systems in Solution
    Cationic arene ruthenium assemblies of the general formulas [Ru6(p-cymene)6(tris-pvb)2(?2-Cl)6]6+, [Ru6(p-cymene)6(tris-pvb)2(OO?OO)3]6+ (tris-pvb = 1,3,5-tris{2-(pyridin-4-yl)vinyl}benzene), and [Ru8(p-cymene)8(NN?NN)2(OO?OO)4]8+ (NN?NN = 1,2,4,5-tetrakis{2-(pyridin-4-yl)vinyl}benzene, 1,2,4,5-tetrakis{2-(pyridin-4-yl)ethynyl}benzene) have been obtained from the corresponding dinuclear arene ruthenium complexes [Ru2(p-cymene)2(?-Cl)2Cl2] and [Ru2(p-cymene)2(OO?OO)Cl2] (OO?OO = oxalato, 2,5-dioxido-1,4-benzoquinonato, 2,5-dichloro-1,4-benzoquinonato, 5,8-dioxido-1,4-naphthoquinonato, 5,8-dioxido-1,4-anthraquinonato, 6,11-dioxido-5,12-naphthacenedionato) by reaction with the multidentate ligands and silver trifluoromethanesulfonate. These cationic hexa- and octanuclear cages have been isolated and characterized as their triflate salts. Addn. of coronene during the synthesis of the large hexanuclear assemblies leads to the direct encapsulation of coronene in the cavity of the trigonal-prismatic complexes. Photosensitizers such as porphin, phthalocyanine, and Zn-phthalocyanine present during the synthesis of these metalla-cages are encapsulated in five of these arene ruthenium complexes to give photosensitizer-encapsulated systems. The host-guest properties of these systems were studied in soln. by DOSY, 2D NOESY and 2D ROESY NMR spectroscopy. The H···H distances between guests and selected metalla-cages were estd. by 2D ROESY NMR spectroscopy and modelization. NMR analyzes indicate that the guest photosensitizers are completely encapsulated in two of these metalla-cages, while in the three other ruthenium cages NMR spectra reveal an equil. between empty and filled cages. [on SciFinder(R)]
  • Publication
    Métadonnées seulement
    Highly cytotoxic diruthenium trithiolato complexes of the type [(?6-p-MeC6H4Pri)2Ru2(?2-SR)3]+: synthesis, characterization, molecular structure and in vitro anticancer activity
    (2013)
    Giannini, Federico
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    Paul, Lydia E. H.
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    Furrer, Julien
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    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)]
  • Publication
    Métadonnées seulement
    Synthesis, characterisation and in vitro anticancer activity of hexanuclear thiolato-bridged arene ruthenium metalla-prisms
    (2013)
    Furrer, Mona A.
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    Denoyelle-Di-Muro, Emmanuel
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    Trouillas, Patrick
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    Giannini, Federico
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    Furrer, Julien
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    Clavel, Catherine M.
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    Dyson, Paul J.
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    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
  • Publication
    Métadonnées seulement
    Synthesis, Characterization and
    (2013)
    Giannini, Frederico
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    Furrer, Julien
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    Clavel, Catherine M.
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    Dyson, Paul J.