published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

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The thesis “Ancillary Ligand Effects on the Anticancer Activity of Ruthenium (II) Piano Stool Complexes” is an effort to design better antitumor metallodrugs based on ruthenium(II) complexes with various H-bond donor/acceptor ligands and to understand their mechanism of action. Chapter 1 presents a brief review of metallodrugs and their mechanism of action. Different classes of metallodrugs are discussed. A short discussion on ruthenium based anticancer drugs and their established mechanism of action is also included in this chapter. Chapter 2 deals with the synthesis, characterization and anticancer activity of Ru(II) complexes with P(III) and P(V) ligands. The effect of a strong hydrogen bond acceptor on the cytotoxicity of the complexes has been investigated which allows comparison of complexes with ligands possessing a strong hydrogen bond donor or hydrogen bond acceptor. Partial oxidation of the tertiary phosphine ligands leads to a decrease in cytotoxicity of the ligand, while coordination to ruthenium resulted in a significant increase in the cytotoxicity. A molecular mechanism of action for these complexes was suggested on the basis of various biophysical studies. These complexes bind DNA through non-intercalative interactions which lead to the destabilization of the double helix of the DNA and also unwinding of the negatively supercoiled DNA. Results show that the presence of a hydrogen bond acceptor on the ligand is not capable of enhancing interactions with DNA in comparison with hydrogen bond donor groups. Cellular studies of these complexes showed that inhibition of DNA synthesis and apoptosis occur on treatment with these complexes. Interestingly, these complexes are found to be not only cytotoxic but also antimetastatic. Chapter 3 deals with the synthesis, characterization and anticancer activity of Ru(II) complexes with biologically active S containing heterocyclic ligands and their mechanistic study. Complexation of ruthenium with mercaptobenzothiazole (MBT) gave the most cytotoxic complex (H3) in the series. Heterocyclic Ru(II) complexes behave differently as evidenced by cellular and biophysical studies. Unlike phosphine complexes, H3 shows biphasic melting of DNA at higher concentrations which suggests two different types of interaction with DNA. Chapter 4 deals with synthesis and characterization of water soluble multiruthenated hydrophilic ruthenium(II) complexes with urotropine. An increase in cytotoxicity and binding affinity has been observed with increase in the number of ruthenium atoms per molecule. The complex with three ruthenium atoms showed the best activity. However cytotoxicity of the complexes decreases with decrease in the lipophilicity of the complexes. Chapter 5 describes studies on the interaction of Ru complexes with water, ss-DNA, AMP, GMP and GSH by various spectroscopic techniques. Hydrolysis of Ru-Cl bond in the complexes correlates with the cytotoxicity. Chapter 6 reports the summary of the observations of the thesis and the future prospects of metallodrugs.

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Thesis (PhD)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: The synthesis of a range of siloxane functionalized Ru(arene)Cl(N,N) complexes allowing for the synthesis of novel MCM-41 and SBA-15 immobilized ruthenium(II) catalysts, is described in this thesis. Two distinctly different approaches were envisaged to achieve successful heterogenization of these siloxane functionalized complexes. Condensation of the siloxane functionalized complexes, C2.4-C2.6 (siloxane tether attached to imine nitrogen) and C3.5-C3.7 (siloxane tether via the arene ring), with the surface silanols of the synthesized silica support materials MCM-41 and SBA-15, afforded immobilized catalysts IC4.1-IC4.6 (siloxane tether attached to imine nitrogen) and IC4.7-IC4.12 (siloxane tether via the arene ring). Model and siloxane functionalized complexes C2.1-C2.6 were prepared by the reaction of diimine Schiff base ligands L2.1-L2.6 with the [Ru(p-cymene)2Cl2]2 dimer. A second, novel, approach involved the introduction of the siloxane tether on the arene ligand of the complex. Cationic arene functionalized Ru(arene)Cl(N,N) complexes, C3.1-C3.4, were prepared with varying N,N ligands including bipyridine and a range of diimine ligands, with either propyl or diisopropyl(phenyl) substituents at the imine nitrogen (greater steric bulk around the metal center). The reaction of these propanol functionalized complexes with 3-(triethoxysilyl)propyl isocyanate, afforded urethane linked siloxane functionalized complexes C3.5-C3.8, where the siloxane tether is attached to the arene ring of the complex. The complexes were fully characterized by FT-IR spectroscopy, NMR (1H and 13C) spectroscopy, ESI-MS analysis and microanalysis. Suitable crystals for the alcohol functionalized complex C3.1 were obtained and the resultant orange crystals were analyzed by single crystal XRD. The heterogenized catalysts, IC4.1-IC4.12, were characterized by smallangle powder X-ray diffraction, scanning and transmission electron microscopy (SEM and TEM), thermal gravimetric analysis (TGA), inductively coupled plasma optical emission spectroscopy (ICP-OES) and nitrogen adsorption/desorption (BET) surface analysis to name but a few. ICP-OES allowed for direct comparison of the model and immobilized systems during catalysis ensuring that the ruthenium loadings were kept constant. The application of the model complexes C2.1-C2.3 and C3.1-C3.3, as well as their immobilized counterparts, IC4.1-IC4.12, as catalyst precursors in the oxidative cleavage of alkenes (1-octene and styrene), were investigated. The proposed active species for the cleavage reactions was confirmed to be RuO4 (UV-Vis spectroscopy). In general it was observed that at lower conversions, aldehyde was formed as the major product. Increased reaction times resulted in the conversion of the formed aldehyde to the corresponding carboxylic acid. For the oxidative cleavage of 1-octene using the systems with the siloxane tether attached to the imine nitrogen, the immobilized systems outperformed the model systems in all regards. Higher conversions and selectivities of 1-octene towards heptaldehyde were obtained when using immobilized catalysts IC4.1-IC4.6, as compared to their non-immobilized model counterparts (C2.1-C2.3) at similar times. It was found that the immobilized catalysts could be used at ruthenium loadings as low as 0.05 mol %, compared to the model systems where 0.5 mol % ruthenium was required to give favorable results. Complete conversion of 1-octene could be achieved at almost half the time needed when using the model systems as catalyst precursors. The activity of the model systems seems to increase with the increase in steric bulk around the metal center. These model and immobilized systems were also found to cleave styrene affording benzaldehyde in almost quantitative yield in some case (shorter reaction times). The systems, with the siloxane tether via the arene ring, were found to be less active for the cleavage of 1-octene when compared to the above mentioned systems (siloxane tether attached to the imine nitrogen). The immobilized systems IC4.7-IC4.12 performed well compared to their model counterparts, but could not achieve the same conversions at the shorter reaction times as were the case for IC4.1-IC4.6. This lower activity was ascribed to the decreased stability of these systems in solution compared to the above mentioned systems with the tether attached to the imine nitrogen. This was confirmed by monitoring the conversion of the complex (catalyst precursor) to the active species in the absence of substrate (monitored by UV-Vis spectroscopy). It was observed that model complex C3.1 could not be detected in solution after 1 hour, compared to complex C2.2 which was detected in solution even after 24 hours. Experiments were carried out where MCM-41 was added to a solution of model complex C2.2 under typical cleavage reaction conditions. A dramatic increase in the conversion was achieved when compared to a reaction in the absence of MCM-41. An investigation into the effect of the support material on the formation of the expected active species was carried out using UV-Vis spectroscopy. The presence of the active species, RuO4, could be observed at shorter reaction times in the presence of MCM-41. This suggested that the silica support facilitates the formation of the active species from the complex during the reaction, therefore resulting in an increased activity. It was also observed that RuO4 is present in solution in reactions where the immobilized catalyst systems are used after very short reaction times, compared to the prolonged times required for this to occur as is the case for the model systems. Model and immobilized catalysts, C2.1-C2.3 and IC4.1-IC4.6, were also applied as catalysts for the transfer hydrogenation of various ketones. The immobilized systems could be recovered and reused for three consecutive runs before the catalysts became inactive (transfer hydrogenation of acetophenone). Moderate to good conversion were obtained using the immobilized systems, but were found to be less active their model counterparts C2.1-C2.3. / AFRIKAANSE OPSOMMING: Die sintese van `n reeks siloksaan gefunksioneerde Ru(areen)Cl(N,N) komplekse, wat die sintese van nuwe MCM-41 en SBA-15 geimmobiliseerede rutenium(II) katalisatore toelaat, word in hierdie tesis beskryf. Twee ooglopend verskillende metodes is voorgestel om die suksesvolle immobilisering van die siloksaan gefunksioneerde komplekse te bereik. Die kondensasie van die siloksaan gefunksioneerde komplekse, C2.4-C2.6 (siloksaan ketting geheg aan die imien stikstof) en C3.5-C3.7 (siloksaan ketting geheg aan die areen ligand), met die oppervlak silanol groepe van die silika materiale MCM-41 en SBA-15, laat die sintese van geimmobiliseerde katalisatore IC4.1-IC4.6 (siloksaan ketting geheg aan die imien stikstof) en IC4.7-IC4.12 (siloksaan ketting geheg aan die areen ligand) toe. Model en siloksaan gefunksioneerde komplekse C2.6-C2.6 is berei deur die reaksie tussen Schiff basis ligande, L2.1-L2.6, en die [Ru(p-simeen)2Cl2]2 dimeer. `n Tweede, nuwe benadering wat die sintese van komplekse met die siloksaan ketting geheg aan die areen ligand behels, is ook gevolg. Kationiese areen gefunksioneerde Ru(areen)Cl(N,N) komplekse, C3.1-C3.4, is berei deur die N,N ligande rondom die metaal sentrum te wissel vanaf bipiridien tot `n reeks diimien ligande met propiel of diisopropielfeniel substituente by die imien stikstof. Hierdie propanol gefunksioneerde komplekse is met 3-(triëtoksiesiliel)propiel-isosianaat gereageer om sodoende die uretaan gekoppelde siloksaan gefunksioneerde komplekse C3.5-C3.8 op te lewer. Al die komplekse is ten volle gekaraktariseer deur van FT-IR spektroskopie, KMR (1H and 13C) spektroskopie, ESI-MS analise en mikroanalise gebruik te maak. In die geval van model kompleks C3.1, is `n kristalstruktuurbepaling ook uitgevoer. Die heterogene katalisatore, IC4.1- IC4.12, is gekaraktariseer deur poeier X-straaldiffraksie, skandeer- en transmissieelektronmikroskopie, termogravimetriese analise (TGA), induktief gekoppelde plasma optiese emissie spektroskopie (IKP-OES) en BET oppervlak analises, om net `n paar te noem. IKP-OES het ons toegelaat om `n direkte vergelyking te tref tussen die model en geimmobiliseerde sisteme tydens die katalise reaksies. Model komplekse C2.1-C2.3 en C3.1-C3.3, sowel as hul geimmobiliseerde eweknieë IC4.1- IC4.12, is vir die oksidatiewe splyting van alkene (1-okteen en stireen) getoets. Die voorgestelde aktiewe spesie wat tydens hierdie reaksie gevorm word, RuO4, is bevestig deur van UV-Vis spektroskopie gebruik te maak. Oor die algemeen is dit gevind dat aldehied oorheersend gevorm word by laer omsetting. Wanneer die reaksietyd verleng is, is daar gevind dat die aldehied na die ooreenstemmende karboksielsuur omgeskakel is. Wanneer die geimmobiliseerde katalisatore gebruik is tydens die oksidatiewe splitsing van 1-okteen, het die sisteme, met die ketting geheg aan die imien stikstof, deurgangs beter as die model sisteme gevaar. Hoër omskakelings van 1-okteen en hoë selektiwiteite vir heptaldehied is behaal wanneer die geimobiliseerded katalisatore IC4.1-IC4.6 met die nie-geimmobiliseerde model sisteme (C2.1- C2.3) vergelyk is by dieselfde reaksietye. Die geimobiliseerde sisteme kon by rutenium beladings van so laag as 0.05 mol % gebruik word. Dit is in teenstelling met die model sisteme waar 0.5 mol % rutenium nodig was om die reaksie suksesvol te laat plaasvind. Die totale omskakeling van 1-okteen is bereik in die helfte van die tyd wat nodig was wanneer die model sisteme gebruik is. Dit is gevind dat die aktiwiteit van die model sisteme toeneem met `n toename in die steriese grootte van die ligand rondom die metaal. Beide die model en geimmobilseerde sisteme kon ook gebruik word vir die oksidatiewe splyting van stireen. Bensaldehied kon in kwantitiewe opbrengs gevorm word in sommige gevalle. `n Laer aktiwiteit vir die oksidatiewe splyting van 1-okteen is vir die sisteme waar die siloksaan ketting aan die areen ligand geheg is, waargeneem. Hoewel die geimmobiliseerde sisteme IC4.7-IC4.12 beter as hul model eweknieë gevaar het, kon die aktiwiteite wat met IC4.1-IC4.6 bereik is nie geewenaar word nie. Hierdie laer aktiwiteit is toegeskryf aan die verlaagde stabiliteit van dié sisteme in oplossing in vergelyking met IC4.1-IC4.6 (ketting geheg aan die imine stikstof). Die stabiliteit van beide sisteme is getoets deur die omskakeling van die model komplekse (C2.2 en C3.1; katalise voorgangers) na die aktiewe spesie te monitor (UV-Vis spektroskopie). Na 1 uur kon die model kompleks C3.1 nie meer in die oplossing waargeneem word nie. In teenstelling kon model kompleks C2.2 nog selfs na 24 uur in die oplossing bespeur word. Om die rol van die silika materiale tydens die reaksie te ondersoek, is `n eksperiment uitgevoer waar MCM-41 by `n oplossing van kompleks C2.2 gevoeg is. `n Toename in die omskakeling van 1-okteen is waargeneem in vergelyking met `n reaksie waar geen silika teenwoordig was nie. UV-Vis spektroskopie is gebruik om die invloed van die silika op die vorming van die aktiewe spesie te ondersoek. In eksperimente waar MCM-41 teenwoordig was, kon die aktiewe spesie, RuO4, by baie korter reaksietye waargeneem word. Dit wil blyk of die silika materiaal die vorming van die aktiewe spesie vanaf die kompleks aanhelp en sodoende `n toename in die spoed van die reaksie bewerkstellig. RuO4 kon ook by baie korter reaksietye waargeneem word wanneer die geimmobiliseerde sisteme gebruik is. Beide model en geimmobiliseerde sisteme, C2.1-C2.3 en IC4.1-IC4.6, is getoets vir die oordrag hidrogenering van verskilende ketone. Dit was moontlik om die geimmobiliseerde sisteme drie keer te herwin en vir daaropvolgende reaksies te gebruik. Vir die geimmobiliseerde sisteme kon egter slegs gemiddelde omskakelings verkryg word en het swakker gevaar as hul model ekwivalente sisteme, C2.1-C2.3.

A series of ruthenium complexes of the general type Ru(CO)2(P(n-Bu)3)2(O2CR)2 (4a, R = Me; 4b, R = Et; 4c, R = i-Pr; 4d, R = t-Bu; 4e, R = CH2OCH3; 4f, R = CF3; 4g, R = CF2CF3) was synthesized by a single-step reaction of Ru3(CO)12 with P(n-Bu)3 and the respective carboxylic acid. The molecular structures of 4b, 4c and 4e–g in the solid state are discussed. All ruthenium complexes are stable against air and moisture and possess low melting points. The physical properties including the vapor pressure can be adjusted by modification of the carboxylate ligands. The chemical vapor deposition of ruthenium precursors 4a–f was carried out in a vertical cold-wall CVD reactor at substrate temperatures between 350 and 400 °C in a nitrogen atmosphere. These experiments show that all precursors are well suited for the deposition of phosphorus-doped ruthenium layers without addition of any reactive gas or an additional phosphorus source. In the films, phosphorus contents between 11 and 16 mol% were determined by XPS analysis. The obtained layers possess thicknesses between 25 and 65 nm and are highly conformal and dense as proven by SEM and AFM studies. / Dieser Beitrag ist aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

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FAPEMIG - Fundação de Amparo a Pesquisa do Estado de Minas Gerais / Finep - Financiadora de Estudos e Projetos / RQMG - Rede Mineira de Química / Complexos rutênio-arenos são amplamente estudados como catalisadores homogêneos ao longo dos últimos anos, principalmente com aplicações em reações de hidrogenação de ligações polares. Estes complexos são promissores na redução de ligações polares do tipo C=O de arilcetonas. Como consequência destes estudos o objetivo do trabalho foi aplicar uma série de complexos rutênio-areno coordenados a ligantes iminopiridínicos na redução de cetonas. Inicialmente foram sintetizados e caracterizados seis ligantes iminopiridínicos N-N doadores {N-(priridina-2-metileno)anilina (Amp); 4-cloro-N-(priridina-2-metileno)anilina (Clmp); 4-metil-N-(priridina-2-metileno)anilina (Memp); 4-terc-butil-N-(priridina-2- metileno)anilina (Tbmp); 2,6-dietil-N-(priridina-2 metileno)anilina (Diemp); 2,6-diisopropil- N-(priridina-2-metileno)anilina (Diipmp)} a partir de uma reação de condensação entre a anilinas orto- ou para- substituída e a 2-piridinocarboxialdeído, na presença de ácido p- toluenosulfônico como catalisador. O complexo binuclear de Ru(II) [RuCl(g-Cl)(p-cym)]2 {onde p-cym = para-cimeno} foi utilizado como precursor de síntese para preparar seis complexos com fórmula geral [RuCl(^-cym)(N-N)]PF6. As caracterizações dos ligantes e complexos foram realizadas através das técnicas de análise elementar, condutividade molar iônica, espectroscopia eletrônica na região do ultravioleta, espectroscopia vibracional na região infravermelho, voltametria cíclica e RMN XH. As estruturas dos complexos [RuCl(p-cym)(Diipmp)]PF6 e [RuCl(p-cym)(Memp)]PF6 foram determinadas por difração de raios X de monocristal. A análise elementar dos ligantes e dos complexos estão de acordo com a estrutura química sugerida. A condutividade molar iônica para os complexos em solução de acetonitrila e diclorometano confirmam que estes são eletrólito 1:1. Os complexos apresentaram processo anódico próximo a 1,80 V, processo irreversível, que proporciona a descoordenação do ligante p-cym e consequente formação in situ de solvatos complexos de formula geral [RuCl(N-N)(CH3CN)3]+ os quais apresentam valores de E1/2 próximos a 1,1 V. Os espectros de RMN 1H para os ligantes livres apresentaram sinais próximos de 8,15-8,30 ppm e 8,50-8,73 ppm para a série de ligantes N-N, que são referentes aos núcleos de hidrogênios ligados a carbonos adjacentes aos nitrogênios imínicos e piridínicos. Para os complexos foram observados a presença de deslocamentos químicos mais desblindados, confirmando a coordenação dos ligantes N-N ao centro metálico. A presença do ligante p-cym foi confirmada a partir dos deslocamentos químicos do núcleo de hidrogeno isopropílico, o qual gera um dubleto próximo a 0,98-1,30 ppm e septeto próximo a 2,30-3,15 ppm, que é referente ao acoplamento das metilas com o hidrogênio isopropílico. Os complexos apresentaram uma boa atividade catalítica em reações de transferência de hidrogênio para redução dos substratos analisados utilizando isopropanol como doador de hidrogênio e solvente, destacando aos complexos [RuCl(p-cym)(Clmp)]PF6 e [RuCl(p-cym)(Memp)]PF6 que apresentaram conversões acima de 80% e o menor valor de desvio padrão relativo para os dois substratos. Utilizando estes complexos, foi realizado o estudo cinético das reações de transferências de hidrogênio onde foi possível verificar a dependência da conversão do substrato em relação à mudança de temperatura. Também foram determinados os parâmetros termodinâmicos como a energia livre de Gibbs de ativação (AG*), entalpia de ativação (AH*) e entropia de ativação (AS*), correlacionando-os com o comportamento reacional de cada complexo. / Ruthenium-arene complexes are widely studied as homogeneous catalysts over the last years, especially in applications with polar bonds hydrogenation reactions. These ruthenium-arene complexes are promising in the reduction of polar C=O type bonds of arylketones. As a consequence of these studies the objective of this work was to apply a series of coordinated ruthenium-arene complexes to iminopyridine ligands in the reduction of ketones. Initially were synthesized and characterized six iminopyridines ligands N-N donor {N-(pyridine-2- methylene)aniline (Amp); 4-chloro-N-(pyridine-2-methylene)aniline (Clmp); 4-methyl-N- (pyridine-2-methylene)aniline (Memp); 4-tert-butyl-N-(pyridine-2-methylene)aniline (Tbmp); 2,6-diethyl-N-(pyridine-2-methylene)aniline (Diemp); 2,6-diisopropyl-N-(pyridine-2- methylene)aniline (Diipmp)} by the condensation reaction between an aniline ortho- orpara- substituted and 2-pyridinecarboxaldehyde in the presence of p-toluenesulfonic acid as catalyst. The binuclear ruthenium(II) complexes [RuCl(^-Cl){p-cym)]2 { p-cym = para- cymene} was using as the synthesis precursor to prepare six complexes of general formula [RuCl(p-cym)(N-N)]PF6. The ligands and complexes characterizations were performed using XH NMR, cyclic voltammetry, infrared vibrational spectroscopy, ultraviolet and visible electron spectroscopy, elemental analysis and molar conductivity. The structure of the complexes [RuCl(p-cym)(Dipimp)]PF6 and [RuCl(p-cym)(Memp)]PF6 were determined by single-crystal X-ray diffraction. The elemental analysis of the ligands and the complexes are according to the suggested chemical structure. The ionic molar conductivity for the solution complexes of acetonitrile and dichloromethane confirm that these are 1:1 electrolyte. The complexes presented an anode process close to 1.80 V, an irreversible process, which leads to the incoordination of the p-cym ligand and consequent in situ formation of complex solvates of the general formula [RuCl(N-N)(CH3CN)3]+ which have values of E1/2 near 1.1 V. 1H NMR spectra for the free ligands showed singlets and doublets close to 8.15-8.30 ppm and 8.50-8.73 ppm for the ligands series N-N, these chemical shifts are due to the carbon-bonded hydrogen core adjacent to the imine e pyridine nitrogens. The complexes also showed the presence of theses chemical shifts a little more deshielding, confirming the ligands N-N coordination. The presence of the p-cym ligand was confirmed by the chemical shifts of the hydrogen core of the isopropyl radical, which yields doublets close to 0.98-1.30 ppm and septets close to 2.30-3.15 ppm, which is related to the coupling of methyl with isopropyl hydrogen. The complexes presented good catalytic activity in hydrogen transfer reactions to reduce the substrates analyzed using isopropanol as a source of hydrogen and solvent, emphasizing the complexes [RuCl(p-cym)(Clmp)]PF6 and [RuQ(p-cym)(Memp)]PF6 which showed conversions above 80% and the lowest relative standard deviation value for the two substrates. Using these complexes, a kinetic study of the hydrogen transfer reactions was carried out, where it was possible to verify the dependence of the substrate conversion on the temperature change. It was also determined the thermodynamic parameters such as the free energy of Gibbs of activation (AG*), enthalpy of activation (A#*) and entropy of activation (AS*), correlating them with the reaction behavior of each complex. / Dissertação (Mestrado)

Submitted by JÚLIO HEBER SILVA (julioheber@yahoo.com.br) on 2017-06-05T19:35:37Z No. of bitstreams: 2 Dissertação - Aline Monezi Montel - 2015.pdf: 4015331 bytes, checksum: 793195b96d26505a33dde69ed1f9eee3 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2017-06-06T12:36:41Z (GMT) No. of bitstreams: 2 Dissertação - Aline Monezi Montel - 2015.pdf: 4015331 bytes, checksum: 793195b96d26505a33dde69ed1f9eee3 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-06-06T12:36:41Z (GMT). No. of bitstreams: 2 Dissertação - Aline Monezi Montel - 2015.pdf: 4015331 bytes, checksum: 793195b96d26505a33dde69ed1f9eee3 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2015-04-24 / Glioblastoma multiforme (GBM) is the malignant brain tumor most frequent in adults characterized by its high proliferative and invasive properties in addition of its high resistance to the available treatments. Therefore, the investigation of novel agents able to improve survival and overall life quality of GBM patients is extremely needed. Ruthenium compounds have revealed to be good candidates as antitumor drugs demonstrating antiproliferative activity in some types of cancer such as breast, prostate and lung. Besides the chemical properties specific for these compounds, ruthenium also presents a variety of radioisotopes that can be potentially used in radionuclide therapy (RT). In this work we investigated the antitumor effect of non-radioactive and radioactive Ruthenium II Fosfinic Complexes (RFCs) [Ru(pic)(bipy)(dppb)]PF6, [Ru(pic)(bipy)(dppe)]PF6, [Ru(pic)(bipy)(dppf)]PF6 and [Ru(pic)(bipy)(dppp)]PF6 on GBM cell lines and evaluated its potential use for RT. The GBM cell lines: U87 (expressing native p53 protein) and T98 (expressing mutant p53 protein), as well as human pulmonary fibroblast (MRC5) were treated with diffferent concentrations of non radioactive and radioactive RFCs. Radioactive ruthenium complexes containing 103Ru were produced by neutron activation at the TRIGA MARK-I IPR-RI with a thermal neutronic flux of 4.3x1012 n.cm-2.s-1. Cell viability were evaluated by MTT assay, morphological alterations and RFCs mechanism of action were analyzed by phase contrast and fluorescence microscopy with DAPI and double acridine orange/ethidium bromide staining. Generation of oxygen reactive species (ROS) by RFCs was detected by diclorofluorescein (DCF) assay and quantification of the produced fluorescence was analyzed in ImageJ software (NIH, Bethesda, MD, USA). All tested compounds were cytotoxic to the cells in a dose-dependent manner presenting IC50 in the range of 1.49 µM to 27.8 µM and between 2.3x10-4 µM to 6.2x10-4 µM for non-radioactive and radioactive RFCs respectively. The RFCs induced morphological alterations indicative of cell death by apoptosis and/or necrosis such as decreasing cell size, cell roundness, nuclear fragmentation, cromatin condensation and formation of apoptotic bodies. RFCs neutronic activated demonstrated higher cytotoxic activity than its non-radioactive counterparts suggesting that upon neutronic activation 103Ru,  particles emitter, showed sinergistic antitumor effect. Therefore, ruthenium based complexes can serve as a prototype for the development of new anticancer drugs, as well as, the use of its radioisotopes may be considered for RT. Based on the published literature and to the best of our knowledge so far this is the first report describing the potential use of radioactive ruthenium compounds in GBM. / O glioblastoma multiforme (GBM) é o tumor cerebral maligno mais frequente em adultos, caracterizado por uma alta capacidade proliferativa e invasiva, além da alta resistência aos tratamentos disponíveis. Por isso, a investigação de novos agentes que possam melhorar a sobrevida e a qualidade de vida dos pacientes com GBM é extremamente necessária. Os compostos de rutênio têm se revelado bons candidatos como drogas antitumorais, apresentando atividade antiproliferativa em alguns tipos de câncer, tais como: mama, próstata e pulmão. Além das propriedades químicas, específicas destes compostos, o rutênio apresenta também radioisótopos que podem ser potencialmente usados na terapia por radionuclídeos (TR). Neste trabalho investigou-se o efeito antitumoral dos complexos fosfínicos de Rutênio (II) (CFRs): [Ru(pic)(bipy)(dppb)]PF6, [Ru(pic)(bipy)(dppe)]PF6, [Ru(pic)(bipy)(dppf)]PF6 e [Ru(pic)(bipy)(dppp)]PF6, não radioativos e radioativos, sobre linhagens celulares de GBM e avaliou-se o seu potencial uso em TR. As linhagens celulares de GBM: U87 (proteína p53 nativa) e T98 (proteína p53 mutante), assim como, células de fibroblastos pulmonares humanos (MRC5) foram tratadas com diferentes concentrações dos CFRs não radioativos ou radioativos. Os CFRs radioativos contendo 103Ru foram ativados neutronicamente utilizando o reator nuclear TRIGA MARK-I IPR-RI, com fluxo neutrônico de 4,3x1012 n.cm-2.s-1. A viabilidade celular foi avaliada pelo ensaio de MTT, alterações morfológicas e mecanismo de morte induzido pelos CFRs nas células tratadas foram identificados por microscopia de contraste de fase e de fluorescência utilizando coloração com DAPI ou dupla coloração com Laranja de acridina/Brometo de etídeo. A capacidade de geração de espécies reativas de oxigênio (ROS) pelos CFRs foi detectada pelo ensaio com diclorofluoresceína (DCF) e a quantificação da fluorescência produzida foi analisada no software image J (NIH, Bethesda, MD, USA). Todos os compostos foram citotóxicos de maneira dose-dependente, apresentando valores de IC50 variando de 1,49 µM a 27,8 µM e entre 2,3x10-4 µM a 6,2x10-4 µM em células de GBM para os compostos não radioativos e radioativos, respectivamente. Os compostos induziram alterações morfológicas indicativas de morte por apoptose e/ou necrose, como encolhimento e arredondamento celular, fragmentação nuclear, condensação da cromatina, formação de corpos apoptóticos. Os CFRs ativados neutronicamente apresentaram maior atividade citotóxica que os CFRs não-radioativos, indicando que os isótopos 103Ru, emissores de partículas β apresentaram efeito antitumoral sinergístico. Portanto, os complexos a base de rutênio podem servir como protótipo para o desenvolvimento de novos antineoplásicos, assim como, a utilização de seus radioisótopos podem ser considerados para TR. Com base na literatura, até a presente data, este é o primeiro relato do uso de compostos radioativos de rutênio em GBM.

Dans le domaine des nanomachines, des progrès considérables ont été réalisés. Il est désormais possible de synthétiser une machine moléculaire et de contrôler son mouvement grâce à une source d'énergie chimique, lumineuse ou électrique, de façon à ce qu'il soit unidirectionnel. Un nouveau défi a surgi : comment rendre ce mouvement utile ? Comment utiliser le travail d'une machine moléculaire au niveau nanoscopique, mésoscopique ou macroscopique ? Cette thèse s'inscrit à la suite de la démonstration du contrôle de la rotation d'un moteur moléculaire. Ce moteur est un complexe de ruthénium(II) dont la rotation de la partie mobile, le rotor, est contrôlée par la pointe d'un microscope à effet tunnel. Afin de déterminer le travail limite fournit par ce moteur, nous avons synthétisé un nanotreuil intégrant le moteur moléculaire déjà étudié dans l'équipe avec une chaîne latérale permettant d'accrocher par chimie clic différents types de fragments moléculaires. Ces fragments ayant des natures chimiques différentes (fullerènes, triptycènes, porphyrines), ils interagiront de manière plus ou moins importante avec la surface. De ce fait, la rotation du moteur pourra ou ne pourra pas entraîner leur déplacement sur la surface, ce qui nous permettra d'estimer le travail du moteur. Cette thèse décrit la synthèse des différentes sous-unités de ce nanotreuil : le moteur dissymétrique, la chaîne et les différentes charges. Après avoir développé différentes stratégies visant à intégrer la chaîne sur le rotor, la synthèse de chacun des fragments moléculaires fera l'objet des chapitres suivants. Enfin, un chapitre mettra en perspective l'intégration possible du moteur dans des systèmes d'engrenages en vue de la récupération du travail dans un réseau supramoléculaire. / In the field of molecular machines, considerable developments have been achieved. Nowadays, it is possible to synthesize a molecular machine with a directional control on its motion thanks to chemical, light or electrical energy source. A new challenge has arised: how make that movement useful ? How use the work of a molecular machine at a nano-, meso- or macro-level ? This thesis is in line with the demonstration and control of the molecular motor rotation. This motor consists in a ruthenium(II) complexe whom rotation of the movable part, i.e. the rotor, is controlled by the scanning tunnelling microscope tip. In order to estimate its motive power, we have synthesized a nanowinch incorporating the molecular motor synthesized in the team. This motor has been desymmetrized to be able to incorporate a chain allowing to connect by click chemistry several kind of molecular fragments. These fragments (fullerenes, triptycenes, porphyrines) will interact more or less with the surface of deposition. Therefore, the motor rotation will or will not make them move on the surface, giving us the possibility to estimate the motor torque. In this thesis, the synthesis of the different parts of the nanowinch is described : the dissymmetric molecular motor, the linker and the loads. After developping the synthetic strategies allowing us to incorporate the linker on the rotor, the synthesis of each fragment will be detailled in the following chapters. A concluding chapter will deal with the possible integration of that type of complexes into molecular gears in order to exploit the torque in a supramolecular network.