Gold compounds have been used in medicine dating back as early as 2500 BC. Over the years gold(I) and gold(III) compounds have been used and designed to target rheumatoid arthritis, cancer, and viral diseases. New drug targets have been found for gold compounds that give insight into their mechanisms of action. Here we focus on the synthesis of Au(III) compounds designed to selectively target zinc finger (ZF) proteins. ZF proteins exhibit a variety of functions, including transcription, DNA repair, and apoptosis. Displacement of the central zinc ion, along with mutation of coordinated amino acids can result in a loss of biological function. Synthesis of complexes that selectively target zinc finger proteins, in turn inhibiting DNA/ZF interactions and therefore resulting in loss of protein function, is of great interest. Of particular interest here is the Cys3His (Cys = cysteine, His = histidine) HIV nucleocapsid zinc finger protein, NCp7. NCp7 is involved in multiple steps of the HIV life cycle, thus making it a desirable drug target. Previous studies from our group show platinated nucleobases such as [Pt(dien)(9-EtG)]2+ (dien = diethylenetriamine; 9-EtG = 9-ethylguanine) to stack effectively in a non-covalent manner with tryptophan of the C-terminal finger of HIV Nucleocapsid, NCp7(F2), a key residue involved in nucleic acid recognition. Due to the isoelectronic and isostructural relationship of Au(III) to Pt(II), we have expanded this system to Au(III)-(nucleobase/N-heterocycle) compounds. Novel Au(III)(dien)(N-heterocycle) compounds, including the first Au(III)N3(N-purine) examples, were synthesized. As previously reported for [AuCl(dien)]Cl2, these compounds exhibit pH dependency of the 1H NMR chemical shifts of the dien ligand. The acidity of the dien ligand is affected by the nature of the fourth ligand as a leaving group. The presence of an inert nitrogen donor, compared to that of the more labile Cl-, as the leaving group stabilizes the Au(III) metal center towards reduction, resulting in significant enhancement of π−π stacking interactions with tryptophan relative to platinum(II) and palladium(II) compounds. The presence of a more inert N-donor as the leaving group slows down the reaction with the sulfur-containing amino acid N-Acetylmethionine (N-AcMet); essentially no reaction was observed for the Au(III)-N-heterocycle compounds. All compounds react readily with N-Acetylcysteine (N-AcCys), however lack of N-heterocycle ligand dissociation indicates, to our knowledge, the first long-lived N-heterocycle-Au-S species in solution. Electrospray ionization mass spectrometry (ESI-MS) studies with NCp7(F2) indicate [Au(dien)(DMAP)]3+ (DMAP = 4-dimethylaminopyridine) to be the least reactive of the Au(III) compounds studied, showing the presence of intact NCp7(F2) zinc finger at initial reaction times. Reactivity of the Au-compounds was compared with that of Sp1(F3), a Cys2His2 ZF; in contrast, no intact ZF was observed for any of the compounds studied, suggesting the mode of action of these compounds is dependent on the nature of the zinc binding core. ESI-MS studies were expanded to that of the full HIV NCp7 zinc finger. [Au(dien)(9-EtG)]3+ reacts quickly with NCp7, resulting in immediate zinc ejection and replacement with up to three gold ions. Unlike with [Au(dien)(DMAP)]3+, no intact NCp7 was observed. Addition of [Au(dien)(9-EtG)]3+ to preformed NC-SL2 complex results in release of free RNA; based on EMSA (electrophoretic mobility shift assay) studies, [Au(dien)(9-EtG)]3+ disrupts the NCp7-RNA complex with an IC50 of ~450 µM. It is possible that this HIV nucleocapsid-nucleic acid antagonism may result in a loss of viral activity.

Este trabalho apresenta a síntese de complexos de ouro(III) com ligante (dietilaminotiocarbonil)benzimidoíla-morfolinil-tiossemicarbazona e co-ligante L variando entre Cl-, CN-, SCN-, C3H5OS2- e C9H13N. Para a caracterização destes complexos foram envolvidas diversas técnicas, como espectroscopia na região do infravermelho e do UV-Vis, ponto de fusão, condutividade, espectroscopia de ressonância magnética nuclear 1H e 13C, espectrometria de massas ESI(+)-MS e análise elementar (C,H,N). O estudo consiste na avaliação da influência do ligante L frente a atividade antitumoral e anti-Trypanossoma cruzi, assim como na avaliação de sua influência em interações com possíveis alvos biológicos (DNA e albumina). Nos experimentos biológicos foi verificada a potencial atividade antitumoral destes complexos em células HepG2, HeLa, DU-145 e MDA-MB-231, dando destaque aos resultados obtidos para os complexos do tipo [AuCl(dmstc)] (IC50 = 8,05 ?molL-1) e [Au(xant)(dmstc)] (IC50 = 28,5 ?molL-1) frente à célula MDA-MB-231, ao complexo [AuCl(dmstc)] (IC50 = 8,37 ?molL-1) frente à célula DU-145 e ao complexo [AuSCN(dmstc)] o qual apresentou resultados promissores para todas as linhagens celulares tumorais avaliadas. Os ensaios in vitro contra cepas Tulahuen LacZ de Trypanossoma cruzi apresentaram resultados promissores, demonstrando uma elevada atividade contra o parasita e citotoxicidade geral negligenciável frente à células de baço de camundongo Swiss para todos os complexos avaliados, com exceção do complexo [Au(xant)(dmstc)]. Através do estudo de interação destes complexos com DNA-ct e albumina humana (HSA), é possível descartar o DNA como principal alvo biológico responsável pelas atividades observadas e sugerir uma adequada distribuição in vivo por meio da HSA. / This work describes the synthesis of gold(III) complexes with the ligand (diethylaminocarbonyl)benzimidoyl-morpholinyl thiosemicarbazone and the co-ligand L varying between Cl-, CN-, SCN-, C3H5OS2- and C9H13N. The complexes characterization involved various techniques such as melting point, conductivity, infrared, UV-Vis, 1H and 13C NMR spectroscopies, ESI(+)-MS mass spectrometry and elemental analysis (C, H, N). The study consists on the evaluation of the influence of the ligand L front anti-tumor and anti-Trypanosoma cruzi activities, as well as in assessing their influence on interactions with possible biological targets (DNA and albumin). The biological experiments showed potential antitumor activity for the complexes against HepG2, HeLa, DU-145 and MDA-MB-231 cells, especially the results obtained for the complexes of the type [AuCl(dmstc)] (IC50 = 8,05 ?molL-1) and [Au(xant)(dmstc)] (IC50 = 28,5 ?molL-1) against the MDA-MB-231 cell, the complex [AuCl(dmstc)] (IC50 = 8,37 ?molL-1) against the DU-145 cell, and the complex [AuSCN(dmstc)] which showed promising results for all tumor cells lines evaluated. In vitro assays against LacZ Tulahuen Trypanosoma cruzi presented promising results, showing high activity against the parasite with negligible general cytotoxicity against the Swiss mouse spleen cells in all evaluating complexes, except for complex [Au(xant)(dmstc)]. Through the studies of interaction of the complexes with DNA-ct and human albumin (HSA) can discard the DNA as the primary biological target responsible for the observed activities and suggest a proper distribution in vivo through the HSA.

Este trabalho apresenta a síntese de complexos de ouro(III) com ligante (dietilaminotiocarbonil)benzimidoíla-morfolinil-tiossemicarbazona e co-ligante L variando entre Cl-, CN-, SCN-, C3H5OS2- e C9H13N. Para a caracterização destes complexos foram envolvidas diversas técnicas, como espectroscopia na região do infravermelho e do UV-Vis, ponto de fusão, condutividade, espectroscopia de ressonância magnética nuclear 1H e 13C, espectrometria de massas ESI(+)-MS e análise elementar (C,H,N). O estudo consiste na avaliação da influência do ligante L frente a atividade antitumoral e anti-Trypanossoma cruzi, assim como na avaliação de sua influência em interações com possíveis alvos biológicos (DNA e albumina). Nos experimentos biológicos foi verificada a potencial atividade antitumoral destes complexos em células HepG2, HeLa, DU-145 e MDA-MB-231, dando destaque aos resultados obtidos para os complexos do tipo [AuCl(dmstc)] (IC50 = 8,05 ?molL-1) e [Au(xant)(dmstc)] (IC50 = 28,5 ?molL-1) frente à célula MDA-MB-231, ao complexo [AuCl(dmstc)] (IC50 = 8,37 ?molL-1) frente à célula DU-145 e ao complexo [AuSCN(dmstc)] o qual apresentou resultados promissores para todas as linhagens celulares tumorais avaliadas. Os ensaios in vitro contra cepas Tulahuen LacZ de Trypanossoma cruzi apresentaram resultados promissores, demonstrando uma elevada atividade contra o parasita e citotoxicidade geral negligenciável frente à células de baço de camundongo Swiss para todos os complexos avaliados, com exceção do complexo [Au(xant)(dmstc)]. Através do estudo de interação destes complexos com DNA-ct e albumina humana (HSA), é possível descartar o DNA como principal alvo biológico responsável pelas atividades observadas e sugerir uma adequada distribuição in vivo por meio da HSA. / This work describes the synthesis of gold(III) complexes with the ligand (diethylaminocarbonyl)benzimidoyl-morpholinyl thiosemicarbazone and the co-ligand L varying between Cl-, CN-, SCN-, C3H5OS2- and C9H13N. The complexes characterization involved various techniques such as melting point, conductivity, infrared, UV-Vis, 1H and 13C NMR spectroscopies, ESI(+)-MS mass spectrometry and elemental analysis (C, H, N). The study consists on the evaluation of the influence of the ligand L front anti-tumor and anti-Trypanosoma cruzi activities, as well as in assessing their influence on interactions with possible biological targets (DNA and albumin). The biological experiments showed potential antitumor activity for the complexes against HepG2, HeLa, DU-145 and MDA-MB-231 cells, especially the results obtained for the complexes of the type [AuCl(dmstc)] (IC50 = 8,05 ?molL-1) and [Au(xant)(dmstc)] (IC50 = 28,5 ?molL-1) against the MDA-MB-231 cell, the complex [AuCl(dmstc)] (IC50 = 8,37 ?molL-1) against the DU-145 cell, and the complex [AuSCN(dmstc)] which showed promising results for all tumor cells lines evaluated. In vitro assays against LacZ Tulahuen Trypanosoma cruzi presented promising results, showing high activity against the parasite with negligible general cytotoxicity against the Swiss mouse spleen cells in all evaluating complexes, except for complex [Au(xant)(dmstc)]. Through the studies of interaction of the complexes with DNA-ct and human albumin (HSA) can discard the DNA as the primary biological target responsible for the observed activities and suggest a proper distribution in vivo through the HSA.

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Cette thèse porte sur la synthèse de composés d'Au(III) et de Cu(III) ainsi que sur l'étude de leur stabilité et de leur réactivité vis-à-vis de substrats p. Une approche conjointe expérimentale et théorique a été exploitée afin d'accéder à des complexes capables d'induire des processus d'insertion migratoire. Le premier chapitre aborde de manière globale la chimie organométallique de l'or et du cuivre sur le plan bibliographique. L'importance du degré d'oxydation +III est mis en évidence par la description des principaux exemples ayant contribué à la compréhension des processus associés à l'accès et la réactivité des complexes d'Au(III) et de Cu(III). Le second chapitre traite de la synthèse de deux complexes p-arènes d'Au(III) par insertion migratoire d'oléfines dans la liaison Au-C(sp)2 d'un composé (P,C) cyclométallé. Les interactions entre les systèmes aromatiques et l'or ont été mises en évidence par RMN, DFT et DRX pour un des complexes. Sur la base de cette réactivité, un processus d'arylation directe de l'éthylène a été mis en évidence. Le chapitre trois a pour objet la mise au point d'une réaction d'hydroarylation intermoléculaire d'alcynes catalysée par des complexes de type [(P,C)Au(III)(OAcF)2]. Ces derniers se sont avérés très actifs et robustes en présence d'acide trifluoroacétique. La réaction a pu être généralisée à un large panel de substrats et une étude comparative, notamment avec des complexes (N,C) cyclométallés, a mis en évidence la supériorité des complexes (P,C) pour l'hydroarylation des alcynes. Le quatrième chapitre expose la stratégie envisagée pour le développer d'un processus d'oligomérisation de l'éthylène catalysé par le cuivre. Une approche prédictive basée sur les calculs DFT a permis de mettre en évidence des insertions migratoires plus aisées dans les liaisons Cu(III)-C que dans les Cu(I)-C. Deux stratégies d'accès aux complexes de Cu(III) par addition oxydante de liaisons C-I sur des précurseurs de Cu(I) ont été évaluées théoriquement. Les calculs les plus favorables ont orienté le choix des modèles de ligands envisagés dans les chapitres cinq et six. Le cinquième chapitre aborde l'étude expérimentale associée à la première stratégie d'accès au Cu(III) : l'addition oxydante intramoléculaire dirigée par des ligands naphthylphosphine et naphthylamine peri-iodées. [...] / The present work deals with the synthesis of Au(III) and Cu(III) compounds and the study of their stability and reactivity toward p substrates. An experimental and theoretical approach has been used in order to access complexes capable of undergoing migratory insertion processes. The first chapter delivers a bibliographic overview of the organometallic chemistry of gold and copper. The importance of the high oxidation state +III is highlighted by the description of important examples having contributed to the understanding of processes associated to the access and reactivity of Au(III) and Cu(III) complexes. The second chapter describes the synthesis of two p-arene Au(III) complexes by migratory insertion of olefins in the Au-C(sp)2 bond of a (P,C) cyclometallated complex. Interactions between the metallic center and the aromatic systems have been characterized by NMR, DFT and XRD for one of the complexes. Based on this insertion reactivity, a process of direct arylation of ethylene has been evidenced. The third chapter concerns the development of an intermolecular hydroarylation of alkynes process, catalyzed by [(P,C)Au(III)(OAcF)2] complexes. These have shown great activity and robustness in presence of trifluoroacetic acid. The reaction has been generalized to a broad substrate scope and a comparative study has been carried on, especially with (N,C) cyclometallated complexes, showing the superiority of (P,C) complexes for the hydroarylation of alkynes. The fourth chapter presents the envisioned strategy to develop a copper-catalyzed oligomerization of ethylene process. A predictive approach based on DFT calculations permitted to evidence easier migratory insertions in the Cu(III)-C bond than in the Cu(I)-C bond. Two strategies for the access to Cu(III) species have been theoretically evaluated. The most favourable calculations have oriented the choice of ligand models used in chapters five and six. The fifth chapter deals with the experimental study related to the first strategy of access to Cu(III) species: the directed intramolecular oxidative addition by peri-iodo napthylphosphine and naphthylamine ligands. [...]