Alloys, intermetallic compounds and multi-metal oxides are generally made by traditional solid-state methods that often require melting or grinding/pressing powders followed by high temperature annealing (> 1000 degrees C) for days or weeks. The research presented here takes advantage of the fact that nanoparticles have a large fraction of their atoms on the surface making them highly reactive and their small size virtually eliminates the solid-solid diffusion process as the rate limiting step. Materials that normally require high temperatures and long annealing times become more accessible at relatively low-temperatures because of the increased interfacial contact between the nanoparticle reactants. Metal nanoparticles, formed via reduction of metal salts in an aqueous solution and stabilized by PVP (polyvinylpyrrolidone), were mixed into nanoparticle composites in stoichometric proportions. The composite mixtures were then annealed at relatively low temperatures to form alloy and intermetallic compounds at or below 600 degrees C. This method was further extended to synthesizing multi-metal oxide systems by annealing metal oxide nanoparticle composites hundreds of degrees lower than more traditional methods. Nanoparticles of Pt (supported or unsupported) were added to a metal salt solution of tetraethylene glycol and heated to obtain alloy and intermetallic nanoparticles. The supported intermetallic nanoparticles were tested as catalysts and PtPb/Vulcan XC-72 showed enhanced catalytic activity for formic acid oxidation while Pt3Sn/Vulcan XC-72 and Cu3Pt/y-Al2O3 catalyzed CO oxidiation at lower temperatures than supported Pt. Intermetallic nanoparticles of Pd were synthesized by conversion chemistry methods previously mentioned and were supported on carbon and alumina. These nanoparticles were tested for Suzuki cross-coupling reactions. However; the homocoupled product was generally favored. The catalytic activity of Pd3Pb/y-Al2O3 was tested for the Heck reaction and gave results comparable to Pd/y-Al2O3 with a slightly better selectivity. Conversion chemistry techniques were used to convert Pt nanocubes into Ptbased intermetallic nanocrystals in solution. It was discovered that aggregated clusters of Pt nanoparticles were capable of converting to FePt3; however, when Pt nanocubes were used the intermetallic phase did not form. Alternatively, it was possible to form PtSn nanocubes by a conversion reaction with SnCl2.

Τα ινδολοκαρβαζόλια είναι αλκαλοειδή και παρουσιάζουν ενα ευρύ φάσμα βιολογικών ιδιοτήτων, όπως αντιβακτηριακές, αντιμυκησιακές, αντιικές, υποτασικές, νευροπροστατευτικές ιδιότητες. Όμως η σημαντικότερη δράση τους είναι η αντικαρκινική. Η εργασία αυτή είναι ένα review των συνθετικών μεθόδων και των βιολογικών ιδιοτήτων των ινδολοκαρβαζολίων. Επίσης σχολιάζονται η βιοσύνθεσή τους, παράγωγες ενώσεις των ινδολοκαρβαζολίων αλλά και υποψήφια φάρμακα με δομή ινδοκαρβαζολίου. / Indolocarbazoles are alkaloids which display a wide range of biological properties including antibacterial, antifungal, hypotensive and neuroprotective properties. Their greatest interest is their antitumour properties. This is a review of the synthetic methods and biological properties of indolocarbazoles. Τheir biosynthesis, their derivatives and possible drugs are also included.

A significant focus of toxicological research is the identification of electrophiles that covalently modify DNA to form addition products (adducts). These products can be generated when aryl radical species react at the C8-site of 2'-deoxyguanosine (dG) to form C8-aryl-dG adducts, which are mutagenic lesions. While this form of DNA modification is detrimental, C8-aryl-dG adducts also possess intriguing properties that can be exploited for beneficial purposes. This thesis is an investigation of one mechanism believed to contribute to the mutagenicity of C8-aryl-dG adducts, as well as a study of the photophysical properties of adducts that allow for their application as fluorescent probes. A common property of C8-aryl-dG adduction is accompaniment of abasic site formation. To determine how the C8-aryl moiety contributes to sugar loss, UV-Vis spectroscopy has been employed to determine hydrolysis kinetics, with C8-aryl-dG adducts found to be more prone than dG to acid-catalyzed hydrolysis. Despite adduct reactivity in acidic media, all adducts are relatively stable at pH 7, suggesting they are unlikely intermediates of abasic site formation at physiological pH. These results have allowed for development of a new rationale for depurination observed upon C8-aryl-dG adduction within duplex DNA. The determination of photophysical parameters of C8-heteroaryl-dG adducts reveals that these nucleosides behave as fluorophores with high fluorescence quantum yields (φfl). These adducts also exhibit emission sensitivity to their solvent environment and H-bonding interactions. C8-Heteroaryl-dG adducts were incorporated in the oligonucleotide 5'-CTCG1G2CG3CCATC, at the G1 and G3 sites, that contains the recognition sequence of the NarI Type II restriction enzyme. Hybridization of the modified NarI oligonucleotides to the complementary strand containing either the C or G nucleobase opposite the adduct allowed for characterization of duplex structures by circular dichroism (CD), UV melting temperature analysis and fluorescence spectroscopy. Results suggest that the C8-heteroaryl-dG adduct favours an anti conformation with base-paired with C, while a syn conformation is favoured when base-paired to G. Adduct conformation of bulky C8-dG adducts is believed to be correlated with their known mutagenic activity. C8-Heteroaryl-dG modified nucleosides could therefore be used as fluorescent models of these adducts to aid in elucidation of adduct-induced mutagenesis in biological systems. / NSERC

Ce travail de thèse s’articule autour de la synthèse totale des alcaloïdes de la famille Rhazinilam, potentiels agents anticancéreux. Dans ce contexte, deux méthodologies clés ont été développées. Premièrement, une réaction de cyclisation-migration de groupements sulfonyles catalysée à l'or (I) conduisant à des sulfonates de pyrroles a été optimisée et le champ d'application a été largement étendu. En tirant profit de la carbophilie des catalyseurs d’or (I), une réaction en cascade comprenant une séquence de cyclisation-migration-hydrocarbonation a été mise en place, permettant la synthèse d’indolizines ou de pyrroloazépines dans un procédé en un seul pot. Deuxièmement, des conditions réactionnelles sans précèdent par catalyse au palladium ont été développées pour le couplage de Suzuki-Miyaura impliquant des substrats de types sulfonates de pyrroles. Ces conditions ont été appliquées de façon efficace sur divers types de partenaires (aryle, hétéroaryle, vinyle sulfonates ou analogues halogénés) mais également utilisées dans différents types de couplages (Sonogashira, Buchwald). Ces méthodologies ont ensuite été appliquées à la synthèse totale du Rhazinilam et permis d’ouvrir la voie à la synthèse des Kopsiyunnanines et du Leuconolam. En parallèle, de nouveaux complexes associant des polyoxométallates et des carbènes d'or (I) ont été synthétisés, caractérisés et utilisés en catalyse hétérogène. / This PhD work was articulated around the total synthesis of the Rhazinilam family alkaloids, potential anticancer agents. In this context, two key methodologies have been developed. Firstly, a gold(I)-catalyzed cyclization-sulfonyl migration reaction leading to pyrrole sulfonates has been optimized and the scope was largely extended. By taking advantage of the carbophilicity of gold(I) catalysts, a cascade reaction including a sequence of cyclization-migration-hydrocarbonation has been implemented, allowing the synthesis of indolizidines or pyrroloazepines in a one pot process. Secondly, unprecedented reaction conditions were developed for palladium-catalyzed Suzuki−Miyaura cross-coupling using pyrrole sulfonates as substrates. These conditions have been applied efficiently on various types of partners (aryl, heteroaryl, vinyl sulfonates or halogenated analogues) but also used in different types of cross-coupling (Sonogashira, Buchwald). These methodologies were then applied to the total synthesis of Rhazinilam and to open the way to the synthesis of Kopsiyunnanines and Leuconolam natural products. In parallel, new complexes combining polyoxometalates and gold(I) carbenes have been synthesized, characterized and used in heterogeneous catalysis.

Les fichiers additionnels sont les données cristallographiques en format CIF. Voir le site de la Cambridge Crystallographic Data Centre pour un visualiseur: http://www.ccdc.cam.ac.uk / Ce projet de recherche vise l’élaboration de systèmes métallosupramoléculaires artificiels imitant le processus naturel de la photosynthèse. Idéalement, ces systèmes seraient capables de fournir l’énergie et la séparation de charge nécessaire pour catalyser des réactions à transfert multiélectroniques, tel que l’hydrolyse de l’eau ou la réduction du gaz carbonique. La réalisation d’un tel système catalytique créerait une source d’énergie renouvelable, sous forme d’énergie chimique, crée directement à partir de l’énergie solaire. Le système envisagé, schématisé sous la forme d’une antenne, possède trois parties distinctes. Tout d’abord, des chromophores forment un état excité en captant l’énergie de la lumière visible du soleil. Vient ensuite un centre de liaison qui lie tous les chromophores et qui collecte l’énergie de cet état excité à travers un transfert d’électron. Cet électron est de nouveau transféré vers la dernière partie, un centre réactionnel catalytique. Cet assemblage permet de créer une séparation de charge entre le chromophore et le centre réactionnel qui sont séparés par le centre de liaison, évitant ainsi la recombinaison de charge. Le projet se focalise sur la synthèse, la caractérisation et l’application en photocatalyse d’assemblages chromophore–centre de liaison–catalyseur. Tout d’abord, une étude de chromophores à base de fluorène et de rhénium a été effectuée dans le but d’évaluer le transfert électronique entre ces deux composants. Ensuite, des centres de liaisons à base de dimère de rhodium tétraamidinate ont été créés et étudiés afin d’établir leurs caractéristiques photophysiques et électrochimiques. Puis un d’entre eux a été assemblé avec des chromophores de rhénium, créant ainsi des espèces moléculaires discrètes contenant d’un à quatre chromophores. Et pour finir, ces assemblages ont été combinés avec un catalyseur à base de cobalt, puis ont été testés dans des expériences de photoproduction d’hydrogène. Cette dernière partie a requis l’élaboration d’un photoréacteur qui est aussi décrite en détail dans cet ouvrage. / This research project involves synthetic metallosupramolecular systems developed to mimic the natural process of photosynthesis. Ideally, these systems would be able to provide the energy and the charge separation needed to catalyze multielectron-transfer reactions, such as water-splitting or carbon dioxide reduction. The realization of such a catalytic system would create a renewable energy source, in the form of chemical energy, created directly from solar energy. The system envisioned has three distinct parts in the form of an antenna. First of all, chromophores go into an excited state, while capturing the visible light energy of the Sun. Then comes a hub which binds all the chromophores and collects this excited state energy through an electron transfer. This electron is then transferred again to the last part, a catalytic reaction center. This assembly creates a charge separation between the chromophore and the reaction center which are separated by the hub, thus avoiding the recombination of charge. The project focuses on the synthesis, characterization and application in photocatalysis of chromophore-hub-catalyst assemblies. First of all, a study of fluorene and rhenium based chromophores was made to assess the electronic transfer between these two components. Then, tetraamidinate rhodium dimer based hubs have been created and studied in order to establish their photophysical and electrochemical characteristics. Then one of these assemblies was formed with chromophores of rhenium, thus creating discrete molecular species containing one to four chromophores. And finally, these assemblies were combined with a cobalt-based catalyst and were tested for hydrogen photoproduction. The latter required the development of a photoreactor which is also described in detail in this thesis.

La régulation de l’apoptose fait partie des nouvelles cibles thérapeutiques dans la lutte contre le cancer. L’apoptose est l’autodestruction programmée des cellules qui, suite à un besoin physiologique, permet de réguler le développement des cellules. Dans de nombreux cancers, ce mécanisme est inhibé par une surexpression des protéines anti-apoptotiques de la famille Bcl-2 comme Bcl-xL et Mcl-1. Ce phénomène entraîne le développement des cellules tumorales et des résistances aux chimiothérapies. Dans cette optique, notre équipe à l’Institut de Chimie des Substances Naturelles a développé un criblage de plantes tropicales sur ces cibles. Des écorces d’une annonacée de Malaisie, Meiogyne Cylindrocarpa, a été isolé un sesquiterpène dimère, la meiogynine A, présentant une bonne affinité vis-à-vis de Bcl-xL (Ki = 10.7 M). Sa synthèse totale a été réalisée au laboratoire afin de déterminer sa configuration absolue et d’étudier les premières relations structure activité. Un de ses diastéréoisomères a également présenté une bonne affinité vis-à-vis de la protéine Bcl-xL.Afin d’étudier et d’approfondir les premières relations structure activité, la modulation de la meiogynine A a été réalisée. La synthèse des diénophiles acides a été optimisée afin de conduire majoritairement aux diénophiles précurseurs des composés actifs. Différents triènes ont également été synthétisés au laboratoire en vue de modifier la partie Sud de la meiogynine A. Plusieurs analogues ont ainsi pu être obtenus et ont été évalués biologiquement sur des tests in vitro et ex vivo. Des études de modélisation moléculaire et de RMN structurale ont également été réalisées. / The control of the apoptosis is one of the new modern key to fight against the cancer. The apoptosis is the self destruction of cells, part of the homeostasis, which regulates the cell developement. In several cancers, the over-expression of anti-apoptotic proteins, as Bcl-xL and Mcl-1 parts of the Bcl-2 proteins family, inhibate this naturel process. This phenomenum induce the tumoral cells developement and the chemotherapy’s resistance. In order to find new compounds which can regulate the apoptosis, our group in the Institut de Chimie des Substances Naturelles has screened different tropical plants on these targets. A Malaysian plant, Meiogynine Cylindrocarpa, was selected and the phyotchemist work on this plant gave us a new sesquiterpen , the meiogynin A (Ki = 10.7 M on Bcl-xL). Its total synthesis was realised in our laboratory in order to determine its absolute configuration and find the first structure activity relation. One of the synthetised diastereoisomers has presented a better affinity toward the protein. In order to precise these first structure activity relations, the modulation of the meiogynin A was initiated. The synthesis of the acid dienophiles was optimised, the main compounds are the precursors of the active decalins. New triene was also obtained in order to modulate the South Part of the meiogynin A. Thanks to a Diels-Alder reaction, these precursors were combined in order to form new analogues of the meiogynin A. All these compounds were biologically tested (in vitro et ex vivo). Experiments of molecular docking and 2D NMR were also realised.

As of today, Alzheimer’s disease is the leading cause of dementia among neurodegenerative disorders, affecting many millions of people worldwide. As the average life span of populations increase, more and more people succumb to the illness each year. Like other neurodegenerative disorders, Alzheimer’s disease can be attributed to the accumulation of protein aggregates in the brain. These amyloid-β peptides and tau proteins can presumably be detected in the brain many years before the onset of clinical symptoms. Development of fluorescent ligands, capable of binding to these neuropathological hallmarks and highlighting them, could serve as molecular diagnostic tools and facilitate an early diagnosis of the disease. The method could also be useful in studying disease progression and evaluating the effects of novel treatments. One such ligand is HS-259. The aim of this project was to synthetize different analogues of HS-259, and test their selectivity towards the aforementioned aggregates in brain tissue from an individual with Alzheimer’s disease. Staining of tissue samples with analogue solution enables visualization of aggregate sites through fluorescence imaging. In the end, five analogues were synthetized, albeit in relatively low overall yields. Synthetic methods included Suzuki-Miyara cross-couplings, Ullmann-type arylations and condensations. Liquid Chromatography-Mass Spectrometry (LC-MS) and Nuclear Magnetic Resonance (NMR) were used for analysis of the compounds. Two of the five analogues could be tested for staining of aggregates and assessed for photophysical characteristics, i.e. absorption- and emission spectra. One analogue stained both amyloid-β aggregates and some tau aggregates, whereas the other stained neither. Since only two analogues were tested and rendered inconsistent results, further studies are needed to assess the binding properties of HS-259 analogues in general.