Abstract The first part of this work consisted of a study of the coordination chemistry of aromatic (P,S) and (P,O) heterodonor phosphanes with Cr(CO) 6 , Mo(CO) 6 and W(CO) 6 . The (P,S) donor ligands having one or two o -thiomethoxyphenyl groups, preferred bidentate coordination mode, while the (P,O) donor ligands, having one, two or three o -methoxyphenyls, formed monodentate phosphorus bound complexes. Steric and electronic parameters affecting the coordination chemistry of the phosphanes are discussed for the monodentate complexes. In the second part, triphenylphosphane and 2- and 4-pyridyldiphenylphosphane substituted tungsten tetracarbonyl derivatives was prepared, and attractive intramolecular interactions between the phosphane ligands were studied for both the neutral and the protonated complexes. Hydrogen bonding, π -stacking and cation-π bonding interactions were established, and observed to influence the cis/trans isomerism of the complexes. Cis/trans isomerism could be tuned by protonation, and deprotonation of the pyridyldiphenylphosphane derivatives. All the complexes were characterised by 1 H, 13 C-{ 1 H} and 31 P-{ 1 H} NMR spectroscopy, X-ray crystallography, IR spectroscopy, and either elemental analysis or mass spectroscopy.

La myopathie centronucléaire (CNM) est un groupe de maladies génétiques caractérisées au niveau histologique par des noyaux au centre des myofibres au lieu de la périphérie. Des mutations dans trois gènes (MTM1, DNM2 et BIN1) sont associées à cette pathologie. Récemment, l’implication d’un nouveau gène a été révélée dans une myopathie congénitale, le gène PYROXD1. Cependant, la base moléculaire responsable du déséquilibre à l'intérieur de la cellule reste incertaine et la relation entre le niveau histologique et les symptômes chez les patients n'est pas comprise. De plus, aucun traitement n'est disponible pour ces maladies. Au cours de ma thèse, j'ai centré mon travail sur l'utilisation du modèle de levure S. cerevisiae pour comprendre trois protéines associées au CNM : la myotubularine Mtm1, l'oxydoréductase Pyroxd1 et la dynamine Dnm2. Ces données révèlent qu’il est possible d’utiliser une simple cellule eucaryote afin d'élucider certains aspects moléculaires de ces protéines impliquées dans des maladies humaines. / Centronuclear myopathy (CNM) is a group of genetic disorders characterized at the histological level by nuclei at the center of the myofibers instead of the periphery. Mutations in three genes (MTM1, DNM2 and BIN1) are associated with this pathology. Recently the implication of a new gene has been revealed in a congenital myopathy, the PYROXD1 gene.However, the molecular basis responsible for the imbalance inside the cell remains unclear and the relation between the histological level and the symptoms in patients is not understood. Moreover, there is no treatment available for these diseases.During my thesis I have focused my work on using yeast S. cerevisiae model to understand three proteins associated to CNM: the myotubularin Mtm1, the oxidoreductase Pyroxd1 and the dynamin Dnm2. These data reveal that it is possible to use a single eukaryote cell to elucidate some molecular aspects of these proteins implicated in human disorders.

Made available in DSpace on 2015-08-19T13:52:53Z (GMT). No. of bitstreams: 2 5.pdf: 3872815 bytes, checksum: 455a971c4daecfecb98403b32be14999 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2012 / Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos/Farmanguinhos. Rio de Janeiro, RJ, Brasil. / O efavirenz (EFA) está classificado como um fármaco de classe II, pois é pouco hidrossolúvel e altamente permeável pelo trato gastrointestinal. Estas duas características básicas são essenciais para sua biodisponibilidade. Assim, a escolha de uma formulação adequada para esse fármaco é essencial no desenvolvimento de comprimidos, para garantir melhor disponibilização no trato gastrointestinal, de forma a alcançar a biodisponibilidade e o efeito terapêutico desejados. Nesse trabalho, oEFA e a mistura EFA:polivinilpirrolidona (PVP), preparados por processos de micronização com intuito de aumentar a dissolução do fármaco, foram espectroscopicamente estudados e caracterizados. No caso do EFA sua estrutura foi modelada usando o método B3LYP com intuito de auxiliar na análise dos resultados experimentais. A caracterização espectroscópica foi realizada utilizando diversas técnicas como infravermelho (IV) e ressonância magnética nuclear (RMN)em solução e de sólidos. A análise térmica por calorimetria diferencial de varredura(DSC) e a análise termogravimétrica (TGA) mostraram que os processos de comicronização não afetaram a estrutura cristalina do fármaco puro e nem a do fármaco nas misturas. A RMN comprovou a integridade dos mesmos, em solução eno estado sólido, indicando que o EFA encontra-se dimerizado. Os estudos de RMN também mostraram que, tanto no estado líquido quanto no sólido, ocorrem interações intermoleculares via ligação de hidrogênio do EFA com a PVP. Os espectros de RMN de sólido indicaram que ocorre dissolução parcial do EFA na matriz polimérica / Efavirenz (EFA) is classified as a class II drug because it is poorly water soluble and highly permeable through the gastrointestinal tract. These two basic characteristics are essential for its bioavailability. Thus, the choice of a suitable formulation for this drug is essential in the development of tablets to ensure better gastrointestinal tract in order to achieve both the bioavailability and the therapeutic effect desired. In this work, EFA and the blends EFA:polyvinylpyrrolidone (PVP) were prepared by spray drying and grinding processes in order to increase the solubility of the drug, were studied and characterized spectroscopically. In the case of EFA its structure was modeled using the B3LYP in order to aid the analysis of the experimental results. The spectroscopic characterization was performed using various techniques such as infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR) in solution and solid state. Thermal analysis by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), showed that the micronization process neither affected the crystal structure of the pure drug nor the drug in blends. NMR confirmed the integrity of the solution and the solid form and identified that the EFA is dimerized. The NMR studies also showed that both liquid and solid interactions occur via intermolecular hydrogen bonding of EFA with PVP. The NMR spectra indicated that occurs the solid partial dissolution of the EFA in the polymer matrix.

Ces travaux de thèse ont pour but l’étude théorique et la caractérisation d’interactions non-covalentes par des méthodes QCT (Quantum Chemical Topology), qui sont des outils interprétatifs de chimie quantique. Plusieurs interactions furent étudiées du point de vue de la densité électronique (calculs DFT), notamment des interactions intramoléculaires entre atomes halogènes ainsi que des liaisons halogène inter- et intramoléculaires. L’analyse topologique QTAIM complétée par la décomposition énergétique IQA (Interacting Quantum Atoms) nous a permis de dévoiler la nature physique des interactions étudiées, i.e. la part d’interaction électrostatique et la part d’échange (covalence). Il a été montré que l’échange tient un rôle majeur dans la stabilisation de telles interactions et permet de rationnaliser les différentes topologies observées en terme de compétition entre canaux d’échange primaires et secondaires. Aussi, la formation et la rupture d’une liaison hydrogène au cours de transferts de protons a été étudiée grâce à la décomposition de grandeurs globales (de DFTConceptuelle) en contributions monoatomiques ; le schéma de décomposition proposé se base sur la partition QTAIM et la décomposition énergétique IQA. Cette approche permet de suivre l’évolution, le long d’un chemin réactionnel, de la contribution de chaque atome à la réactivité du système. Une nouvelle façon de caractériser les barrières d’énergie potentielle et les états de transition a ainsi été proposée. / This work aims to theoretically investigate and characterize non-covalent interactions by means of Quantum Chemical Topology (QCT) methods, which are quantum chemistry interpretative tools. Several interactions were studied from the point of view of the electron density (DFT calculations), including intramolecular interactions between halogen atoms as well as inter- and intramolecular halogen bonds. The QTAIM topological analysis complemented by the Interacting Quantum Atoms (IQA) energy decomposition revealed the physical nature of those interactions, i. e. the part of electrostatics and the part of exchange (covalency). It has been shown that exchange plays a significant role in stabilizing such interactions and enables rationalizing the different topologies observed in terms of competition between primary and secondary exchange channels. Also, the formation and breaking of a hydrogen bond during proton transfer reactions has been analyzed by utilizing an atomic decomposition of global quantities (from Conceptual DFT), the new decompositionscheme being based on the QTAIM partition and the IQA energy decomposition. This approach allows following the contribution of every atom to the reactivity of the whole system along a reaction path, introducing a new way of characterizing energy barriers and transition.