Le fondaparinux (Arixtra®), anticoagulant de la classe des pentasaccharides de synthèse, est le premier inhibiteur d'origine synthétique, spécifique et indirect du facteur Xa de la coagulation. Il résulte de la synthèse chimique de l'unité pentasaccharidique des héparines, capable de se lier à l'antithrombine, une protéine endogène, inhibitrice de la coagulation. Cependant, son utilisation reste limitée par son administration uniquement possible par voie parentérale.L'objectif de ce travail de thèse est de développer une forme orale du fondaparinux en l'associant à un dérivé squalénique. Le squalène, terpénoïde naturel précurseur de la synthèse du cholestérol, possède une très bonne absorption orale (supérieure à 60 %). Dans ce contexte, deux stratégies d'association ont été développées: la première consistant à associer par liaison covalente le fondaparinux à un dérivé squalénique selon le concept de la « squalénisation » et la deuxième à associer par interactions non covalentes le fondaparinux à un dérivé squalénique cationique.Les travaux expérimentaux ont montré que la première stratégie était délicate à mettre en œuvre en raison d'une part de la difficulté à synthétiser un bioconjugué fondaparinux-squalène et d'autre part de la perte de l'activité anticoagulante du fondaparinux. En raison de ces obstacles, le concept de la « squalénisation » n'est pas adapté à ce type de molécule active. En revanche, la deuxième stratégie s'est montrée très prometteuse. Elle a consisté à formuler des nanoparticules par association non covalente du fondaparinux, chargé négativement, à un dérivé squalénique cationique. Cette approche a permis de mettre en évidence l’excellente capacité d'auto-assemblage en milieu aqueux de ces deux composés, liée à l’établissement de deux types d’interactions, électrostatiques et hydrophobes (entre les molécules de squalène). L'absorption orale du fondaparinux a été considérablement augmentée grâce à ce nouveau système nanoparticulaire. Cette nouvelle approche à base de squalène a ainsi montré son efficacité dans l'amélioration de l'administration orale du fondaparinux et pourrait représenter un système thérapeutique potentiel dans le traitement des maladies thromboemboliques. / Since its introduction in the market in 2002, fondaparinux (Arixtra®) is a drug of choice in the anticoagulant therapy. Its structure corresponds to the heparin pentasaccharide sequence that mediates its interaction with the natural plasma inhibitor of coagulation, antithrombin. However, like heparin, its application is limited due its unique administration by parenteral route. The aim of this project is to develop an efficient oral delivery system for fondaparinux by association with a squalene derivative. Squalene, a natural precursor of cholesterol in sterol biosynthesis, is well-known for its excellent oral absorption (i.e. more than 60 %). In this context, two strategies were investigated. The first consisted in achieving a covalent coupling between fondaparinux and a squalene derivative according to the concept of “squalenoylation”. The second was to associate fondaparinux to a cationic squalenoyl derivative by non-covalent association.Experimental work showed that the first strategy was delicate to implement due to the difficulty to synthesize a fondaparinux-squalene bioconjugate and, the loss of the anticoagulant properties of fondaparinux. Because of these obstacles, the concept of "squalenoylation" was not suitable for this type of active molecule. In contrast, the second strategy has been very promising. It consisted in the formulation of a nanoparticulate delivery system by ion-pairing of fondaparinux and a cationic squalenoyl derivative. This approach permitted to highlight the self-assembly of these two compounds in water as monodisperse nanoparticles thanks to electrostatic and hydrophobic interactions. Furthermore, the oral absorption of fondaparinux was significantly increased with this new nanoparticulate system. This new squalene-based approach has shown its effectiveness in improving the oral administration of fondaparinux and could be a potential delivery system in the treatment of thromboembolic diseases.

A Interconsulta Psiquiátrica é considerada por muitos pesquisadores como sendo a área prática e aplicada da Medicina Psicossomática, de conhecimento concernente à investigação da interação entre fatores biológicos e psicossociais no desenvolvi-mento, curso e resultado de todas as doenças. A prevalência de transtornos psiqui-átricos em hospitais gerais pode variar de 20 a 40% entre pacientes internados, po-rém uma reduzida parcela é assistida pela Interconsulta e consequentemente recebe tratamento psiquiátrico. Sendo assim, o presente estudo teve por objetivos: a) obter informações dos dados sociodemográficos dos pacientes e seus históricos em sa¬úde mental (tratamentos anteriores e tentativa de suicídio); b) analisar o uso do ser¬viço de Interconsulta Psiquiátrica, tais como as clínicas solicitantes, função dos pro¬fissionais solicitantes, motivos de solicitação, tempo de internação dos pacientes assistidos, tempo de solicitação do PI e de sua resposta, e o número de atendimen-tos realizados; c) descrever os diagnósticos clínicos e psiquiátricos dos pacientes avaliados através dos critérios estabelecidos pela CID-10; d) analisar intervenções farmacoterapêuticas e não medicamentosas, tais como as condutas sugeridas pelo interconsultor, profissionais solicitados durante a internação, as medicações psico-trópicas em uso e prescritas; e) caracterizar aspectos relacionados aos médicos clí-nicos, aos profissionais de saúde e aos interconsultores; e f) avaliar a qualidade es-trutural da solicitação psiquiátrica realizada pelo profissional clínico e a resposta dada pelo interconsultor. Para tanto, foi realizada uma análise retrospectiva de todas as solicitações consecutivas realizadas entre janeiro de 1981 a dezembro de 2010 para a Psiquiatria do Serviço de Interconsulta em Saúde Mental do Hospital das Clí-nicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo assim como a consulta dos prontuários de todos os pacientes assistidos pelo serviço para obter outras informações. Foram realizadas 4882 solicitações psiquiátricas e a taxa de encaminhamento variou de 0,7 a 1,1%. Dados sociodemográficos dos paci-entes que foram atendidos com mais fre¬quência relacionados ao sexo, cor e/ou et-nia, estado civil, com quem os pacientes residiam (somente para os homens), situa-ção laboral (somente para as mulheres), escolaridade e procedência tenderam a permanecer relativamente estáveis ao longo dos anos. As mulheres apresentaram idade média menor que os homens e foram atendidos com mais frequência: homens e mulheres casados (e mais homens soltei¬ros quando comparados com as mulhe¬res), homens que residiam com seus pais e mulheres que residiam com seus cônju¬ges e filhos, homens afastados de seus tra¬balhos e mulheres responsáveis pelos cuidados da casa, e também pacientes de ambos os sexos com idades entre 21 e 50 anos, pacientes caucasianos, pacientes procedentes do estado de São Paulo e pacientes com escolaridade até ensino fun¬damental completo. As mulheres foram mais frequentemente assistidas pelo serviço de Intercon¬sulta Psiquiátrica ao longo de todos os anos, assim como ficaram menos tempo in¬ternadas e também tiveram solicitações psiquiátricas realizadas em um menor inter¬valo de tempo após a admis¬são hospitalar. Em trinta anos, a Clínica Médica Geral foi a clínica que mais realizou solicitações psiquiátricas, o motivo de solicitação mais frequente foi a presença de sintomas psiquiátricos e o tempo de internação dos pacientes assistidos pela Inter¬consulta foi maior quando comparado aos pacientes internados no hospital de modo geral. Os transtornos neuróticos, somatoformes e relacionados ao estresse foram os diagnósticos psiquiátricos mais comuns entre as mulheres e homens atendidos pelo SISMen, seguido pelos transtornos de humor e transtornos mentais orgânicos nas mulheres e transtornos mentais orgânicos e transtornos devido ao uso de substân¬cias nos homens. Já em relação ao diagnóstico clínico, foram atendidos com mais frequência mulheres com doenças endócrinas, metabólicas e nutricionais e homens com doenças infecciosas e parasitárias; e casos de múltiplas comorbidades clínicas se tornaram mais frequentes com o passar dos anos. As principais condutas sugeri¬das pelos interconsultores foram: atendimento individual, orientação à equipe e prescrição de psicofármacos para ambos os pacientes, permanecendo frequentes ao longo dos anos, com destaque para um aumento progressivo de casos em que medicações psicotrópicas foram prescritas a partir de meados dos anos 90. E com o passar dos anos, os planos de tratamento se tornaram mais complexos e abran¬gentes e houve um aumento progressivo no número de encaminhamentos para atendimento psiquiátrico ambulatorial. Em relação à qualidade estrutural das solici¬tações psiquiátricas e das respostas dadas pelos interconsultores, ambas foram consideradas aceitáveis ou boas na maioria dos casos, sendo um indicativo positivo na qualidade de comunicação entre os profissionais. Pode-se dizer que este foi o primeiro estudo longitudinal a analisar consecutivamente trinta anos e também toda a população assistida por um serviço de Interconsulta Psiquiátrica / Consultation-liaison Psychiatry is considered by many researchers as the practical and applied area of psychosomatic medicine, which is an area of knowledge concerning the investigation of the interaction between biological and psychosocial factors in the development, course and outcome of all diseases. The prevalence of psychiatric disorders in general hospitals range from 20 to 40% of hospitalized patients, but a small portion is assisted by the consultation-liaison and consequently receives psychiatric treatment. Considering this background, this study aimed: a) to obtain information about sociodemographic characteristics of patients and their mental health history (previous treatment and attempted suicide); b) to analyze the referral patterns of consultation-liaison psychiatry, such as referral sources, reasons for referral, length of stay, lagtime and other; c) to describe clinical and psychiatric diagnoses according by ICD-10; d) to analyze pharmacotherapeutic and non-drug interventions; e) to describe aspects related to physicians, health professionals and psychiatrists; and f) to analyze the structural quality of the request made by the physicians and psychiatrists. For this purpose, it was performed a retrospective analysis of all consecutive referrals made between January 1981 and December 2010 to consultation-liaison psychiatry of Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo as well as the review of medical charts of all patients assisted by the service. 4882 referrals were made and consultation rate ranged from 0.7 to 1.1%. Sociodemographic characteristics related to sex, color or ethnicity, marital status, patients who lived (for men), employment status (for women), education and origin tended to remain relatively stable over the years. Women had a lower average age than men and were seen more frequently: married men and women (and more single men compared with women), men who lived with their parents and women who lived with their spouses and children, and also patients of both sexes aged between 21 and 50 years, caucasian patients and patients from the state of Sao Paulo. Women were more often assisted by the consultation-liaison service over the years and the length of stay and lagtime were lower than men. In thirty years, internal medicine was the most frequent referral source, presence of psychiatric symptoms was the common reason for referral and the length of stay of patients assisted by consultation-liaison psychiatry was higher compared to those admitted to the hospital in general. The main clinical diagnoses for women and men were endocrine, nutritional and metabolic, cardiovascular diseases and infectious and parasitic diseases and cases with multiple morbidities have become more frequent over the years. One third of patients were diagnosed with neurotic disorders, stress related and somatoform disorders in women and men, followed by mood disorders and organic mental disorders in women, and organic mental disorders and due to substance use in men. The main interventions were individual therapy, guidelines for staff and prescription of psychotropic drugs for women and men. There was a increase in the number of referrals to outpatient psychiatric care. Psychiatric referrals and responses by psychiatrist were considered acceptable or good in most cases, a positive indicative on the quality of communication between professionals. This was the first longitudinal study to examine thirty years consecutively and also the entire population assisted by Consultation-liaison Psychiatry.

La reconnaissance moléculaire est un problème très intéressant et surtout un défi actuel pour la chimie biophysique. Avoir des prévisions fiables sur la reconnaissance spécifique entre les molécules est hautement prioritaire, car il fournira un aperçu des problèmes fondamentaux et suscitera des applications technologiques pertinentes. La thèse présentée ici est centrée sur une analyse quantitatif de la reconnaissance moléculaire en solution pour la liaison l'hôte-invité, la liaison protéine-ligand et la catalyse. Le cadre de la mécanique statistique utilisé pour décrire l'état de la technique de liaison récepteur-ligand est un point d'inflexion pour le développement de nouvelles méthodes améliorées. En fait, un modèle très performant et précis a été obtenu pour l'analyse de la liaison hôte-invité. Enfin, les modèles présentés ont été utilisés comme outils prédictifs fiables pour la découverte de nouvelles entités chimiques destinées à améliorer la catalyse en solution. / Molecular recognition is a very interesting problem, and foremost, a current challenge for biophysical chemistry. Having reliable predictions on the specific recognition between molecules is highly priority as it will provide an insight of fundamental problems and will raise relevant technological applications. The dissertation presented here is centered on a quantitative analysis of molecular recognition in solution for host-guest, protein-ligand binding and catalysis. The statistical mechanics framework used to describe the state-of-the-art for receptor-ligand binding is an inflection point for the developing of new improved and methods. In fact, a highly performanced and accurate model was obtained for the analysis of host-guest binding. Finally, the presented models were used as a reliable predictive tools for discovering new chemical entities for enhance catalysis in solution.

Les cellules souches embryonnaires (CSE) sont un outil essentiel pour la recherche biomédicale. Elles ont à la fois la particularité de se multiplier de manière indéfinie tout en gardant leurs propriétés souches et l’incroyable capacité de donner naissance à tous les types cellulaires de l’organisme. Ces caractéristiques ouvrent de nouvelles perspectives pour la médecine régénérative mais également pour la mise au point de nouveaux essais thérapeutiques. Une des révolutions majeures reposant sur la reprogrammation cellulaire des cellules somatiques adultes en cellules souches, permet notamment d’entrevoir de nouvelles applications thérapeutiques. Les mécanismes moléculaires, tels que la méthylation de l’ADN, les modifications d’histones, et l’intervention de facteurs épigénétiques dans le remodelage de la chromatine, jouent un rôle essentiel dans la reprogrammation cellulaire et le contrôle de la pluripotence des cellules souches. L’épigénome des CSE doit non seulement maintenir l’expression des gènes associés à la pluripotence, mais également permettre une activation rapide et spécifique des gènes impliqués dans les étapes de différenciation cellulaire. Une des modifications ayant un rôle important dans l’homéostasie des CSE correspond aux méthylations d’histones H3K9 et H3K27 essentiellement associées à une répression transcriptionnelle. Ces modifications sont effectuées par des lysines méthyltransferases (HKM) dont G9a, ou bien EZH2 appartenant au complexe Polycomb PRC2. Elles recrutent également ces complexes protéiques permettant le maintien et la propagation de la modification le long du génome. Ainsi, dans ce contexte, mes travaux de thèse ont eu pour objectif de caractériser deux facteurs épigénétiques potentiels reconnaissant les histones H3K9me et H3K27me et interagissant avec le complexe PRC2. Ces études ont permis de mieux comprendre le rôle de ces protéines dans la régulation des cellules souches embryonnaires murines. Nos premières données ont montré que nos gènes candidats sont fortement exprimés dans les cellules souches embryonnaires murines (mESC) contrairement aux cellules différenciées. Par la suite, l’expression forcée d’un de ces facteurs altère la différenciation des CSE induite par le retrait de la cytokine LIF. Pour mieux comprendre comment le maintien de l’expression de notre facteur empêche la différenciation des cellules souches embryonnaires, nous avons analysé l’expression des facteurs de pluripotence Oct4, Nanog, Sox2 et Klf4. Nous avons noté un maintien de l’expression de ces facteurs ainsi que le maintien de la régulation des signaux intracellulaires intervenant en amont tels que: l’activation de la voie JAK-STAT3 pour le maintien à l’état pluripotent des ESC, et la diminution de la voie MAPK-ERK impliquée dans les processus de différenciation / Embryonic stem cells (ES cells) are an essential tool for biomedical research. They have the particularity to multiply indefinitely while keeping their stemness properties, and the incredible ability to generate all cell types of the body. These characteristics open up new perspectives for regenerative medicine but also for the development of new therapeutic trials. One of the major revolutions based on the cellular reprogramming of adult somatic cells into stem cells makes it possible to glimpse new therapeutic applications. Molecular mechanisms, such as DNA methylation, histone modifications, and the intervention of epigenetic factors in chromatin remodeling, play a critical role in cell reprogramming and pluripotency. The CSE epigenome must maintain not only the expression of genes associated with pluripotency but also allow rapid and specific activation of genes involved in cell differentiation. One of the modifications having an important role in the homeostasis of the CSE corresponds to histone methylations H3K9 and H3K27 essentially associated with transcriptional repression. These modifications are carried out by lysine methyltransferases (HKM) including G9a, or EZH2 belonging to the Polycomb PRC2 complex. They also recruit these protein complexes to maintain and propagate the change along the genome. Thus, in this context, my thesis work aimed to characterize two potential epigenetic factors recognizing histones H3K9me and H3K27me and interacting with the PRC2 complex. These studies have provided a better understanding of the role of these proteins in the regulation of murine embryonic stem cells. Our first data showed that our candidate genes are strongly expressed in murine embryonic stem cells CGR8 (mESC), unlike differentiated cells. Subsequently, the forced expression of one of these factors alters the CSE differentiation (CGR8) induced by LIF cytokine withdrawal. To better understand how maintaining the expression of our factor prevents the differentiation of embryonic stem cells, we analyzed the expression of pluripotency factors Oct4, Nanog, Sox2 and Klf4. We noted maintenance of the expression of these factors as well as the maintenance of the regulation of signals intervening upstream: including the maintenance of the activation of the JAK-STAT3 pathway for the maintenance of the pluripotent state, and the decrease of the MAPK-ERK pathway involved in differentiation processes

Les nanoparticules métalliques (MNPs) appliquées en catalyse représentent un domaine attractif en raison de leurs propriétés physiques et chimiques intéressantes. D'autre part, l'ajout d'un autre métal au métal hôte (ici nanoparticules bimétalliques, BMNPs) peut modifier les propriétés électroniques (transfert de charge, hybridation d'orbitales, etc.) et/ou géométriques (alliage, coeurcoquille, hétérodimères, etc.), ce qui peut conduire à améliorer le comportement catalytique, voire envisager une nouvelle réactivité. Le glycérol, quant à lui, possède une structure supramoléculaire complexe qui favorise l'immobilisation des MNPs, et évite leur agglomération, et donc facilite le recyclage de la phase catalytique. Des nanoparticules de Cu(0) (CuNPs) immobilisées dans du glycérol ont été synthétisées en présence de poly(vinylpyrrolidone) (PVP) comme stabilisant sous pression d'hydrogène. Les CuNPs dispersées dans le glycérol se sont avérées être un catalyseur robuste pour diverses réactions : formation de liaison C-N, synthèse d'amines propargyliques di- (via couplage croisé déshydrogénant), tri- (via un couplage aldéhyde-amine-alcyne A3) et tétra-substituées (via un couplage cétone-amine-alcyne KA2) ainsi que pour la synthèse d'hétérocycles: indolizines, benzofuranes et quinolines, par des procédés tandem de cycloisomérisation-couplage A3 en utilisant des benzaldéhydes ortho-fonctionnalisés. La phase catalytique de glycérol peut être recyclée plus de cinq fois (formation de liaisons C-N et pour le couplage A3), sans détecter de traces significatives de cuivre dans les produits organiques extraits. Des nanoparticules bimétalliques de palladium-cuivre (PdCuNPs) immobilisées dans le glycérol ont été synthétisées par des méthodes de co-réduction. Selon les différents rapports métalliques, les PdCuNPs peuvent être considérées comme des petits coeurs de Pd enrobés par du Cu (Pd/Cu = 1/1), des alliages aléatoires (Pd/Cu = 1/2) ou un mélange de nanoparticules monométalliques (Pd/Cu = 2/1). Par une voie de synthèse séquentielle, nous obtenons un mélange de nanoparticules monométalliques. La structure des PdCuNPs a également été confirmée par la réactivité observée pour l'hydrogénation des alcynes, montrant Pd1Cu1 et Pd1Cu2 comme structures bimétalliques. Ainsi, ces catalyseurs ont permis d'ajuster la sélectivité des alcènes. En outre, l'influence de Pd incorporé dans le Cu a également été étudiée dans la cycloaddition d'un azidure avec un alcyne (CuAAC). Plus intéressant, des nanoparticules bimétalliques Pd1Cu1 dans le glycérol, agissant comme système catalytique multitâche, ont été utilisées pour les réactions "onepot", notamment la réaction CuAAC et les réactions de couplage croisé C-C (Sonogashira, Suzuki- Miyaura et Heck) (catalysées au Pd). Grâce à des cinétiques différentes entre les réactions CuAAC et couplages C-C, ces procédés tandem ont permis d'obtenir les produits en rendements élevés. De plus, l'hydroaminométhylation d'oléfines catalysée par des complexes de Rh pour synthétiser les amines peut se dérouler dans le glycérol et a montré de meilleures réactivités que dans les solvants organiques. Ces résultats positifs permettent de concevoir un nouveau système biphasique dans le but de recycler la phase catalytique. / Metal nanoparticles (MNPs) applied in catalysis represent an attractive field due to their interesting physical and chemical properties. Besides, the addition of another metal to the host metal in the same entity (bimetallic nanoparticles, BMNPs) can trigger changes in electronic properties (charge transfer, orbital hybridization, etc.) and/or geometric features (alloy, core-shell, heterodimers, etc.), inducing modifications in their catalytic behavior, in terms of activity, selectivity, robustness, or even leading to new reactivity. Concerning the solvent, glycerol, showing a complex supramolecular structure, favors the dispersion of metal nanoparticles, avoiding their agglomeration and then facilitating the recycling of catalytic phase. Small and spherical zero-valent copper nanoparticles (CuNPs) immobilized in glycerol were synthesized using poly(vinylpyrrolidone) (PVP) as stabilizer under hydrogen pressure. CuNPs dispersed in glycerol proved to be a robust and versatile catalyst for a diversity of C-N bond formation reactions, synthesis of di- (via cross-dehydrogenative coupling), tri- (via aldehydeamine- alkyne A3 coupling) and tetra-substituted propargylic amines (via ketone-amine-alkyne KA2 coupling) as well as different types of heterocycles, in particular indolizines, benzofurans and quinolines, by tandem A3-cycloisomerization processes using ortho-functionalized benzaldehydes as substrates. Interestingly, the catalytic glycerol phase could be recycled more than five times in C-N bond formation and A3 coupling reactions, preserving their reactivity, without detecting a significant copper content in the extracted organic products. Bimetallic palladium-copper nanoparticles (PdCuNPs) dispersed in glycerol were prepared by co-reduction methodology. Depending on the different metal ratios used, Pd nanoparticles coated by Cu (Pd/Cu = 1/1), random alloy (Pd/Cu = 1/2) or mainly mixture of monometallic nanoparticles (Pd/Cu = 2/1) were obtained. By a sequential way of synthesis, a mixture of monometallic nanoparticles was mainly observed. In terms of reactivity, the effect of one metal to other one, on catalytic activity and selectivity was evaluated. The structure of the different PdCuNPs was also confirmed by the observed reactivity in the selective formation of alkenes by hydrogenation of alkynes, proving that Pd1Cu1 and Pd1Cu2 correspond to bimetallic structures. Besides, the influence of Pd incorporated into Cu on azide-alkyne cycloaddition (CuAAC) was also studied. Interestingly, Pd1Cu1 in glycerol were applied in one-pot processes acting as multitask catalytic system, involving CuAAC and Pd-catalyzed C-C cross couplings (Sonogashira, Suzuki-Miyaura and Heck). Thanks to the different rates between CuAAC and C-C couplings, these tandem processes permitted to obtain the desired products in high yields. Furthermore, Rh-catalyzed hydroaminomethylation of olefins, in order to synthesize amines, could be carried out in glycerol, generally showing a better reactivity compared to common organic solvents. These preliminary encouraging results permit to plan the design of a new biphasic system, including the recycling of the catalytic phase.

Les seuls complexes carbéniques stables (hors NHC) des métaux f présentent des groupes R2C(2-) comportant un ou deux atomes de phosphore en position alpha du carbone central. L’objectif de ce travail a été de développer la chimie des carbènes de l’uranium (métal 5f) avec le dianion C{Ph2P(=S)}2(2-) (SCS(2-)) afin d’étendre la chimie organométallique de cet élément à ses divers degrés d’oxydation (+3 à +6), et pour révéler l’effet des orbitales 5f sur la nature et la réactivité de la liaison double U=C.Nous avons tout d’abord isolé les réactifs M(SCHS) (M = Li et K) et montré le rôle du cation M+ sur l’évolution du dianion M2SCS (M = Li, K, Tl) qui se transforme dans le THF en LiSCHS ou en produit de cyclisation intramoléculaire K2[C(PhPS)2(C6H4)]. Nous avons mis au point les conditions pour obtenir les composés mono-, bis- et tris- carbéniques directement à partir du dianion SCS(2-) et de UCl4, le précurseur le plus utilisé dans la chimie de l’uranium. Les réactions de protonolyse de composés amidures (liaison U-NEt2) par le ligand neutre SCH2S ont également été étudiées.Les composés [Li(THF)]2[U(SCS)Cl3] et [U(SCS)Cl2(THF)2] ont ensuite servi à préparer une variété de composés carbéniques cyclopentadiényliques et monocyclooctatétraényliques de l’U(IV). L’analyse DFT des composés [M(SCS)Cl2(py)2] et [M(Cp)2(SCS)] (M = U, Zr) révèle la forte polarisation de la liaison double M=C, renseigne sur la nature des interactions σ et π dans cette liaison, et montre le rôle notable des orbitales f. L'influence des ligands ancillaires sur la liaison M=C est révélée en examinant les effets du remplacement des ligands Cl- et pyridine par des groupements C5H5-. Les analyses Mulliken et NBO montrent que la liaison U=C, contrairement à la liaison Zr=C, n’est pas modifiée par le changement d’environnement du centre métallique.Alors que les essais d’oxydation de complexes carbéniques de l’U(IV) ont été décevants, le premier complexe carbénique de l’uranium(VI), [UO2(SCS)(THF)2], a été isolé avec l’ion uranyle UO2(2+). Les réactions des composés UO2X2 (X = I, OTf) avec les anions SCS(2-) et SCHS- offrent les premiers développements notables de la chimie organométallique de l’ion uranyle. Des études DFT montrent la nature essentiellement ionique de la liaison U(VI)−R et U(VI)=C et la faible contribution de covalence des orbitales 5f. / The only stable f-metal carbene complexes (excluding NHC) metals f present R2C(2-) groups having one or two phosphorus atoms in the central carbon in alpha position. The objective of this work was to develop the chemistry of carbenes for uranium (metal 5f) with the dianion C{Ph2P(=S)}2(2-) (SCS(2-)) to extend the organometallic chemistry of this element in its various oxidation states (+3-6), and to reveal the influence of the 5f orbitals on the nature and reactivity of the double bond C=U.We first isolated the reactants M(SCHS) (M = Li and K) and demonstrated the role of the cation M+ on the evolution of the dianion M2SCS (M = Li, K, Tl) which is transformed into LiSCHS in THF or into product of intramolecular cyclization K2[C(PhPS)2(C6H4)]. We have developed the necessary conditions mono-, bis- and tris-carbene directly from the dianion SCS(2-) and UCl4, as the precursor used in uranium chemistry. The protonolysis reactions of amides compounds (U-NEt2) by the neutral ligand SCH2S were also studied.The compounds [Li(THF)]2[U(SCS)Cl3] and [U(SCS)Cl2(THF)2] were then used to prepare a variety of cyclopentadienyl and monocyclooctatétraényliques uranium(IV) carbene compounds of the DFT analysis of compounds [M(SCS)Cl2(py)2] and [M(Cp)2(SCS)] (M = U, Zr) reveals the strong polarization of the M=C double bond, provides information on the nature of the σ and π interactions in this binding, and shows the important role of f orbitals. The influence of ancillary ligands on the M=C bond is revealed by examining the effects of replacing Cl- ligands and pyridine by C5H5- groups. Mulliken and NBO analyzes show that U=C bond, unlike the Zr=C bond, is not affected by the change in environment of the metal center.While the oxidation tests of carbene complexes of U(IV) were disappointing, the first carbene complex of uranium(VI), [UO2(SCS)(THF)2], was isolated with the uranyl ion UO2(2+). The reactions of compounds UO2X2 (X = I, OTf) with anions SCS(2-) and SCHS- provide the first notable developments in the organometallic chemistry of the uranyl ion. DFT studies show the essentially ionic binding U(VI)-R and U(VI)=C and the small contribution of 5f orbitals covalently.

La grande variété de propriétés biologiques associées au noyau purine en fait une structure privilégiée pour la conception et la synthèse de nouvelles molécules à visée thérapeutique. Cette spécificité est étroitement liée à la grande diversité de substituants pouvant être introduits sur les différentes positions du noyau purine et en particulier sur C2, C6, C8 et N9. Par conséquent, le développement de méthodes de fonctionnalisation rapides de cette famille de composés est d’un grand intérêt synthétique. Nous nous sommes focalisés sur la formation de liaisons C-C et C-N sur les positions 6 et 8 du noyau purine pour pouvoir présenter de nouveaux outils de synthèse permettant d’introduire une plus grande diversité fonctionnelle. D’une part, nous avons étudié la fonctionnalisation directe de liaisons C-H de purines, sujet encore peu exploré. En effet, de nos jours, le traditionnel couplage croisé (Negishi, Suzuki-Miyaura), utilisé pour la création de liaisons C-C, se voit de plus en plus concurrencé par ces réactions puisqu’elles ne nécessitent pas la préparation d’un partenaire organométallique. Ce sont des réactions dites à économie d’atomes. En nous basant sur l’expérience du laboratoire dans le domaine de la fonctionnalisation directe de liaisons C-H, nous avons envisagé l’alcénylation et l’alcynylation directes en position 8 de la purine, les motifs alcényle et alcynyle étant présents dans certaines purines d’intérêt biologique. D’autre part, nous nous sommes intéressés à deux méthodes de couplage croisé pallado-catalysé permettant la formation de liaisons C-N et C-C : le couplage de Buchwald – Hartwig entre une 8-iodopurine et des amides ou des amines aromatiques, et le couplage de Liebeskind – Srogl entre une 6-thioétherpurine et divers acides boroniques. / Purine is the most widely distributed N-heterocycle scaffold in the nature and its derivatives are well known for their biological and fluorescent properties. These characteristics are linked to the diversity of substituents that can be introduced, especially on the C-2, C-6, C-8 and N-9 positions. Therefore, the development of methods for rapid functionalization of this family of compounds represent a valuable asset. We focused on the formation of C-C and C-N bonds at positions 6 and 8 of the purine ring in order to provide new synthesis tools allowing the introduction of functional diversity. On the one hand, we studied the direct functionalization of C-H bonds of purines, subject still little explored. Indeed, nowadays, traditional cross-coupling reactions (Negishi, Suzuki-Miyaura), used for the creation of C-C bonds, are increasingly challenged by these reactions since they do not require the preparation of an organometallic partner. Their advantage lies in step and atom economy. Based on previous experience in our laboratory in the field of direct functionalization of C-H bonds, we envisioned direct alkenylation and alkynylation at position 8 of the purine, knowing that alkenyl and alkynyl patterns are found in purines of biological interest. On the other hand, we were interested in two pallado-catalyzed cross-coupling methods for the formation of C-N and C-C bonds : Buchwald – Hartwig coupling between 8-iodopurine and aromatic amines or amides, and Liebeskind – Srogl coupling between 6-thioétherpurine and a range of boronic acids.

Les lymphomes anaplasiques à grandes cellules (LAGC) sont des lymphomes non-hodgkiniens dits de type T ou nul, représentant la majorité des lymphomes T pédiatriques (20 à 30%). Dans plus de 80% des cas, une translocation chromosomique réciproque aboutissant à l'expression anormale de protéines chimères de type X-ALK qui arborent constitutivement et de manière anormale l'activité tyrosine-kinase ALK (Anaplastic Lymphoma Kinase) est le moteur de la tumorigenèse (LAGC dits "ALK+ "). L'une des particularités de ces lymphomes, mise en évidence par mon équipe, est le fait que B-Cell Lymphoma-2 (BCL-2) demeure indétectable dans les cas ALK+ contrairement aux cas ALK-. Ce point est d'autant plus surprenant que BCL-2, oncogène largement établi comme prototype de protéines anti-apoptotiques ainsi que régulateur clé de l'autophagie, est fortement surexprimé dans la majorité des lymphomes. A l'inverse, Human Antigen R (HuR) est surexprimée dans les LAGC (comme dans la plupart des cancers). Il a été démontré que cette protéine de liaison aux ARN participait au maintien du phénotype tumoral, et que sa localisation subcellulaire et ses fonctions dépendaient étroitement de son statut de phosphorylation, lequel est régulé par ALK dans les LAGC ALK+. Au niveau du cytoplasme, HuR permet de stabiliser et d'augmenter la traduction d'ARNm possédant, dans leur région 3'-UTR, des séquences riches en adénine et uridine (AU-rich elements, "ARE"). De manière plus générale, HuR a la capacité de dialoguer avec les microARNs (miARN), soit en empêchant leur action par compétition, soit à l'inverse en coopérant avec ces derniers et en promouvant ainsi leur fonction de régulateur négatif sur certains transcrits cibles communs. Le transcrit Bcl-2, dont l'expression est réprimée dans les LAGC ALK+, fait partie des cibles potentielles de HuR. Au cours de ma thèse, j'ai ainsi cherché à comprendre les mécanismes moléculaires mis en jeu dans la répression de l'expression de Bcl-2, en me focalisant sur le rôle de HuR et de miARN "partenaires" dans ce processus. Mes données semblent indiquer que ce mécanisme implique le recrutement par HuR du miR-34a sur l'ARNm Bcl-2, conduisant à la mise en silence de ce dernier. A l'inverse, quand l'activité tyrosine- kinase de ALK est inhibée, l'interaction entre HuR et le transcrit Bcl-2 diminue, ce qui limite le recrutement de miR-34a et conduit à une restauration de l'expression de cette oncogène majeur dans les cellules lymphomateuses. Dans le contexte des essais cliniques d'inhibiteurs ciblant l'activité tyrosine kinase de ALK tels que le Crizotinib, la question de cette ré-expression de BCL-2 éclaire d'une lumière nouvelle certains échecs thérapeutiques subis par cette molécule pourtant prometteuse. Je me suis donc également consacré, pendant ma thèse, à l'étude des conséquences de cette ré-expression de BCL-2 sur les LAGC ALK+ traités par le Crizotinib. Les résultats que j'ai obtenus in vitro et in vivo montrent que contrecarrer, par interférence à l'ARN, l'élévation du taux de BCL-2 consécutive au traitement par le Crizotinib, permet de potentialiser les effets de la drogue : cela se traduit en particulier par une potentialisation de la mort par apoptose induite par le traitement mais aussi, de manière fascinante, par une conversion de la réponse autophagique initialement cytoprotectrice et pro-tumorale en une autophagie incontrôlée et délétère, qui participe alors à l'effet thérapeutique accru de la drogue. De manière globale, ce travail permet d'envisager de nouvelles combinaisons et alternatives thérapeutiques pour les patients souffrants de LAGC ALK+, et illustre la complexité des régulations croisées entre processus apoptotiques et autophagiques. / Anaplastic large cell lymphoma (ALCL) are T/-null non-hodgkin lymphoma representing most of childhood T-cell lymphoma (up to 30%). More than 80% of cases bear reciprocal chromosomic translocation responsible for abnormal expression and constitutive activation of X-ALK type (Anaplastic Lymphoma Kinase) chimeric proteins (ALK+ ALCL). A striking characteristic of this lymphoma is that B-Cell Lymphoma-2 (BCL-2) remains undetectable in ALK+ cases compared to ALK- cases. This is all the more surprising as the BCL-2 oncogene, which is firmly established as a prototypic anti-apoptotic factor as well as a key autophagy regulator, has been shown to be overexpressed in a majority of lymphomas. On the other hand, the RNA-binding protein HuR (Human Antigen R) is overexpressed in ALCL (as in most cancers). It has been demonstrated that this protein was involved in the sustainability of the tumoral phenotype, and that its subcellular localization and functions were closely related to its phosphorylation status, which in turn heavily depends on ALK activity in ALK+ ALCL. In the cytoplasm, HuR has the ability to bind adenine and uridine-rich elements (ARE) located on the 3'-UTR of target mRNAs, and both protect them from degradation and increase their translation. From a general point of view, HuR is able to establish an interplay with microRNAs (miRNAs), either blocking them through competition, or actually cooperating with them and thus promote their function of negative regulators of gene expression on common target transcripts. The BCL-2 transcript, which expression seems to be silenced in ALK-expressing ALCL, has been described as a potential target of HuR. During my PhD work, I dedicated myself to understand the molecular mechanism at work in the silencing of BCL-2 expression with a focus on HuR and collaborating miRNA. The data I obtained point at a cooperation between HuR and miR-34a leading to the silencing of the BCL-2 transcript. However, when the ALK tyrosine kinase activity is inhibited, it appears the interaction between the BCL-2 mRNA diminishes, which limitates the miR-34a 's access to this transcript and ultimately results in a re-expression of the BCL-2 oncogene in these lymphoma cells. In the current context of clinical trials for ALK-targeting inhibitors, such as the Crizotinib, this BCL-2 re-expression observed upon ALK inhibition shed light on potential reasons behind some therapeutic failures that have recently been reported. Indeed, during my PhD work, I also studied the consequences of the BCL-2 re-expression observed in Crizotinib-treated cells. The data I obtained in vitro and in vivo show that, by blocking this re-expression using RNA interference, the Crizotinib anti-tumoral efficiency can be greatly potentiated. This potentiation took the form of an increase of apoptotic cell death induction and, interestingly, also affected the autophagic response triggered by the drug, making it switch from a cytoprotective- type, protumoral autophagic flux to an enhanced, deletary-type and tumor suppressive flux, adding to the therapeutic effect of the drug. This work in general provides insights for new therapeutic combinations that could potentially benefit to ALK+ ALCL patients, and illustrates the complex cross-regulations between apoptotic and autophagic pathway.

Le but de cette dissertation est de développer une théorie manifestationaliste du contexte. Cet objectif sera atteint en deux étapes. Premièrement, nous essaierons de spécifier le rôle explicatif du contexte dans l'interprétation de l'énoncé en développant une notion de « force du contexte » et un modèle de « contribution contextuelle ». Deuxièmement, nous allons essayer de montrer comment la force du contexte peut être rendue manifeste par les connecteurs du discours. La thèse comprend deux parties. La première partie est composée de trois chapitres. Le premier chapitre établit principalement un cadre conceptuel dérivé d'une analyse des entrées de dictionnaire pour le contexte afin de capturer notre notion intuitive de contexte. Il y a quatre composantes conceptuelles, « situation », « texte (quelque chose de parlé ou d'écrit) », « connexion », « signification », qui sont indispensables à la compréhension de la notion. La connectivité du contexte, enracinée dans la notion de « connexion », est la base conceptuelle de la notion de « force contextuelle ». Le deuxième chapitre est consacré aux spécifications de certaines conceptions et distinctions fondamentales : la définition du « discours », la distinction entre « phrase » et « énoncé », et la notion de « signification du locuteur » de Paul Grice. Le troisième chapitre est une critique détaillée de deux grandes théories du contexte. La première théorie, adaptée aux indexicaux, commence avec le travail pionnier d'Arthur W. Burks et de Yehoshua Bar-Hillel sur la signification indexicale et aboutit à l'approche bien développée du contexte dans la théorie des indexicaux de Kaplan. La seconde, grâce à Robert Stalnaker, prend le contexte comme le savoir couramment présupposé entre interlocuteurs dans une conversation, ou selon les propres termes de Stalnaker, « terrain d'entente ». La deuxième partie comprend deux chapitres. Dans le premier chapitre, nous clarifions d'abord la différence entre les approches de Kaplanian et de Stalnakerian et les nôtres : les premiers fondent leurs théories sur le concept intuitif de « contexte-comme-situation », à savoir que le contexte est une situation où un explanandum a lieu ; les nôtres ont l'intention de fonder une théorie du contexte sur le concept intuitif de « contexte-en-utilisation ». Grâce au concept de « contexte-en-utilisation », nous sommes donc intéressés par : ∂. La force (pas le contenu) du contexte. ß. La manifestation (pas la représentation) du contexte. / The aim of this dissertation is to develop a manifestationalist theory of context. This aim will be achieved by two steps. First, we will try to give a new specification of the explanatory role of context in utterance interpretation by developing a notion of the “force of context” and an account of “contextual contribution”. Second, we will try to show how the force of context can be made manifest by discourse connectives. The dissertation includes two parts. The first part is comprised of three chapters. The first chapter mainly establishes a conceptual framework derived from an analysis of dictionary entries for “context” to capture our intuitive notion of it. There are four conceptual components, “situation”, “text (something spoken or written)”, “connection”, “meaning”, which are indispensable for an understanding of the notion. The connectedness of context, rooted in the very notion of “connection”, is the conceptual basis of the notion of “context force”. The second chapter is dedicated to specifications of some related fundamental conceptions and distinctions: the definition of “discourse”, the distinction between “sentence” and “utterance”, and the Gricean notion of “speaker meaning”. The third chapter is a detailed review of two major theories of context. The first, tailoring context to indexicals, begins with the pioneering work of Arthur W. Burks and Yehoshua Bar-Hillel on indexical meaning and culminates in the well-developed approach to context in Kaplan’s theory of indexicals. The second, due to Robert Stalnaker, takes context as the knowledge commonly presupposed between interlocutors in a conversation, or in Stalnaker’s own terms, “common ground”. The second part includes two chapter. In the first chapter, we primarily clarify the difference between Kaplan and Stalnaker’s approaches and ours: the former base their theories on the intuitive concept of context-as-situation, namely that the context is a situation where some explanandum occurs; the latter intends to base a theory of context on the intuitive concept of context-in-use. Stemming from the concept of context-in-use, we are thus interested in: ∂. The force (not the content) of context. ß. The manifestation (not the representation) of context.

A Interconsulta Psiquiátrica é considerada por muitos pesquisadores como sendo a área prática e aplicada da Medicina Psicossomática, de conhecimento concernente à investigação da interação entre fatores biológicos e psicossociais no desenvolvi-mento, curso e resultado de todas as doenças. A prevalência de transtornos psiqui-átricos em hospitais gerais pode variar de 20 a 40% entre pacientes internados, po-rém uma reduzida parcela é assistida pela Interconsulta e consequentemente recebe tratamento psiquiátrico. Sendo assim, o presente estudo teve por objetivos: a) obter informações dos dados sociodemográficos dos pacientes e seus históricos em sa¬úde mental (tratamentos anteriores e tentativa de suicídio); b) analisar o uso do ser¬viço de Interconsulta Psiquiátrica, tais como as clínicas solicitantes, função dos pro¬fissionais solicitantes, motivos de solicitação, tempo de internação dos pacientes assistidos, tempo de solicitação do PI e de sua resposta, e o número de atendimen-tos realizados; c) descrever os diagnósticos clínicos e psiquiátricos dos pacientes avaliados através dos critérios estabelecidos pela CID-10; d) analisar intervenções farmacoterapêuticas e não medicamentosas, tais como as condutas sugeridas pelo interconsultor, profissionais solicitados durante a internação, as medicações psico-trópicas em uso e prescritas; e) caracterizar aspectos relacionados aos médicos clí-nicos, aos profissionais de saúde e aos interconsultores; e f) avaliar a qualidade es-trutural da solicitação psiquiátrica realizada pelo profissional clínico e a resposta dada pelo interconsultor. Para tanto, foi realizada uma análise retrospectiva de todas as solicitações consecutivas realizadas entre janeiro de 1981 a dezembro de 2010 para a Psiquiatria do Serviço de Interconsulta em Saúde Mental do Hospital das Clí-nicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo assim como a consulta dos prontuários de todos os pacientes assistidos pelo serviço para obter outras informações. Foram realizadas 4882 solicitações psiquiátricas e a taxa de encaminhamento variou de 0,7 a 1,1%. Dados sociodemográficos dos paci-entes que foram atendidos com mais fre¬quência relacionados ao sexo, cor e/ou et-nia, estado civil, com quem os pacientes residiam (somente para os homens), situa-ção laboral (somente para as mulheres), escolaridade e procedência tenderam a permanecer relativamente estáveis ao longo dos anos. As mulheres apresentaram idade média menor que os homens e foram atendidos com mais frequência: homens e mulheres casados (e mais homens soltei¬ros quando comparados com as mulhe¬res), homens que residiam com seus pais e mulheres que residiam com seus cônju¬ges e filhos, homens afastados de seus tra¬balhos e mulheres responsáveis pelos cuidados da casa, e também pacientes de ambos os sexos com idades entre 21 e 50 anos, pacientes caucasianos, pacientes procedentes do estado de São Paulo e pacientes com escolaridade até ensino fun¬damental completo. As mulheres foram mais frequentemente assistidas pelo serviço de Intercon¬sulta Psiquiátrica ao longo de todos os anos, assim como ficaram menos tempo in¬ternadas e também tiveram solicitações psiquiátricas realizadas em um menor inter¬valo de tempo após a admis¬são hospitalar. Em trinta anos, a Clínica Médica Geral foi a clínica que mais realizou solicitações psiquiátricas, o motivo de solicitação mais frequente foi a presença de sintomas psiquiátricos e o tempo de internação dos pacientes assistidos pela Inter¬consulta foi maior quando comparado aos pacientes internados no hospital de modo geral. Os transtornos neuróticos, somatoformes e relacionados ao estresse foram os diagnósticos psiquiátricos mais comuns entre as mulheres e homens atendidos pelo SISMen, seguido pelos transtornos de humor e transtornos mentais orgânicos nas mulheres e transtornos mentais orgânicos e transtornos devido ao uso de substân¬cias nos homens. Já em relação ao diagnóstico clínico, foram atendidos com mais frequência mulheres com doenças endócrinas, metabólicas e nutricionais e homens com doenças infecciosas e parasitárias; e casos de múltiplas comorbidades clínicas se tornaram mais frequentes com o passar dos anos. As principais condutas sugeri¬das pelos interconsultores foram: atendimento individual, orientação à equipe e prescrição de psicofármacos para ambos os pacientes, permanecendo frequentes ao longo dos anos, com destaque para um aumento progressivo de casos em que medicações psicotrópicas foram prescritas a partir de meados dos anos 90. E com o passar dos anos, os planos de tratamento se tornaram mais complexos e abran¬gentes e houve um aumento progressivo no número de encaminhamentos para atendimento psiquiátrico ambulatorial. Em relação à qualidade estrutural das solici¬tações psiquiátricas e das respostas dadas pelos interconsultores, ambas foram consideradas aceitáveis ou boas na maioria dos casos, sendo um indicativo positivo na qualidade de comunicação entre os profissionais. Pode-se dizer que este foi o primeiro estudo longitudinal a analisar consecutivamente trinta anos e também toda a população assistida por um serviço de Interconsulta Psiquiátrica / Consultation-liaison Psychiatry is considered by many researchers as the practical and applied area of psychosomatic medicine, which is an area of knowledge concerning the investigation of the interaction between biological and psychosocial factors in the development, course and outcome of all diseases. The prevalence of psychiatric disorders in general hospitals range from 20 to 40% of hospitalized patients, but a small portion is assisted by the consultation-liaison and consequently receives psychiatric treatment. Considering this background, this study aimed: a) to obtain information about sociodemographic characteristics of patients and their mental health history (previous treatment and attempted suicide); b) to analyze the referral patterns of consultation-liaison psychiatry, such as referral sources, reasons for referral, length of stay, lagtime and other; c) to describe clinical and psychiatric diagnoses according by ICD-10; d) to analyze pharmacotherapeutic and non-drug interventions; e) to describe aspects related to physicians, health professionals and psychiatrists; and f) to analyze the structural quality of the request made by the physicians and psychiatrists. For this purpose, it was performed a retrospective analysis of all consecutive referrals made between January 1981 and December 2010 to consultation-liaison psychiatry of Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo as well as the review of medical charts of all patients assisted by the service. 4882 referrals were made and consultation rate ranged from 0.7 to 1.1%. Sociodemographic characteristics related to sex, color or ethnicity, marital status, patients who lived (for men), employment status (for women), education and origin tended to remain relatively stable over the years. Women had a lower average age than men and were seen more frequently: married men and women (and more single men compared with women), men who lived with their parents and women who lived with their spouses and children, and also patients of both sexes aged between 21 and 50 years, caucasian patients and patients from the state of Sao Paulo. Women were more often assisted by the consultation-liaison service over the years and the length of stay and lagtime were lower than men. In thirty years, internal medicine was the most frequent referral source, presence of psychiatric symptoms was the common reason for referral and the length of stay of patients assisted by consultation-liaison psychiatry was higher compared to those admitted to the hospital in general. The main clinical diagnoses for women and men were endocrine, nutritional and metabolic, cardiovascular diseases and infectious and parasitic diseases and cases with multiple morbidities have become more frequent over the years. One third of patients were diagnosed with neurotic disorders, stress related and somatoform disorders in women and men, followed by mood disorders and organic mental disorders in women, and organic mental disorders and due to substance use in men. The main interventions were individual therapy, guidelines for staff and prescription of psychotropic drugs for women and men. There was a increase in the number of referrals to outpatient psychiatric care. Psychiatric referrals and responses by psychiatrist were considered acceptable or good in most cases, a positive indicative on the quality of communication between professionals. This was the first longitudinal study to examine thirty years consecutively and also the entire population assisted by Consultation-liaison Psychiatry.