Les travaux de thèse retranscrits dans ce mémoire ont pour sujet l’élaboration de nouveaux ligands pour la coordination de métaux et l’application des complexes correspondants pour la catalyse et la thérapie.La première partie du manuscrit traite de l’élaboration de ligands phosphine-diène, de leurs analogues saturés et des complexes arène-ruthénium correspondants. Le départ d’arène permet au ligand phosphine-cycloheptadiène de former avec le ruthénium un complexe bimétallique cationique où le ligand est chélate κ-P/diène-η4. Ces complexes ont été appliqués en catalyse pour l’addition radicalaire par transfert d’atome (ATRA) de CCl4 au styrène. Lors de l’utilisation de conditions dures, la supériorité des complexes « diène » a pu être mise en évidence par rapport aux analogues saturés.La seconde partie rapporte le développement de nouveaux analogues de base de Schiff : les « salicylamidines ». L’utilisation de différentes voies de synthèse a permis d’obtenir plusieurs générations de ligands. Ils ont été utilisés pour la coordination de métaux et sont particulièrement adaptés à la formation de complexes avec le zinc et l’aluminium. Certains de ces composés ont été utilisés pour la polymérisation par ouverture de cycle (ROP) de lactides et ont démontré une bonne activité.La dernière partie concerne la synthèse et l’évaluation de complexes métalliques comme agents anticancéreux. Des complexes phosphine-or et phosphine-ruthénium ont été synthétisés et évalués pour leur activité antiproliférative. Les complexes phosphine-or présentent une activité remarquable, meilleure que le cisplatine. La nature de l’arène des complexes phosphine-ruthénium influe fortement sur leur activité, les dérivés « benzoate d’éthyle » donnent des cytotoxicités significativement meilleures que les analogues « p-cymène ». Des complexes de titane et de zirconium avec un ligand de type aza-dipyrrométhène ont été synthétisés. Une étude préliminaire de leurs propriétés photophysiques a été réalisée et a indiqué que les composés étaient fluorescents. L’étude de leur propriété anticancéreuse a démontré une faible cytotoxicité. / The subject of this thesis concerns the development of new ligands, their coordination chemistry, and the synthesis of the corresponding metal complexes for catalysis and therapy.The first part of this work relates to the synthesis of diene-phosphine ligands, their saturated analogs, and the corresponding arene-ruthenium complexes. Arene decoordination allows the formation of a cationic bimetallic complex where the ligand is diène-η4/κ-P coordinated to the ruthenium. These complexes have been applied to atom transfer radical addition (ATRA) of CCl4 to styrene. When harsh reaction conditions are used, the superiority of the “diene” complexes is highlighted comparing to saturated analogs.The second part concerns the development of new Schiff base analogs: the “salicylamidines”. Several ligand generations have been obtained following different synthetic paths. They have been used for metal coordination, and are especially well-suited for the formation of zinc and aluminium complexes. Some of the compounds have been applied to ring opening polymerization (ROP) of lactides, and demonstrated good activity.The last part reports on the synthesis and assessment of metal-based anticancer agents. Some phosphine-gold and phosphine-ruthenium complexes have been synthesized and tested for their antiproliferative activity on several cancer cell lines. The phosphine-gold complexes showed impressive activities, better than cisplatine. Activity of phosphine-ruthenium is strongly influenced by the nature of the arene, ethyl benzoate derivatives are significantly more cytotoxic than p-cymene ones. Titanium and zirconium complexes with aza-dipyrromethene ligand were synthesized. Preliminary photophysical study was performed and indicated fluorescence. Their anticancer properties were assessed, and they are only poorly cytotoxic.

Le syndrome de Goldenhar ou OAVS est une maladie du développement impliquant les deux premiers arcs branchiaux. Très hétérogène, elle est caractérisée par des anomalies des oreilles,des yeux et des vertèbres ainsi que par une microsomie hémifaciale. Des causes environnementales (exposition à l’Acide Rétinoïque (AR) durant la grossesse) et des causes génétiques (anomalies chromosomiques) ont été évoquées, mais aucun gène n’était directement associé à ce spectre. L’objectif de ce projet est donc d’identifier des gènes impliqués dans le spectre OAV. Des approches pangénomiques par séquençage nouvelle génération (exome,panels de gènes ciblés) ont été utilisées pour identifier des gènes candidats. L’identification de mutations dans MYT1 et l’inactivation transitoire de son l’homologue myt1a chez le poisson zèbre ont confirmé son rôle dans le développement cranio-facial et son implication dans l’OAVS. La validation fonctionnelle de ces mutations a été réalisée in vitro. Cible de la voie de l’Acide Rétinoïque (AR), MYT1 agit également comme répresseur des Récepteurs de l’AR permettant son rétrocontrôle négatif. Une approche toxicologique (traitements à l’AR de souris gestantes pendant une période clef du développement embryonnaire) a permis l’identification de protéines et de voies de signalisation dérégulées chez les embryons traités. L’étude de ces protéines modulées et notamment de celles déjà impliquées dans le développement cranio-facial tend à renforcer le lien entre AR et OAVS et offre des pistes intéressantes quant à l’identification de nouveaux gènes candidats pour ce syndrome, ces protéines pouvant être codées par des gènes potentiellement mutés chez des patients OAVS. / Goldenhar syndrome or Oculo-Auriculo-Vertebral Spectrum (OAVS) is a rare developmental disorder involving the first and the second pharyngeal arches. Extremely heterogeneous, it is characterized by hemifacial microsomia, asymmetric ears, ocular and vertebral abnormalities. Various etiologies have been suggested including environmental factors, especially embryonic Retinoic Acid (RA) exposure during pregnancy, and genetic causes (various chromosomal abnormalities). However, no gene had been formally implicated in this syndrome so far. The goal of this project is to identify genes involved in OAVS. Novel pangenomic approaches by Next generation Sequencing (Whole Exome Sequencing and Target genes Panel) were used to find new candidate genes. Identification of mutations in MYT1 and the transient knockdown experiments in zebrafish confirmed its implication in OAVS. Our in vitro studies provided functional characterization of these mutations and supported the link between MYT1 and RA signaling pathway. Thus, MYT1 is a target of RA but also acts as a repressor of RA Receptors and so, participates at the negative feedback. Toxicological approach was also performed by treatment of gestational mice by all-trans RA during a critical window of embryonic development. It led to a deregulation of proteins and to a modulation of cellular pathways in treated embryos. Studying the proteins whose expression is altered following the treatment, especially the proteins already involved in craniofacial development, could led to the identification of new candidate genes for OAVS and thus, may allow to better decipher the pathogenic mechanisms.

Macromolecular engineering is one of the most powerful tools to control the molecular parameters, including architecture of polymers, and to improve their performances or to impart them new properties. This contribution aims at reporting on a novel strategy for the macromolecular engineering of poly-ε-caprolactone (PCL) which is based on the use of functional ε-caprolactone, the α-chloro-ε-caprolactone (αClεCL). Indeed, αClεCL is a precursor of polymers and copolymers with εCL that bear pendant activated chlorides well suited to grafting from reaction. These (co)polyesters have been used as macroinitiators for the Atom Transfer Radical Polymerization (ATRP) of methyl methacrylate leading to the corresponding graft copolymer. They have also been involved in an Atom Transfer Radical Addition (ATRA) reaction with a series of olefins bearing different functional groups (hydroxyl, carboxylic acid and epoxy group) in order to functionalize the polyester backbone without deleterious degradation. ATRA of PEO chains with an unsaturation end groups has also been carried out in order to prepare PCL-g-PEO of different compositions to be used as stabilizers of polyester nanoparticles. Combination of ring-opening polymerization of ε-caprolactone and the copper-catalyzed Huisgens [3+2] cycloaddition is a novel strategy for going a step further in the macromolecular engineering of poly-ε-caprolactone (PCL). This click reaction is very well-suited to the chemical modification of aliphatic polyesters because, its implementation under very mild conditions prevents chain degradation from occurring. Indeed, alkynes were cycloadded onto azide containing PCL at low temperature (35°C) in an organic solvent (DMF or THF). Originally, α-chloro-ε-caprolactone and ε-caprolactone were randomly copolymerized in toluene at room temperature followed by reaction of the activated chlorides with sodium azide. In order to make a wide range of functional aliphatic polyesters available, poly(α-azide-ε-caprolactone-co-ε-caprolactone) copolyesters were reacted with a series of alkynes substituted by a functional group, e.g., hydroxyl, acrylate and quaternary ammonium salts, This strategy turned out to be efficient to synthesize for instance hydrophilic, photo-cross-linkable and hydrosoluble PCL. Moreover, a variety of graft copolymers were prepared by both the grafting from and the grafting onto techniques. Indeed, an ATRP initiator was attached onto PCL followed by polymerization of vinyl monomers, whereas alkyne endcapped PEO was cycloadded onto azide-containing PCL with formation of amphiphilic PCL-g-PEO copolymers. Last but not least, the click chemistry was very instrumental in imparting an antimicrobial activity to PCL or for the preparation of new functionalized caprolactones.

<p>All aspects of cell life are regulated by signal transduction mechanisms. This thesis describes the regulatory roles of a few key signal transduction molecules involved in three major biological responses. The studied pathways include platelet derived growth factor (PDGF)-BB induced transformation of murine fibroblasts, interferon (IFN)-γ stimulated monocyte activation and all-trans retinoic acid (ATRA) induced myeloid differentiation. </p><p>We found that intact phosphoinositide 3OH-kinase (PI3K) activity is essential in the signaling pathway that leads to the morphological alterations and migration pattern characteristic of PDGF-BB transformed NIH/sis and NIH/COL1A1 fibroblasts. Furthermore, our data indicated that the small Rho-GTPase, Rac1 is the predominant mediator of these signals downstream of PI3K.</p><p>The study of the IFN-γ induced activation of monocytic U-937 cells showed that upregulation of the high affinity receptor for IgG (FcγRI) is dependent on the coordination of several regulatory events: the PKR-mediated serine 727 phosphorylation of Stat1, the expression of the hematopoietic lineage specific transcription factor PU.I, and the activation of the NFκB pathway.</p><p>ATRA-induced differentiation and cell cycle arrest are impaired in U-937 sublines expressing phosphorylation deficient Stat1 (Stat1Y701F and Stat1S727A). The findings in paper III indicated that the expression pattern of the myeloid specific transcription factors Stat2, ICSBP and c/EBPε was altered in the sublines and that intact Stat1 activation is critical for maintaining the balance of the transcriptional network during ATRA induced terminal differentiation.</p><p>Finally, ATRA-induced differentiation and growth arrest were blocked by treatment with the IKKα/β inhibitor BMS345541 or by ectopic expression of the NFκB super repressor IκBα (S32A/S36A). The fact that IκB(AA) sublines differentiated normally in response to vitamin D3, showed that NFκB inhibition specifically affected ATRA induced responses. Notably we suggest that the activity of the NFκB pathway may interfere with the differentiation process via a direct effect on the RAR/RXR mediated transcription.</p>

All aspects of cell life are regulated by signal transduction mechanisms. This thesis describes the regulatory roles of a few key signal transduction molecules involved in three major biological responses. The studied pathways include platelet derived growth factor (PDGF)-BB induced transformation of murine fibroblasts, interferon (IFN)-γ stimulated monocyte activation and all-trans retinoic acid (ATRA) induced myeloid differentiation. We found that intact phosphoinositide 3OH-kinase (PI3K) activity is essential in the signaling pathway that leads to the morphological alterations and migration pattern characteristic of PDGF-BB transformed NIH/sis and NIH/COL1A1 fibroblasts. Furthermore, our data indicated that the small Rho-GTPase, Rac1 is the predominant mediator of these signals downstream of PI3K. The study of the IFN-γ induced activation of monocytic U-937 cells showed that upregulation of the high affinity receptor for IgG (FcγRI) is dependent on the coordination of several regulatory events: the PKR-mediated serine 727 phosphorylation of Stat1, the expression of the hematopoietic lineage specific transcription factor PU.I, and the activation of the NFκB pathway. ATRA-induced differentiation and cell cycle arrest are impaired in U-937 sublines expressing phosphorylation deficient Stat1 (Stat1Y701F and Stat1S727A). The findings in paper III indicated that the expression pattern of the myeloid specific transcription factors Stat2, ICSBP and c/EBPε was altered in the sublines and that intact Stat1 activation is critical for maintaining the balance of the transcriptional network during ATRA induced terminal differentiation. Finally, ATRA-induced differentiation and growth arrest were blocked by treatment with the IKKα/β inhibitor BMS345541 or by ectopic expression of the NFκB super repressor IκBα (S32A/S36A). The fact that IκB(AA) sublines differentiated normally in response to vitamin D3, showed that NFκB inhibition specifically affected ATRA induced responses. Notably we suggest that the activity of the NFκB pathway may interfere with the differentiation process via a direct effect on the RAR/RXR mediated transcription.

Made available in DSpace on 2014-12-17T13:53:17Z (GMT). No. of bitstreams: 1 CasioCPB.pdf: 223119 bytes, checksum: 97c79c2a5739a0243c398cc767f21c7c (MD5) Previous issue date: 2008-09-04 / This study addresses the question of attraction and retention of talent in companies that produce engineering projects in the area of oil and natural gas in the city of Natal. The objectives were to identify the mechanisms that these companies use to attract and retain talented professionals and what the relationship between these practices and performance of these organizations in the market. This is a case study of a qualitative nature which were included in the fullness of companies that work in that class in the capital Potiguar. Have been applied to the managers of these companies structured questionnaires with eleven issues orientativas based on theoretical reference adopted. The research finds that managers understand the word "talent", recognize the importance of the appreciation of its employees and the development of their innate abilities to better organizational performance, much due to the fact they are acting in a market of fierce competition. His companies - though not submit the formal procedures related to the subject in question - have mechanisms that can be characterized as the attraction and retention of talent. The relationships identified in this study are consistent with the results found in other studies and put the information here can serve as the basis for that other managers, including other areas, to reach excellence in their respective industries / O presente estudo aborda a quest?o da atra??o e reten??o de talentos nas empresas que elaboram projetos de engenharia na ?rea de petr?leo e g?s natural na cidade do Natal. Os objetivos foram identificar os mecanismos que essas empresas utilizam para atrair e reter profissionais talentosos e quais as rela??es existentes entre essas pr?ticas e o desempenho das referidas organiza??es no mercado. Trata-se de um estudo de caso de natureza qualitativa no qual foram inclu?das a plenitude das empresas que atuam nesse ramo na capital potiguar. Foram aplicados aos gerentes dessas empresas question?rios estruturados com onze quest?es orientativas fundamentadas no referencial te?rico adotado. A pesquisa constata que os gestores compreendem o termo talento , reconhecem a import?ncia da valoriza??o de seus funcion?rios e do desenvolvimento de suas habilidades inatas para um melhor desempenho organizacional, muito devido ao fato de estarem atuando em um mercado de acirrada competi??o. Suas empresas apesar de n?o apresentarem processos formais relacionados ao tema em quest?o apresentam mecanismos que podem ser caracterizados como de atra??o e reten??o de talentos. As rela??es identificadas neste estudo s?o consistentes com os resultados encontrados em outros trabalhos e as informa??es aqui postas podem servir de base para que demais gestores, inclusive de outras ?reas, consigam atingir a excel?ncia em seus respectivos setores

Vitamin A metabolites and retinoids may slow the progression of breast cancer and elicit anti-neoplastic properties similar to those of omega-3 fatty acids. Studies using animal models show a decrease in the incidence, growth and metastisis of mammary tumors in the presence of specific fatty acids. This effect is also seen with use of retinoids, specifically all-trans retinoic acid (AtRA). Thus, fatty acids may also alter retinoid homeostasis in mammary carcinoma cells (MCF-7s). The potential for inter/co dependency among fatty acids and retinoids is considerable, and here it has been hypothesized that a decrease in cancer progression will occur in the presence of both compounds. MCF-7’s were seeded in a 48 well plate at 5,000 cells per well. After 24 hr, cells were treated with either 1 µM AtRA alone, fatty acids alone, or AtRA + fatty acids. Fatty acid treatments (Linoleic, and Linolenic) were administered at 2.5 uM concentrations. Each fatty acid treatment was also combined with 1 µM AtRA to determine if there is a synergistic effect on slowing cell growth. Both culture media and treatments were changed at 24 hour intervals over a 3 day trial. When compared to the controls, cells treated with 1 µM AtRA or 2.5 µM Linolenic acid both inhibited cell growth. Interestingly, when combined with Linolenic acid, AtRA treatment resulted in a significant (nearly 50%) additional growth inhibition when compared to treatment with AtRA alone. Our results suggest that AtRA and Linolenic acid have a inter/co dependency that significantly inhibits breast cancer cell growth in vitro by 73.4 % compared to control, and 49.7% compared to AtRA alone over 72 hours. We conclude that AtRA and linolenic acid have a combined effect in breast cancer cell proliferation in-vitro and their role in dietary prevention warrants further investigation.

No description available.