Le but de ce travail était d'identifier les fonctions régulées par quorum-sensing (QS) chez la bactérie phytostimulatrice Azospirillum. Les effets phytobénéfiques in vitro des souches B518 et TVV3 (isolées du riz) ne sont pas altérées par l'inactivation des molécules signal impliquées dans le QS. La combinaison d'une approche ciblée et d'une approche globale par protéomique montre que le QS régule des fonctions liées à l'adaptation à la plante, notamment à la colonisation racinaire chez B518. Chez TVV3, aucune fonction régulée par QS n'a pu être identifiée mais les gènes impliqués dans le QS sont localisés dans un environnement atypique, constitué de gènes prophagiques. La mise en évidence d'un prophage chez TVV3 a conduit à la caractérisation de phages tempérés chez dix autres souches et au séquençage du premier génome d'un bactériophage isolé d'Azospirillum. Ce travail montre que la régulation de type QS est souche spécifique et révèle la prévalence des phages chez Azospirillum.

The following study investigates the intramolecular and intermolecular interactions responsible for invoking stereoselectivity and stereospecificity in the synthesis of a chiral original species and amino acid receptor. The former commences with a brief overview of the nature, scope and applications of helical chirality, and culminates in the formation of a permanent helix via the synthesis of a novel chiral lactone. The latter is discussed as an extension of a naturally occurring cofactor whose identity is modulated to furnish a tailored receptor selective to the binding of amino-acid enantiomers. The study and analysis is executed via both synthetic and computational methods.

The following study investigates the intramolecular and intermolecular interactions responsible for invoking stereoselectivity and stereospecificity in the synthesis of a chiral original species and amino acid receptor. The former commences with a brief overview of the nature, scope and applications of helical chirality, and culminates in the formation of a permanent helix via the synthesis of a novel chiral lactone. The latter is discussed as an extension of a naturally occurring cofactor whose identity is modulated to furnish a tailored receptor selective to the binding of amino-acid enantiomers. The study and analysis is executed via both synthetic and computational methods.

Natural products continue to inspire synthetic chemists to develop novel methodologies to provide efficient and expedient syntheses of the target molecules. Haterumalide NA aroused our interest and prompted development of four differing methodologies. Three of the strategies pursued involved use of B-lactone scaffolds as intermediates. Extensions of the nucleophile catalyzed, aldol-lactonization (NCAL) reaction were also pursued and targeted toward alternative natural product targets. The reactivity of the unexpectedly stable strained spirocycle, spiroepoxy-B- lactone, was explored. Spiroepoxy-B-lactones exhibited a wide range of reactivity, but largely rearranged to tetronic acids. The desired reaction manifold remained inaccessible and led to application of the NCAL process to tetrahydrofuran-fused B-lactones. Several tetrahydrofuran-fused B-lactones were prepared, which displayed low diastereoselectivity. The diastereoselectivity could be somewhat improved in a double diastereoselective NCAL process with varied solvent systems, yet the carbocyclic analogues gave much more promising results. The use of carbocycle-fused !-lactones ultimately culminated in a double diastereoselective NCAL process, and overall led to improvements in diastereoselectivities from 1:1-2 up to >19:1. Further expansion of the substrate scope for the NCAL process was studied for application to bridged tricyclic B- lactones, access to carbocycle-fused y-lactones, and towards development of a dynamic kinetic resolution NCAL process. With our interest aimed at haterumalide NA, a modified Negishi cross coupling between zincates and dichloroolefins was also revisited. The stringent anhydrous reaction conditions led to reexamination of initial leads, which provided user-friendly anhydrous conditions by utilizing commercially available anhydrous solvent. However, application was implemented solely to a simplified model system.

L'objectif de cette étude est de synthétiser et de caractériser des polyesters entre le diméthylcétène et des composés carbonylés choisis (acétone, méthyléthylcétone et acéthaldéhyde) par deux voies distinctes : une copolymérisation directe, et une voie passant d'abord par la synthèse de la beta-lactone puis sa polymérisation par ouverture de cycle. La caractérisation a mis en évidence la structure parfaitement alternée du polyester entre le diméthylcétène et l'acétone, et des structures plus complexes avec la méthyléthylcétone et l'acétaldéhyde. Les analyses ont également montré le caractère polymorphe complexe de ces copolymères. Les trois beta-lactones correspondantes ont également été synthétisées. Seule la polymérisation de la beta-lactone avec l'acétaldéhyde a été menée à bien, du fait de son faible encombrement stérique. Enfin, une étude cinétique par infrarouge a également été effectuée et a permis de mieux connaître les cinétiques de polymérisation par ouverture de cycle.

The third generation camptothecin analog, AR-67, is undergoing early phase clinical trials as a chemotherapeutic agent. Like all camptothecins it undergoes pH dependent reversible hydrolysis between the lipophilic lactone and the hydrophilic carboxylate. The physicochemical differences between the lactone and carboxylate could potentially give rise to differences in transport across and/or entry into cells. In vitro studies indicated reduced intracellular accumulation and/or apical to basolateral transport of AR-67 lactone in P-gp and/or BCRP overexpressing MDCKII cells and increased cellular uptake of carboxylate in OATP1B1 and OATP1B3 overexpressing HeLa-pIRESneo cells. Pharmacokinetic studies were conducted in rats to study the disposition and oral bioavailability of the lactone and carboxylate and to evaluate the extent of the interaction with uptake and efflux transporters. A pharmacokinetic model accounting for interconversion in the plasma was developed and its performance evaluated through simulations and in vivo transporter inhibition studies using GF120918 and rifampin. The model predicted well the likely scenarios to be encountered clinically from pharmacogenetic differences in transporter proteins, drug-drug interactions and organ function alterations. Oral bioavailability studies showed similarity following lactone and carboxylate administration and indicated the significant role ABC transporters play in limiting the oral bioavailability.

Techn. Univ., Diss.--Berlin, 1997.

Universiẗat, Diss., 2000--Hannover.

Th.--Pharm.--Paris 5, 1979. N°: E 35.

Orientador: Anita Jocelyne Marsaioli / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-13T13:06:45Z (GMT). No. of bitstreams: 1 Pomini_ArmandoMateus_D.pdf: 4501241 bytes, checksum: 249f7514962993874b22ddcad9831cc8 (MD5) Previous issue date: 2009 / As bactérias Gram-positivas e Gram-negativas possuem um mecanismo de comunicação química intra-específico conhecido como ¿quorum-sensing¿, regulando a expressão de uma vasta gama de atividades biológicas. As bactérias Gram-negativas utilizam acil-homosserina lactonas (acil-HSLs) como principais substâncias sinalizadoras. Na presente tese, relatamos a determinação da configuração absoluta do raro metabólito (S)-(-)-N-heptanoil-HSL produzida pela bactéria fitopatogênica Pantoea ananatis. A configuração absoluta desta substância foi determinada através da técnica de cromatografia gasosa com detecção por ionização em chama com coluna quiral, através de comparações de tempo de retenção e co-injeção com padrões sintetizados. Avaliou-se também a importância da configuração absoluta para a atividade antimicrobiana de acil-HSLs contra bactérias Gram-positivas (Bacillus subtilis, Bacillus cereus e Staphylococcus aureus). Curiosamente, o enantiômero não natural (R)-N-3-oxo-octanoil-HSL foi tão ativo quanto o produto natural (S). Estudou-se também as interações da (S)-N-3-oxo-octanoil-HSL com células de Agrobacterium tumefaciens NTL4(pZLR4) através da técnica de ressonância magnética nuclear de hidrogênio por diferença de transferência de saturação (STD-RMN), revelando que o primeiro evento de interação da substância com a célula ocorre com a região lipídica da membrana celular externa. Finalmente, realizou-se o estudo químico das substâncias sinalizadoras produzidas pela bactéria Methylobacterium mesophilicum, que ocorre simbioticamente com a bactéria Xylella fastidiosa nos vasos condutores de laranjeiras atacadas pela clorose variegada dos citros. Entre os vários resultados inéditos, reportamos a caracterização e síntese do produto natural inédito (S)-N-(2E)-dodecenoil-HSL e a primeira síntese do metabólito (S)-N-(2E, 7Z)-tetradecadienil-HSL. Outrossim, reportamos a primeira caracterização da configuração absoluta de cinco acil-HSLs naturais de cadeia longa. Realizou-se também estudos relacionados aos efeitos das acil-HSLs sintéticas contra bactérias Gram-positivas endofíticas da laranjeira. Adicionalmente, caracterizou-se a secreção de defesa do opilião Hoplobunus mexicanus. O repertório de defesa deste animal é composto por dois componentes voláteis de alta irritabilidade (2,5-dimetil-fenol e 2-metil-5-etil-fenol), além da tanatose e emissão de sons, uma característica inédita em opiliões / Gram-positive and Gram-negative bacteria use quorum sensing communication circuits to regulate a diverse array of physiological activities. In general, Gram-negative bacteria use acylated homoserine lactones (acyl-HSLs) as autoinducers, and Gram-positive bacteria use processed oligo-peptides. In the present work, we relate the absolute configuration determination of the rare metabolite (S)-(-)-N-heptanoyl-HSL produced by the phytopathogen Pantoea ananatis. The absolute configuration was determined by gas chromatography coupled to flame ionization detection with chiral column, through retention time comparison and co-injections with synthetic products. The importance of the absolute configuration for the antimicrobial activity of acyl-HSL against Gram-positive bacteria (Bacillus subtilis, Bacillus cereus and Staphylococcus aureus) was assessed. Curiously, non-natural (R)-N-3-oxo-octanoyl-HSL was as active as the natural product with (S) absolute configuration. The interaction of (S)-N-3-oxo-octanoil-HSL with Agrobacterium tumefaciens NTL4(pZLR4) cells was further studied using hydrogen nuclear magnetic resonance experiments with saturation transfer difference (STD-NMR) revealing that the first binding event is the diffusion through the lipidic part of the outer membrane. Finally, we have investigated the chemical study of the signaling substances produced by Methylobacterium mesophilicum, which co-occurs with Xylella fastidiosa in orange trees affected by the citrus variegated chlorosis disease. Among several results, we report herein the characterization and synthesis of a new natural product [(S)-N-(2E)-dodecenoyl-HSL], the first synthetic procedure for the rare (S)-N-(2E,7Z)-tetradecadienyl-HSL and the occurrence of a rare long, odd chain representative (N-tridecanoyl-HSL) in trace amounts. We report the first absolute configuration determination for five natural acyl-HSLs. We have also studied the effects of synthetic acyl-HSLs on Gram positive bacteria isolated from orange tissues. Additionally, the defensive secretion produced by the harvestman Hoplobunus mexicanus was characterized. The defensive repertory of this arachnid includes two irritating and volatile components (2,5-dimethyl-phenol and 2-methyl-5-ethyl-phenol), besides thanatosis and sound emission, a new behavioral artifice in opilionids / Doutorado / Quimica Organica / Doutor em Ciências