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Lors de ces travaux de thèse, nous nous sommes intéressés à de nouveaux développements méthodologiques en cycloaddition 1,3-dipolaire de nitrones suivant deux axes principaux :<br />• l'étude de la réactivité des N-alcényloxazolidin-2-ones en tant que nouveaux dipolarophiles aza-substitués en cycloaddition 1,3-dipolaire à demande inverse vis-à-vis de nitrones.<br />• la mise en jeu de nitrones aspartiques originales en cycloaddition vis-à-vis de différents alcènes pour fournir des précurseurs d'aspartates α-substitués par une chaîne fonctionnelle.<br />Dans un premier temps, nous avons mis au point deux méthodes inspirées de celles de la littérature en partant d'une oxazolidin-2-ones pour synthétiser les N-alcényloxazolidin-2-ones: (i) vinylation cupro-catalysée utilisant un bromure d'alcényle, (ii) condensation avec un aldéhyde. Ces méthodes simples, générales, directes et à hauts rendements nous ont permis d'accéder aux N-alcényloxazolidin-2-ones de structure diverse.<br />Ces N-alcényloxazolidin-2-ones ont montré une grande réactivité en tant que dipolarophile vis-à-vis de diverses nitrones dans différentes conditions : thermiques (avec/sans solvant) et promues par TMSOTf. Les 5-aza-isoxazolidines diversement substituées originales ont été obtenues avec des rendements élevés mais de faibles stéréosélectivités. Cette limitation − due à l'instabilité configurationnelle des nitrones activées et à la flexibilité conformationnelle des N-alcényloxazolidin-2-ones − a été résolue par utilisation de la nitrone chirale à géométrie fixe de Tamura : les adduits trans-β sont obtenus avec d'excellents sélectivités<br />La tranformation des adduits issus de la N-benzyl-α-carbonyloxyéthylnitrone en dérivés aspartates carboxy-différenciés a été ensuite étudiée par une séquence en deux étapes (i) ouverture du cycle isoxazolidinique en aspartimide via N-quaternarisation par benzylation (ii) attaque chimiosélective d'un hétéronucléophile sur la fonction amide. Les aspartates carboxy-différenciés ont été obtenus avec de bons rendements, des excès énantiomériques élevés en version non-racémique, et un grand degré de diversité fontionnelle en ω (ester, amide, acide).<br />L'étude a été étendu à la cycloaddition 1,3-dipolaire des N-vinyloxazolidin-2-ones β,β-difluorées originales avec la N-benzyl-α-carbonyloxyéthylnitrone : les 4,4-difluoro-5-aza-isoxazolidines sont obtenues avec de bons rendements malgré une faible stéréosélectivité probablement due à un mécanisme non-concerté.<br />Notre étude a été complétée par l'accès à des dérivés d'α-aminoacides α,α-disubstitués via cycloaddition 1,3-dipolaire mettant en jeu de nouvelles nitrones aspartiques d'une stablilité configurationnelle inédite. Ce type de nitrones − préparé facilement par addition d'une N-benzylhydroxylamine sur un acétylènedicarboxylate – a montré une grande réactivité vis-à-vis d'une large gamme d'alcènes de différents natures électroniques. Les adduits issus des éthers vinyliques ont été obtenus avec de hauts sélectivités trans. L'extension asymétrique utilisant soit un éther vinylique chiral , soit une nitrone chirale a été effectuée et a permis l'obtention facile des adduits diastéréomériquement enrichis. A partie de ces adduits, un premier accès réussi aux dérivés aminoacides α,α-disubstitués a été réalisé en trois étapes. La diversification de cette méthodologie a été effectuée en utilisant une nitrone aspartique carboxy-différenciée.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2018-07-27T14:20:48Z No. of bitstreams: 2 Dissertação - Aleckson Souto Silva - 2018.pdf: 4136117 bytes, checksum: 733a03156cbc3f72a6ac8bc4daff6b54 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2018-07-27T14:36:23Z (GMT) No. of bitstreams: 2 Dissertação - Aleckson Souto Silva - 2018.pdf: 4136117 bytes, checksum: 733a03156cbc3f72a6ac8bc4daff6b54 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-07-27T14:36:23Z (GMT). No. of bitstreams: 2 Dissertação - Aleckson Souto Silva - 2018.pdf: 4136117 bytes, checksum: 733a03156cbc3f72a6ac8bc4daff6b54 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2018-06-18 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / The present work aims to the development of voltammetric sensors based on α-Ni(OH) 2 /GO and α- Ni(OH) 2 /rGO nanocomposites for detection and determination of uric acid, paracetamol and ascorbic acid by differential pulse voltammetry. For this, nanostructured nickel hydroxide stabilized in the alpha polymorphic form associated with graphene oxide (GO) or reduced graphene oxide (rGO) were synthesized and characterized. The method used for synthesis of α- Ni(OH) 2 was Tower’s modified, for oxidized graphite was that of Hummers and reduced graphene oxide was that of Stankovich. X-ray diffractometry, confocal Raman spectroscopy, cyclic voltammetry, transmission electron microscopy, infrared spectroscopy and thermogravimetric analysis were used to characterize the synthesized nanomaterials. The presence of graphene oxide and reduced graphene oxide with nickel hydroxide was confirmed by the results. The nickel hydroxide/graphene composites arouse great interest for the development of electrochemical sensors due to their good cost-effectiveness, biocompatibility and high catalytic effect. The thin films of α-Ni(OH) 2 /GO and α-Ni(OH) 2 /rGO showed better electrical properties compared to thin film of α-Ni (OH) 2 and it can be attributed to the increase in surface area and electrical conductivity. Through the differential pulse voltammetry, α-Ni(OH) 2 /GO and α-Ni(OH) 2 /rGO films presented good linear relationship between peak current and uric acid, ascorbic acid and paracetamol concentrations in the range concentration of 0.099 mmol.L -1 – 1.38 mmol.L -1 , with linear coefficients higher than 0.993 and detection limit lower than 2,645x10 -5 mol.L -1 for uric acid, 2,080x10 -5 mol. L -1 for ascorbic acid and 4.248x10 -5 mol. L -1 for paracetamol. / Este trabalho tem como objetivo o desenvolvimento de sensores voltamétricos baseados em nanocompósitos de α-Ni(OH) 2 /GO e α-Ni(OH) 2 /rGO para detecção e determinação de ácido úrico, paracetamol e ácido ascórbico através da voltametria de pulso diferencial. Para isso, hidróxido de níquel nanoestruturado e estabilizado na fase polimórfica alfa associado a óxido de grafeno (GO)ou óxido de grafeno reduzido (rGO) foram sintetizados e caracterizados. O método utilizado para a síntese do α-Ni(OH) 2 foi o de Tower modificado, o óxido de grafeno foi o de Hummers e o óxido de grafeno reduzido foi o de Stankovich. Para a caracterização dos nanomateriais sintetizados foram empregados a difratometria de raios-X, espectroscopia Raman confocal, voltametria cíclica, microscopia eletrônica de transmissão, espectroscopia no infravermelho e análises termogravimétricas. Sendo confirmados através dos resultados a presença de óxido de grafeno e óxido de grafeno reduzido junto ao hidróxido de níquel. Os compósitos de hidróxido de níquel/grafeno despertam grande interesse para o desenvolvimento de sensores eletroquímicos, devido a sua boa relação custo-benefício, biocompatibilidade e alto efeito catalítico. Os filmes finos de α-Ni(OH) 2 /GO e α-Ni(OH) 2 /rGO apontaram melhores propriedades elétricas compara ao filme fino de α-Ni(OH) 2 podendo ser atribuído ao aumento da área superficial e aumento da condutividade elétrica. Através da voltametria de pulso diferencial os filmes α-Ni(OH) 2 /GO e α- Ni(OH) 2 /rGO apresentaram boa relação linear entre a corrente de pico e a concentração de ácido úrico, ácido ascórbico e paracetamol na faixa de concentração de 0,099 mmol.L -1 – 1,38 mmol.L -1 , com coeficientes lineares superiores a 0,993 e limite de detecção inferiores a 2,645x10 -5 mol.L -1 para o ácido úrico, 2,080x10 -5 mol.L -1 para o ácido ascórbico e 4,288x10 -5 para o paracetamol.

京都大学 / 0048 / 新制・論文博士 / 博士(理学) / 乙第13190号 / 論理博第1558号 / 新制||理||1635(附属図書館) / (主査)教授 丸岡 啓二, 教授 大須賀 篤弘, 教授 依光 英樹 / 学位規則第4条第2項該当 / Doctor of Science / Kyoto University / DGAM

Aicardi-Goutières syndrome (AGS) is a rare inflammatory encephalopathy mimicking in utero acquired viral infection. Cardinal findings comprise leukodystrophy, basal ganglia calcifications and cerebral atrophy along with cerebrospinal fluid lymphocytosis and elevated interferon-α. In the majority of cases AGS is inherited as an autosomal recessive trait and caused by mutations in six genes including RNASEH2A, RNASEH2B, RNASEH2C, TREX1, SAMHD1 and ADAR1, all of which encode enzymes acting on nucleic acid species. Most patients present with first neurological signs in early infancy and experience severe global developmental delay. Here, we report on the unusual divergent phenotype of two siblings who both carry the most frequent AGS causing p.A177T (c.529G > A) RNASEH2B mutation in the homozygous state. While one sibling showed a typical AGS presentation with early onset and severe statomotor and mental impairment, the older sibling was intellectually completely normal. She was only diagnosed because of mild spasticity of the legs and serological signs of autoimmunity. These findings highlight the phenotypic variability of AGS and suggest that AGS may be underdiagnosed among children with mild cerebral palsy.

Rhododendron tomentosum is an evergreen shrub with a high content of secondary metabolites, particularly essential oils with antimicrobial effects. Diversity of endophytic fungi in this species and their possible adaptation to growth in the essential oil environment is not much explored. Therefore, the first aim of this thesis was to reveal the diversity of endophytic fungi colonising leaves of R. tomentosum on seven localities in the Czech Republic and one in Estonia. I isolated and determined (using comparison of ITS1 and ITS2 rDNA with the sequences from GenBank and morphological signs) 37 species of endophytic fungi. Among them the ubiquitous species colonising the most of the plants as endophytes were dominant. The second aim of my thesis was to explore whether the essential oil from R. tomentosum influences its endophytic fungi. The hypothesis that the strains obtained from R. tomentosum would be adapted to growth in the environment of the essential oil was postulated. I supposed that they would grow better on mediums with different concentrations of these chemical compounds added, in comparison with strains of the same species obtained from different substrates. Within four of seven species tested, the strains obtained from R. tomentosum grew better, but also on the medium without the...

First part is focused on finding suitable reaction conditions for organocatalytic domino Michael/Michael reaction of ethyl (E)-3-(2-thiophenyl)acrylate with α,β-unsaturated aldehydes. Second part deals with the preparation of pyrazolone derivatives from commercially available compounds and describes effects of various substituents in α-position on chemical efficiency and stereoselectivity of amination with azodicarboxylate catalyzed by quinine.

Au cours de ces travaux nous nous sommes intéressés au développement de nouvelles transformations énantiosélectives combinant les outils modernes de la synthèse organique que sont les « Multiples Bond-Forming Transformations » et l'organocatalyse afin de synthétiser des molécules d'intérêt structural et biologique. Dans ce contexte, nous avons d'abord mis au point deux nouvelles réactions domino initiées par une addition de Michael. La première, une cascade addition de Michael-acylation, permet la synthèse de spiroglutarimides optiquement actifs à partir de β-cétoamides et de nouveaux bis-électrophiles, les cyanures d'acyle α,β-insaturés. La deuxième, une réaction domino addition de Michaelhémiacétalisation- hémiaminalisation, permet la synthèse de d'hétérocycles azotés à sept chaînons à partir d'α-cétoamides comme nouveaux bis-nucléophiles. / This work focused on the development of novel enantioselective transformations combining Multiples Bond-Forming Transformations and organocatalysis which are modern tools of organic synthesis in order to synthetize molecules of structural and biological interests. In this context, we developed two new Michael addition initiated domino reactions. The first one, a domino Michael addition-acylation, allows the synthesis of optically active spiroglutarimides starting from β-ketoamides and α,β-unsaturated acyles cyanides as new biselectrophiles.The second one, a domino Michael addition-hemiaminalizationhemiacetalization, allows the synthesis of seven-membered aza-cycles using α-ketoamides as new bis-nucleophiles.

Submitted by Angela Maria de Oliveira (amolivei@uepg.br) on 2018-04-20T12:04:40Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Karla Miky.pdf: 833137 bytes, checksum: 4aac692850a86aaeabe93d6bbcf5af02 (MD5) / Made available in DSpace on 2018-04-20T12:04:40Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Karla Miky.pdf: 833137 bytes, checksum: 4aac692850a86aaeabe93d6bbcf5af02 (MD5) Previous issue date: 2018-03-09 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O óleo de linhaça tem se destacado como alimento funcional para humanos, sendo a fonte mais rica de ácido graxo α-linolênico. Quatro dietas isentas de farinha de peixe foram formuladas para serem isoproteicas (321,2 g/kg de proteína brua), isocalóricas (17,1 Mcal/kg de energia bruta) e isolipídicas (73,1 g/kg de lipídios totais), contendo duas fontes de óleos vegetais (óleo de soja ou óleo de linhaça) suplementadas em dois níveis (15 ou 30 g / kg). Foram distribuídos ao acaso 144 peixes (1076,3 ± 37,2 g) em esquema fatorial 2x2, em 12 gaiolas flutuantes de 1000 L cada, alimentadas manualmente até saciedade aparente. Observou-se maior aumento de peso, consumo de ração e melhor conversão alimentar em peixes alimentados com 30 g/kg de óleo de linhaça em comparação com peixes alimentados com 15 e 30 g/kg de óleo de soja. O rendimento de filé foi maior em peixes alimentados com 30 g/kg de óleo de linhaça em relação aos peixes alimentados com 30 g/kg de óleo de soja. Não foram observadas diferenças no peso corporal inicial, índice hepatosomático e composição próxima dos filés. Peixes alimentados com 30 g/kg de óleo de linhaça apresentaram maior teor de 18: 3 n-3 e menor teor de 18:2n-6 nos filés em comparação com peixes alimentados com 15 e 30 g/kg de óleo de soja. As maiores somas de SFA, MUFA e AG n-3 foram observados em filés de peixes alimentados com 15 g/kg de óleo de soja. Peixes alimentados com 30 g/kg de óleo de linhaça apresentaram maiores somas de ácidos graxos PUFA e de ácidos graxos n-3 nos filés. Filés de peixes alimentados com óleo de linhaça apresentaram menor relação de ácidos graxos n-6/n-3 em comparação com peixes alimentados com óleo de soja. A cor, capacidade de retenção de água, pH e a dureza dos filés não foram afetados. A adesividade dos filés analisada um e sete dias pós mortem foi maior em peixes alimentados com óleo de linhaça, enquanto observou-se menor mastigabilidade em filés de peixes alimentados com 30 g/kg de óleo de soja e de linhaça em relação aos peixes alimentados com 15 g/kg de óleo de soja e linhaça. Em conclusão, o óleo de linhaça demonstrou ser um alimento funcional como fonte de AG α-linolênico e para aumentar a relação de ácidos graxos n-6/n-3 nos filés. Além disso, recomenda-se 30 g/kg de óleo de 8 linhaça em dietas de terminação para melhorar o desempenho produtivo de tilápias do Nilo em terminação. / Linseed oil has emerging as functional food for human being one richest source of α-linolenic fatty acid. Four fishmeal-free diets were formulated to be isonitrogenous (321.2 g/kg of crude protein), isocaloric (17.1 Mcal/kg of gross energy) and isolipidic (73.1 g/kg of total lipids), containing two sources of vegetable oils (soybean oil or linseed oil) supplemented at two levels (15 or 30 g/kg). A hundred and forty-four fish (1076.3 ± 37.2 g) were distributed in a completely randomized in a 2x2 factorial scheme, into twelve 1000 L each floating cage, hand fed until apparent satiety and reared at 18 to 24 oC, during 6 wk. Higher weight gain, feed intake and improved feed conversion ratio were observed in fish fed 30 g/kg of linseed oil compared to fish fed 15 and 30 g/kg of soybean oil. Fillet yield of fish fed 30 g/kg of linseed oil was higher compared to observed in fish fed 30 g/kg of soybean oil. No differences on initial body weight, hepatosomatic index and proximate composition of fillets were observed. Fish fed 30 g/kg of linseed oil showed higher 18:3 n-3 and lower 18:2 n-6 content in the fillets compared to fish fed 15 and 30 g/kg of soybean oil. Higher sum of SFA, MUFA and n-3 FA were observed in fillets of fish fed 15 g/kg of soybean oil. Fish fed 30 g/kg of linseed oil showed higher sum of PUFA and sum of n-3 fatty acids in the fillets. Fillet of fish fed linseed oil showed lower ratio of n-6/n-3 fatty acids compared to fish fed soybean oil. Color, water holding capacity, pH and hardness of fillets were not affected. The adhesiveness of fillets analyzed at one and seven days post-mortem was increased in fish fed linseed oil, while lower chewiness was observed in fillet of fish fed 30 g/kg of soybean or linseed oil compared to observed in fish fed 15 g/kg of soybean or linseel oil. In conclusion, linseed oil was demonstrated to be functional food as α-linolenic source to enhance n-6/n-3 ratio of the fillets. In addition, linseed oil at 30 g/kg is recommended in finishing diets