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Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2013-10-15T17:14:57Z No. of bitstreams: 1 Gustavo Santos. Padronização de condições experimentais.2011.pdf: 3612850 bytes, checksum: 6681f5cbe674b715c7de996edc26d29d (MD5) / Made available in DSpace on 2013-10-15T17:14:57Z (GMT). No. of bitstreams: 1 Gustavo Santos. Padronização de condições experimentais.2011.pdf: 3612850 bytes, checksum: 6681f5cbe674b715c7de996edc26d29d (MD5) Previous issue date: 2011 / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / O protozoário, Entamoeba histolytica, constitui a etiologia de milhares de óbitos anuais e, em muitos casos, a falta de saneamento, o grau de instrução e a falta de higiene da população podem favorecer a transmissão e a manutenção desses patógenos em uma comunidade. Por causar tantas mortes e problemas na saúde pública trabalhos que facilitem o estudo deste parasito fazem-se importantes. Uma vez que a padronização de cultivo de E. histolytica em placas de poços vai Existem indicações que mostram que este parasito pode se tornar resistente ao medicamento utilizado no tratamento desta protozoose, por isso, a busca por novas substâncias que possam atuar como tratamento alternativo é de suma importância. Portanto, o objetivo do presente trabalho foi otimizar e padronizar o cultivo e a contagem deste parasito in vitro, além de identificar substâncias com potencial amebicida, que possam ser utilizadas no futuro como fármacos no tratamento da amebíase, sugerindo também uma via possível de ação das substâncias que apresentaram os melhores efeitos. Para tanto, os trofozoítos foram cultivados em placas de 24 poços sobre diferentes condições, quatro métodos de contagem de células foram comparados e 74 (setenta e quatro) substâncias foram testadas. Destas 13 (treze) apresentaram uma inibição na proliferação axênica dos trofozoítos de cerca de 70%. Destas, três compostos foram estudados em mais detalhes, os mesoiônicos derivados da piperina (as MII, MVI e MIX). Estas substâncias pertencem ao grupo dos compostos mesoiônicos, substâncias formadas por um anel heteroatômico composto por nitrogênio, carbono e enxofre, capazes de atravessar membranas e interagir com biomoléculas. Além disso, alguns mesoiônicos são doadores de radicais NO e tais grupamentos são capazes de induzir uma morte celular semelhante à apoptose em E. histolytica, como sugerido pela expressão de fosfatidil-serina revelada por anexina-V. Confirmando os resultados descritos na literatura, estas substâncias foram capazes de induzir uma morte programada, porém observações da ultra-estrutura, tais como figuras de mielina, das células tratadas apontaram para autofagia que também foi evidenciada por testes com MDC gerando apoptose tipo II, que pode ser iniciada pela presença de ROS, que neste caso foram por DCFDA. / The protozoan parasite, Entamoeba histolytica, is the etiology of thousands of deaths annually and in many cases lack of sanitation, education level and poor hygiene of the population may facilitate the transmission and maintenance of these pathogens in a community. There are indications showing that this parasite may become resistant to the drug used in treatment of protozoal disease, so the search for new substances that can act as an alternative treatment is of paramount importance. Therefore, the aim of this study was to optimize and standardize the cultivation and enumeration of this parasite in vitro, and identify substances with potential amebicidal, which can be used in future as drugs for the treatment of amoebiasis, suggesting a possible route of action of the compounds that showed the greatest effects. For this purpose, trophozoites were cultured in 24-well plates under different conditions, four methods of cell count were compared and 74 (seventy four) substances were tested. Of these thirteen (13) showed an inhibition in the proliferation of axenic trophozoites of about 70%. Of these, three compounds were studied in more detail, the mesoionic derivatives of piperine (the MII, MVI and MIX). These substances belong to the group of mesoionic compounds, formed by a heteroatomic ring composed of nitrogen, carbon and sulfur, able to traverse membranes and interact with biomolecules. Moreover, some donors are mesoionic radicals NO and such groups are able to induce a cell death similar to apoptosis in E. histolytica, as suggested by the expression of phosphatidyl-serine revealed by annexin-V. Confirming the results described in the literature, these substances were capable to inducing a programmed death, but observations of the ultra-structure, such as myelin figures, treated cells pointed out that autophagy was also evidenced by tests with MDC generating apoptosis type II can be initiated by the presence of ROS, which in this case were by DCFDA.

Submitted by Maike Costa (maiksebas@gmail.com) on 2017-06-20T14:41:46Z No. of bitstreams: 1 arquivototal.pdf: 4206052 bytes, checksum: 763f7d238671bd04ad2fa14a2f8e48c0 (MD5) / Made available in DSpace on 2017-06-20T14:41:46Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 4206052 bytes, checksum: 763f7d238671bd04ad2fa14a2f8e48c0 (MD5) Previous issue date: 2017-07-08 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The mesoionic compounds comprise a class of heterocycles with wide range of biological and technological applications. Despite many theoretical and experimental studies, some of their properties are still controversial or poorly understood; in particular: charge distribution, the nature of the chemical bonds in the mesoionic ring and the noncovalent interactions in mesoionic complexes. In this work, we sought to clarify these issues through the theoreticalcomputational study of 54 mesoionic compounds and 12 combinations of dimers. Compounds belonging to the 1,3-oxazol-5-one; 1,3-diazole-4-thione and 1,3-thiazole-5-thione rings have been evaluated by a combination of topological methods and charge models. Atomic, bond and ring properties and interactions in mesoionic dimers have been assessed. Results showed that the ring electron density and ring Laplacian were restricted to characteristic range of values for each group studied, which allows us the ring identification using those properties. The bond properties confirmed a prevalance of shared interactions in the mesoionic ring bonds, but with important charge transfers and significant and heterogeous π contribution. When individual atoms were considered, the different charge models exhibited similar qualitative results, but none of them agreed with existing mesoionic definitions. On the other hand, when net charges were considered in rings and fragments, the different models showed large differences and only one of them (QTAIM) agreed with one of the mesoionic definitions. Hence, it is unclear which of the charge models is the most suitable for these compounds. The assessment of mesoionic complexes revealed that interactions in dimers are favored at antiparallel orientations and in the presence of aromatic substituents, that suggests that charge separation and the groups bonded to the ring are paramount in those interactions. Finally, it is concluded that classical mesoionic models do not satisfactorily describe either the charge distribution or the π character of bonds in mesoionic rings. / Os compostos mesoiônicos constituem uma classe de heterociclos com ampla variedade de aplicações biológicas e tecnológicas. Apesar dos vários estudos teóricos e experimentais, algumas de suas propriedades são controversas ou mal compreendidas; em particular: a distribuição de carga, a natureza das ligações químicas no anel mesoiônico e as interações não covalentes em complexos de mesoiônicos. Neste trabalho, buscou-se elucidar esses pontos através do estudo teórico-computacional de 54 compostos mesoiônicos e 12 combinações de dímeros. Compostos das classes 1,3-oxazólio-5-ona; 1,3-diazólio-4-tiona e 1,3-tiazólio-5- tiona foram avaliados através de uma combinação de métodos topológicos e modelos de carga. Propriedades atômicas, de ligação, de anel e interações em dímeros de mesoiônicos foram avaliadas. Os resultados mostraram que a densidade eletrônica e o laplaciano de anel restringiram-se a faixas de valores características para cada grupo estudado, permitindo a identificação do tipo de anel através dessas propriedades. As propriedades de ligação apontaram uma prevalência de interações compartilhadas nas ligações do anel mesoiônico, mas com importante transferência de carga e uma contribuição significativa e heterogênea de caráter π. Considerando átomos individuais, os diferentes modelos de carga apresentaram resultados qualitativos similares, mas nenhum dos modelos corroborou as definições existentes de mesoiônicos quanto à carga. Por outro lado, quando cargas líquidas de anel e de fragmentos foram consideradas, os diferentes modelos apresentaram grandes discrepâncias e apenas um deles (QTAIM) mostrou-se de acordo com uma das definições de mesoiônicos. A avaliação dos complexos de mesoiônicos revelou que as interações em dímeros são favorecidas em orientações antiparalelas e na presença de substituintes aromáticos, sugerindo que a separação de cargas e os grupos ligados ao anel são fundamentais nessas interações. Por fim, conclui-se que os modelos clássicos de mesoiônico não descrevem de forma satisfatória nem a distribuição de carga nem o caráter π das ligações dos anéis mesoiônicos.

Made available in DSpace on 2015-05-14T13:21:22Z (GMT). No. of bitstreams: 1 ArquivoTotalLucinez.pdf: 2070839 bytes, checksum: 3d56c7860a648e855f328fcab8ae6afb (MD5) Previous issue date: 2013-05-27 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The mesoionic compounds can not be represented by a purely ionic or covalent structure. Are neutral compounds that have well-separated regions of positive and negative charges, leading to a high dipole moment. They show wide range of applications, through biology and medicinal chemistry, as well in the obtaining products of technological interest. In this study, the stability and diradicalar character of four mesoionic rings were investigated: 1,3-oxazol-5- one, 1,3-oxazol-5-thione, 1,3-thiazol-5-one and 1,3-thiazol-5-thione. Many criteria to quantify the diradicalar character were used: (I) HOMO-LUMO energy difference (EHL, inversely proportional to the diradicalar character; EHL = 0 corresponding to a pure diradical), (ii) determination of the energy difference due to the broken symmetry in the unrestricted formalism (ESS), (iii) determination of the energy difference between the singlet and triplet wave functions (EST); and (iv) diradicalar character (Y0, calculated from the occupation numbers n of HOMO and LUMO natural orbitals, in the unrestricted formalism). Various methods of electronic structure (DFT/B3LYP, MP2, CCSD and QCISD) with different basis sets (6-311+ G* and aug-cc-pVDZ) were employed. It was observed that: (i) a suitable choice of the substituent at R position (the outer ring) is important for the structural stability; (ii) substitution of oxygen by sulfur in the R and R positions (into the ring) do a little contribution for the diradicalar character (Y0 < 1% in all cases, indicating pronounced mesoionic character in the investigated structures); and (iii) the use of an electron donating group at R position and an electron withdrawing group at R position contribute to maximize the mesoionic character. Thus, it was possible to describe the dependencies of the molecular structure on the electronic properties, and the effect of substitutions, which is of great importance for the control of mesoionic character. / Os compostos mesoiônicos não podem ser representados por uma estrutura totalmente covalente ou puramente iônica. São compostos neutros que possuem regiões bem separadas de cargas positiva e negativa, conferindo-lhes elevado momento de dipolo. Apresentam faixa ampla de aplicações, passando pela biologia e a química medicinal, bem como na obtenção de produtos de interesse tecnológico. Neste trabalho, investigou-se o caráter dirradicalar de quatro anéis mesoiônicos: 1,3-oxazol-5-ona, 1,3- oxazol-5-tiona, 1,3-tiazol-5-ona e 1,3-tiazol-5-tiona, procurando a melhor representação eletrônica, e como a reatividade influencia no tipo de reação em que participam. Foram utilizados diferentes critérios para a quantificação do caráter dirradicalar: (i) diferença de energia HOMO-LUMO (EHL, inversamente proporcional ao caráter dirradicalar; EHL = 0 correspondendo a um dirradical puro); (ii) determinação da diferença de energia devida à quebra de simetria no formalismo irrestrito (ESS); (iii) determinação da diferença de energia entre as funções de onda singleto e tripleto (EST); e (iv) caráter dirradicalar (Y0, calculado a partir dos números de ocupação n dos orbitais naturais HOMO e LUMO, determinados no formalismo irrestrito). Foram empregados diversos métodos de estrutura eletrônica (DFT/B3LYP, MP2, CCSD e QCISD) com diferentes conjuntos de bases (6-311+G* e aug-cc-pVDZ). Observou-se que: (i) a escolha adequada do substituinte na posição R (externa ao anel) é importante para a estabilidade estrutural; (ii) a substituição do oxigênio por enxofre nas posições R e R (no anel) pouco contribui para o caráter dirradicalar (Y0 < 1% em todos os casos, indicando caráter mesoiônico pronunciado nas estruturas investigadas); e (iii) a utilização de um grupo doador de elétrons na posição R e retirador na R contribui para maximizar o caráter mesoiônico. Dessa forma, foi possível descrever as dependências da estrutura molecular sobre as propriedades eletrônicas, e o efeito das substituições, que é relevante para o controle do caráter mesoiônico.

Submitted by Maria Medeiros (maria.dilva1@ufcg.edu.br) on 2018-09-27T14:29:18Z No. of bitstreams: 1 RAILDA SHELSEA TAVEIRA ROCHA DO NASCIMENTO - TESE (PPGEP) 2008.pdf: 2253809 bytes, checksum: ec04359cafb5760ae50bf56746b420d4 (MD5) / Made available in DSpace on 2018-09-27T14:29:18Z (GMT). No. of bitstreams: 1 RAILDA SHELSEA TAVEIRA ROCHA DO NASCIMENTO - TESE (PPGEP) 2008.pdf: 2253809 bytes, checksum: ec04359cafb5760ae50bf56746b420d4 (MD5) Previous issue date: 2008-11-17 / Sólidos obtidos em escala nanométrica têm demandado um grande interesse científico e tecnológico, dadas às significativas alterações nas propriedades físicas e químicas observadas em materiais com estas características, potencializando assim as aplicações tecnológicas. Neste trabalho foram sintetizados quatro nanocomplexos do tipo Ln(MI)3.3H2O onde, Ln = Er ou Eu e MI = 5(4-clorofenil)-3-fenil-1,3,4-tiodiazólio-2-tiolato (MI-1) ou 5(4-clorofenil)-3-metil-4-fenil-1,3-tioazólio-2-tiolato (MI-2). Estes complexos foram caracterizados através de técnicas físico-químicas, espectroscópicas, térmicas e estrutural. A metodologia utilizada para a síntese dos complexos partiu de uma solução etanólica de LnCl3 adicionando-se o mesoiônico, sob agitação e temperatura constante de 65oC, mantendo em refluxo por quatro horas. O resultado da análise elementar de C, H e N dos complexos Er(MI-1)3.3H2O, Eu(MI-1)3.3H2O, Er(MI-2)3.3H2O e Eu(MI-2)3.3H2O mostraram uma boa concordância entre os valores experimentais e os calculados. Os espectros de infravermelho indicam que a coordenação dos compostos mesoiônicos com os cátions Eu+3 e Er+3 acontece possivelmente através do átomo de enxofre exocíclico onde, pode-se perceber um deslocamento considerável na ligação carbono-enxofre (C-S-). Os espectros de RMN 1H dos complexos revelaram a presença de todos os sinais dos hidrogênios aromáticos, evidenciados nos compostos mesoiônicos. Através dos espectros de RMN 13C (APT), foi possível reconhecer o padrão de hidrogenação correspondente a cada átomo de carbono, possibilitando atribuir com segurança o deslocamento químico dos carbonos (C-2) e (C-5) do anel mesoiônico. Nos espectros de absorção na região do UV-visível as bandas dos complexos se deslocam quando comparadas às bandas dos compostos mesoiônicos, sendo possível atribuir a inserção dos cátions de lantanídeos à modificação das bandas de absorção, visto que os complexos apresentaram energias em comprimento inferior. Os espectros de emissão dos compostos MI-1 e MI-2 assim como os dos complexos Eu(MI-1)3.3H2O e Er(MI-2)3.3H2O apresentaram comportamento semelhante com uma banda larga de emissão entre 560 e 720 nm, não sendo possível a observação das bandas de emissão dos íons lantanídeo. As curvas TG/DTG indicaram que os compostos mesoiônicos se decompuseram em cinco etapas, diferentemente da decomposição dos complexos Er(MI-1)3.3H2O, Eu(MI-1)3.3H2O, Er(MI-2)3.3H2O e Eu(MI-2)3.3H2O que ocorreu em 5, 4, 7 e 6 etapas, respectivamente. Os complexos sintetizados com Eu apresentaram maior estabilidade térmica em detrimento dos complexos de Er, independente do mesoiônico utilizado. As curvas DSC, mostraram que os complexos estudados neste trabalho iniciam a reação de decomposição térmica ainda em estado sólido, antes da fusão. Os difratogramas de raios-x dos compostos mesoiônicos e dos complexos, apresentaram mais de uma fase, com características cristalinas, e cristalito inferior a 60nm. / The solids obtained in nanometric scale has been attracted the technological and scientific interest due to the significant modifications observed on their physical and chemical properties which increases the technological applications. In this work, four nanocomplex materials were synthesized: Ln(MI)3.3H2O where, Ln = Er or Eu and MI = 5(4-chlorophenyl)-3-phenyl-1,3,4-thiodiazole-2-tiolat (MI-1) or 5(4-chlorophenyl)-3-methyl-4-phenyl-1,3-thioazole-2-thiolate (MI-2). These complexes were characterized using physico-chemical, spectroscopic, thermal and structural techniques. To synthesize the complexes, it was used a LnCl3 ethanolic solution mixed with the mesoionic, maintained under agitation and at a constant temperature at 65oC and refluxed for a period of four hours. It was observed a good agreement between the experimental and calculated results of the C, H and N elemental analysis of Er(MI-1)3.3H2O, Eu(MI-1)3.3H2O, Er(MI-2)3.3H2O and Eu(MI-2)3.3H2O. The IR spectra indicates that the coordination of the mesoionic compounds with cations Eu+3 and Er+3, must happen probably because of the exocyclic sulfur atom and it can be perceived a considerable displacement in the carbon-sulfur (C-S-) ligation. The RMN 1H spectra suggested the presence of aromatic hydrogen evidenced in the mesoionic compounds. Through the RMN 13C (APT), it was possible to recognize the hydrogenation standard corresponding to each carbon atom. It can be safely attributed the carbon chemical displacement (C-2) and (C-5) of the mesoionic ring. In the UV-visible absorption spectra of the UV the complexes bands are displaced comparing to the mesoionic compound bands. It can be possible to attribute the insertion of the lanthanide cations to the modification of the absorption bands, once the complexes presented energies at inferior length. The MI-1 and MI-2 compounds emission spectra and the complexes Eu(MI-1)3.3H2O and Er(MI-2)3.3H2O presented a behavior similar to a large emission band between 560 and 720 nm. It was not possible to observe the emission bands of the lanthanide ions. The TG/DTG curves indicate that the mesoionic compounds were decomposed in five levels, with a different behavior of the Er(MI-1)3.3H2O, Eu(MI-1)3.3H2O, Er(MI-2)3.3H2O and Eu(MI-2)3.3H2O, which decomposition occurred in 5,4,7 and 6 steps, respectively. The complexes synthesized with Eu presented a higher thermal stability than the ones that used Er, independently of the kind of mesoionic compound that was used. The DSC curves showed that the studied complexes begin the thermal decomposition reaction before the fusion, in the solid state. The x-ray diffractograms of the complexes and mesoionic compounds present more than a level, with crystalline characteristics and crystallite size inferior to 60nm.

Le premier objectif de ce travail a consisté à développer la réaction CuSAC (découverte au laboratoire) pour la synthèse régiosélective de pyrazoles poly-substitués, dans un contexte de méthodologie de synthèse. Il existe de nombreux composés biologiquement actifs contenant le motif pyrazole et peu de méthodes régiosélectives décrites pour les synthétiser. Développer une nouvelle réaction pour obtenir des pyrazoles poly-substitués de façon contrôlée était donc très intéressant pour des applications synthétiques.Le deuxième objectif a été d’appliquer cette réaction à la bioconjugaison et notamment au développement de sondes profluorescentes Des coumarines-sydnones subissant un effet d’extinction de fluorescence par le phénomène PeT ont été développées. Suite au couplage avec un alcyne, le pyrazole formé n’éteint plus lafluorescence de la coumarine. Ce type de sondes est très intéressant pour le marquage de biomolécules, car il n’y a aucun parasitage de fluorescence et donc ne nécessite aucun lavage.Le troisième objectif de la thèse a été d’explorer la réactivité des composés mésoioniques pour un alcyne, sous une catalyse au cuivre, dans le but de découvrir de nouvelles réactions click. Un criblage de 24 composés dans 9 conditions de catalyses différentes, faisant plus de 200 réactions réalisées, a été effectué. Deux réactions ont été révélées, dont une très prometteuse. Celle-ci permet dans la même opération de lier deux partenaires tout en libérant un fragment d’un des deux partenaires. Cette réaction a été étudiée dans le but de développer un outil de théranostique où être utilisée pour la mise au point de nouveaux espaceurs clivables. / The first aim of this work was the development of a new regioselective synthetic access to poly-substituted pyrazoles via the CuSAC reaction, previously discovered in the laboratory. The development of new reactions leading to poly-substituted pyrazoles with a full control of regioselectivity is highly interesting for synthetic applications.The second aim of this work was the application of this reaction for the labeling of complex biomolecules. To broaden the scope of the CuSAC, fluorogenic coumarin-sydnones which undergo fluorescence extinction via PeT have been designed and synthetized. Following the coupling reaction, the newly formed pyrazole core allows huge enhancement of the fluorescence signal.This kind of probes is highly interesting in the specific labelling of biomolecules avoiding washing steps.The last project of this thesis have been focused on the discovery of new [3+2] cycloaddition reaction implying a mesoionic compound and a terminal alkyne under copper catalysis. 24 mesoionic dipoles were screened for their ability to react with a terminal alkyne in 9 different catalytic conditions, yielding to more than 200 reactions screened. Two hits were identified, one of them holding great promise. This hit allows an efficient “click and release” reaction which should find tremendous applications, especially in the fields of theranostic and cleavable linker development.

Notre laboratoire a récemment mis en évidence la réaction de cycloaddition entre les sydnones et les alcynes terminaux ou cycliques. Ces réactions sont bioorthogonales et possèdent la particularité de former deux produits : l’un provenant de la ligation (click) des deux partenaires réactionnels par cycloaddition (3+2), l’autre provenant d’un relargage (release) par réaction de rétro Diels-Alder. Le potentiel de ce type de réaction est très grand de par le nombre d’applications possibles que ce soit dans le domaine de la bioconjugaison, du marquage fluorescent ou de la libération de principes actifs.Les sydnones sont des composés hétérocycliques dipolaires qui appartiennent à la famille des mésoioniques. Cette thèse vise à découvrir de nouvelles réactions de ligation et de coupure mettant en jeu ces mésoioniques et des dipolarophiles. Vingt-cinq mésoioniques et trois familles de dipolarophiles ont été synthétisés et criblées.Lors du premier criblage, la réactivité des composés mésoioniques avec un alcyne terminal, sous une catalyse au cuivre, a été explorée. Neuf conditions de catalyse ont été testées. Ce criblage a mis en évidence la cycloaddition entre les aza-iminosydnones et les alcynes terminaux dont le produit formé dépend du système catalytique et de la nature de l’alcyne.La deuxième famille de dipolarophiles testée est celle des cycloalcynes. Nous avons découvert que, les dithiolium-olates réagissaient avec les cycloalcynes peu encombrés et que les sydnone-imines réagissent avec tous les cyloalcynes de manière bioorthogonale en libérant une molécule complexe.Enfin, les cycloalcènes ont été testés comme dipolarophiles. Dans cette partie, les résultats préliminaires du criblage nous ont amené à modifier la structure de la sydnone pour permettre la libération d’une molécule complexe. / Our laboratory has recently discovered the cycloaddition between sydnones and cyclic or terminal alkynes. These reactions are bioorthogonal and generate two products: one coming from the (3+2) cycloaddition (click) between both partners and the second from a cleavage step (release) through a retro Diels-Alder reaction. This type of new reactions would be of prime importance in the development of new reagents useful for bioconjugation and drug delivery applications.Sydnones are dipolar heterocycles belonging to the large family of compounds known as mesoionics. This work aims at discovering new chemoselective and bioorthogonal processes between mesoionic compounds and various dipolarophiles, that undergo in a same reaction both ligation and cleavage. Twenty-five mesoionics and three types of dipolarophiles were synthetized and screened.For the first screening, the reactivity between mesoionics and terminal alkyne, under a copper catalysis, was studied. Nine conditions of catalysis were tested. This screening revealed the cycloaddition between aza-iminosydnones and terminal alkynes. The structure of the formed products depends on the catalytic system and the nature of the alkyne used.The second type of dipolarophiles screened was cyclic alkynes. Dithiolium-olates were found to react with non-hindered cyclic alkynes. On the other side, imino-sydnones react with all cycloalkynes to afford a click product together with a released molecule.Finally, cycloalkenes were screened. Thanks to preliminary results from a screening, we engineered new sydnones to allow the release of a complex molecule after the cycloaddition step

Très récemment, notre équipe a mis en évidence une réaction dite de ligation et coupure entre une famille de composés mésoioniques, les sydnone-imines, et les cyclooctynes. Cette réaction bioorthogonale agit selon un processus en deux étapes, une cycloaddition [3+2] suivie d’une rétro Diels-Alder, qui génère deux nouveaux composés : un produit de ligation et un produit de coupure. L’objectif de cette thèse consiste à améliorer la cinétique de réaction entre ces deux partenaires afin de pouvoir l’utiliser en tant qu’outil pour la libération contrôlée de principes actifs in vivo.Trois stratégies ont été développées lors de cette thèse afin d’optimiser ce système réactionnel : l’étude d’une relation structure/réactivité du partenaire sydnone-imine vis-à-vis de la réaction bioorthogonale; l’utilisation de micelles constituées d’amphiphiles possédant un motif sydnone-imine en tant que lien clivable entre la partie hydrophobe et la partie hydrophile de la molécule; et enfin, l’étude de l’utilisation de la reconnaissance moléculaire entre deux brins d’acides nucléiques peptidiques (ANP) complémentaires. / Recently, our laboratory has discovered a click and release reaction involving iminosydnones, a family of mesoionic compounds, and cyclooctynes. This bioorthogonal reaction occurs via a two step process: a [3+2] cycloaddition followed by a retro Diels-Alder, to give two new compounds: a click product and a release product.The main goal of this work is to improve the kinetic of the reaction between these two partners in order to use it as a powerful tool for in vivo drug delivery. Three strategies were developed during this thesis to optimize this reaction system: the study of a structure/reactivity relationship of the iminosydnone partner regarding the bioorthogonal reaction; the development of micelles built by amphiphiles containing an iminosydnone moiety as a cleavable linker, strategically located between the hydrophobic and the hydrophilic part of the compound and finally, the use of molecular recognition between two peptide nucleic acids (PNA) complementary strands.