Nitrogen heterocycles are present in nearly 60% of all small-molecule drugs approved by the US Food and Drug Administration. New innovative methods that streamline the synthesis of such heterocycles are therefore highly desirable. The use of new or underdeveloped reactive intermediates provides an excellent opportunity to develop novel heterocyclic syntheses. For example, nitrogen-substituted isocyanates (N-isocyanates) are a class of rare amphoteric isocyanates with high, but severely underdeveloped synthetic potential. The research efforts presented in this thesis have been directed towards the use of such intermediates for the rapid construction of heterocycles using cascade reactions. Using an in situ generation approach from masked (blocked) isocyanate precursors, we were able to control the homo dimerization of these species and design several cascade reactions forming more than 10 different classes of heterocycles using appropriate nitrogen nucleophiles. Given the importance of the N-N-C=O motif in pharmaceuticals and agrochemicals, N-isocyanates provide the opportunity to synthesize highly desirable cores for different industrial applications. To illustrate the potential of this new tool in heterocyclic chemistry, more than 200 heterocycles were synthesized using this methodology. In Chapter 2, heterocycles incorporating only one atom from the N-isocyanate will be presented. More precisely, the first cascade reaction involving N-isocyanates for the rapid synthesis of saturated heterocycles will be presented. The incorporation of 2 atoms within the ring will then be discussed in Chapter 3 with the synthesis of hydantoins, imidazolones, thiazolines, pyrazoles and phthalazinones. Chapter 4 will focus on the incorporation of every atom in the heterocycle to form other bioactive cores such as azauracils, pyridazinones and azadiketopiperazines. Lastly, Chapter 5 will describe our efforts for the synthesis of acyclic molecules such as semicarbazides and aza-peptides.

Beaucoup de données infrmatiques sont structurées de manière arborescente. Dans le contexte du Web, c'est le cas en particulier des données au format XML. De par sa généricité, ce format est rapidement devenu un standard pour l'échange et la sauvegarde d'informations. A l'instar des langages de requêtes pour les bases de données relationnelles, le besoin d'avoir des langages de requêtes pour les documents XML est devenu crucial. On distingue les requêtes unaires (sélection d'un ensemble de sous-parties d'un document) des requêtes n-aires (sélection d'un ensemble de n-uplets de sous-parties d'un document). Beaucoup de formalismes logiques pour les requêtes unaires ont été étudiés, en revanche, peu d'approches logiques existent pour les requêtes n-aires. Cette thèse étudie de manière fondamentale les requêtes n-aires, en proposant et en étudiant principalement deux formalismes logiques pour requêtes n-aires: une extension du paradigme navigationnel du standard W3C XPath au cas n-aire, appelée langage de composition, et une adaptation de la logique spatiale d'arbres TQL, introduite par Cardelli et Ghelli. Les questions de pouvoir d'expressivité, de complexité d'évaluation des requêtes ainsi que leur satisfiabilité sont abordées. L'étude du problème de satisfiabilité pour la logique TQL a nécessité l'introduction de nouveaux automates d'arbres avec tests globaux, dont l'étude est réalisée de manière indépendante. / Ln computer science many data are shaped as trees. ln the context of the Web, it is the case for XML formatted data in particular. XML is a markup language that has rapidly become a standard for information storage and data exchange. As query languages for relational databases are not well-suited to XML data, the need to have query languages specific to XML documents has increased. We distinguish unary queries which select a set of subparts of a document from n-ary queries which select a set of n-tuples of subparts of a document. Many logical formalisms for unary queries have been proposed, but less work has been done on logical formalisms for n-ary queries. This thesis is a fundamental study of n-ary queries that proposes two logical formalisms for n-ary queries: an extension of the navigational paradigm of the W3C standard XPath to n-ary queries, called the composition language, and an adapation of the spatiallogie TQL introduced by Cardelli and Ghelli. The question of expressive power, the complexity of the query evaluation problem as well as the satisfiability problem are considered. ln particular, the satisfiability problem for a TQL fragment is proved to be decidable by reduction to the emptiness test of a new class of tree automata with global constraints that is studied independently.

The development of cost-effective and sustainable catalytic methods for the production of enantiomerically pure chiral amines is a key challenge facing the pharmaceutical and fine chemical industries. There is an increasing demand for broadly applicable synthetic methods which deliver the desired amine product in high yield and enantiomeric excess (e.e.). Previously we have described the development of variants of monoamine oxidase from Aspergillus niger (MAO-N) which are able to mediate the complete conversion of racemic amines to the corresponding enantiomerically pure products in a single step. In this thesis we report a panel of MAO-N variants (D5, D9 and D11) developed in our laboratory, which are able to mediate the deracemisation of primary, secondary and tertiary amines with broad structural features. In particular, we have synthesized and subjected to deracemisation a broad range of tetrahydroisoquinolines and tetrahydro-β-carbolines checking enantioselectivity and enantiopreference of our biocatalysts. A relation between lipophilicity of the substituents and enantiopreference of the enzyme has been identified. We have also engineered a new MAO-N variant (D11) with a greatly increased substrate scope and enhanced tolerance for bulky substrates. Application of this engineered biocatalyst is highlighted by the asymmetric synthesis of the generic drugs Solifenacin and Levocetirizine as well as a number of important classes of biologically active alkaloid natural products. We also report a novel MAO-N mediated asymmetric oxidative Pictet-Spengler approach to the synthesis of (R)-harmicine.Another challenge facing the chemist in the new millennium is the development of cleaner and more efficient chemical processes. To this aim the combination of two or more catalytic systems to complete a series of cascade reactions is considered particularly appealing. We have reported a concurrent redox cascade for the deracemisation of pyrrolidines and tetrahydroisoquinolines using our monoamine oxidase-N with a biotinylated Ir-complex within streptavidin (SAV). To achieve the final goal it is necessary to shield the metal inside a host to avoid the mutual inactivation of the two catalysts. We have also described the combination of MAO-N with berberine bridge enzyme (BBE) for the synthesis of berbines (tetrahydroprotoberberines), which represent a sub-class of tetrahydro-isoquinoline alkaloids found in various plants. This bi-enzymatic cascade allows the synthesis of these structures achieving a theoretical 100% yield instead of the 50% given by the kinetic resolution using BBE itself.

In many series of compounds, intensity of biological activity and chemical reactivity are proportional. Generally whenever a alkyl group replaces a reactive hydrogen atom, as would be the case for an N-substituted hydroxylamine as compared to hydroxylamine, the over-all biological activity of the resulting compound is lower than that of its nonalkylated analogue. Since toxicity and physiological activity are not proportional, this comparison can only suggest possible types of derivatives to prepare and test.

The cultural and popular media landscape of the United States of America changed after the Civil-Rights movement of the 1960s. The word “Nigger” was changed during that same period of American history. There are several authors and a comic that helped change this word during the 1960s. The post Civil-Rights American has a different experience and understanding with this word than those born before 1970. This work triangulates the current cultural location of the word “Nigger,” “nigga,” and “the n-word” using linguistics, law, and two media case studies. The “Nigger” trinity is a model that adds value to the discourse that surrounds this one word in post civil-rights/post 1960s America.

Soybean [Glycine max (L.) Merr.] biomass and yield has increased over the past several decades in the midsouthern United States; therefore, a better understanding of the nutrient requirements of the crop is needed. Nutrient uptake and partitioning in soybean is fundamental to understanding the physiology of nutrient accumulation relative to crop yield. Technological advances and improved management strategies in soybean production have contributed to significant yield increases. Research was established in 2017 and 2018 in Stoneville, MS, to evaluate soybean nutrient uptake and partitioning across multiple soybean cultivars and two planting dates. Coarse- and fine-textured soils commonly cropped in Mississippi under furrow irrigation were utilized. Soybean total aboveground biomass was collected at multiple growth stages, including V4, R2, R5.5, R6.5, and R8. At reproductive stages R5.5 to R8, soybean aboveground biomass was partitioned into senesced leaves, pods, and seeds. All biomass components were analyzed for content of primary macronutrients. Two soybean cultivars for each of four herbicide-resistant technologies were selected to represent subplot treatments. The greatest yield was produced by dicamba- and glyphosate-tolerant HT, followed by glufosinate tolerant, followed by conventional HT. Soybean planted in April produced grain yield greater than May planted soybean. Averaged across four site years, field removal of total N, P2O5, and K2O partitioned into the seed at physiological maturity was approximately 175 kg N ha-1, 33 kg P2O5 ha-1, and 120 kg K2O ha-1.

No description available.

Glycosylation O-linked β-N-acetylglucosamine (O-GlcNAc) is post-translational modification of proteins, regulated by β-N-acetylglucosaminyltransferase (OGT) and β-N-acetylglucosaminidase (OGA). This intracellular glycosylation differs from the other glycosylation types - it is dynamically regulated, similarly to phosphorylation, β-N-acetylglucosamine serves as a nutrient and stress sensor in cell. Chronically dysregulated O-linked glycosylation by GlcNAc is associated with pathology of various diseases, such as diabetes mellitus type II, oncological and neurodegenerative diseases. Expression of enzymes OGT and OGA is very sensitive for homeostasis of GlcNAc, which is the product of hexosamine biosynthetic pathway. Changes in expressions of these ezymes could be used as a potencial blood marker, e.g. in early stage of diabetes. The aim of this master thesis was to study changes in expression of genes encoding ezymes OGT and OGA in cohort of obese patients in comparison with healthy controls and also to compare the state before and after change of lifestyle (loosing weight). Analysed cohort comprised of 34 samples of isolated lymphocytes from peripheral blood from obese adolescent patients and 80 samples of adults patients. RNA was isolated by TriReagent, quantification of the expression of mRNA was...

A via oral é considerada preferencial para a administração de fármacos, sobretudo no tratamento de doenças crônicas. Entretanto, princípios ativos administrados por essa via podem apresentar biodisponibilidade variável e/ou limitada. Diversos tipos de sistemas de liberação vêm sendo desenvolvidos com o objetivo de melhorar esse parâmetro, dentre os quais se destacam as nanopartículas de poli (alquil-cianoacrilato) (PACA). Pelo exposto, no presente trabalho foram desenvolvidas nanopartículas de poli(n-butilcianoacrilato) (PBCA) contendo aciclovir (ACV), revestidas por N,N,N-trimetilquitosana (TMQ), um promissor promotor de absorção. A TMQ foi sintetizada com elevado rendimento e grau de quaternização de aproximadamente 73%. As nanopartículas de PBCA foram obtidas com rendimento adequado e apresentaram características físico-químicas semelhantes às descritas na literatura. Após o revestimento, foi observado um aumento no diâmetro médio, bem com uma inversão nos valores de potencial zeta. Essas observações podem indicar a ocorrência do revestimento. A partir das análises de DSC, pôde-se comprovar a eficiência do revestimento das nanopartículas pelo derivado sintetizado, já que o comportamento das nanopartículas de PBCA-TMQ foi diferente daquele obtido para a mistura física entre os constituintes da formulação. Nessa mesma perspectiva, análises de FTIR foram conduzidas e a ocorrência do revestimento foi corroborada. Além disso, as análises morfológicas por Microscopia de Força Atômica (AFM) revelaram que as nanopartículas revestidas apresentam baixa tendência à agregação, o que pode ser um indicativo de estabilidade para a formulação desenvolvida. Em relação aos ensaios de citotoxicidade, foi evidenciado que as nanopartículas de PBCA não apresentaram toxicidade significativa frente às células Caco-2, ao passo que a formulação revestida mostrou um efeito tóxico dose-dependente influenciado pelo grau de quaternização. Além disso, as nanopartículas desenvolvidas foram capazes de diminuir, reversivelmente, a Resistência Elétrica Transepitelial (RET) da monocamada de células. A fim de quantificar o fármaco associado às nanopartículas, foi desenvolvido e validado método analítico por espectrofotometria derivada com detecção no UV. Tal método mostrou-se capaz de eliminar a interferência dos excipientes, permitindo a quantificação do ACV na formulação de nanopartículas com precisão e exatidão adequadas. Assim, a porcentagem de fármaco associado às nanoestruturas pode ser calculada, obtendo-se um valor satisfatório. De maneira semelhante, foi desenvolvido e validado método por CLAE para a quantificação do fármaco nos ensaios de permeação. A metodologia proposta mostrou-se adequada considerando-se as recomendações da RE 899/03. Por meio dos ensaios de permeabilidade em células Caco-2, foi constatado que a formulação desenvolvida aumentou em 3 vezes o valor de Permeabilidade aparente (Papp) do fármaco em estudo. Além disso, as nanopartículas revestidas foram capazes de propiciar a liberação controlada do ACV nos ensaios de liberação in vitro utilizando meios com diferentes valores de pH (1,2; 6,8 e 7,4). / The oral route is considered for the administration of drugs, especially in the treatment of chronic diseases. However, drugs administered by this route may have variable and/or limited bioavailability. Various types of delivery systems have been developed with the goal of improving this parameter, among which stand out the nanoparticles of poly (alkylcyanoacrylate) (PACA).Such nanomaterials have been coated to improve stability in the gastrointestinal tract, promote greater solubility or enhance permeation. Therefore, in this work were developed nanoparticles of poly (n-butilcianoacrilato) (PBCA) containing acyclovir (ACV), coated with N,N,N-trimethylchitosan (TMC), a promising absorption promoter. The TMC was synthesized with high-yield and approximately 73% of quaternization. The PBCA nanoparticles presented physico-chemical characteristics similar to those described in the literature. After the coating, it was observed an increase in the average diameter, and a inversion on the values of zeta potential. These observations may indicate the occurrence of coating. DSC analysis could proved the efficiency of the coating of nanoparticles, since the behavior of nanoparticles of PBCA-TMC was different from those obtained for the physical mixture between the constituents of the formulation. In this same perspective, FTIR analyses were conducted and the occurrence of coating was corroborated. In addition, morphological analyses by Atomic Force Microscopy (AFM) showed that nanoparticles coated presented low tendency to aggregate, which can be an indication of stability for the formulation developed. In relation to cytotoxicity assays, it was evidenced that the PBCA nanoparticles showed no significant toxicity against the Caco-2 cells, whereas the coated formulation showed a dose-dependent toxic effect influenced by the degree of quaternization. In addition, the nanoparticles developed were able to decrease, reversibly, Transepitelial Electric Resistance (TEER) of the monolayer. In order to quantify the drug associated with nanoparticles, was developed and validated analytical method by derivative spectrophotometry with UV detection. This method was able to eliminate the interference of excipients, allowing the quantification of ACV in the formulation of nanoparticles with appropriate precision and accuracy. Thus, the percentage of drug associated with nanostructures can be calculated, obtaining a satisfactory value. Similarly, has been developed and validated HPLC method for the quantification of drug permeation tests. The proposed methodology was appropriate considering the recommendations of the RE 899/03. Through the permeability assays in Caco-2 cells, it has been found that the formulation developed increased by 3 times the value os Apparent Permeability (Papp) of ACV. In addition, the nanoparticles were able to provide controlled release of ACV in vitro using media with different pH values (1.2; 6.8 and 7.4).

A via oral é considerada preferencial para a administração de fármacos, sobretudo no tratamento de doenças crônicas. Entretanto, princípios ativos administrados por essa via podem apresentar biodisponibilidade variável e/ou limitada. Diversos tipos de sistemas de liberação vêm sendo desenvolvidos com o objetivo de melhorar esse parâmetro, dentre os quais se destacam as nanopartículas de poli (alquil-cianoacrilato) (PACA). Pelo exposto, no presente trabalho foram desenvolvidas nanopartículas de poli(n-butilcianoacrilato) (PBCA) contendo aciclovir (ACV), revestidas por N,N,N-trimetilquitosana (TMQ), um promissor promotor de absorção. A TMQ foi sintetizada com elevado rendimento e grau de quaternização de aproximadamente 73%. As nanopartículas de PBCA foram obtidas com rendimento adequado e apresentaram características físico-químicas semelhantes às descritas na literatura. Após o revestimento, foi observado um aumento no diâmetro médio, bem com uma inversão nos valores de potencial zeta. Essas observações podem indicar a ocorrência do revestimento. A partir das análises de DSC, pôde-se comprovar a eficiência do revestimento das nanopartículas pelo derivado sintetizado, já que o comportamento das nanopartículas de PBCA-TMQ foi diferente daquele obtido para a mistura física entre os constituintes da formulação. Nessa mesma perspectiva, análises de FTIR foram conduzidas e a ocorrência do revestimento foi corroborada. Além disso, as análises morfológicas por Microscopia de Força Atômica (AFM) revelaram que as nanopartículas revestidas apresentam baixa tendência à agregação, o que pode ser um indicativo de estabilidade para a formulação desenvolvida. Em relação aos ensaios de citotoxicidade, foi evidenciado que as nanopartículas de PBCA não apresentaram toxicidade significativa frente às células Caco-2, ao passo que a formulação revestida mostrou um efeito tóxico dose-dependente influenciado pelo grau de quaternização. Além disso, as nanopartículas desenvolvidas foram capazes de diminuir, reversivelmente, a Resistência Elétrica Transepitelial (RET) da monocamada de células. A fim de quantificar o fármaco associado às nanopartículas, foi desenvolvido e validado método analítico por espectrofotometria derivada com detecção no UV. Tal método mostrou-se capaz de eliminar a interferência dos excipientes, permitindo a quantificação do ACV na formulação de nanopartículas com precisão e exatidão adequadas. Assim, a porcentagem de fármaco associado às nanoestruturas pode ser calculada, obtendo-se um valor satisfatório. De maneira semelhante, foi desenvolvido e validado método por CLAE para a quantificação do fármaco nos ensaios de permeação. A metodologia proposta mostrou-se adequada considerando-se as recomendações da RE 899/03. Por meio dos ensaios de permeabilidade em células Caco-2, foi constatado que a formulação desenvolvida aumentou em 3 vezes o valor de Permeabilidade aparente (Papp) do fármaco em estudo. Além disso, as nanopartículas revestidas foram capazes de propiciar a liberação controlada do ACV nos ensaios de liberação in vitro utilizando meios com diferentes valores de pH (1,2; 6,8 e 7,4). / The oral route is considered for the administration of drugs, especially in the treatment of chronic diseases. However, drugs administered by this route may have variable and/or limited bioavailability. Various types of delivery systems have been developed with the goal of improving this parameter, among which stand out the nanoparticles of poly (alkylcyanoacrylate) (PACA).Such nanomaterials have been coated to improve stability in the gastrointestinal tract, promote greater solubility or enhance permeation. Therefore, in this work were developed nanoparticles of poly (n-butilcianoacrilato) (PBCA) containing acyclovir (ACV), coated with N,N,N-trimethylchitosan (TMC), a promising absorption promoter. The TMC was synthesized with high-yield and approximately 73% of quaternization. The PBCA nanoparticles presented physico-chemical characteristics similar to those described in the literature. After the coating, it was observed an increase in the average diameter, and a inversion on the values of zeta potential. These observations may indicate the occurrence of coating. DSC analysis could proved the efficiency of the coating of nanoparticles, since the behavior of nanoparticles of PBCA-TMC was different from those obtained for the physical mixture between the constituents of the formulation. In this same perspective, FTIR analyses were conducted and the occurrence of coating was corroborated. In addition, morphological analyses by Atomic Force Microscopy (AFM) showed that nanoparticles coated presented low tendency to aggregate, which can be an indication of stability for the formulation developed. In relation to cytotoxicity assays, it was evidenced that the PBCA nanoparticles showed no significant toxicity against the Caco-2 cells, whereas the coated formulation showed a dose-dependent toxic effect influenced by the degree of quaternization. In addition, the nanoparticles developed were able to decrease, reversibly, Transepitelial Electric Resistance (TEER) of the monolayer. In order to quantify the drug associated with nanoparticles, was developed and validated analytical method by derivative spectrophotometry with UV detection. This method was able to eliminate the interference of excipients, allowing the quantification of ACV in the formulation of nanoparticles with appropriate precision and accuracy. Thus, the percentage of drug associated with nanostructures can be calculated, obtaining a satisfactory value. Similarly, has been developed and validated HPLC method for the quantification of drug permeation tests. The proposed methodology was appropriate considering the recommendations of the RE 899/03. Through the permeability assays in Caco-2 cells, it has been found that the formulation developed increased by 3 times the value os Apparent Permeability (Papp) of ACV. In addition, the nanoparticles were able to provide controlled release of ACV in vitro using media with different pH values (1.2; 6.8 and 7.4).