Reproduction de : Thèse d'exercice : Médecine : Nancy 1 : 2006. / Titre provenant de l'écran-titre.

Thesis (Ph. D.)--Institute of Paper Chemistry, 1956. / Includes bibliographical references (p. 58-60).

Thesis (Ph. D.)--Institute of Paper Chemistry, 1975. / Bibliography: leaves 101-103.

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Studies using Mongolian gerbils found that during a primary infection with Giardia lamblia trophozoites, disaccharidase activities were decreased from day 10 post-infection (p.i.) until well past elimination of the parasite. However, during a challenge infection, enzyme deficiencies were short-lived. A challenge with a soluble extract of G. lamblia trophozoites also resulted in reductions in disaccharidase activity. The degree of these reductions in enzyme activity was dependent on the extract dose. Gel filtration of the trophozoite crude extract resulted in fractions F1, F2, and F3. However, only a challenge with F1 led to disaccharidase deficiencies. Further separation of F1 resulted in fractions F1a and F1b. Impairments of enzyme activity were obtained only in gerbils challenged with F1b. Protein analysis of F1b revealed several high and low molecular weight bands. When gerbils previously exposed to G. lamblia were challenged with an extract of Entamoeba histolytica trophozoites, disaccharidase activities remained comparable to controls. Moreover, enzyme levels in gerbils challenged with excretory/secretory G. lumblia products were affected in a manner which was inconsistent with the live parasitic challenge. Results suggest that the disaccharidase deficiencies in giardiasis are parasite-specific and are induced by a heat-stable constituent(s) of fraction F1b, possibly through an immune response to an antigenic component of this parasite fraction.

[Truncated abstract] The development of several carbohydrate-based pharmaceuticals has stimulated an increased interest in the field of carbohydrate chemistry. The discovery of Acarbose and invention of Miglitol, treatments for type II diabetes, as well as the influenza treatments, Relenza and Tamiflu, have been largely responsible for this increased interest. These treatments operate by the inhibition of glycoside hydrolases, a group of enzymes important in a variety of biological processes. This thesis involves the study of a group of glycoside hydrolase inhibitors known as azasugars, which are nitrogen-containing sugar mimics . . . The final chapter, Chapter 4, focuses on the testing of these disaccharides as a possible alternative carbohydrate source for pre-term infants. Initially, commercially available glycoside hydrolases were used to detect any hydrolysis of the four disaccharides, with (206) exhibiting the most promising results (to provide D-glucose and D-galactose). Detailed kinetic studies were then conducted using homogenates obtained from pig intestinal mucosa. Unfortunately, the results indicated that (206) was unsuitable as an alternative carbohydrate source for pre-term infants.

trans-Sialidase de Trypanosoma cruzi (TcTS) pertence à família de glicoproteínas de superfície do parasita e constitui um dos poucos exemplos naturais de glicosiltransferases superficiais encontradas em eucariotes. T. cruzi é incapaz de sintetizar ácido siálico e utiliza esta enzima para retirar este monossacarídeo de glicoconjugados do hospedeiro para sialilar moléculas aceptoras, como mucina-GPI (glicosilfosfatidilinositol), presentes na sua membrana plasmática. Esta enzima é específica em catalisar, preferencialmente, a transferência de ácido siálico para moléculas de mucina, originando ligações -2,3 com moléculas de galactose aceptoras na superfície do parasita. Considerando a heterogeneidade das moléculas de mucina de T. cruzi, é necessário que novas moléculas sejam sintetizadas a fim de que estas atuem como substratos glicopeptídicos, os quais podem levar ao melhor entendimento das interações entre enzima e substratos e permitir o planejamento racional de inibidores seletivos. Por isso, o trabalho foi divido em três rotas sintéticas: (i) preparação do doador de galactose, (ii) preparação dos aceptores-doadores e (iii) acoplamento dos dissacarídeos com aminoácidos aceptores para obtenção dos blocos de construção. Apesar dos objetivos propostos inicialmente não terem sido totalmente alcançados, o trabalho desenvolvido durante esse período permitiu a síntese do doador de galactose (3) em três etapas, aceptor de galactose (6) em cinco etapas, dissacarídeo (11) na glicosilação de 6 com 3, aminoácidos aceptores (13 e 14) e também dos blocos de construção (17 e 18) decorrente do acoplamento de 11 com os aminoácidos aceptores. Não obstante, é importante ressaltar que apesar da extensa rota planejada, porém necessária, a síntese dos blocos de construção é inédita. Portanto, pode-se concluir que o trabalho trouxe relevante contribuição no que diz respeito à química de carboidratos e à disponibilização de dados espectrométricos de compostos orgânicos para a literatura. / Trypanosoma cruzi trans-sialidase (TcTS) belongs to the family of glycoproteins expressed on the surface of the parasite and constitutes one of the few examples of natural surface glycosyltransferases found in eucariotes. T. cruzi can not synthesize sialic acid itself and uses this enzyme to scavenge this monosaccharide from host glycoconjugates to sialylate acceptors molecules, such as GPI (glycosylphosphatidylinositol) mucins, that are present in parasite plasma membrane. This enzyme is specific to catalyze, preferentially, the transference of sialic acid to mucin glycoproteins, generating -2,3-linkages with acceptor galactose molecules in the parasite surface. Considering the heterogeneity of T. cruzi mucin molecules, its necessary to synthesize new compounds that can act as glycopeptide substrates, leading to a better understanding concerning the enzyme and substrates and allow the rational design of some selective inhibitors. Thus, this work was developed in three synthetic routes: (i) the synthesis of galactose donor, (ii) synthesis of donor-acceptors and (iii) coupling between disaccharides and acceptors amino acids in order to obtain building blocks. Despite of some objectives initially proposed had not been accomplished, the developed work during this period allow the synthesis of the galactose donor (3) in three steps, donor-acceptor (6) in five steps, disaccharide (11), acceptors amino acids (13 and 14) and also the building blocks (17 and 18). However, its important highlight that the synthesis of the building blocks by this necessary, but extensive, synthetic route is unpublished. Therefore, it can be concluded that the present work brought rich contribution concerning the carbohydrate chemistry and the availability of spectrometric data of organic compounds to the literature.

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Os aminoglicosídeos são antibióticos utilizados para o tratamento de muitas infecções bacterianas graves. A maioria é produzida por microorganismos (gêneros Streptomyces e Actinomyces), mas a semi-síntese resultam na descoberta de notáveis aminoglicosídeos. Apesar de seu mecanismo de ação seletivo, os aminoglicosídeos são extremamente tóxicos. A nefrotoxicidade e ototoxicidade são mais freqüentemente observadas. Sabe-se que a Doença de Ménière pode ser tratada através da destruição seletiva das células vestibulares, preservando-se as células cocleares (tecidos da orelha interna). Antibióticos aminoglicosídeos são usados para esta finalidade, mas podem paralelamente causar danos cocleares (surdez). O estudo de relação estrutura-toxicidade dos resíduos de fragmentação de antibióticos aminoglicosídeos pode originar produtos simplificados, com atividade vestibular seletiva, dissociada da atividade coclear, mais seguros para o tratamento da Doença de Ménière. Em trabalhos anteriores, os ensaios envolvendo 2-desoxi-estreptamina e estreptidina demonstraram que não são tóxicos ao tecido coclear, quando comparados com os compostos originais. Neamina, outro fragmento de neomicina, se mostrou mais tóxica ao vestíbulo que a própria neomicina, mas aprensentou também grande toxicidade coclear. A substituição da unidade diamino-glicosídica de neamina, contendo o grupo 2-desoxi-estreptamina, por outras unidades glicosídicas (glicose, galactose, glicosamina) representa uma tentativa de eliminar a atividade cocleotóxica e manter a atividade vestibulotóxica original (100%). A mesma idéia pode ser também aplicada ao resíduo de estreptidina. Desta forma, foram sintetizados, dois pseudos-dissacarídeos, 2-desoxi-estreptamina ligado a galactose (48) e 2-desoxi-estreptamina ligado a glicose (49), ambas as ligações em posição referente ao carbono glicosídico anomérico. Apenas o pseudo-dissacarídeo 2-desoxi-estreptamina ligado a galactose (48) foi obtido com massa suficiente para analise ototóxica, o qual apresentou atividade vestibular seletiva como desejado, no tratamento da doença de Ménière. Ensaios de atividade antimicrobiana foram realizados empregando ambos pseudos-dissacarídeos sintetizados, 2-desoxi-estreptamina ligada a galactose (48) e 2-desoxi-estreptamina ligada a glicose (49), porém não apresentaram uma concentração inibitória mínima (MIC) significativa para as cepas testadas. / Aminoglycosides are antibiotics used for the treatment of many serious bacterial infections. Most are produced by microorganisms (genera Streptomyces and Actinomyces), but products obtained by semi-synthesis resulted in the discovery of remarkable aminoglycosides. Despite their selective mechanism of action, the aminoglycosides are highly toxic. The nephrotoxicity and ototoxicity are more frequently observed. It is known that Ménière\'s disease can be treated by selective destruction of the vestibular cells, preserving the cells cochlear (inner ear tissues). Aminoglycoside antibiotics are used for this purpose but may cause cochlear damage (deafness). The study of structure-toxicity of residues fragmentation of aminoglycoside antibiotics may lead to simplified products, with selective vestibular activity, dissociated from the cochlear activity, safer for the treatment of Ménière\'s disease. In previous work, the experiments involving 2-deoxy-streptamine and streptidine demonstrated that they are not toxic to the cochlear tissue, when compared with the original compound. Neamina, another fragment of neomycin, was more toxic to the vestibular tissue than neomycin, but also presented great cochlear toxicity. The replacement of the diamino-glycoside unit of neamina containing the 2-deoxy-streptamine by other glycosidic units (glucose, galactose, glucosamine) is an attempt to eliminate the cochlear toxicity and maintain the original vestibular toxicity (100%). The same idea can also be applied to the streptidine residue. Thus, two pseudo-disaccharides, 2-deoxy-streptamine linked to galactose (48) and 2-deoxy-streptamine linked to glucose (49), both linked to the position on the glycoside anomeric carbon. Only the pseudo-disaccharide 2-deoxy-streptamine linked to galactose (48) was obtained in sufficient quantity to perform the ototoxic assay, which presented selective vestibular activity as desired in the treatment of Ménière\'s disease. Antimicrobial activity assays were performed with both pseudo-disaccharides synthesized 2-deoxy-streptamine linked to galactose (48) and 2-deoxy- streptamine linked to glucose (49), but did not show a minimum inhibitory concentration (MIC) significant against the strains tested.