Les Phostines représentent une nouvelle classe de glycomimétiques contenant un atome de phosphore à la place du carbone anomérique. Leur synthèse a été réalisée par la condensation de furanoses protégés et de différents H-phosphinates en milieu basique. Ces phostines se sont révélées être très efficaces in vitro et in vivo contre des cellules cancéreuses de glioblastome de rat et humaines. Dans ce projet, nous avons eu pour premier but d’obtenir, majoritairement, le diastéréoisomère le plus actif. Différentes réactions ont été réalisées, en changeant la nature de la base ou le contre-ion de cette dernière. Une très légère amélioration a été notée avec le méthylate de césium au profit du dérivé de type glucose. Dans un deuxième temps, et dans le but d’améliorer l’activité anticancéreuse et de pouvoir étudier la biodistribution des phostines, différentes modifications chimiques ont été réalisées. Des dihydroxy-2,3- et 2,6-oxaphosphinanes, des thiophostines et des phostines de la série L ont été synthétisées. Par la suite, des variations, en alpha de l’atome de phosphore, nous ont permis d’obtenir des phostines halogénées, ainsi que deux nouveaux produits: un acide furanosylphosphinique et l’oxaphosphine-3-ène. La réactivité chimique de la fonction éther d’énol de ce dernier a été examinée, en synthétisant un beta-cétophosphinate et des beta-énaminophosphinates. Finalement des pseudo-disaccharides ont été synthétisés afin d’améliorer la biodisponibilité des phostines. Les phostines testées ont manifesté des propriétés anticancéreuses à une concentration de l’ordre du nanomolaire envers différentes lignées cellulaires, montrant la capacité de cette famille de composés de lutter contre certains types de cancers. / The Phostines represent a new class of glycomimetics, containing a phosphinolactone function instead of the anomeric carbon. Their synthesis was achieved by the reaction of protected furanose with various H-phosphinates, in the presence of a base. These compounds have been found to be very effective in vitro and in vivo against rat and human glioblastoma cells.In this project, our first goal was to obtain the most active phostine with higher diastereoselectivity. Different reactions were tested, changing the base or its counter ion. A very slight improvement was noted with cesium methoxide, favoring the glucose-like derivative.In the context of improving the anticancer activity and to study the biodistribution of the phostines, different chemical modifications were carried out. Dihydroxy-2,3- and 2,6-oxaphosphinanes, thiophostines and phostines of the L series were synthesized. Therefore, variations in alpha position of the phosphorus atom have produced halogenated phostines and two new products: furanosylphosphinic acid and the oxaphosphine-3-ene.The chemical reactivity of the enol ether of this latter has been examined by synthesizing beta-ketophosphinate and beta-enaminophosphinates. Finally, pseudo-disaccharides were synthesized to improve the bioavailability of phostines.The tested phostines have exhibited anticancer properties at nanomolar concentration against different cell lines, showing the ability of this family of compounds to fight some types of cancers.

Glucosidases são enzimas que catalisam a hidrólise de ligações glicosídicas liberando unidades monossacarídicas de um terminal não redutor de um oligossacarídeo ou glicoconjugado. Iminoaçúcares são alcalóides piperidínicos polihidroxilados isolados de plantas (gênero Morus) e microrganismos (Bacillus), como nojirimicina (NJ) (1) e 1-desoxinojirimicina (DNJ) (2), os quais são descritos como inibidores de glucosidase. O potencial uso destes inibidores no tratamento de infecções virais, crescimento tumoral, metástases, diabetes, doença de Gaucher e osteoartrite tem motivado a comunidade científica na busca por novos derivados iminoaçúcares. Desse modo, a síntese de pseudodissacarídeos, contendo ambos resíduos de iminoaçúcar e glicopiranose, constitui uma estratégia interessante de obtenção desses derivados, apesar dos desafios envolvidos na geração da ligação entre estes dois açúcares. Por esta razão, foi utilizada a estratégia de click chemistry como uma ferramenta para introduzir uma ponte de grupo 1,2,3-triazol entre os açúcares a partir do acoplamento de azido-glicosídeo com N-propargil-iminoaçúcar. Desta forma, a síntese do iminoaçúcar N-propargílico (73), com função acetileno terminal, foi realizada em cinco etapas e foi usado na reação de cicloadição 1,3- dipolar com três derivados glicosídicos contendo grupo azido nas posições anomérica (C-1), C-3 ou C-6. A partir desta reação CuAAC (Copper(I)-catalyzed Azide-Alkyne Cycloaddition), três novos pseudo-dissacarídeos (77, 81 e 85) foram sintetizados em rendimentos moderados e foram, então, avaliados em ensaios de - D-glucosidase isolada de Sacharomyces cerevisiae. Nestes testes preliminares, o composto 77 foi o mais ativo, o qual foi capaz de inibir a atividade da enzima em 40% a 1mM. Esses resultados encorajam a realização de novos experimentos, principalmente, a determinação de Ki e avaliação da atividade relativa à replicação do vírus HIV. Portanto, a obtenção destes pseudodissacarídeos trouxe uma contribuição importante no que diz respeito à química de carboidratos e também ao tratamento das doenças citadas. / Glucosidases are enzymes that catalyze the hydrolysis of glycosidic bonds releasing monosaccharide units from a non-reducing end of an oligosaccharide or glycoconjugate. Iminosugars are polihydroxilate piperidinic alkaloids isolated from plants (Morus alba) and microorganisms (Bacillus), such as nojirimicin (NJ) (1) and 1- deoxynojirimicin (2), which are described as glucosidase inhibitors. The potential use of these inhibitors in the treatment of viral infection, tumoral growing, metastasis, diabetes, Gaucher´s disease and osteoarthritis has stimulated the scientific community on the search for novel iminosugar derivatives. Thereby, the synthesis of pseudodisaccharides, having both iminosugar and glycopyranose residues, represents an interesting strategy to obtain these derivatives, despite the challenges involved in generating the link between these two sugars. For this reason, we have used click chemistry as a tool to introduce a 1,2,3-triazole bridge between the sugars from the coupling of azide-glycosides with N-propargyl-iminosugar. Thus, the synthesis of N-propargyl-iminosugar (73), containing the terminal acetylene function, was performed in five steps, and was used in the 1,3-dipolar cycloaddition reaction with three glycosidic derivatives containing the azide group at anomeric (C-1), C-3 or C-6 positions. By applying this CuAAC (Copper(I)-catalyzed Azide-Alkyne Cycloaddition), three novel pseudo-disaccharides (77, 81 and 85) were synthesized in moderate yields and then, evaluated in -D-glucosidase assays isolated from Sacharomyces cerevisiae. In these preliminary test, compound 77 was the most active from the series, which was able to inhibit 40% of the enzyme activity at 1 mM. These results encourage us to perform new experiments, notably the determination of Ki and evaluation towards HIV replication. Thus, a contribution regarding carbohydrate chemistry and treatment of the supracited diseases was achieved by the synthesis of these pseudodisaccharides.

Glucosidases são enzimas que catalisam a hidrólise de ligações glicosídicas liberando unidades monossacarídicas de um terminal não redutor de um oligossacarídeo ou glicoconjugado. Iminoaçúcares são alcalóides piperidínicos polihidroxilados isolados de plantas (gênero Morus) e microrganismos (Bacillus), como nojirimicina (NJ) (1) e 1-desoxinojirimicina (DNJ) (2), os quais são descritos como inibidores de glucosidase. O potencial uso destes inibidores no tratamento de infecções virais, crescimento tumoral, metástases, diabetes, doença de Gaucher e osteoartrite tem motivado a comunidade científica na busca por novos derivados iminoaçúcares. Desse modo, a síntese de pseudodissacarídeos, contendo ambos resíduos de iminoaçúcar e glicopiranose, constitui uma estratégia interessante de obtenção desses derivados, apesar dos desafios envolvidos na geração da ligação entre estes dois açúcares. Por esta razão, foi utilizada a estratégia de click chemistry como uma ferramenta para introduzir uma ponte de grupo 1,2,3-triazol entre os açúcares a partir do acoplamento de azido-glicosídeo com N-propargil-iminoaçúcar. Desta forma, a síntese do iminoaçúcar N-propargílico (73), com função acetileno terminal, foi realizada em cinco etapas e foi usado na reação de cicloadição 1,3- dipolar com três derivados glicosídicos contendo grupo azido nas posições anomérica (C-1), C-3 ou C-6. A partir desta reação CuAAC (Copper(I)-catalyzed Azide-Alkyne Cycloaddition), três novos pseudo-dissacarídeos (77, 81 e 85) foram sintetizados em rendimentos moderados e foram, então, avaliados em ensaios de - D-glucosidase isolada de Sacharomyces cerevisiae. Nestes testes preliminares, o composto 77 foi o mais ativo, o qual foi capaz de inibir a atividade da enzima em 40% a 1mM. Esses resultados encorajam a realização de novos experimentos, principalmente, a determinação de Ki e avaliação da atividade relativa à replicação do vírus HIV. Portanto, a obtenção destes pseudodissacarídeos trouxe uma contribuição importante no que diz respeito à química de carboidratos e também ao tratamento das doenças citadas. / Glucosidases are enzymes that catalyze the hydrolysis of glycosidic bonds releasing monosaccharide units from a non-reducing end of an oligosaccharide or glycoconjugate. Iminosugars are polihydroxilate piperidinic alkaloids isolated from plants (Morus alba) and microorganisms (Bacillus), such as nojirimicin (NJ) (1) and 1- deoxynojirimicin (2), which are described as glucosidase inhibitors. The potential use of these inhibitors in the treatment of viral infection, tumoral growing, metastasis, diabetes, Gaucher´s disease and osteoarthritis has stimulated the scientific community on the search for novel iminosugar derivatives. Thereby, the synthesis of pseudodisaccharides, having both iminosugar and glycopyranose residues, represents an interesting strategy to obtain these derivatives, despite the challenges involved in generating the link between these two sugars. For this reason, we have used click chemistry as a tool to introduce a 1,2,3-triazole bridge between the sugars from the coupling of azide-glycosides with N-propargyl-iminosugar. Thus, the synthesis of N-propargyl-iminosugar (73), containing the terminal acetylene function, was performed in five steps, and was used in the 1,3-dipolar cycloaddition reaction with three glycosidic derivatives containing the azide group at anomeric (C-1), C-3 or C-6 positions. By applying this CuAAC (Copper(I)-catalyzed Azide-Alkyne Cycloaddition), three novel pseudo-disaccharides (77, 81 and 85) were synthesized in moderate yields and then, evaluated in -D-glucosidase assays isolated from Sacharomyces cerevisiae. In these preliminary test, compound 77 was the most active from the series, which was able to inhibit 40% of the enzyme activity at 1 mM. These results encourage us to perform new experiments, notably the determination of Ki and evaluation towards HIV replication. Thus, a contribution regarding carbohydrate chemistry and treatment of the supracited diseases was achieved by the synthesis of these pseudodisaccharides.