No description available.

Iminosugars are polyhydroxylated alkaloids, and can be generally defined as sugar mimetics in which the endocyclic oxygen atom has been replaced with a basic nitrogen. A common affect of this atomic substitution is to bestow these compounds with the ability to inhibit various sugarprocessing enzymes; most significantly the glycosidases (glycoside hydrolases) which areintimately involved in a huge array of biological functions. Compounds which inhibit these enzymes concordantly possess much potential as medicinal agents for the treatment of a variety of diseases. Several iminosugars have already achieved market approval as drugs, and many more are promising candidates in the late stages of clinical development. As such there remains considerable interest in this class of compound, both in terms of the exploration of novel iminosugar structures, as well as the continual development of more efficient general methodology for their synthesis. The densely-packed functionality and stereochemical information present in iminosugars makes them challenging targets for asymmetric chemical synthesis, whereas carbohydrates are clearly very attractive as chiral-pool starting materials for this purpose. Indeed, the majority of the most successful syntheses of iminosugars use the latter approach, and such is the focus of this thesis. Chapter 1 presents a relatively brief introduction to iminosugars, including their types of structure, natural occurrence and biological mode of action. The rationale behind their use as therapeutic agents for the treatment of some significant disease targets is also discussed. Chapter 2 is concerned with the preparation of a number of novel polyhydroxylated azetidines, and their evaluation as glycosidase inhibitors. Such compounds represent an almost entirely neglected class of iminosugars within the literature. An overview of natural and synthetic products incorporating an azetidine motif is given, as well as a brief review of preparative methods and known azetidine iminosugars. A highly efficient and flexible method for the key azetidine ring formation is demonstrated by the cyclisations of 3,5-di-O-triflates of pentoses and hexoses, and of a 2,4-di-O-triflate of glucose, with various primary amines. In this manner, many azetidine triols and tetrols were prepared in good yield. Furthermore, this process is readily adaptable to the installation of added functionality to the azetidine scaffold, as demonstrated by the preparation of 1-acetamido analogues. The initial biological screening of these compounds showed a promising array of glycosidase inhibition, including that of selective inhibition of fungal enzymes. Chapter 3 describes a strategy with which to prepare all sixteen stereoisomers of a known piperidine iminosugar, alpha-homonojirimycin (alpha-HNJ), in a highly divergent manner from just four of the possible thirty-two 6-azidoheptitols using traditional chemical synthesis in tandem with biotechnological transformations. One half of the execution of this strategy is described in this thesis. Two 6-azidoheptitols were prepared from D-mannose, thereby providing access to four 6-azidoketoheptoses through a combination of microbial oxidation and enzymatic epimerisation. Catalytic hydrogenation of these 6-azidoketoheptoses furnished four diastereomeric mixtures of 2,6-iminoheptitols, with varying degrees of stereoselectivity. Purification of these mixtures allowed six 2,6-iminoheptitols to be isolated, two of which have never previously been tested for glycosidase inhibition. Significantly, one of them was found to be a potent and highly selectiveinhibitor of alpha-galactosidases, and may therefore be of interest in the treatment of Fabry disease.

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.