SYNTHESIS AND BIOLOGICAL EVALUATION OF C-DISACCHARIDES

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This application is for the continuation of a research program supported by grant DK35766. The principal objectives of this program are the synthesis of C-disaccharides (chemically inert isosters of the natural disaccharides in which the interglycosidic oxygen atom is replaced by a methylene, -CH2-, group and the evaluation of their biological activity as glycosidase inhibitors. The study will be extended to a new class of biochemically highly significant disaccharide analogs in which the interglycosidic linkage is an aminomethylene (-CHNH2-) group ("homoglycosylamines"). Owing to their extreme structural similarity to the natural substrates of certain glycosidases and to their complete inertness towards hydrolysis, the proposed C-disaccharides are likely to act as efficient, competitive inhibitors of the biochemical process catalyzed by these enzymes. As potential inhibitors of the disaccharidases of the digestive tract, alpha-C disaccharides might prove useful for the treatment of diabetes mellitus and related metabolic diseases, by providing a means of controlling the intestinal glucose uptake. Furthermore, the pseudodisaccharides might be able to interfere with the processing of the oligosaccharide chin of glycoproteins (such as, for example, the envelope glycoprotein of the human HIV virus) and therefore might possess also antiviral or anticancer activity. The synthesis of C-disaccharides is a major challenge of synthetic carbohydrate chemistry. Expeditious approaches to 1,1- and 1,6-linked beta-C disaccharides, based on the nitroaldol reaction, have been developed, and will be applied to the preparation of 1,4-linked beta-C- disaccharides such as C-lactose. A new, equally efficient methodology has been devised for the radical SRN1 reaction of an alpha-C- glycosylmethylmercury compound with a sugar nitronate. 1,1-, 1,4- as well as 1,6-linked alpha-C-disaccharides will be prepared by this short methodology. The effect of the pseudodisaccharides on the glycoside hydrolysis reaction catalyzed by the corresponding alpha- or beta- glycosidases and, when possible, by specific disaccharidases, will be examined.