SYNTHESIS AND BIOLOGICAL EVALUATION OF C-DISACCHARIDES

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The development of a methodology for the synthesis of "C-disaccharides", a yet unknown class of pseudodisaccharides having a methylene group (CH2) instead of an oxygen atom at the interglycosidic linkage, and the investigation of their biological properties are the principal objectives of the proposed research. Owing to their complete inertness with respect to hydrolysis, these pseudodisaccharides are extremely interesting analogues of the natural disaccharides that are expected to act as potent competitive inhibitors of glycosyl hydrolases. As shown with other carbohydrate derivatives including S-disaccharides, glycosidase inhibitors are not only useful biochemical tools, but have found also important applications in the treatment and the study, under physiological conditions, of metabolic diseases such as the lysozomal storage disease and diabetes; for example, acarbose, a pseudosugar-containing oligosaccharide, is known to improve the metabolic condition of insulin-dependent diabetics. The synthetic methodology involves, in the key steps, the Lewis acid-catalyzed condensation of a silyl nitronate derived from a C-glycosyl nitromethane (for non-reducing pseudodisaccharides) or from a C-nitromethyl carbohydrate derivative (for reducing pseudodisaccharides) with a glycosyl acetate for beta-pseudoanomers) or a glycosyl fluoride (for alpha-anomers), followed by radical denitration and deprotection of the resulting intermediates. The synthesis of the C-analogues of trehalose (alpha,alpha and beta,beta) cellobiose, maltose, lactose, and sucrose is planned. For the preparation of 1,6-linked pseudodisaccharides (gluco and/or galacto units), the key coupling reaction will be achieved by nitroaldol condensation of the silyl nitronate of C-glycosyl nitromethanes with dialdosugars. Structural analysis will be performed, with emphasis on the absence of exo-anomeric effect, as well as preliminary biochemical investigations: the inhibitory effect of the pseudodisaccharides on the enzymatic hydrolysis of the corresponding O-disaccharides will be determined.