INHIBITION OF COMPLEX CARBOHYDRATE BIOSYNTHESIS

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This proposal describes the synthesis of several classes of new structures designed specifically to inhibit biologically important glycosidases (glycosyl hydrolases). A rationale for predicting sugar and anomer specificity is presented based on (1) a working hypothesis of enzyme mechanism and (2) results with previously known inhibitors. Target structures are typically polyhydroxylated cyclic amines, which will be prepared in enantiomerically pure form by a new method from D-hexoses. Glycosidases are ubiquitous in nature, being essential for the normal growth and development of all organisms. Glycosidases are involved in a variety of important cellular functions including the breakdown of carbohydrate foodstuffs, the processing of eucaryotic glycoproteins, and the catabolism of polysaccharides and glycoconjugates. One family of glycosidases functions in the biosynthesis and breakdown of complex brain and nervous system sphingolipids known as gangliosides. Disorders of ganglioside breakdown such as Tay-Sachs, Sandhoff's, Gaucher's, Fabry's and Krabbe's diseases are genetically inherited and result from deficiencies of specific glycosidases. Inhibitors of these enzymes could be used to induce disease symptoms in experimental animals, thus facilitating clinical study. In general, glycosidase inhibitors would be useful in studying the biosynthesis of polysaccharides and glycoconjugates. They should find wide application in microbiology, virology, cell biology, immunology, developmental biology and medicine.