Synthesis of sulfonium sulfate analogues of disaccharides and their conversion to chain-extended homologues of salacinol: New glycosidase inhibitors

[graphics] Four chain extended homologues of salacinol, a naturally occurring glycosidase inhibitor, were prepared for evaluation as inhibitors of glucosidase enzymes involved in the breakdown of carbohydrates. The syntheses involved the reactions of 1,4-anhydro-2,3,5-tri-O-benzyl-4-thiO-D-arabinitol with cyclic sulfate derivatives of different monosaccharides. Debenzylation of the products afforded the novel sulfonium sulfate derivatives Of D-glucose, D-galactose, D-arabinose, and D-Xylose that are of interest in their own right as glycosidase inhibitors. Reduction to the corresponding alditols then afforded the homologues of salacinol containing polyhydroxylated, acyclic chains of 5- and 6-carbons, differing in stereochemistry at the stereogenic centers. Three of the chain-extended homologues inhibited recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the sinall intestine, with K-i values in the low microinolar range, of approximately the saine inagnitude as salacinol, thus providing lead candidates for the treatment of Type 2 diabetes.