Synthesis of sulfonium sulfate analogues of disaccharides and their conversion to chain-extended homologues of salacinol: new glycosidase inhibitors.
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 small intestine, with Ki values in the low micromolar range, of approximately the same magnitude as salacinol, thus providing lead candidates for the treatment of Type 2 diabetes.
Johnston
Blair D
BD
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6.
Jensen
Henrik H
HH
Pinto
B Mario
BM
D000478:Alkylation; D002384:Catalysis; D004187:Disaccharides / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005959:Glucosidases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008024:Ligands; D015394:Molecular Structure; D010720:Phosphines / Q000737:chemistry; D017905:Phosphites / Q000737:chemistry; D013402:Sugar Alcohols / Q000737:chemistry*; D013431:Sulfates / Q000737:chemistry*; D013452:Sulfonium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D004187:Disaccharides; D004791:Enzyme Inhibitors; D008024:Ligands; D010720:Phosphines; D017905:Phosphites; D013402:Sugar Alcohols; D013431:Sulfates; D013452:Sulfonium Compounds; C427963:salacinol; D005959:Glucosidases; C044646:phosphine