A new class of glucosidase inhibitor: analogues of the naturally occurring glucosidase inhibitor salacinol with different ring heteroatom substituents and acyclic chain extension.
Six chain-extended analogues of the naturally occurring glycosidase inhibitor salacinol, with ring-heteroatom variation, were synthesized for structure-activity studies with different glycosidase enzymes. The syntheses involved the reaction of PMB-protected D- and L- seleno-, thio-, and iminoarabinitol with a benzylidene- and isopropylidene-protected 1,3-cyclic sulfate, derived from commercially available D-sorbitol, in 1,1,1,3,3,3-hexafluoro-2-propanol containing potassium carbonate. Deprotection of the products afforded the novel selenonium, sulfonium, and iminium analogues of salacinol containing polyhydroxylated, monosulfated, extended acyclic chains of 6-carbons, differing in stereochemistry at the stereogenic centers and ring-heteroatom constitution. Four of these compounds inhibit 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 micromolar range, thus providing lead candidates for the treatment of Type 2 diabetes.
Liu
Hui
H
Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada V5A 1S6.
Sim
Lyann
L
Rose
David R
DR
Pinto
B Mario
BM
D000144:Acids, Acyclic / Q000737:chemistry*; D001688:Biological Products / Q000037:antagonists & inhibitors / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D065089:Glycoside Hydrolase Inhibitors; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013402:Sugar Alcohols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013431:Sulfates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000520:alpha-Glucosidases / Q000378:metabolism
D000144:Acids, Acyclic; D001688:Biological Products; D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D006573:Heterocyclic Compounds, 1-Ring; D013402:Sugar Alcohols; D013431:Sulfates; C427963:salacinol; D000520:alpha-Glucosidases