Synthesis of nitrogen analogues of salacinol and their evaluation as glycosidase inhibitors.
The syntheses of two nitrogen analogues (11 and 12) of the naturally occurring sulfonium ion, salacinol (7) are described. The latter compound is one of the active principles in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of diabetes. The synthetic strategy relies on the nucleophilic attack of a 1,4-dideoxy-1,4-imino-D- or L-arabinitol at the least hindered carbon of 2,4-O-benzylidene D- or L-erythritol-1,3-cyclic sulfate. The nitrogen analogues bear a permanent positive charge and serve as mimics of the sulfonium ion. We reasoned that these ammonium derivatives should function in a manner similar to that of known glycosidase inhibitors of the alkaloid class such as castanospermine (4) and deoxynojirimycin (5). Enzyme inhibition assays indicate that salacinol (7) is a weak (K(i) = 1.7 mM) inhibitor of glucoamylase, whereas compounds 11 and 12 inhibit glucoamylase with K(i) values in the range approximately 10-fold higher. The nitrogen analogues 11 and 12 showed no significant inhibitory effect of either barley alpha-amylase (AMY1) or porcine pancreatic alpha-amylase (PPA) at concentrations of 5 mM. In contrast, salacinol (7) inhibited AMY1 and PPA in the micromolar range, with K(i) values of 15 +/- 1 and 10 +/- 2 microM, respectively.
Ghavami
A
A
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6.
Johnston
B D
BD
Jensen
M T
MT
Svensson
B
B
Pinto
B M
BM
D000681:Amylases / Q000037:antagonists & inhibitors*; D000818:Animals; D001089:Arabinose; D002240:Carbohydrate Sequence; D003920:Diabetes Mellitus / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D004896:Erythritol; D005087:Glucan 1,4-alpha-Glucosidase / Q000037:antagonists & inhibitors; D006801:Humans; D050113:Imino Furanoses; D007212:Indolizines / Q000737:chemistry; D007527:Isoenzymes; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009005:Monosaccharides / Q000737:chemistry / Q000627:therapeutic use; D010936:Plant Extracts / Q000737:chemistry* / Q000627:therapeutic use; D000644:Quaternary Ammonium Compounds / Q000737:chemistry* / Q000627:therapeutic use; D013237:Stereoisomerism; D013402:Sugar Alcohols / Q000138:chemical synthesis* / Q000737:chemistry* / Q000627:therapeutic use; D013431:Sulfates; D013552:Swine; D000516:alpha-Amylases / Q000037:antagonists & inhibitors; D054836:Indolizidines
D000681:Amylases; D001089:Arabinose; D004791:Enzyme Inhibitors; D004896:Erythritol; D005087:Glucan 1,4-alpha-Glucosidase; D050113:Imino Furanoses; D007212:Indolizines; D007527:Isoenzymes; D009005:Monosaccharides; D010936:Plant Extracts; D000644:Quaternary Ammonium Compounds; D013402:Sugar Alcohols; D013431:Sulfates; D000516:alpha-Amylases; C431728:1'-((1,4-dideoxy-1,4-iminoarabinitol)-4-N-ammonium)-1'-deoxyerythritol-3'-sulfate; C114502:Kotalanol; C427963:salacinol; C037806:castanospermine; D054836:Indolizidines