Synthesis of Nitrogen Analogues of Salacinol and Their Evaluation as Glycosidase Inhibitors
| Autor: | Morten T. Jensen, Ahmad Ghavami, Birte Svensson, Blair D. Johnston, B. M. Pinto |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Arabinose
Salacia reticulata Magnetic Resonance Spectroscopy Swine Sulfonium Stereochemistry Molecular Sequence Data Stereoisomerism Biochemistry Catalysis chemistry.chemical_compound Sugar Alcohols Colloid and Surface Chemistry Diabetes Mellitus Animals Humans Glycoside hydrolase Ammonium Enzyme Inhibitors Molecular Structure biology Plant Extracts Sulfates Alkaloid Monosaccharides Indolizines General Chemistry biology.organism_classification Isoenzymes Quaternary Ammonium Compounds Erythritol Carbohydrate Sequence chemistry Castanospermine Amylases Imino Furanoses Glucan 1 4-alpha-Glucosidase alpha-Amylases |
| Zdroj: | Technical University of Denmark Orbit |
| ISSN: | 1520-5126 0002-7863 |
| DOI: | 10.1021/ja0103750 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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