Synthesis of nitrogen analogues of salacinol and their evaluation as glycosidase inhibitors

The syntheses of two nitrogen analogues (11 and 12) of the naturally occurr ing 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 diabete s. The synthetic strategy relies on the nucleophilic attack of a 1.4-dideox y-1,4-imino-D- or L-arabinitol at the least hindered carbon of 2,4-O-benzyl idene 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 reas oned that these ammonium derivatives should function in a manner similar to that of known glycosidase inhibitors of the alkaloid class such as castano spermine (4) and deoxynojirimycin (5). Enzyme inhibition assays indicate th at salacinol (7) is a weak (K-i = 1.7 mM) inhibitor of glucoamylase, wherea s compounds 11 and 12 inhibit glucoamylase with K-i values in the range sim ilar to 10-fold higher. The nitrogen analogues 11 and 12 showed no signific ant inhibitory effect of either barley alpha -amylase (AMY 1) or porcine pa ncreatic alpha -amylase (PPA) at concentrations of 5 mM. In contrast, salac inol (7) inhibited AMY1 and PPA in the micromolar range, with K-i values of 15 +/- 1 and 10 +/- 2 muM, respectively.