Synthesis of 1,4-anhydro-D-xylitol heteroanalogues of the naturally-occurring glycosidase inhibitor salacinol and their evaluation as glycosidase inhibitors

The syntheses of two 1,4-anhydro-D-xylitol heteroanalogues (8 and 9) of the naturally occurring sulfonium ion, salacinol (3), containing a sulfur or nitrogen atom in the ring are described. Salacinol (3) 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 Type 2 diabetes. The synthetic strategy relies on the nucleophilic attack of sulfur or nitrogen analogues of 1,4-anhydro-D-Xylitol at the least-hindered carbon of 2,4- O-benzylidene-L-erythritol-1, 3 -cyclic sulfate. The sulfonium ion 8 inhibited barley-alpha-amylase (AMY1) and porcine pancreatic-alpha-amylase (PPA), with K-i values of 109 +/- 11 and 55 +/- 5 muM, respectively. In contrast, the ammonium ion 9 showed no significant inhibition of either AMY1 or PPA. Compounds 8 and 9 also showed no significant inhibition of glucoamylase.