In search of glycogen phosphorylase inhibitors:: 5-substituted 3-C-glucopyranosyl-1,2,4-oxadiazoles from β-D-glucopyranosyl cyanides upon cyclization of O-acylamidoxime intermediates

Upon treatment with hydroxylamine-, benzyl- and benzoyl-protected beta-D-glucopyranosyl cyanides efficiently afforded the corresponding amidoximes. They reacted by O-acylation in the presence of carboxylic acids or acyl chlorides to provide benzyl- and benzoyl-protected O-acylamidoximes. The latter were isolated and fully characterized. Thermal cyclization of O-acylamidoximes yielded the corresponding 5-substituted 3-C-beta-D-glucopyranosyl-1,2,4-oxadiazoles, either in a "one-pot" procedure (benzylated series), or in two steps (benzoylated series). The twelve 5-substituted 1,2,4-oxadiazoles obtained upon debenzoylation were assayed against glycogen phosphorylase (GP). 3-C-(beta-D-Glucopyranosyl)-5-(2-naphthyl)-1,2,4-oxadiazole was the best inhibitor of rabbit muscle glycogen phosphorylase b (K-i = 38.4 +/- 3.0 mu m). (c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006.