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

• Published in: European Journal of Organic Chemistry 2006-09, Vol.2006 (18), p.4242-4256
• Main Authors: Benltifa, Mahmoud, Vidal, Sébastien, Fenet, Bernard, Msaddek, Moncef, Goekjian, Peter G., Praly, Jean-Pierre, Brunyánszki, Attila, Docsa, Tibor, Gergely, Pál
• Format: Article
• Language: English
• Subjects: 1,2,4‐Oxadiazoles; 4-Oxadiazoles; C-Glycosides; Chemical Sciences; Cyanides; Glycogen phosphorylase (GP); Heterocycles; Organic chemistry
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.200600073

Upon treatment with hydroxylamine‐, benzyl‐ and benzoyl‐protected β‐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‐β‐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‐(β‐D‐Glucopyranosyl)‐5‐(2‐naphthyl)‐1,2,4‐oxadiazole was the best inhibitor of rabbit muscle glycogen phosphorylase b (Ki = 38.4 ±3.0 μM). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)