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

Abstract

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)

Glucose derived inhibitors of glycogen phosphorylase

“…1,3-dipolar cycloaddition with nitrile-oxides generated in situ furnished 5-b-D-glucopyranosyl-3-substituted-1,2,4-oxadiazoles 43 [60,62]. Addition of hydroxylamine to 36 produced amidoxime 42 which upon O-acylation with either carboxylic acids or acid chlorides followed by cyclodehydration gave 3-b-D-glucopyranosyl-5-substituted-1,2,4-oxadiazoles 44 [63]. The protecting groups were removed by standard methods.…”

New synthesis of 3-(β-D-glucopyranosyl)-5-substituted-1,2,4-triazoles, nanomolar inhibitors of glycogen phosphorylase

“…The 4-tolyl derivative 6e was ~4 times better than 6d, and comparing it to the relevant amide I (R = 4-CH 3 -C 6 H 4 : IC 50 4.5 mM [41]) revealed a very large increase of the…”

“…Compounds 6a-c with aliphatic substituents proved weak inhibitors and were much less efficient than the corresponding "parent" amides I (shown in Chart 1; for R = CH 3 : K i 32 µM [39]; R = C(CH 3 ) 3 : IC 50 7.5 mM [41]; R = CH 2 OH: K i 18 [42] or 20 [49] µM), however, the trend in the strength of inhibition remained the same (t-butyl derivatives were the less efficient followed by the methyl and hydroxymethyl compounds in both series).…”

C-(2-Deoxy-d-arabino-hex-1-enopyranosyl)-oxadiazoles: synthesis of possible isomers and their evaluation as glycogen phosphorylase inhibitors

“…The latter method proved to be more efficient both in terms of purity of the product and overall yields (compare yields under conditions a and b in Scheme 1 taking into account that 24 can be obtained almost quantitatively 49 ). By adaptation of a literature method 43 25 was then transformed into amidoxime 26, which was acylated by acid chlorides to give compounds 27 and 28 in high yields. Subsequent TBAF promoted ring closure 54 introduction of the double bond into the sugar moiety of 39e41 by using DBU failed (no or low conversions were observed at either rt.…”