In the search of glycogen phosphorylase inhibitors: 4. Synthesis of C-D-glycopyranosylbenzo(hydro)quinones - Inhibition of and binding to glycogen phosphorylase in the crystal

Penta-O-acetyl-beta-D-glycopyranoses and 1,4-dimethoxybenzene led selectively by electrophilic substitution to C-beta-D-glycopyranosyl-1,4-dimethoxybenzenes which were converted by simple and efficient reactions (oxidation, reduction and deacetylation) to the corresponding C-glycosylhydro- and C-glycosylbenzoquinones, with either an acetylated or deprotected sugar moiety. C-beta-D-Glucosylbenzoquinone 19 and C-beta-D-Glucosylhydroquinone 23 were found to be competitive inhibitors of rabbit muscle glycogen phosphorylase b (GPb), with respect to the substrate a-D-glucose-1-phosphate, with K-i values of 1.3 and 0.9 mm, respectively, whereas C-beta-D-glucosylhydroquinone 17 was not effective up to a concentration of 8 mm. In order to elucidate the structural basis of inhibition, we determined the crystal structures of 19 and 23 in complex with GPb at a 2.03-2.05 angstrom resolution. The complex structures reveal that the inhibitors can be accommodated at the catalytic site at approximately the same position as a-D-glucose and stabilise the transition state conformation of the 280s loop by making several favourable contacts to Asp283 and Asn284 of this loop. (C) Wiley-VCH Verlag GmbH & Co.