In the Search of Glycogen Phosphorylase Inhibitors: Synthesis of C‐D‐Glycopyranosylbenzo(hydro)quinones – Inhibition of and Binding to Glycogen Phosphorylase in the Crystal

Abstract

AbstractPenta‐O‐acetyl‐β‐D‐glycopyranoses and 1,4‐dimethoxybenzene led selectively by electrophilic substitution to C‐β‐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‐β‐D‐Glucosylbenzoquinone 19 and C‐β‐D‐Glucosylhydroquinone 23 were found to be competitive inhibitors of rabbit muscle glycogen phosphorylase b (GPb), with respect to the substrate α‐D‐glucose‐1‐phosphate, with Ki values of 1.3 and 0.9 mM, respectively, whereas C‐β‐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 Å resolution. The complex structures reveal that the inhibitors can be accommodated at the catalytic site at approximately the same position as α‐D‐glucose and stabilise the transition state conformation of the 280s loop by making several favourable contacts to Asp283 and Asn284 of this loop. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)