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

Penta‐ 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 K i values of 1.3 and 0.9 m M , respectively, whereas C‐β‐ D ‐glucosylhydroquinone 17 was not effective up to a concentration of 8 m M . 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)