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In the Search of Glycogen Phosphorylase Inhibitors: Synthesis of C‐ D ‐Glycopyranosylbenzo(hydro)quinones – Inhibition of and Binding to Glycogen Phosphorylase in the Crystal
Author(s) -
He Li,
Zhi Zhang Yun,
Tanoh Marcelle,
Chen GuoRong,
Praly JeanPierre,
Chrysina Evangelia D.,
Tiraidis Costas,
Kosmopoulou Magda,
Leonidas Demetres D.,
Oikonomakos Nikos G.
Publication year - 2007
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200600548
Subject(s) - chemistry , glycogen phosphorylase , stereochemistry , substrate (aquarium) , moiety , acetylation , d glucose , crystal structure , glycogen , biochemistry , organic chemistry , oceanography , gene , geology
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)