Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Halogen-substituted (C-beta-D-glucopyranosyl)-hydroquinone regioisomers: Synthesis, enzymatic evaluation and their binding to glycogen phosphorylase
Δημιουργός/Συγγραφέας:	Alexacou, Kyra-Melinda Zhang, Yun Zhi Praly, Jean-Pierre [EL] Ζωγράφος, Σπύρος Ε.[EN] Zographos, Spyros E. [EL] Χρυσίνα, Ευαγγελία Δ.[EN] Chrysina, Evangelia D. [EL] Οικονομάκος, Νίκος Γ.[EN] Oikonomakos, Nikos G. [EL] Λεωνίδας, Δημήτρης Δ.[EN] Leonidas, Demetres D.
Εκδότης:	Pergamon
Τόπος έκδοσης:	OXFORD
Ημερομηνία:	2011-09-01
Γλώσσα:	Αγγλικά
ISSN:	0968-0896
DOI:	10.1016/j.bmc.2011.07.024
Περίληψη:	Electrophilic halogenation of C-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl) 1,4-dimethoxybenzene (1) afforded regioselectively products halogenated at the para position to the D-glucosyl moiety (8, 9) that were deacetylated to 3 (chloride) and 16 (bromide). For preparing meta regioisomers, 1 was efficiently oxidized with CAN to afford C-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl) 1,4-benzoquinone 2 which, in either MeOH or H2O-THF containing few equivalents of AcCl, added hydrochloric acid to produce predominantly meta (with respect to the sugar moiety) chlorinated hydroquinone derivatives 5 and 18, this latter being deacetylated to 4. The deacetylated meta (4, 5) or para (3, 16) halohydroquinones were evaluated as inhibitors of glycogen phosphorylase (GP, a molecular target for inhibition of hepatic glycogenolysis under high glucose concentrations) by kinetics and X-ray crystallography. These compounds are competitive inhibitors of GPb with respect to alpha-D-glucose-1-phosphate. The measured IC50 values (mu M) [169.9 +/- 10.0 (3), 95 (4), 39.8 +/- 0.3 (5) 136.4 +/- 4.9 (16)] showed that the meta halogenated inhibitors (4, 5) are more potent than their para analogs (3, 16). The crystal structures of GPb in complex with these compounds at high resolution (1.97-2.05 angstrom) revealed that the inhibitors are accommodated at the catalytic site and stabilize the T conformation of the enzyme. The differences in their inhibitory potency can be interpreted in terms of variations in the interactions with protein residues of the different substituents on the aromatic part of the inhibitors.
Τίτλος πηγής δημοσίευσης:	Bioorganic & Medicinal Chemistry
Τόμος/Κεφάλαιο:	19
Τεύχος:	17
Σελίδες:	5125-5136
Θεματική Κατηγορία:	[EL] Βιολογία (Γενικά)[EN] Biology (General) [EL] Χημεία (Γενικά)[EN] Chemistry (General) [EL] Οργανική χημεία[EN] Organic chemistry [EL] Φαρμακευτική[EN] Pharmacy and materia medica
Λέξεις-Κλειδιά:	Type 2 diabetes Glycogen phosphorylase C-glucosyl aryl C-glucopyranosyl hydroquinone Inhibition X-ray crystallography Chemistry, Medicinal
Αξιολόγηση από ομότιμους (peer reviewed):	Ναι
EU Grant identifier:	info:eu-repo/grantAgreement/EC/FP7/230146
Κάτοχος πνευματικών δικαιωμάτων:	© 2011 Elsevier Ltd. All rights reserved.
Ηλεκτρονική διεύθυνση περιοδικού (link) :	http://www.elsevier.com/locate/bmc
ΙΒΦΧΒ: αρχειακή συλλογή:	Ινστιτούτο Οργανικής και Φαρμακευτικής Χημείας (ΙΟΦΧ) (έως 2012)
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο