Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Glucopyranosylidene-spiro-iminothiazolidinone, a new bicyclic ring system: Synthesis, derivatization, and evaluation for inhibition of glycogen phosphorylase by enzyme kinetic and crystallographic methods
Δημιουργός/Συγγραφέας:	Czifrák K. Páhi A. Deák S. Kiss-Szikszai A. Kövér K.E. Docsa T. Gergely P. Alexacou K.-M. Papakonstantinou M. [EL] Λεωνίδας, Δημήτρης Δ.[EN] Leonidas, Demetres D. [EL] Ζωγράφος, Σπύρος Ε.[EN] Zographos, Spyros E. [EL] Χρυσίνα, Ευαγγελία Δ.[EN] Chrysina, Evangelia D. Somsák L.
Εκδότης:	Elsevier Ltd
Ημερομηνία:	2014
Γλώσσα:	Αγγλικά
ISSN:	0968-0896
DOI:	10.1016/j.bmc.2014.05.076
Άλλο:	PubMed ID: 25009003
Περίληψη:	The reaction of thiourea with O-perbenzoylated C-(1-bromo-1-deoxy-β-d- glucopyranosyl)formamide gave the new anomeric spirocycle 1R-1,5-anhydro-d- glucitol-spiro-[1,5]-2-imino-1,3-thiazolidin-4-one. Acylation and sulfonylation with the corresponding acyl chlorides (RCOCl or RSO2Cl where R = tBu, Ph, 4-Me-C6H4, 1- and 2-naphthyl) produced the corresponding 2-acylimino- and 2-sulfonylimino-thiazolidinones, respectively. Alkylation by MeI, allyl-bromide and BnBr produced mixtures of the respective N-alkylimino- and N,N′-dialkyl-imino-thiazolidinones, while reactions with 1,2-dibromoethane and 1,3-dibromopropane furnished spirocyclic 5,6-dihydro-imidazo[2,1-b]thiazolidin-3-one and 6,7-dihydro-5H-thiazolidino[3,2- a]pyrimidin-3-one, respectively. Removal of the O-benzoyl protecting groups by the Zemplén protocol led to test compounds most of which proved micromolar inhibitors of rabbit muscle glycogen phosphorylase b (RMGPb). Best inhibitors were the 2-benzoylimino- (Ki = 9 μM) and the 2-naphthoylimino-thiazolidinones (Ki = 10 μM). Crystallographic studies of the unsubstituted spiro-thiazolidinone and the above most efficient inhibitors in complex with RMGPb confirmed the preference and inhibitory effect that aromatic (and especially 2-naphthyl) derivatives show for the catalytic site promoting the inactive conformation of the enzyme.
Τίτλος πηγής δημοσίευσης:	Bioorganic and Medicinal Chemistry
Τόμος/Κεφάλαιο:	22
Τεύχος:	15
Σελίδες:	4028-4041
Θεματική Κατηγορία:	[EL] Βιολογία (Γενικά)[EN] Biology (General) [EL] Χημεία (Γενικά)[EN] Chemistry (General)
Λέξεις-Κλειδιά:	Anomeric spirocycle Glycogen phosphorylase Inhibitor Structure-based drug design Thiazolidinone Type 2 diabetes X-ray protein crystallography
Αξιολόγηση από ομότιμους (peer reviewed):	Ναι
Κάτοχος πνευματικών δικαιωμάτων:	© 2014 Elsevier Ltd. All rights reserved.
Όροι και προϋποθέσεις δικαιωμάτων:	All Open Access, Green
Σημειώσεις:	MEST-CT-020575, MTKD-CT-2006-042776; IHPP HPRI-CT-1999-00012, RII3/CT/2004/5060008; Seventh Framework Programme, FP7: 283570; Sixth Framework Programme, FP6; European Commission, EC; Hungarian Scientific Research Fund, OTKA: 109450, BAROSS REG_EA_09-1-2009-0028, OTKA 46081; Magyar Tudományos Akadémia, MTA; European Social Fund, ESF; Seventh Framework Programme, FP7; Debreceni Egyetem, DE: 5N5X 1IJ0 KUDT 320. This work was supported in Greece by the EU Marie Curie Early Stage Training (EST) contract No MEST-CT-020575 ; a Marie Curie Host Fellowships for the Transfer of Knowledge (ToK) contract No MTKD-CT-2006-042776 under FP6; the FP7 Capacities coordination and support actions REGPOT-2009-1-No 245866 ′ARCADE′; The research leading to these results has received funding from the European Community′s Sixth ( RII3/CT/2004/5060008 , IHPP HPRI-CT-1999-00012 ) and Seventh Framework Programme ( FP7/2007–2013 ) under BioStruct-X (Grant agreement N°283570 ) awarded to both SRS-Daresbury Laboratory and EMBL-Hamburg. This work was supported in Hungary by the Hungarian Scientific Research Fund ( OTKA 46081 , 109450 ), as well as by the projects BAROSS REG_EA_09-1-2009-0028 (LCMS_TAN), TÁMOP 4.2.1./B-09/1/KONV-2010-0007, TÁMOP-4.2.2.A-11/1/KONV-2012-0025, co-financed by the European Union and the European Social Fund. TD thanks for a Bolyai János Research Fellowship from the Hungarian Academy of Sciences, and research support from the University of Debrecen ( 5N5X 1IJ0 KUDT 320 ).
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο