title: Glucopyranosylidene-spiro-iminothiazolidinone, a new bicyclic ring system: synthesis, derivatization, and evaluation for inhibition of glycogen phosphorylase by enzyme kinetic and crystallographic methods.
abstract: 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=9μM) 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.
authors.affiliation: Department of Organic Chemistry, University of Debrecen, POB 20, H-4010 Debrecen, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Czifrák
authors.affiliation: Department of Organic Chemistry, University of Debrecen, POB 20, H-4010 Debrecen, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Páhi
authors.affiliation: Department of Organic Chemistry, University of Debrecen, POB 20, H-4010 Debrecen, Hungary.
authors.forename: Szabina
authors.initials: S
authors.lastname: Deák
authors.affiliation: Department of Organic Chemistry, University of Debrecen, POB 20, H-4010 Debrecen, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Kiss-Szikszai
authors.affiliation: Department of Inorganic and Analytical Chemistry, University of Debrecen, POB 21, H-4010 Debrecen, Hungary.
authors.forename: Katalin E
authors.initials: KE
authors.lastname: Kövér
authors.affiliation: Department of Medical Chemistry, Medical and Health Science Centre, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Docsa
authors.affiliation: Department of Medical Chemistry, Medical and Health Science Centre, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary.
authors.forename: Pál
authors.initials: P
authors.lastname: Gergely
authors.affiliation: Institute of Biology, Medicinal Chemistry and Biotechnology, The National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, GR-116 35 Athens, Greece.
authors.forename: Kyra-Melinda
authors.initials: KM
authors.lastname: Alexacou
authors.affiliation: Institute of Biology, Medicinal Chemistry and Biotechnology, The National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, GR-116 35 Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Papakonstantinou
authors.affiliation: Institute of Biology, Medicinal Chemistry and Biotechnology, The National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, GR-116 35 Athens, Greece.
authors.forename: Demetres D
authors.initials: DD
authors.lastname: Leonidas
authors.affiliation: Institute of Biology, Medicinal Chemistry and Biotechnology, The National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, GR-116 35 Athens, Greece.
authors.forename: Spyros E
authors.initials: SE
authors.lastname: Zographos
authors.affiliation: Institute of Biology, Medicinal Chemistry and Biotechnology, The National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, GR-116 35 Athens, Greece. Electronic address: echrysina@eie.gr.
authors.forename: Evangelia D
authors.initials: ED
authors.lastname: Chrysina
authors.affiliation: Department of Organic Chemistry, University of Debrecen, POB 20, H-4010 Debrecen, Hungary. Electronic address: somsak@tigris.unideb.hu.
authors.forename: László
authors.initials: L
authors.lastname: Somsák
mesh_terms: D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D024982:Glycogen Phosphorylase, Muscle Form / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009005:Monosaccharides / Q000737:chemistry*; D011407:Propane / Q000031:analogs & derivatives / Q000737:chemistry; D011485:Protein Binding; D011817:Rabbits; D013141:Spiro Compounds / Q000737:chemistry*; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D009005:Monosaccharides; D013141:Spiro Compounds; D053778:Thiazolidines; D024982:Glycogen Phosphorylase, Muscle Form; D011407:Propane; C032699:1,3-dibromopropane
keywords: Anomeric spirocycle; Glycogen phosphorylase; Inhibitor; Structure-based drug design; Thiazolidinone; Type 2 diabetes; X-ray protein crystallography