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Glucopyranosylidene-spiro-iminothiazolidinone, a New Bicyclic Ring System: Synthesis, Derivatization, and Evaluation as Glycogen Phosphorylase Inhibitors by Enzyme Kinetic and Crystallographic MethodsGlucopyranosylidene-spiro-iminothiazolidinone, a New Bicyclic Ring System: Synthesis, Derivatization, and Evaluation as Glycogen Phosphorylase Inhibitors by Enzyme Kinetic and Crystallographic Methods
Structural highlights
FunctionPYGM_RABIT Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties. Publication Abstract from PubMedThe reaction of thiourea with O-perbenzoylated C-(1-bromo-1-deoxy-beta-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 Zemplen 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=9muM) and the 2-naphthoylimino-thiazolidinones (Ki=10muM). 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. Glucopyranosylidene-spiro-iminothiazolidinone, a new bicyclic ring system: Synthesis, derivatization, and evaluation for inhibition of glycogen phosphorylase by enzyme kinetic and crystallographic methods.,Czifrak K, Pahi A, Deak S, Kiss-Szikszai A, Kover KE, Docsa T, Gergely P, Alexacou KM, Papakonstantinou M, Leonidas DD, Zographos SE, Chrysina ED, Somsak L Bioorg Med Chem. 2014 Aug 1;22(15):4028-41. doi: 10.1016/j.bmc.2014.05.076. Epub , 2014 Jun 16. PMID:25009003[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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