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Glucopyranosylidene-spiro-imidazolinones, a New Ring System: Synthesis and Evaluation as Glycogen Phosphorylase Inhibitors by Enzyme Kinetics and X-ray Crystallography
dc.creator | Szabó K.E., Kyriakis E., Psarra A.-M.G., Karra A.G., Sipos Á., Docsa T., Stravodimos G.A., Katsidou E., Skamnaki V.T., Liggri P.G.V., Zographos S.E., Mándi A., Király S.B., Kurtán T., Leonidas D.D., Somsák L. | en |
dc.date.accessioned | 2023-01-31T10:05:32Z | |
dc.date.available | 2023-01-31T10:05:32Z | |
dc.date.issued | 2019 | |
dc.identifier | 10.1021/acs.jmedchem.9b00356 | |
dc.identifier.issn | 00222623 | |
dc.identifier.uri | http://hdl.handle.net/11615/79566 | |
dc.description.abstract | Epimeric series of aryl-substituted glucopyranosylidene-spiro-imidazolinones, an unprecedented new ring system, were synthesized from the corresponding Schiff bases of O-perbenzoylated (gluculopyranosylamine)onamides by intramolecular ring closure of the aldimine moieties with the carboxamide group elicited by N-bromosuccinimide in pyridine. Test compounds were obtained by Zemplén O-debenzoylation. Stereochemistry and ring tautomers of the new compounds were investigated by NMR, time-dependent density functional theory (TDDFT)-electronic circular dichroism, and DFT-NMR methods. Kinetic studies with rabbit muscle and human liver glycogen phosphorylases showed that the (R)-imidazolinones were 14-216 times more potent than the (S) epimers. The 2-naphthyl-substituted (R)-imidazolinone was the best inhibitor of the human enzyme (Ki 1.7 μM) and also acted on HepG2 cells (IC50 177 μM). X-ray crystallography revealed that only the (R) epimers bound in the crystal. Their inhibitory efficacy is based on the hydrogen-bonding interactions of the carbonyl oxygen and the NH of the imidazolinone ring. © 2019 American Chemical Society. | en |
dc.language.iso | en | en |
dc.source | Journal of Medicinal Chemistry | en |
dc.source.uri | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85069627561&doi=10.1021%2facs.jmedchem.9b00356&partnerID=40&md5=d7ab0ac44b9677c5d2be42dcb5f9f252 | |
dc.subject | 1',5 anhydro 2',3',4',6' tetra o benzoyl dextro glucitol spiro(1',5] 2 (1 naphthyl) imidazolin 4 one | en |
dc.subject | 1',5 anhydro 2',3',4',6' tetra o benzoyl dextro glucitol spiro(1',5] 2 (2 naphthyl) imidazolin 4 one | en |
dc.subject | 1',5 anhydro 2',3',4',6' tetra o benzoyl dextro glucitol spiro(1',5] 2 (4 trifluoromethylphenyl) imidazolin 4 one | en |
dc.subject | 1',5 anhydro 2',3',4',6' tetra o benzoyl dextro glucitol spiro(1',5] 2 phenyl imidazolin 4 one | en |
dc.subject | 1',5' anhydro 2',3',4',6' tetra o benzoyl dextro glucitol spiro[1',5] 2 (1 naphthyl) imidazolin 4 one | en |
dc.subject | 1',5' anhydro 2',3',4',6' tetra o benzoyl dextro glucitol spiro[1',5] 2 (2 naphthyl) imidazolin 4 one | en |
dc.subject | 1',5' anhydro 2',3',4',6' tetra o benzoyl dextro glucitol spiro[1',5] 2 (4 trifluoromethylphenyl) imidazolin 4 one | en |
dc.subject | 1',5' anhydro 2',3',4',6' tetra o benzoyl dextro glucitol spiro[1',5] 2 phenyl imidazolin 4 one | en |
dc.subject | 1',5' anhydro dextro glucitol spiro [1',5] 2 (1 naphthyl) imidazolin 4 one | en |
dc.subject | 1',5' anhydro dextro glucitol spiro [1',5] 2 (1 naphthyl)imidazolin 4 one | en |
dc.subject | 1',5' anhydro dextro glucitol spiro [1',5] 2 (2 naphthyl) imidazolin 4 one | en |
dc.subject | 1',5' anhydro dextro glucitol spiro [1',5] 2 (2 naphthyl)imidazolin 4 one | en |
dc.subject | 1',5' anhydro dextro glucitol spiro [1',5] 2 (4 trifluoromethylphenyl) imidazolin 4 one | en |
dc.subject | 1',5' anhydro dextro glucitol spiro [1',5] 2 (4 trifluoromethylphenyl)imidazolin 4 one | en |
dc.subject | 1',5' anhydro dextro glucitol spiro [1',5] 2 phenyl imidazolin 4 one | en |
dc.subject | c (2,3,4,6 tetra o benzoyl 1 benzylideneamino 1 alpha dextro deoxy glucopyranosyl)formamide | en |
dc.subject | c (2,3,4,6 tetra o benzoyl 1 benzylidenetriazenyl 1 alpha dextro deoxy glucopyranosyl)formamide | en |
dc.subject | c (2,3,4,6 tetra o benzoyl 1 deoxy beta dextro glucopyranosyl)formamide | en |
dc.subject | c [2,3,4,6 tetra o benzoyl 1 deoxy 1 (4 trifluoromethylbenzylidene)amino beta dextro glucopyranosyl]formamide | en |
dc.subject | c [2,3,4,6 tetra o benzoyl 1 deoxy 1 (naphth 1 ylmethylidene)amino alpha dextro glucopyranosyl]formamide | en |
dc.subject | c [2,3,4,6 tetra o benzoyl 1 deoxy 1 (naphth 1 ylmethylidene)amino beta dextro glucopyranosyl]formamide | en |
dc.subject | c [2,3,4,6 tetra o benzoyl 1 deoxy 1 (naphth 2 ylmethylidene)amino alpha dextro glucopyranosyl]formamide | en |
dc.subject | c [2,3,4,6 tetra o benzoyl 1 deoxy 1 (naphth 2 ylmethylidene)amino beta dextro glucopyranosyl]formamide | en |
dc.subject | c [2,3,4,6 tetra o benzoyl 1 deoxy 1(4 trifluoromethylbenzylidene)amino alpha dextro glucopyranosyl]formamide | en |
dc.subject | glycogen phosphorylase | en |
dc.subject | glycosyltransferase inhibitor | en |
dc.subject | imidazoline derivative | en |
dc.subject | spiro compound | en |
dc.subject | unclassified drug | en |
dc.subject | enzyme inhibitor | en |
dc.subject | glucoside | en |
dc.subject | glycogen phosphorylase | en |
dc.subject | imidazoline derivative | en |
dc.subject | protein binding | en |
dc.subject | spiro compound | en |
dc.subject | animal tissue | en |
dc.subject | Article | en |
dc.subject | conformational transition | en |
dc.subject | decomposition | en |
dc.subject | density functional theory | en |
dc.subject | drug structure | en |
dc.subject | drug synthesis | en |
dc.subject | electronic circular dichroism | en |
dc.subject | enzyme inhibition | en |
dc.subject | enzyme kinetics | en |
dc.subject | ex vivo study | en |
dc.subject | Hep-G2 cell line | en |
dc.subject | human | en |
dc.subject | human cell | en |
dc.subject | human tissue | en |
dc.subject | hydrogen bond | en |
dc.subject | Leporidae | en |
dc.subject | liver cell | en |
dc.subject | microwave irradiation | en |
dc.subject | molecular model | en |
dc.subject | nonhuman | en |
dc.subject | nuclear magnetic resonance | en |
dc.subject | stereochemistry | en |
dc.subject | tautomer | en |
dc.subject | tautomerization | en |
dc.subject | X ray crystallography | en |
dc.subject | animal | en |
dc.subject | chemistry | en |
dc.subject | conformation | en |
dc.subject | enzyme active site | en |
dc.subject | kinetics | en |
dc.subject | metabolism | en |
dc.subject | stereoisomerism | en |
dc.subject | synthesis | en |
dc.subject | X ray crystallography | en |
dc.subject | Animals | en |
dc.subject | Catalytic Domain | en |
dc.subject | Crystallography, X-Ray | en |
dc.subject | Enzyme Inhibitors | en |
dc.subject | Glucosides | en |
dc.subject | Glycogen Phosphorylase | en |
dc.subject | Hep G2 Cells | en |
dc.subject | Humans | en |
dc.subject | Hydrogen Bonding | en |
dc.subject | Imidazolines | en |
dc.subject | Kinetics | en |
dc.subject | Models, Molecular | en |
dc.subject | Molecular Conformation | en |
dc.subject | Protein Binding | en |
dc.subject | Rabbits | en |
dc.subject | Spiro Compounds | en |
dc.subject | Stereoisomerism | en |
dc.subject | American Chemical Society | en |
dc.title | Glucopyranosylidene-spiro-imidazolinones, a New Ring System: Synthesis and Evaluation as Glycogen Phosphorylase Inhibitors by Enzyme Kinetics and X-ray Crystallography | en |
dc.type | journalArticle | en |
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