4CTO

Glucopyranosylidene-spiro-iminothiazolidinone, a New Bicyclic Ring System: Synthesis, Derivatization, and Evaluation as Glycogen Phosphorylase Inhibitors by Enzyme Kinetic and Crystallographic Methods

Summary for 4CTO

• Entry DOI: 10.2210/pdb4cto/pdb
• Related: 4CTM 4CTN
• Descriptor: GLYCOGEN PHOSPHORYLASE, MUSCLE FORM, N-[(2Z,5R,7R,8S,9S,10R)-8,9,10-trihydroxy-7-(hydroxymethyl)-4-oxo-6-oxa-1-thia-3-azaspiro[4.5]dec-2-ylidene]benzamide, PYRIDOXAL-5'-PHOSPHATE, ... (5 entities in total)
• Functional Keywords: transferase, type 2 diabetes, inhibitor, structure-based drug design
• Biological source: ORYCTOLAGUS CUNICULUS (RABBIT)
• Total number of polymer chains: 1
• Total formula weight: 98132.87

Authors

Alexacou, K.M.,Papakonstantinou, M.,Leonidas, D.D.,Zographos, S.E.,Chrysina, E.D. (deposition date: 2014-03-15, release date: 2014-08-06, Last modification date: 2023-12-20)

Primary citation

Czifrak, K.,Deak, S.,Pahi, A.,Kover, K.E.,Docsa, T.,Gergely, P.,Alexacou, K.M.,Papakonstantinou, M.,Leonidas, D.D.,Zographos, S.E.,Chrysina, E.D.,Somsak, L.
Glucopyranosylidene-Spiro-Iminothiazolidinone, a New Bicyclic Ring System: Synthesis, Derivatization, and Evaluation for Inhibition of Glycogen Phosphorylase by Enzyme Kinetic and Crystallographic Methods.
Bioorg.Med.Chem., 22:4028-, 2014

PubMed 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.

PubMed: 25009003
DOI: 10.1016/J.BMC.2014.05.076

Experimental method

X-RAY DIFFRACTION (1.9 Å)