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.

DOI: 10.1016/j.bmc.2014.05.076

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Cite this paper

@article{Czifrk2014Glucopyranosylidenespiroiminothiazo, title={Glucopyranosylidene-spiro-iminothiazolidinone, a new bicyclic ring system: synthesis, derivatization, and evaluation for inhibition of glycogen phosphorylase by enzyme kinetic and crystallographic methods.}, author={Katalin Czifr{\'a}k and Andras Pahi and Szabina De{\'a}k and Attila Kiss-Szikszai and Katalin E. K{\"{o}v{\'e}r and Tibor Docsa and P{\'a}l Gergely and Kyra-Melinda Alexacou and Maria Papakonstantinou and Demetres D Leonidas and Spyros E Zographos and Evangelia D Chrysina and L{\'a}szl{\'o} Soms{\'a}k}, journal={Bioorganic & medicinal chemistry}, year={2014}, volume={22 15}, pages={4028-41} }