Glucopyranosylidene-spiro-iminothiazolidinone, a new bicyclic ring system

Synthesis, derivatization, and evaluation for inhibition of glycogen phosphorylase by enzyme kinetic and crystallographic methods

K. Czifrák, András Páhi, Szabina Deák, Attila Kiss-Szikszai, K. Kövér, T. Docsa, P. Gergely, Kyra Melinda Alexacou, Maria Papakonstantinou, Demetres D. Leonidas, Spyros E. Zographos, Evangelia D. Chrysina, L. Somsák

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 = 9 μM) 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.

Original languageEnglish
Pages (from-to)4028-4041
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number15
DOIs
Publication statusPublished - Aug 1 2014

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Phosphorylase b
Enzyme inhibition
Glycogen Phosphorylase
Enzyme kinetics
Muscle
Ethylene Dibromide
Rabbits
Acylation
Muscles
Thiourea
Sorbitol
Alkylation
Enzymes
Conformations
Chlorides
Catalytic Domain
Derivatives

Keywords

  • Anomeric spirocycle
  • Glycogen phosphorylase
  • Inhibitor
  • Structure-based drug design
  • Thiazolidinone
  • Type 2 diabetes
  • X-ray protein crystallography

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Glucopyranosylidene-spiro-iminothiazolidinone, a new bicyclic ring system : Synthesis, derivatization, and evaluation for inhibition of glycogen phosphorylase by enzyme kinetic and crystallographic methods. / Czifrák, K.; Páhi, András; Deák, Szabina; Kiss-Szikszai, Attila; Kövér, K.; Docsa, T.; Gergely, P.; Alexacou, Kyra Melinda; Papakonstantinou, Maria; Leonidas, Demetres D.; Zographos, Spyros E.; Chrysina, Evangelia D.; Somsák, L.

In: Bioorganic and Medicinal Chemistry, Vol. 22, No. 15, 01.08.2014, p. 4028-4041.

Research output: Contribution to journalArticle

Czifrák, K. ; Páhi, András ; Deák, Szabina ; Kiss-Szikszai, Attila ; Kövér, K. ; Docsa, T. ; Gergely, P. ; Alexacou, Kyra Melinda ; Papakonstantinou, Maria ; Leonidas, Demetres D. ; Zographos, Spyros E. ; Chrysina, Evangelia D. ; Somsák, L. / Glucopyranosylidene-spiro-iminothiazolidinone, a new bicyclic ring system : Synthesis, derivatization, and evaluation for inhibition of glycogen phosphorylase by enzyme kinetic and crystallographic methods. In: Bioorganic and Medicinal Chemistry. 2014 ; Vol. 22, No. 15. pp. 4028-4041.
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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 Zempl{\'e}n 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 = 9 μM) 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.",
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T2 - Synthesis, derivatization, and evaluation for inhibition of glycogen phosphorylase by enzyme kinetic and crystallographic methods

AU - Czifrák, K.

AU - Páhi, András

AU - Deák, Szabina

AU - Kiss-Szikszai, Attila

AU - Kövér, K.

AU - Docsa, T.

AU - Gergely, P.

AU - Alexacou, Kyra Melinda

AU - Papakonstantinou, Maria

AU - Leonidas, Demetres D.

AU - Zographos, Spyros E.

AU - Chrysina, Evangelia D.

AU - Somsák, L.

PY - 2014/8/1

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N2 - 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 = 9 μM) 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.

AB - 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 = 9 μM) 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.

KW - Anomeric spirocycle

KW - Glycogen phosphorylase

KW - Inhibitor

KW - Structure-based drug design

KW - Thiazolidinone

KW - Type 2 diabetes

KW - X-ray protein crystallography

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