Synthetic, enzyme kinetic, and protein crystallographic studies of C-β-D-glucopyranosyl pyrroles and imidazoles reveal and explain low nanomolar inhibition of human liver glycogen phosphorylase

Anastassia L. Kantsadi, Éva Bokor, Sándor Kun, George A. Stravodimos, Demetra S M Chatzileontiadou, Demetres D. Leonidas, Éva Juhász-Tóth, Andrea Szakács, G. Batta, T. Docsa, P. Gergely, L. Somsák

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

C-β-D-Glucopyranosyl pyrrole derivatives were prepared in the reactions of pyrrole, 2-, and 3-aryl-pyrroles with O-peracetylated β-D-glucopyranosyl trichloroacetimidate, while 2-(β-D-glucopyranosyl) indole was obtained by a cross coupling of O-perbenzylated β-D-glucopyranosyl acetylene with N-tosyl-2-iodoaniline followed by spontaneous ring closure. An improved synthesis of O-perbenzoylated 2-(β-D-glucopyranosyl) imidazoles was achieved by reacting C-glucopyranosyl formimidates with α-aminoketones. The deprotected compounds were assayed with isoforms of glycogen phosphorylase (GP) to show no activity of the pyrroles against rabbit muscle GPb. The imidazoles proved to be the best known glucose derived inhibitors of not only the muscle enzymes (both a and b) but also of the pharmacologically relevant human liver GPa (Ki = 156 and 26 nM for the 4(5)-phenyl and -(2-naphthyl) derivatives, respectively). An X-ray crystallographic study of the rmGPb-imidazole complexes revealed structural features of the strong binding, and also allowed to explain the absence of inhibition for the pyrrole derivatives.

Original languageEnglish
Pages (from-to)737-745
Number of pages9
JournalEuropean Journal of Medicinal Chemistry
Volume123
DOIs
Publication statusPublished - Nov 10 2016

Fingerprint

Imidazoles
Glycogen Phosphorylase
Enzyme kinetics
Liver Glycogen
Pyrroles
Enzymes
Proteins
Derivatives
Muscle
Acetylene
Muscles
Liver
Protein Isoforms
X-Rays
Rabbits
Glucose
X rays

Keywords

  • C-Glucopyranosyl derivative
  • Diabetes type 2
  • Glycogen phosphorylase inhibitor
  • Imidazole
  • Indole
  • Pyrrole

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Synthetic, enzyme kinetic, and protein crystallographic studies of C-β-D-glucopyranosyl pyrroles and imidazoles reveal and explain low nanomolar inhibition of human liver glycogen phosphorylase. / Kantsadi, Anastassia L.; Bokor, Éva; Kun, Sándor; Stravodimos, George A.; Chatzileontiadou, Demetra S M; Leonidas, Demetres D.; Juhász-Tóth, Éva; Szakács, Andrea; Batta, G.; Docsa, T.; Gergely, P.; Somsák, L.

In: European Journal of Medicinal Chemistry, Vol. 123, 10.11.2016, p. 737-745.

Research output: Contribution to journalArticle

Kantsadi, Anastassia L. ; Bokor, Éva ; Kun, Sándor ; Stravodimos, George A. ; Chatzileontiadou, Demetra S M ; Leonidas, Demetres D. ; Juhász-Tóth, Éva ; Szakács, Andrea ; Batta, G. ; Docsa, T. ; Gergely, P. ; Somsák, L. / Synthetic, enzyme kinetic, and protein crystallographic studies of C-β-D-glucopyranosyl pyrroles and imidazoles reveal and explain low nanomolar inhibition of human liver glycogen phosphorylase. In: European Journal of Medicinal Chemistry. 2016 ; Vol. 123. pp. 737-745.
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AU - Kantsadi, Anastassia L.

AU - Bokor, Éva

AU - Kun, Sándor

AU - Stravodimos, George A.

AU - Chatzileontiadou, Demetra S M

AU - Leonidas, Demetres D.

AU - Juhász-Tóth, Éva

AU - Szakács, Andrea

AU - Batta, G.

AU - Docsa, T.

AU - Gergely, P.

AU - Somsák, L.

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