Synthesis of New C- and N-β-D-Glucopyranosyl Derivatives of Imidazole, 1,2,3-Triazole and Tetrazole, and Their Evaluation as Inhibitors of Glycogen Phosphorylase

Sándor Kun, Éva Bokor, Ádám Sipos, Tibor Docsa, László Somsák

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Abstract

The aim of the present study was to broaden the structure-activity relationships of C- and N-β-D-glucopyranosyl azole type inhibitors of glycogen phosphorylase. 1-Aryl-4-β-D-gluco-pyranosyl-1,2,3-triazoles were prepared by copper catalyzed azide-alkyne cycloadditions between O-perbenzylated or O-peracetylated β-D-glucopyranosyl ethynes and aryl azides. 1-β-D-Gluco-pyranosyl-4-phenyl imidazole was obtained in a glycosylation of 4(5)-phenylimidazole with O-peracetylated α-D-glucopyranosyl bromide. C-β-D-Glucopyranosyl-N-substituted-tetrazoles were synthesized by alkylation/arylation of O-perbenzoylated 5-β-D-glucopyranosyl-tetrazole or from a 2,6-anhydroheptose tosylhydrazone and arenediazonium salts. 5-Substituted tetrazoles were glycosylated by O-peracetylated α-D-glucopyranosyl bromide to give N-β-D-glucopyranosyl-C-substituted-tetrazoles. Standard deprotections gave test compounds which were assayed against rabbit muscle glycogen phosphorylase b. Most of the compounds proved inactive, the best inhibitor was 2-β-D-glucopyranosyl-5-phenyltetrazole (IC50 600 µM). These studies extended the structure-activity relationships of β-D-glucopyranosyl azole type inhibitors and revealed the extreme sensitivity of such type of inhibitors towards the structure of the azole moiety.

Original languageEnglish
Article number666
JournalMolecules
Volume23
Issue number3
DOIs
Publication statusPublished - Jan 1 2018

Fingerprint

Tetrazoles
glycogens
tetrazoles
Glycogen Phosphorylase
Azoles
Triazoles
azoles
imidazoles
inhibitors
Azides
Structure-Activity Relationship
Derivatives
Bromides
evaluation
synthesis
Phosphorylase b
Glycosylation
bromides
Dilatation and Curettage
Acetylene

Keywords

  • 1,2,3-triazole
  • C-glucosyl heterocycle
  • Glycogen phosphorylase
  • Imidazole
  • Inhibitor
  • N-glucosyl heterocycle
  • Structure-activity relationship
  • Tetrazole

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

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title = "Synthesis of New C- and N-β-D-Glucopyranosyl Derivatives of Imidazole, 1,2,3-Triazole and Tetrazole, and Their Evaluation as Inhibitors of Glycogen Phosphorylase",
abstract = "The aim of the present study was to broaden the structure-activity relationships of C- and N-β-D-glucopyranosyl azole type inhibitors of glycogen phosphorylase. 1-Aryl-4-β-D-gluco-pyranosyl-1,2,3-triazoles were prepared by copper catalyzed azide-alkyne cycloadditions between O-perbenzylated or O-peracetylated β-D-glucopyranosyl ethynes and aryl azides. 1-β-D-Gluco-pyranosyl-4-phenyl imidazole was obtained in a glycosylation of 4(5)-phenylimidazole with O-peracetylated α-D-glucopyranosyl bromide. C-β-D-Glucopyranosyl-N-substituted-tetrazoles were synthesized by alkylation/arylation of O-perbenzoylated 5-β-D-glucopyranosyl-tetrazole or from a 2,6-anhydroheptose tosylhydrazone and arenediazonium salts. 5-Substituted tetrazoles were glycosylated by O-peracetylated α-D-glucopyranosyl bromide to give N-β-D-glucopyranosyl-C-substituted-tetrazoles. Standard deprotections gave test compounds which were assayed against rabbit muscle glycogen phosphorylase b. Most of the compounds proved inactive, the best inhibitor was 2-β-D-glucopyranosyl-5-phenyltetrazole (IC50 600 µM). These studies extended the structure-activity relationships of β-D-glucopyranosyl azole type inhibitors and revealed the extreme sensitivity of such type of inhibitors towards the structure of the azole moiety.",
keywords = "1,2,3-triazole, C-glucosyl heterocycle, Glycogen phosphorylase, Imidazole, Inhibitor, N-glucosyl heterocycle, Structure-activity relationship, Tetrazole",
author = "S{\'a}ndor Kun and {\'E}va Bokor and {\'A}d{\'a}m Sipos and Tibor Docsa and L{\'a}szl{\'o} Soms{\'a}k",
year = "2018",
month = "1",
day = "1",
doi = "10.3390/molecules23030666",
language = "English",
volume = "23",
journal = "Molecules",
issn = "1420-3049",
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TY - JOUR

T1 - Synthesis of New C- and N-β-D-Glucopyranosyl Derivatives of Imidazole, 1,2,3-Triazole and Tetrazole, and Their Evaluation as Inhibitors of Glycogen Phosphorylase

AU - Kun, Sándor

AU - Bokor, Éva

AU - Sipos, Ádám

AU - Docsa, Tibor

AU - Somsák, László

PY - 2018/1/1

Y1 - 2018/1/1

N2 - The aim of the present study was to broaden the structure-activity relationships of C- and N-β-D-glucopyranosyl azole type inhibitors of glycogen phosphorylase. 1-Aryl-4-β-D-gluco-pyranosyl-1,2,3-triazoles were prepared by copper catalyzed azide-alkyne cycloadditions between O-perbenzylated or O-peracetylated β-D-glucopyranosyl ethynes and aryl azides. 1-β-D-Gluco-pyranosyl-4-phenyl imidazole was obtained in a glycosylation of 4(5)-phenylimidazole with O-peracetylated α-D-glucopyranosyl bromide. C-β-D-Glucopyranosyl-N-substituted-tetrazoles were synthesized by alkylation/arylation of O-perbenzoylated 5-β-D-glucopyranosyl-tetrazole or from a 2,6-anhydroheptose tosylhydrazone and arenediazonium salts. 5-Substituted tetrazoles were glycosylated by O-peracetylated α-D-glucopyranosyl bromide to give N-β-D-glucopyranosyl-C-substituted-tetrazoles. Standard deprotections gave test compounds which were assayed against rabbit muscle glycogen phosphorylase b. Most of the compounds proved inactive, the best inhibitor was 2-β-D-glucopyranosyl-5-phenyltetrazole (IC50 600 µM). These studies extended the structure-activity relationships of β-D-glucopyranosyl azole type inhibitors and revealed the extreme sensitivity of such type of inhibitors towards the structure of the azole moiety.

AB - The aim of the present study was to broaden the structure-activity relationships of C- and N-β-D-glucopyranosyl azole type inhibitors of glycogen phosphorylase. 1-Aryl-4-β-D-gluco-pyranosyl-1,2,3-triazoles were prepared by copper catalyzed azide-alkyne cycloadditions between O-perbenzylated or O-peracetylated β-D-glucopyranosyl ethynes and aryl azides. 1-β-D-Gluco-pyranosyl-4-phenyl imidazole was obtained in a glycosylation of 4(5)-phenylimidazole with O-peracetylated α-D-glucopyranosyl bromide. C-β-D-Glucopyranosyl-N-substituted-tetrazoles were synthesized by alkylation/arylation of O-perbenzoylated 5-β-D-glucopyranosyl-tetrazole or from a 2,6-anhydroheptose tosylhydrazone and arenediazonium salts. 5-Substituted tetrazoles were glycosylated by O-peracetylated α-D-glucopyranosyl bromide to give N-β-D-glucopyranosyl-C-substituted-tetrazoles. Standard deprotections gave test compounds which were assayed against rabbit muscle glycogen phosphorylase b. Most of the compounds proved inactive, the best inhibitor was 2-β-D-glucopyranosyl-5-phenyltetrazole (IC50 600 µM). These studies extended the structure-activity relationships of β-D-glucopyranosyl azole type inhibitors and revealed the extreme sensitivity of such type of inhibitors towards the structure of the azole moiety.

KW - 1,2,3-triazole

KW - C-glucosyl heterocycle

KW - Glycogen phosphorylase

KW - Imidazole

KW - Inhibitor

KW - N-glucosyl heterocycle

KW - Structure-activity relationship

KW - Tetrazole

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U2 - 10.3390/molecules23030666

DO - 10.3390/molecules23030666

M3 - Article

VL - 23

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 3

M1 - 666

ER -