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Molecules 2018, 23(3), 666; https://doi.org/10.3390/molecules23030666

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

1
Department of Organic Chemistry, University of Debrecen, P.O. Box 400, H-4002 Debrecen, Hungary
2
Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
*
Author to whom correspondence should be addressed.
Received: 27 February 2018 / Revised: 7 March 2018 / Accepted: 13 March 2018 / Published: 15 March 2018
(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)
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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. View Full-Text
Keywords: C-glucosyl heterocycle; N-glucosyl heterocycle; 1,2,3-triazole; imidazole; tetrazole; glycogen phosphorylase; inhibitor; structure-activity relationship C-glucosyl heterocycle; N-glucosyl heterocycle; 1,2,3-triazole; imidazole; tetrazole; glycogen phosphorylase; inhibitor; structure-activity relationship
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Kun, S.; Bokor, É.; Sipos, Á.; Docsa, T.; Somsák, L. 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. Molecules 2018, 23, 666.

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