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Issue 30, 2019
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The uncommon strong inhibition of α-glucosidase by multivalent glycoclusters based on cyclodextrin scaffolds

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Abstract

The homeostasis disruption of D-glucose causes diabetes, a dramatic chronic disease worldwide. Type 1 diabetes is a successfully treatable form, where blood D-glucose is regulated by insulin treatment. In contrast type 2 diabetes, the non-insulin dependent kind, is problematic. The control of the D-glucose blood level via intestinal α-D-glucosidase inactivation can be achieved by using competitive inhibitors, such as iminosugars (e.g. acarbose) or sulfonium sugar derivatives (e.g. salacinol). Recently, an unprecedented result showed that multivalent diamond nanoparticles grafted with unmodified sugars displayed α-glucosidase inhibition at low micromolar concentrations. Herein we describe the synthesis of multivalent glycoclusters using cyclodextrins (CDs) as scaffolds and an assessment of their role as inhibitors of α-D-glucosidase. The glycoclusters were efficiently obtained from per-azido α, β and γ-CD derivatives and propargyl glycosides using click-chemistry under microwave irradiation. The methodology was successfully applied to various protected and non-protected propargylated monosaccharides, including both O- and S-glycosides, giving clear evidence of its versatility. The targeted 6-per-glycosylated CDs were isolated in moderate to excellent yields (30–90%) by silica gel chromatography. The results showed inhibition of α-glucosidase from Saccharomyces cerevisiae with IC50 values in the 32–132 μM range, lower than that of acarbose (IC50 = ∼250 μM), a well-known competitive inhibitor used in the clinical treatment of type 2 diabetes. Preliminary experiments suggest a mixed-type non-competitive inhibition mode for these new glycoclusters.

Graphical abstract: The uncommon strong inhibition of α-glucosidase by multivalent glycoclusters based on cyclodextrin scaffolds

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Supplementary files

Article information


Submitted
13 Jun 2019
Accepted
01 Jul 2019
First published
02 Jul 2019

Org. Biomol. Chem., 2019,17, 7228-7237
Article type
Paper

The uncommon strong inhibition of α-glucosidase by multivalent glycoclusters based on cyclodextrin scaffolds

U. Alali, A. Vallin, A. Bil, T. Khanchouche, D. Mathiron, C. Przybylski, R. Beaulieu, J. Kovensky, M. Benazza and V. Bonnet, Org. Biomol. Chem., 2019, 17, 7228
DOI: 10.1039/C9OB01344J

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