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Article Dans Une Revue Organic & Biomolecular Chemistry Année : 2019

The Uncommon Strong Inhibition of α-Glucosidase by Multivalent Glycoclusters Based on Cyclodextrin Scaffolds

David Mathiron

Résumé

New inhibitors of α-glucosidase based on perglycosylated cyclodextrins were synthesized via click-chemistry and compared to acarbose. , 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\textendash 90%) by silica gel chromatography. The results showed inhibition of α-glucosidase from Saccharomyces cerevisiae with IC 50 values in the 32\textendash 132 μM range, lower than that of acarbose (IC 50 = ∼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.

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Dates et versions

hal-02885917 , version 1 (01-07-2020)

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Urjwan Alali, Aurélie Vallin, Abed Bil, Takwa Khanchouche, David Mathiron, et al.. The Uncommon Strong Inhibition of α-Glucosidase by Multivalent Glycoclusters Based on Cyclodextrin Scaffolds. Organic & Biomolecular Chemistry, 2019, 17 (30), pp.7228--7237. ⟨10.1039/C9OB01344J⟩. ⟨hal-02885917⟩
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