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Issue 43, 2015
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Synthetic deoxynojirimycin derivatives bearing a thiolated, fluorinated or unsaturated N-alkyl chain: identification of potent α-glucosidase and trehalase inhibitors as well as F508del-CFTR correctors

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Abstract

The synthesis of eleven 1-deoxynojirimycin (DNJ) derivatives presenting either a monofluoro, difluoro, thiolated or unsaturated N-alkyl chain of various length is described. Exploiting the unsaturated moiety on the nitrogen, fluorine has been introduced through a HF/SbF5 superacid catalysed hydrofluorination and thiol–ene click chemistry allowed introduction of sulfur. The synthetic derivatives have been tested for their ability to inhibit glycosidases and correct F508del-CFTR. Two of the unsaturated iminosugars exhibited potency similar to Miglustat as F508del-CFTR correctors. The thioalkyl iminosugars as well as the corresponding alkyl iminosugars demonstrated low micromolar α-glucosidases and trehalases inhibition. Introduction of fluorine abolished F508del-CFTR correction and trehalase inhibition.

Graphical abstract: Synthetic deoxynojirimycin derivatives bearing a thiolated, fluorinated or unsaturated N-alkyl chain: identification of potent α-glucosidase and trehalase inhibitors as well as F508del-CFTR correctors

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Supplementary files

Article information


Submitted
23 Jul 2015
Accepted
03 Sep 2015
First published
03 Sep 2015

Org. Biomol. Chem., 2015,13, 10734-10744
Article type
Paper

Synthetic deoxynojirimycin derivatives bearing a thiolated, fluorinated or unsaturated N-alkyl chain: identification of potent α-glucosidase and trehalase inhibitors as well as F508del-CFTR correctors

V. Cendret, T. Legigan, A. Mingot, S. Thibaudeau, I. Adachi, M. Forcella, P. Parenti, J. Bertrand, F. Becq, C. Norez, J. Désiré, A. Kato and Y. Blériot, Org. Biomol. Chem., 2015, 13, 10734
DOI: 10.1039/C5OB01526J

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