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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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Publication details

The article was received on 23 Jul 2015, accepted on 03 Sep 2015 and first published on 03 Sep 2015


Article type: Paper
DOI: 10.1039/C5OB01526J
Citation: Org. Biomol. Chem., 2015,13, 10734-10744
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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

    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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