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 (1) , T. Legigan (1) , A. Martin-Mingot (1) , S. Thibaudeau (1) , I. Adachi (2) , M. Forcella (3) , P. Parenti (3) , J. Bertrand (4) , F. Becq (4) , C. Norez (4) , J. Désiré (1) , A. Kato (5) , Y. Blériot (1)

1 IC2MP [Poitiers] - Institut de chimie des milieux et matériaux de Poitiers [UMR 7285]
2 Department of Hospital Pharmacy [Toyama]
3 UNIMIB - Università degli Studi di Milano-Bicocca = University of Milano-Bicocca
4 STIM [Poitiers] - Signalisation et Transports Ioniques Membranaires
5 University of Toyama

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.

Domaines: Chimie thérapeutique

V. Cendret, T. Legigan, A. Martin-Mingot, S. Thibaudeau, I. Adachi, et al.. 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.. Organic & Biomolecular Chemistry, 2015, 13 (43), pp.10734-10744. ⟨10.1039/c5ob01526j⟩. ⟨hal-01500682⟩