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

• Published in: Organic & biomolecular chemistry 2015-01, Vol.13 (43), p.10734-10744
• Main Authors: Cendret, V, Legigan, T, Mingot, A, Thibaudeau, S, Adachi, I, Forcella, M, Parenti, P, Bertrand, J, Becq, F, Norez, C, Désiré, J, Kato, A, Blériot, Y
• Format: Article
• Language: English
• Subjects: 1-Deoxynojirimycin - analogs & derivatives; 1-Deoxynojirimycin - pharmacology; alpha-Glucosidases - metabolism; Animals; Chemical Sciences; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Glycoside Hydrolase Inhibitors - chemistry; Glycoside Hydrolase Inhibitors - pharmacology; Halogenation; Humans; Insecta; Medicinal Chemistry; Mutation; Sulfhydryl Compounds - chemistry; Sulfhydryl Compounds - pharmacology; Swine; Trehalase - antagonists & inhibitors; Trehalase - metabolism
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c5ob01526j

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.