title: 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.
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.
authors.affiliation: Université de Poitiers, IC2MP, UMR CNRS 7285 Equipe"Synthèse Organique"4 rue Michel Brunet, 86073 Poitiers cedex 09, France. Jerome.desire@univ-poitiers.fr yves.bleriot@univ-poitiers.fr.
authors.forename: V
authors.initials: V
authors.lastname: Cendret
authors.affiliation: Université de Poitiers, IC2MP, UMR CNRS 7285 Equipe"Synthèse Organique"4 rue Michel Brunet, 86073 Poitiers cedex 09, France. Jerome.desire@univ-poitiers.fr yves.bleriot@univ-poitiers.fr.
authors.forename: T
authors.initials: T
authors.lastname: Legigan
authors.affiliation: Université de Poitiers, IC2MP, UMR CNRS 7285 Equipe"Synthèse Organique"4 rue Michel Brunet, 86073 Poitiers cedex 09, France. Jerome.desire@univ-poitiers.fr yves.bleriot@univ-poitiers.fr.
authors.forename: A
authors.initials: A
authors.lastname: Mingot
authors.affiliation: Université de Poitiers, IC2MP, UMR CNRS 7285 Equipe"Synthèse Organique"4 rue Michel Brunet, 86073 Poitiers cedex 09, France. Jerome.desire@univ-poitiers.fr yves.bleriot@univ-poitiers.fr.
authors.forename: S
authors.initials: S
authors.lastname: Thibaudeau
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. kato@med.u-toyama.ac.jp.
authors.forename: I
authors.initials: I
authors.lastname: Adachi
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza del Scienza 2, 20126 Milano, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Forcella
authors.affiliation: Department of Earth and Environmental Sciences, University of Milano-Bicocca, Piazza del Scienza 1, 20126 Milano, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Parenti
authors.affiliation: Laboratoire STIM Signalisation et Transports Ioniques Membranaires, ERL7368 (0864)- CNRS/Université de Poitiers, TSA 51106 - 1, rue Georges Bonnet, 86073 Poitiers Cedex 9, France.
authors.forename: J
authors.initials: J
authors.lastname: Bertrand
authors.affiliation: Laboratoire STIM Signalisation et Transports Ioniques Membranaires, ERL7368 (0864)- CNRS/Université de Poitiers, TSA 51106 - 1, rue Georges Bonnet, 86073 Poitiers Cedex 9, France.
authors.forename: F
authors.initials: F
authors.lastname: Becq
authors.affiliation: Laboratoire STIM Signalisation et Transports Ioniques Membranaires, ERL7368 (0864)- CNRS/Université de Poitiers, TSA 51106 - 1, rue Georges Bonnet, 86073 Poitiers Cedex 9, France.
authors.forename: C
authors.initials: C
authors.lastname: Norez
authors.affiliation: Université de Poitiers, IC2MP, UMR CNRS 7285 Equipe"Synthèse Organique"4 rue Michel Brunet, 86073 Poitiers cedex 09, France. Jerome.desire@univ-poitiers.fr yves.bleriot@univ-poitiers.fr.
authors.forename: J
authors.initials: J
authors.lastname: Désiré
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. kato@med.u-toyama.ac.jp.
authors.forename: A
authors.initials: A
authors.lastname: Kato
authors.affiliation: Université de Poitiers, IC2MP, UMR CNRS 7285 Equipe"Synthèse Organique"4 rue Michel Brunet, 86073 Poitiers cedex 09, France. Jerome.desire@univ-poitiers.fr yves.bleriot@univ-poitiers.fr.
authors.forename: Y
authors.initials: Y
authors.lastname: Blériot
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D065089:Glycoside Hydrolase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D054879:Halogenation; D006801:Humans; D007313:Insecta; D009154:Mutation; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology; D013552:Swine; D014198:Trehalase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000520:alpha-Glucosidases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D013438:Sulfhydryl Compounds; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D017485:1-Deoxynojirimycin; D000520:alpha-Glucosidases; D014198:Trehalase