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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Deoxynojirimycin / analogs & derivatives*
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1-Deoxynojirimycin / pharmacology
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Animals
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Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
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Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Glycoside Hydrolase Inhibitors / chemistry*
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Glycoside Hydrolase Inhibitors / pharmacology
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Halogenation
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Humans
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Insecta
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Mutation
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Sulfhydryl Compounds / chemistry
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Sulfhydryl Compounds / pharmacology
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Swine
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Trehalase / antagonists & inhibitors*
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Trehalase / metabolism
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alpha-Glucosidases / metabolism
Substances
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Enzyme Inhibitors
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Glycoside Hydrolase Inhibitors
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Sulfhydryl Compounds
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Cystic Fibrosis Transmembrane Conductance Regulator
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1-Deoxynojirimycin
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alpha-Glucosidases
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Trehalase