title: N- and C-alkylation of seven-membered iminosugars generates potent glucocerebrosidase inhibitors and F508del-CFTR correctors.
abstract: The glycosidase inhibitory properties of synthetic C-alkyl and N-alkyl six-membered iminosugars have been extensively studied leading to therapeutic candidates. The related seven-membered iminocyclitols have been less examined despite the report of promising structures. Using an in house ring enlargement/C-alkylation as well as cross-metathesis methodologies as the key steps, we have undertaken the synthesis and biological evaluation of a library of fourteen 2C- and eight N-alkyl tetrahydroxylated azepanes starting from an easily available glucopyranose-derived azidolactol. Four, six, nine and twelve carbon atom alkyl chains have been introduced. The study of two distinct D-gluco and L-ido stereochemistries for the tetrol pattern as well as R and S configurations for the C-2 carbon bearing the C-alkyl chain is reported. We observed that C-alkylation of the L-ido tetrahydroxylated azepane converts it from an α-L-fucosidase to a β-glucosidase and β-galactosidase inhibitor while N-alkylation of the D-gluco iminosugar significantly improves its inhibition profile leading to potent β-glucosidase, β-galactosidase, α-L-rhamnosidase and β-glucuronidase inhibitors whatever the stereochemistry of the alkyl chain. Interestingly, the N-alkyl chain length usually parallels the azepane inhibitor potency as exemplified by the identification of a potent glucocerebrosidase inhibitor (Ki 1 μM) bearing a twelve carbon atom chain. Additionally, several C-alkyl azepanes demonstrated promising F508del-CFTR correction unlike the parent tetrahydroxyazepanes. None of the C-alkyl and N-alkyl azepanes did inhibit ER α-glucosidases I or II.
authors.affiliation: UMR-CNRS7285, IC2MP, Equipe "Synthèse Organique", Groupe "Glycochimie", Université de Poitiers, 4 rue Michel Brunet, 86073 Poitiers Cedex 9, France. jerome.desire@univ-poitiers.fr yves.bleriot@univ-poitiers.fr.
authors.forename: J
authors.initials: J
authors.lastname: Désiré
authors.forename: M
authors.initials: M
authors.lastname: Mondon
authors.forename: N
authors.initials: N
authors.lastname: Fontelle
authors.forename: S
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Y
authors.initials: Y
authors.lastname: Hirokami
authors.forename: I
authors.initials: I
authors.lastname: Adachi
authors.forename: R
authors.initials: R
authors.lastname: Iwaki
authors.forename: G W J
authors.initials: GW
authors.lastname: Fleet
authors.forename: D S
authors.initials: DS
authors.lastname: Alonzi
authors.forename: G
authors.initials: G
authors.lastname: Twigg
authors.forename: T D
authors.initials: TD
authors.lastname: Butters
authors.forename: J
authors.initials: J
authors.lastname: Bertrand
authors.forename: V
authors.initials: V
authors.lastname: Cendret
authors.forename: F
authors.initials: F
authors.lastname: Becq
authors.forename: C
authors.initials: C
authors.lastname: Norez
authors.forename: J
authors.initials: J
authors.lastname: Marrot
authors.forename: A
authors.initials: A
authors.lastname: Kato
authors.forename: Y
authors.initials: Y
authors.lastname: Blériot
mesh_terms: D000478:Alkylation; D018360:Crystallography, X-Ray; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D050111:Imino Sugars / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D050111:Imino Sugars; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005962:Glucosylceramidase