N- and C-alkylation of seven-membered iminosugars generates potent glucocerebrosidase inhibitors and F508del-CFTR correctorsElectronic supplementary information (ESI) available: Copies of the 1H and 13C spectra. CCDC 970784. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ob00325j

• Main Authors: Désiré, J, Mondon, M, Fontelle, N, Nakagawa, S, Hirokami, Y, Adachi, I, Iwaki, R, Fleet, G. W. J, Alonzi, D. S, Twigg, G, Butters, T. D, Bertrand, J, Cendret, V, Becq, F, Norez, C, Marrot, J, Kato, A, Blériot, Y
• Format: Article
• Language: English
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c4ob00325j

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 2 C - 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 ( K i 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. The synthesis and biological evaluation of a library of novel seven-membered iminosugars is reported.