N- and C-alkylation of seven-membered iminosugars generates potent glucocerebrosidase inhibitors and F508del-CFTR correctors.

Désiré, J; Mondon, M; Fontelle, N; Nakagawa, S; Hirokami, Y; Adachi, I; Iwaki, R; Fleet, G; Alonzi, D; Twigg, G; Butters, T; Bertrand, J; Cendret, V; Becq, F; Norez, C; Marrot, J; Kato, A; Blériot, Y

Journal article

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.

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APA Style

Désiré, J., Mondon, M., Fontelle, N., Nakagawa, S., Hirokami, Y., Adachi, I., Iwaki, R., Fleet, G., Alonzi, D., Twigg, G., Butters, T., Bertrand, J., Cendret, V., Becq, F., Norez, C., Marrot, J., Kato, A., & Blériot, Y. (2014). N- and C-alkylation of seven-membered iminosugars generates potent glucocerebrosidase inhibitors and F508del-CFTR correctors. Organic and Biomolecular Chemistry, 12(44), 8977–8996.

MLA Style

Désiré, J., et al. “N- And C-Alkylation of Seven-Membered Iminosugars Generates Potent Glucocerebrosidase Inhibitors and F508del-CFTR Correctors.” Organic and Biomolecular Chemistry, vol. 12, no. 44, Royal Society of Chemistry, 2014, pp. 8977–96.

Chicago Style

Désiré, J, M Mondon, N Fontelle, S Nakagawa, Y Hirokami, I Adachi, R Iwaki, et al. 2014. “N- And C-Alkylation of Seven-Membered Iminosugars Generates Potent Glucocerebrosidase Inhibitors and F508del-CFTR Correctors.” Organic and Biomolecular Chemistry 12 (44): 8977–96.
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