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.

Therapeutic significance of β-glucuronidase activity and its inhibitors: A review

“…However, increasing the lipophilicity of azepane scaffold 84 via C-2 or N-alkylation, while tuning the configuration of alkyl and hydroxy substituents at C-2 and C-6 respectively (Fig. 14b), birthed E. coli bGLU inhibitors with markedly increased potency and highly conserved selectivity [182]. SAR analysis revealed that a combination of (6S)eOH unit and N-alkylation with hexyl, nonyl or dodecyl produced stronger inhibitors and their potency increased with increasing chain length.…”

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

“…Other examples of cross metatheses where one of the partners is simple and readily available include: (1) ethylene with 1,4-butadiene polymers (depolymerization) [481], and with trans 1,4-polyisoprene (also using 1-octene as well as ethylene) [482]; (2) [486], with an allylated pyrroloindoline system for norcardioazine A and B total synthesis [487], and with an allylated flavonoid derivative for total synthesis of poinsettifolin A [488]; (4) cis 3-hexene with an allyltetrahydroquinoline system for total synthesis of angustureine (including many examples of RCM to form six-membered ring α,β-unsaturated lactams) [489], and with a homoallylamine derivative for synthesis of tetraponerines [490]; (5) various 1-alkene derivatives and vinylated seven-membered ring aminosugars [491];…”

Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis

“…Although less popular than piperidines and pyrrolidines, azepane iminosugars exhibit interesting properties as either inhibitors [153] or chaperones [154,155] of carbohydrate-processing enzymes. Accordingly, Désiré and co-workers widened the therapeutic potential of azepanes exploring the capacity of a panel of Nand Calkyl seven membered iminosugars 71-78 (with alkyl chains ranging from 4 to 12 carbon atoms) to rescue the activity of the defective F508del-CFTR [156].…”

“…Hence, elaboration of 80 led to 71 and 72 and the corresponding N-alkylated derivatives 73 and 74, while azepanes 75 and 76 were obtained from 81. Synthesis of C-azepanes 77 and 78 was accomplished by cross metathesis of C-allyl azepanes 82 and 83 in the presence of suitable alkenes (Scheme 10) [156]. When evaluated as CFTR correctors in CF-KM4 cells, azepanes 71 and 72 and the corresponding N-alkylated derivatives 73 and 74 showed no significant activity (Figure 16).…”

“…Notably, iminosugars 78 did not inhibit ER α-glucosidases I and II, as revealed by FOS analysis. The mechanism behind the observed activity was not clear; the authors hypothesized that a binding process to the glycosylated site of the protein could be involved [156].…”