Chain-Branched Polyhydroxylated Octahydro-<i>1H</i>-Indoles as Potential Leads against Lysosomal Storage Diseases

Here, the synthesis and glycosidase inhibition properties of the two first known 3-ethyloctahydro-1H-indole-4,5,6-triols are reported. This study shows the transformation of d-glucose into polyhydroxylated 1-(2-nitrocyclohexane) acetaldehydes, followed by a protocol involving the formation of the azacyclopentane ring. Results of inhibitory potency assays and docking calculations show that at least one of them could be a lead for optimization in the search for compounds that behave like folding chaperones in lysosomal storage diseases

Strategy for designing selective α-L-rhamnosidase inhibitors: Synthesis and biological evaluation of DMDP cyclic isothioureas

This study shows that the cyclization of L-DMDP thioureas to bicyclic L-DMDP isothioureas improved a-Lrhamnosidase inhibition which was further enhanced by increasing the length of the alkyl chain. The addition of a long alkyl chain, such as decyl or dodecyl, to the nitrogen led to the production of highly potent inhibitors of a-L-rhamnosidase; it also caused broad inhibition spectrum against b-glucosidase and b-galactosidase. In contrast, the corresponding N-benzyl-L-DMDP cyclic isothioureas display selective inhibition of a-L-rhamnosidase; 30,40-dichlorobenzyl-L-DMDP cyclic isothiourea (3r) was found to display the most potent and selective inhibition of a-L-rhamnosidase, with IC50 value of 0.22 lM, about 46-fold better than the positive control 5-epi-deoxyrhamnojirimycin (5-epi-DRJ; IC50 = 10 lM) and occupied the active-site of this enzyme (Ki = 0.11 lM). Bicyclic isothioureas of ido-L-DMDP did not inhibit a-L-rhamnosidase. These new mimics of L-rhamnose may affect other enzymes associated with the biochemistry of rhamnose including enzymes involved in progression of tuberculosis.

Strategy for designing selective α-L-rhamnosidase inhibitors: Synthesis and biological evaluation of DMDP cyclic isothioureas

This study shows that the cyclization of L-DMDP thioureas to bicyclic L-DMDP isothioureas improved a-Lrhamnosidase inhibition which was further enhanced by increasing the length of the alkyl chain. The addition of a long alkyl chain, such as decyl or dodecyl, to the nitrogen led to the production of highly potent inhibitors of a-L-rhamnosidase; it also caused broad inhibition spectrum against b-glucosidase and b-galactosidase. In contrast, the corresponding N-benzyl-L-DMDP cyclic isothioureas display selective inhibition of a-L-rhamnosidase; 30,40-dichlorobenzyl-L-DMDP cyclic isothiourea (3r) was found to display the most potent and selective inhibition of a-L-rhamnosidase, with IC50 value of 0.22 lM, about 46-fold better than the positive control 5-epi-deoxyrhamnojirimycin (5-epi-DRJ; IC50 = 10 lM) and occupied the active-site of this enzyme (Ki = 0.11 lM). Bicyclic isothioureas of ido-L-DMDP did not inhibit a-L-rhamnosidase. These new mimics of L-rhamnose may affect other enzymes associated with the biochemistry of rhamnose including enzymes involved in progression of tuberculosis.

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

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

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

International audienceThe 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 alpha-L-fucosidase to a beta-glucosidase and beta-galactosidase inhibitor while N-alkylation of the D-gluco iminosugar significantly improves its inhibition profile leading to potent beta-glucosidase, beta-galactosidase, alpha-L-rhamnosidase and beta-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 mu M) 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 alpha-glucosidases I or II