Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid β-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the potent β-d-galactosidase inhibitor 4-epi-isofagomine. Structure-activity relationships were investigated by X-ray crystallography as well as by alterations in the cyclopentane moiety such as deoxygenation and replacement by fluorine of a “strategic” hydroxyl group. New compounds have revealed highly promising activities with a range of β-galactosidase-compromised human cell lines and may serve as leads towards new pharmacological chaperones for GM1-gangliosidosis and Morquio B disease.
A short survey on selected β-galactosidase inhibitors as potential pharmacological chaperones for G M1 -gangliosidosis and Morquio B associated mutants of human lysosomal βgalactosidase is provided highlighting recent developments in this particular area of lysosomal storage disorders and orphan diseases.
Modified 1,5-dideoxy-1,5-imino-
d
-xylitol analogues with different substitution patterns involving position C-1 and/or the ring nitrogen were prepared, which were designed to serve as precursors for the preparation of iminoxylitol-based ligands and tools for the elucidation and modulation of human lysosomal
β
-glucocerebrosidase. Biological evaluation of the synthesized glycomimetics with a series of glycoside hydrolases revealed that these substitution patterns elicit excellent
β
-glucosidase selectivities.
Graphical abstract
Electronic supplementary material
The online version of this article (10.1007/s00706-019-02427-1) contains supplementary material, which is available to authorized users.
A concise and robust synthesis of new cyclopentanoid competitive inhibitors of α-galactosidases related to Fabry's disease and other α-galactosidase related disorders.
The scope of a series of N-alkylated iminosugar based inhibitors in the d-gluco as well as d-xylo configuration towards their interaction with human lysosomal β-glucocerebrosidase has been evaluated. A versatile synthetic toolbox has been developed for the synthesis of N-alkylated iminosugar scaffolds conjugated to a variety of terminal groups via a benzoic acid ester linker. The terminal groups such as nitrile, azide, alkyne, nonafluoro-tert-butyl and amino substituents enable follow-up chemistry as well as visualisation experiments. All compounds showed promising inhibitory properties as well as selectivities for β-glucosidases, some exhibiting activities in the low nanomolar range for β-glucocerebrosidase.
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