N -Alkylated Iminosugar Based Ligands: Synthesis and Inhibition of Human Lysosomal β-Glucocerebrosidase

The scope of a series of -alkylated iminosugar based inhibitors in the d- as well as d- configuration towards their interaction with human lysosomal β-glucocerebrosidase has been evaluated. A versatile synthetic toolbox has been developed for the synthesis of -alkylated iminosugar scaffolds conjugat...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2020-10, Vol.25 (20), p.4618
Main Authors: Wolfsgruber, Andreas, Thonhofer, Martin, Weber, Patrick, Nasseri, Seyed A, Fischer, Roland, Schalli, Michael, Stütz, Arnold E, Withers, Stephen G, Wrodnigg, Tanja M
Format: Article
Language:English
Subjects:
Acids
Alcohol
Alkylation
Alkynes
Alzheimer's disease
Benzoic acid
Benzoic Acid - metabolism
Enzymes
Ethanol
Glucosylceramidase
Glucosylceramidase - metabolism
glycomimetics
Humans
inhibitors for β-glucocerebrosidase
Kinetics
Ligands
Lysosomes - enzymology
Magnetic Resonance Spectroscopy
Molecular Structure
N-alkylated iminosugars
Nitrogen
Potash
Potassium
Proteins
tools for glycoprocessing enzymes
Tropical diseases
β-glucosidase inhibitors
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Summary:The scope of a series of -alkylated iminosugar based inhibitors in the d- as well as d- configuration towards their interaction with human lysosomal β-glucocerebrosidase has been evaluated. A versatile synthetic toolbox has been developed for the synthesis of -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- -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.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules25204618