N-alkylated iminosugar based ligands: Synthesis and inhibition of human lysosomal β-glucocerebrosidase

Andreas Wolfsgruber; Martin Thonhofer; Patrick Weber; Seyed A. Nasseri; Roland Fischer; Michael Schalli; Arnold E. Stütz; Stephen G. Withers; Tanja M. Wrodnigg

doi:10.3390/molecules25204618

N-alkylated iminosugar based ligands: Synthesis and inhibition of human lysosomal β-glucocerebrosidase

Andreas Wolfsgruber, Martin Thonhofer, Patrick Weber, Seyed A. Nasseri, Roland Fischer, Michael Schalli, Arnold E. Stütz, Stephen G. Withers, Tanja M. Wrodnigg^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Article number	4618
Journal	Molecules
Volume	25
Issue number	20
DOIs	https://doi.org/10.3390/molecules25204618
Publication status	Published - Oct 2020

Keywords

Glycomimetics
Inhibitors for β-glucocerebrosidase
N-alkylated iminosugars
Tools for glycoprocessing enzymes
β-glucosidase inhibitors

ASJC Scopus subject areas

Analytical Chemistry
Chemistry (miscellaneous)
Molecular Medicine
Pharmaceutical Science
Drug Discovery
Physical and Theoretical Chemistry
Organic Chemistry

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title = "N-alkylated iminosugar based ligands: Synthesis and inhibition of human lysosomal β-glucocerebrosidase",

abstract = "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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AU - Wolfsgruber, Andreas

AU - Thonhofer, Martin

AU - Weber, Patrick

AU - Nasseri, Seyed A.

AU - Fischer, Roland

AU - Schalli, Michael

AU - Stütz, Arnold E.

AU - Withers, Stephen G.

AU - Wrodnigg, Tanja M.

PY - 2020/10

Y1 - 2020/10

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AB - 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.

KW - Glycomimetics

KW - Inhibitors for β-glucocerebrosidase

KW - N-alkylated iminosugars

KW - Tools for glycoprocessing enzymes

KW - β-glucosidase inhibitors

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N-alkylated iminosugar based ligands: Synthesis and inhibition of human lysosomal β-glucocerebrosidase

Abstract

Keywords

ASJC Scopus subject areas

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