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

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

doi:10.3390/molecules25204618

Cited by 5 publications

(2 citation statements)

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“…The authors have cited additional references within the Supporting Information. [46][47][48][49][50][51]…”

Section: Competition Labelling Studymentioning

confidence: 99%

Ligand‐Directed Chemistry on Glycoside Hydrolases – A Proof of Concept Study

Prasch,

Wolfsgruber,

Thonhofer

et al. 2023

ChemBioChem

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Selective covalent labelling of enzymes using small molecule probes has advanced the scopes of protein profiling. The covalent bond formation to a specific target is the key step of activity‐based protein profiling (ABPP), a method which has become an indispensable tool for measuring enzyme activity in complex matrices. With respect to carbohydrate processing enzymes, strategies for ABPP so far involve labelling the active site of the enzyme, which results in permanent loss of activity. Here, we report in a proof of concept study the use of ligand‐directed chemistry (LDC) for labelling glycoside hydrolases near to – but not in – the active site. During the labelling process, the competitive inhibitor is cleaved from the probe, departs the active site and the enzyme maintains its catalytic activity. To this end, we designed a building block synthetic concept for small molecule probes containing iminosugar‐based reversible inhibitors for labelling of two model β‐glucosidases. The results indicate that the LDC approach can be adaptable for covalent proximity labelling of glycoside hydrolases.

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“…The authors have cited additional references within the Supporting Information. [46][47][48][49][50][51]…”

Section: Competition Labelling Studymentioning

confidence: 99%

Ligand‐Directed Chemistry on Glycoside Hydrolases – A Proof of Concept Study

Prasch,

Wolfsgruber,

Thonhofer

et al. 2023

ChemBioChem

Self Cite

View full text Add to dashboard Cite

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“…The intrinsic instability of aminoacetal functionalities makes impractical the synthesis of iminosugar O -glycosides or of analogues having other heteroatom substituents at the pseudoanomeric position. Instead, aglycon-like appendages have been incorporated through N -substitution − and C -branching approaches, − which accounts for the two major subclasses of iminosugar derivatives on record.…”

Section: Introductionmentioning

confidence: 99%

Stereoselective Synthesis of Nojirimycin α-C-Glycosides from a Bicyclic Acyliminium Intermediate: A Convenient Entry to N,C-Biantennary Glycomimetics

et al. 2022

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A simple and efficient method for the stereoselective synthesis of nojirimycin α- C -glycoside derivatives has been developed using a bicyclic carbamate-type sp 2 -iminosugar, whose preparation on a gram scale has been optimized, as the starting material. sp 2 -iminosugar O -glycosides or anomeric esters serve as excellent precursors of acyliminium cations, which can add nucleophiles, including C -nucleophiles. The stereochemical outcome of the reaction is governed by stereoelectronic effects, affording the target α-anomer with total stereoselectivity. Thus, the judicious combination of C -allylation, carbamate hydrolysis, cross-metathesis, and hydrogenation reactions provides a very convenient entry to iminosugar α- C -glycosides, which have been transformed into N , C -biantennary derivatives by reductive amination or thiourea-forming reactions. The thiourea adducts undergo intramolecular cyclization to bicyclic iminooxazolidine iminosugar α- C -glycosides upon acid treatment, broadening the opportunities for molecular diversity. A preliminary evaluation against a panel of commercial glycosidases validates the approach for finely tuning the inhibitory profile of glycomimetics.

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