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Synthesis and glycosidase inhibition of 3,4,5-trihydroxypiperidines using a one-pot amination-cyclisation cascade reaction.

Authors :
Dangerfield EM
Meijlink MA
Hunt-Painter AA
Nasseri SA
Withers SG
Stocker BL
Timmer MSM
Source :
Carbohydrate research [Carbohydr Res] 2024 Sep; Vol. 543, pp. 109198. Date of Electronic Publication: 2024 Jun 27.
Publication Year :
2024

Abstract

Trihydroxypiperidines are a therapeutically valuable class of iminosugar. We applied a one-pot amination-cyclisation cascade reaction to synthesise 3,4,5-trihydroxypiperidine stereoisomers in three steps from commercially available pentoses and in excellent overall yields. Using our methodology, the yields of the syntheses of meso-1, meso-2 and 3L are the highest reported to date. The synthetic methodology was readily extended to the three-step synthesis of N-alkyl derivatives by replacing the ammonia nitrogen source with a primary amine. The trihydroxypiperidines and N-alkyl analogues were screened for enzyme inhibitory activity using Fabrazyme (Fabry disease), GCase (Gaucher's disease), Agrobacterium sp. β-glucosidase, and Escherichia coli β-galactosidase. N-Phenylethyl 3,4,5-trihydroxypiperidine (N-phenylethyl-1-(3R,4R,5S)-piperidine-3,4,5-triol) showed good inhibitory activity of Fabrazyme (K <subscript>i</subscript>  = 46 μM). This activity was abolished when the N-phenylethyl group was removed or replaced with a non-aromatic alkyl chain.<br />Competing Interests: Declaration of competing interest The authors y declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Details

Language :
English
ISSN :
1873-426X
Volume :
543
Database :
MEDLINE
Journal :
Carbohydrate research
Publication Type :
Academic Journal
Accession number :
38996783
Full Text :
https://doi.org/10.1016/j.carres.2024.109198