Back to Search Start Over

Synthesis of Uronic Acid 1-Azasugars as Putative Inhibitors of α-Iduronidase, β-Glucuronidase and Heparanase.

Authors :
Doherty GG
Ler GJM
Wimmer N
Bernhardt PV
Ashmus RA
Vocadlo DJ
Armstrong Z
Davies GJ
Maccarana M
Li JP
Kayal Y
Ferro V
Source :
Chembiochem : a European journal of chemical biology [Chembiochem] 2023 Feb 14; Vol. 24 (4), pp. e202200619. Date of Electronic Publication: 2023 Jan 03.
Publication Year :
2023

Abstract

1-Azasugar analogues of l-iduronic acid (l-IdoA) and d-glucuronic acid (d-GlcA) and their corresponding enantiomers have been synthesized as potential pharmacological chaperones for mucopolysaccharidosis I (MPS I), a lysosomal storage disease caused by mutations in the gene encoding α-iduronidase (IDUA). The compounds were efficiently synthesized in nine or ten steps from d- or l-arabinose, and the structures were confirmed by X-ray crystallographic analysis of key intermediates. All compounds were inactive against IDUA, although l-IdoA-configured 8 moderately inhibited β-glucuronidase (β-GLU). The d-GlcA-configured 9 was a potent inhibitor of β-GLU and a moderate inhibitor of the endo-β-glucuronidase heparanase. Co-crystallization of 9 with heparanase revealed that the endocyclic nitrogen of 9 forms close interactions with both the catalytic acid and catalytic nucleophile.<br /> (© 2022 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Details

Language :
English
ISSN :
1439-7633
Volume :
24
Issue :
4
Database :
MEDLINE
Journal :
Chembiochem : a European journal of chemical biology
Publication Type :
Academic Journal
Accession number :
36453606
Full Text :
https://doi.org/10.1002/cbic.202200619