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