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

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.

Metadata

Authors/Creators:

Doherty, Gareth G.
Ler, Geraldine Jia Ming
Wimmer, Norbert
Bernhardt, Paul V.
Ashmus, Roger A.
Vocadlo, David J.
Armstrong, Zachary (za675@york.ac.uk)
Davies, Gideon J. https://orcid.org/0000-0002-7343-776X
Maccarana, Marco
Li, Jin ping
Kayal, Yasmin
Ferro, Vito

Funding Information: We gratefully acknowledge support from the Australian Research Council (DP170104431 to V.F.). G.G.D. acknowledges financial support from the University of Queensland Ph.D. scholarship program. G.J.D. is supported by the Royal Society Ken Murray Research Professorship. The Natural Sciences and Engineering Council of Canada (RGPIN‐05426 to D.J.V.). D.J.V. was supported as a Tier I Canada Research Chair in Chemical Biology. The authors also thank the Centre for High‐Throughput Chemical Biology (HTCB) for access to core facilities. We thank Sean Cuskelly for technical assistance and Prof. Israel Vlodavsky and Dr. Maurice Petitou for useful discussions. Open Access publishing facilitated by The University of Queensland, as part of the Wiley ‐ The University of Queensland agreement via the Council of Australian University Librarians. Funding Information: We gratefully acknowledge support from the Australian Research Council (DP170104431 to V.F.). G.G.D. acknowledges financial support from the University of Queensland Ph.D. scholarship program. G.J.D. is supported by the Royal Society Ken Murray Research Professorship. The Natural Sciences and Engineering Council of Canada (RGPIN-05426 to D.J.V.). D.J.V. was supported as a Tier I Canada Research Chair in Chemical Biology. The authors also thank the Centre for High-Throughput Chemical Biology (HTCB) for access to core facilities. We thank Sean Cuskelly for technical assistance and Prof. Israel Vlodavsky and Dr. Maurice Petitou for useful discussions. Open Access publishing facilitated by The University of Queensland, as part of the Wiley - The University of Queensland agreement via the Council of Australian University Librarians. Publisher Copyright: © 2022 The Authors. ChemBioChem published by Wiley-VCH GmbH.

Keywords:

azasugars, glucuronidases, heparanases, iduronidases, inhibitors, MPS I

Dates: