期刊
ORGANIC & BIOMOLECULAR CHEMISTRY
卷 20, 期 3, 页码 619-629出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/d1ob02280f
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资金
- Vaincre la Mucoviscidose
- European Union (ERDF)
- Region Nouvelle Aquitaine
- Natural Sciences and Engineering Research Council of Canada [RGPIN298406]
- Canada Research Chairs (CRC) Program
- Michael Smith Foundation for Health Research (MSFHR)
- CIHR
The synthesis and evaluation of seven-membered iminosugars derived from a 3S-acetamido-4R,5R,6S-trihydroxyazepane scaffold as inhibitors of functionally related exo-N-acetylhexosaminidases were reported. The study explored the effects of epimerization and C-alkylation at specific positions, leading to the identification of selective inhibitors for different hexosaminidases.
We report the synthesis of seven-membered iminosugars derived from a 3S-acetamido-4R,5R,6S-trihydroxyazepane scaffold and their evaluation as inhibitors of functionally related exo-N-acetylhexosaminidases including human O-GlcNAcase (OGA), human lysosomal beta-hexosaminidase (HexAB), and Escherichia coli NagZ. Capitalizing on the flexibility of azepanes and the active site tolerances of hexosaminidases, we explore the effects of epimerization of stereocenters at C-3, C-5 and C-6 and C-alkylation at the C-2 or C-7 positions. Accordingly, epimerization at C-6 (l-ido) and at C-5 (d-galacto) led to selective HexAB inhibitors whereas introduction of a propyl group at C-7 on the C-3 epimer furnished a potent NagZ inhibitor.
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