Synthesis of anti-inflammatory α-and β-linked acetamidopyranosides as inhibitors of toll-like receptor 4 (TLR4)

Peter Wipf, Benjamin R. Eyer, Yukihiro Yamaguchi, Feng Zhang, Matthew D. Neal, Chhinder P. Sodhi, Misty Good, Maria Branca, Thomas Prindle, Peng Lu, Jeffrey L. Brodsky, David J. Hackam

Research output: Contribution to journalArticlepeer-review

Abstract

Abstract The low-molecular weight isopropyl 2-acetamido-α-glucoside 16 (C34) inhibits toll-like receptor 4 (TLR4) in enterocytes and macrophages in vitro, and reduces systemic inflammation in mouse models of endotoxemia and necrotizing enterocolitis. We used a copper(II)-mediated solvolysis of anomeric oxazolines and an acid-mediated conversion of β-glucosamine and β-galactosamine pentaacetates to generate analogs of 16 at the anomeric carbon and at C-4 of the pyranose ring. These compounds were evaluated for their influence on TLR4-mediated inflammatory signaling in cultured enterocytes and monocytes. Their efficacy was confirmed using a NF-kB-luciferase reporter mouse, thus establishing the first structure-activity relationship (SAR) study in this series and identifying the more efficacious isopropyl 2-acetamido-α-galactoside 17.

Original languageEnglish (US)
Article number45432
Pages (from-to)3097-3100
Number of pages4
JournalTetrahedron Letters
Volume56
Issue number23
DOIs
StatePublished - Jun 3 2015

Keywords

  • Anti-inflammatory
  • Carbohydrates
  • Eritoran
  • Lipid A mimetics
  • Toll-like receptors (TLRs)

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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