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 Sodhi, Misty Good, Maria Branca, Thomas Prindle, Peng Lu, Jeffrey L. Brodsky, David Hackam

Research output: Contribution to journalArticle

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

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Toll-Like Receptor 4
Enterocytes
Anti-Inflammatory Agents
Galactosides
Galactosamine
Necrotizing Enterocolitis
Endotoxemia
NF-kappa B
Macrophages
Glucosamine
Glucosides
Structure-Activity Relationship
Luciferases
Copper
Monocytes
Carbon
Molecular Weight
Molecular weight
Inflammation
Acids

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Drug Discovery

Cite this

Synthesis of anti-inflammatory α-and β-linked acetamidopyranosides as inhibitors of toll-like receptor 4 (TLR4). / Wipf, Peter; Eyer, Benjamin R.; Yamaguchi, Yukihiro; Zhang, Feng; Neal, Matthew D.; Sodhi, Chhinder; Good, Misty; Branca, Maria; Prindle, Thomas; Lu, Peng; Brodsky, Jeffrey L.; Hackam, David.

In: Tetrahedron Letters, Vol. 56, No. 23, 45432, 03.06.2015, p. 3097-3100.

Research output: Contribution to journalArticle

Wipf, Peter ; Eyer, Benjamin R. ; Yamaguchi, Yukihiro ; Zhang, Feng ; Neal, Matthew D. ; Sodhi, Chhinder ; Good, Misty ; Branca, Maria ; Prindle, Thomas ; Lu, Peng ; Brodsky, Jeffrey L. ; Hackam, David. / Synthesis of anti-inflammatory α-and β-linked acetamidopyranosides as inhibitors of toll-like receptor 4 (TLR4). In: Tetrahedron Letters. 2015 ; Vol. 56, No. 23. pp. 3097-3100.
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AB - 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.

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