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 Jr; Peng Lu; Jeffrey L Brodsky; David J Hackam

doi:10.1016/j.tetlet.2014.11.048

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

Tetrahedron Lett. 2015 Jun 3;56(23):3097-3100. doi: 10.1016/j.tetlet.2014.11.048.

Authors

Affiliations

¹ Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA ; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15260, USA.
² Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
³ Division of Pediatric Surgery, Children's Hospital of Pittsburgh of University of Pittsburgh and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh PA 15224, USA ; Division of Pediatric Surgery, Bloomberg Children's Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Division of Pediatric Surgery, Children's Hospital of Pittsburgh of University of Pittsburgh and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh PA 15224, USA.
⁵ Division of Newborn Medicine, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
⁶ Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.

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.

Keywords: anti-inflammatory; cabohydrates; eritoran; lipid A mimetics; toll-like receptors (TLRs).

Abstract

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