title: Synthesis ofanti-inflammatory α-and β-linked acetamidopyranosides as inhibitors of toll-like receptor 4 (TLR4).
abstract: The low-molecular weight isopropyl 2-acetamido-α-glucoside16(C34) inhibits toll-like receptor 4 (TLR4) in enterocytes and macrophagesin 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 of16at 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-galactoside17.
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA ; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Eyer
authors.affiliation: 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.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Neal
authors.affiliation: 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.
authors.forename: Chhinder P
authors.initials: CP
authors.lastname: Sodhi
authors.affiliation: Division of Newborn Medicine, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
authors.forename: Misty
authors.initials: M
authors.lastname: Good
authors.affiliation: 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.
authors.forename: Maria
authors.initials: M
authors.lastname: Branca
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Prindle
authors.affiliation: 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.
authors.forename: Peng
authors.initials: P
authors.lastname: Lu
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Brodsky
authors.affiliation: 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.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hackam
keywords: anti-inflammatory; cabohydrates; eritoran; lipid A mimetics; toll-like receptors (TLRs)