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

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)

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

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 language	English (US)
Article number	45432
Pages (from-to)	3097-3100
Number of pages	4
Journal	Tetrahedron Letters
Volume	56
Issue number	23
DOIs	https://doi.org/10.1016/j.tetlet.2014.11.048
State	Published - 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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10.1016/j.tetlet.2014.11.048

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Wipf, P., Eyer, B. R., Yamaguchi, Y., Zhang, F., Neal, M. D., Sodhi, C. P., Good, M., Branca, M., Prindle, T., Lu, P., Brodsky, J. L., & Hackam, D. J. (2015). Synthesis of anti-inflammatory α-and β-linked acetamidopyranosides as inhibitors of toll-like receptor 4 (TLR4). Tetrahedron Letters, 56(23), 3097-3100. Article 45432. https://doi.org/10.1016/j.tetlet.2014.11.048

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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.",

keywords = "Anti-inflammatory, Carbohydrates, Eritoran, Lipid A mimetics, Toll-like receptors (TLRs)",

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doi = "10.1016/j.tetlet.2014.11.048",

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AU - Zhang, Feng

AU - Neal, Matthew D.

AU - Sodhi, Chhinder P.

AU - Good, Misty

AU - Branca, Maria

AU - Prindle, Thomas

AU - Lu, Peng

AU - Brodsky, Jeffrey L.

AU - Hackam, David J.

PY - 2015/6/3

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N2 - 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.

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.

KW - Anti-inflammatory

KW - Carbohydrates

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KW - Lipid A mimetics

KW - Toll-like receptors (TLRs)

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

Abstract

Keywords

ASJC Scopus subject areas

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