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

ABSTRACT: The low-molecular weight isopropyl 2-acetamido-?-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 ?-glucosamine and ?-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-?-galactoside 17.

SUBMITTER: Wipf P 

PROVIDER: S-EPMC4518473 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Synthesis of <i>anti</i>-inflammatory α-and β-linked acetamidopyranosides as inhibitors of toll-like receptor 4 (TLR4).

Wipf Peter P   Eyer Benjamin R BR   Yamaguchi Yukihiro Y   Zhang Feng F   Neal Matthew D MD   Sodhi Chhinder P CP   Good Misty M   Branca Maria M   Prindle Thomas T   Lu Peng P   Brodsky Jeffrey L JL   Hackam David J DJ  

Tetrahedron letters 20150601 23

The low-molecular weight isopropyl 2-acetamido-α-glucoside <b>16</b> (C34) inhibits toll-like receptor 4 (TLR4) in enterocytes and macrophages <i>in vitro</i>, 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 <b>16</b> at the anomeric carbon and at C-4 of the pyranose ring. These co  ...[more]

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