作为Toll样受体4（TLR4）抑制剂的抗炎α-和β-连接的乙酰氨基吡喃糖苷的合成。
Synthesis of -inflammatory α-and β-linked acetamidopyranosides as inhibitors of toll-like receptor 4 (TLR4).
作者信息
Wipf Peter, Eyer Benjamin R, Yamaguchi Yukihiro, Zhang Feng, Neal Matthew D, Sodhi Chhinder P, Good Misty, Branca Maria, Prindle Thomas, Lu Peng, Brodsky Jeffrey L, Hackam David J
机构信息
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA ; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
出版信息
Tetrahedron Lett. 2015 Jun 3;56(23):3097-3100. doi: 10.1016/j.tetlet.2014.11.048.
The low-molecular weight isopropyl 2-acetamido-α-glucoside (C34) inhibits toll-like receptor 4 (TLR4) in enterocytes and macrophages , 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 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 .
低分子量的2-乙酰氨基-α-葡萄糖苷异丙酯（C34）可抑制肠上皮细胞和巨噬细胞中的Toll样受体4（TLR4），并减轻内毒素血症和坏死性小肠结肠炎小鼠模型中的全身炎症。我们利用铜（II）介导的异头恶唑啉的溶剂解反应以及酸介导的β-葡萄糖胺和β-半乳糖胺五乙酸酯的转化反应，在吡喃糖环的异头碳和C-4位生成类似物。评估了这些化合物对培养的肠上皮细胞和单核细胞中TLR4介导的炎症信号传导的影响。使用NF-κB-荧光素酶报告基因小鼠证实了它们的功效，从而建立了该系列中的首个构效关系（SAR）研究，并确定了更有效的2-乙酰氨基-α-半乳糖苷异丙酯。
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