The School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia Crawley, WA 6009, Australia.
Bioorg Med Chem. 2010 Jan 15;18(2):650-62. doi: 10.1016/j.bmc.2009.12.001. Epub 2009 Dec 6.
A library of new thalidomide C4/5 analogues containing either a phenyl or alkyne tether were synthesized using Sonogashira or Suzuki cross coupling reactions from their aryl halogenated precursors. All thalidomide analogues were tested for their ability to inhibit the expression of the proinflammatory cytokine Tumor Necrosis Factor (TNF). More explicitly the use of a novel reporter system utilizing the promoter region of the TNF gene in a human T-cell line provided a rapid and effective measure of NFkappaB transcriptional activity. Several compounds either containing either an aryl-isobutyl or aryl-isopropoxy group were the most effective in inhibiting TNF expression, and were several times more active than thalidomide itself. Five of the more active derivatives indicated an apoptotic response while one of these compounds, containing an aldehyde tether, showed possible influence of cell cycling effects.
利用 Sonogashira 或 Suzuki 交叉偶联反应，从其芳基卤代前体合成了包含苯基或炔基连接体的新型沙利度胺 C4/5 类似物库。所有沙利度胺类似物均测试其抑制促炎细胞因子肿瘤坏死因子 (TNF) 表达的能力。更确切地说，使用在人 T 细胞系中利用 TNF 基因启动子区域的新型报告系统提供了 NFkappaB 转录活性的快速有效测量。几种含有芳基异丁基或芳基异丙氧基的化合物在抑制 TNF 表达方面最为有效，其活性比沙利度胺本身高几倍。其中 5 种更有效的衍生物表明存在凋亡反应，而其中一种含有醛基连接体的化合物则显示出细胞周期效应的可能影响。
