Base promoted synthesis of novel indole-dithiocarbamate compounds as potential anti-inflammatory therapeutic agents for treatment of acute lung injury.
Base promoted synthesis of novel indole-dithiocarbamate compounds as potential anti-inflammatory therapeutic agents for treatment of acute lung injury.
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DOI：
10.1016/j.ejmech.2019.03.022
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发表时间：
2019-06
影响因子：
6.7
通讯作者：
Zengqiang Song;Yan Zhou;Wenxin Zhang;L. Zhan;Yuanzu Yu;Yuehui Chen;W. Jia;Zhiguo Liu;Jianchang Qian;Yali Zhang;Chenglong Li;G. Liang
中科院分区：
文献类型：
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作者：
Zengqiang Song;Yan Zhou;Wenxin Zhang;L. Zhan;Yuanzu Yu;Yuehui Chen;W. Jia;Zhiguo Liu;Jianchang Qian;Yali Zhang;Chenglong Li;G. Liang
以t-BuOK为促进剂，建立了一种将二硫代氨基甲酸酯类化合物高化学选择性引入二硫代二烷胺硫代羰基吲哚氮位的方法。基于这一方法，在室温下以中等至优异的产率合成了29个新的吲哚二硫代氨基甲酸酯化合物。对所有化合物的抗炎活性进行了评估。大部分化合物具有较强的抑制肿瘤坏死因子-α和白介素6释放的作用。其中四个化合物被发现以剂量依赖的方式抑制体外细胞因子的产生，IC50值在纳摩尔范围内。此外，3-甲基-1H-吲哚-1-二甲基氨基二硫酸酯(3o)可有效改善肺组织的病理变化，减轻脂多糖(LPS)所致的体内急性肺损伤(ALI)。这些数据表明，新的吲哚二硫代氨基甲酸酯衍生物可能对进一步开发治疗ALI的药物特别有用。
An efficient protocol for highly chemoselective introduction of dithiocarbamate groups to nitrogen position of indoles with bis(dialkylaminethiocarbonyl)disulfides was achieved by employingt-BuOK as a promoter. Based on this methodology, twenty nine novel indole-dithiocarbamate compounds were prepared in moderate to excellent yields at room temperature. All compounds were evaluated for their anti-inflammatory activity. Most of the compounds exhibited high potency on inhibiting the releasing of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). Four of them were found to suppressin vitro cytokine production in a dose-dependent manner with IC50values in the nanomolar range. Additionally, 3-methyl-1H-indol-1-yl dimethylcarbamodithioate(3o)effectively ameliorated histopathological changes of lung tissues and attenuated lipopolysaccharides (LPS)-induced acute lung injury (ALI)in vivo. These data suggest that the new indole-dithiocarbamate derivatives could be particularly useful for further pharmaceutical development for the treatment of ALI.