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首页> 外文期刊>RSC Advances >Synthesis and biological evaluation of 1-(2-(adamantane-1-yl)-1H-indol-5-yl)-3-substituted urea/thiourea derivatives as anticancer agents
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Synthesis and biological evaluation of 1-(2-(adamantane-1-yl)-1H-indol-5-yl)-3-substituted urea/thiourea derivatives as anticancer agents

机译：1-（2-（二烷基-1-基）-1H-吲哚-5-基）-3-取代的尿素/硫脲衍生物作为抗癌剂的合成和生物学评价

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摘要

The indole ring, adamantane, and urea groups are important components of bioactive molecules. The orphan nuclear receptor Nur77 as a unique transcription factor encoded by an immediate early gene is a potential therapeutic target for cancer treatment. We synthesized a series of 1-(2-(adamantane-1-yl)1H- indol-5-yl)-3-substituted urea/thiourea derivatives and identified which of these potential anticancer candidates could modulate the expression and activity of Nur77. The synthesized compounds were initially evaluated for their anti-proliferative activity against H460 lung cancer cells, HepG2 liver cancer cells, and MCF-7 breast cancer cells. Major compounds were found to be active against these tested cancer cell lines. The compounds with IC50 values down to 20 mu M exhibited selective cytotoxicity effects on the human lung cancer cell line (H460) and the normal lung cell line (MCR-5). Compounds 7n, 7s, and 7w induced Nur77-expression in a time-and dose-dependent manner in H460 cells. Compounds 7n and 7s strongly induced Parp cleavage in H460 cells, but 7w resulted in a slight induction of apoptosis. The apoptotic effect of 7s was largely inhibited when the Nur77 was knocked down by shRNA. This indicated that Nur77 served as a critical mediator for the anticancer action of 7s. The molecular docking study between Nur77 and 7s revealed that compound 7s exhibited a promising binding affinity with Nur77. These findings will provide a direction for the developing Nur77 regulator as anticancer agents.
机译：吲哚环，金刚烷和尿素基团是生物活性分子的重要组成部分。孤儿核受体NUR77作为立即早期基因编码的独特转录因子是癌症治疗的潜在治疗靶标。我们合成了一系列1-（2-（Adamantane-1-基）1H- Indol-5-Y1）-3-取代的尿素/硫脲衍生物，并确定了哪些潜在的抗癌候选者可以调节Nur77的表达和活性。合成的化合物最初评价它们对H460肺癌细胞，HepG2肝癌细胞，和MCF-7乳腺癌细胞的抗增殖活性。发现主要化合物对这些测试的癌细胞系有活性。具有IC50值下降至20μm的化合物对人肺癌细胞系（H460）和正常肺细胞系（MCR-5）表现出选择性细胞毒性作用。在H460细胞中以时间和剂量依赖性方式诱导NUR77表达化合物7N，7S和7W。化合物7N和7S强烈地诱导H460细胞中的PARP切割，但7W导致细胞凋亡轻微诱导。当Nur77被ShRNA撞击时，7S的凋亡效应大大抑制。这表明NUR77作为7S抗癌动作的关键调解员。 Nur77和7s之间的分子对接研究表明，化合物7S与Nur77表现出有前途的结合亲和力。这些调查结果将为发展中的Nur77监管机构作为抗癌剂提供方向。

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  • 来源
    《RSC Advances》 |2017年第81期|共12页
  • 作者

    Hu Hongyu; Lin Chunrong; Ao Mingtao; Ji Yufen; Tang Bowen; Zhou Xiaoxiao; Fang Meijuan; Zeng Jinzhang; Wu Zhen;

  • 作者单位

    Xiamen Univ Sch Pharmaceut Sci Fujian Prov Key Lab Innovat Drug Target Res South Xiang An Rd Xiamen 361102 Peoples R China;

    Xiamen Univ Sch Pharmaceut Sci Fujian Prov Key Lab Innovat Drug Target Res South Xiang An Rd Xiamen 361102 Peoples R China;

    Xiamen Univ Sch Pharmaceut Sci Fujian Prov Key Lab Innovat Drug Target Res South Xiang An Rd Xiamen 361102 Peoples R China;

    Xiamen Univ Sch Pharmaceut Sci Fujian Prov Key Lab Innovat Drug Target Res South Xiang An Rd Xiamen 361102 Peoples R China;

    Xiamen Univ Sch Pharmaceut Sci Fujian Prov Key Lab Innovat Drug Target Res South Xiang An Rd Xiamen 361102 Peoples R China;

    Xiamen Univ Sch Pharmaceut Sci Fujian Prov Key Lab Innovat Drug Target Res South Xiang An Rd Xiamen 361102 Peoples R China;

    Xiamen Univ Sch Pharmaceut Sci Fujian Prov Key Lab Innovat Drug Target Res South Xiang An Rd Xiamen 361102 Peoples R China;

    Xiamen Univ Sch Pharmaceut Sci Fujian Prov Key Lab Innovat Drug Target Res South Xiang An Rd Xiamen 361102 Peoples R China;

    Xiamen Univ Sch Pharmaceut Sci Fujian Prov Key Lab Innovat Drug Target Res South Xiang An Rd Xiamen 361102 Peoples R China;

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