Synthesis and biological evaluation of 1-(2-(adamantane-1-yl)-1H-indol-5-yl)-3-substituted urea/thiourea derivatives as anticancer agents
Synthesis and biological evaluation of 1-(2-(adamantane-1-yl)-1H-indol-5-yl)-3-substituted urea/thiourea derivatives as anticancer agents
复制标题
抗癌剂1-(2-(金刚烷-1-基)-1H-吲哚-5-基)-3-取代脲/硫脲衍生物的合成及生物学评价
DOI：
10.1039/c7ra08149a
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发表时间：
2017-01-01
期刊：
影响因子：
3.9
通讯作者：
Wu, Zhen
中科院分区：
文献类型：
--
作者：
Hu, Hongyu;Lin, Chunrong;Wu, Zhen
吲哚环、金刚烷和脲基团是生物活性分子的重要组成部分。孤儿核受体Nur 77作为一种由即刻早期基因编码的独特转录因子，是一种潜在的肿瘤治疗靶点。我们合成了一系列1-（2-（金刚烷-1-基）1H-吲哚-5-基）-3-取代的脲/硫脲衍生物，并鉴定了这些潜在的抗癌候选物中哪些可以调节Nur 77的表达和活性。合成的化合物最初评估其对H460肺癌细胞、HepG 2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具有活性。IC_（50）值低至20 μ M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。化合物7 n、7s和7 w在H460细胞中以时间和剂量依赖性方式诱导Nur 77表达。化合物7 n和7s强烈诱导H460细胞中的Parp裂解，但7 w导致轻微的细胞凋亡诱导。当Nur 77被shRNA敲低时，7s的凋亡作用被大大抑制。这表明Nur 77是7s抗癌作用的关键介质。Nur 77与7s的分子对接研究表明，化合物7s与Nur 77具有良好的结合亲和力。这些发现将为开发Nur 77调节剂作为抗癌药物提供方向。
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.