Synthesis and bioevaluation of a series of alpha-pyrone derivatives as potent activators of Nrf2/ARE pathway (part I)
Synthesis and bioevaluation of a series of alpha-pyrone derivatives as potent activators of Nrf2/ARE pathway (part I)
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作为 Nrf2/ARE 通路有效激活剂的一系列 α-吡喃酮衍生物的合成和生物评价（第一部分）
DOI：
10.1016/j.ejmech.2013.06.007
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发表时间：
2013
影响因子：
6.7
通讯作者：
You Qi-dong
中科院分区：
文献类型：
--
作者：
Xi Mei-yang;Sun Zhong-ying;Sun Hao-peng;Jia Jian-min;Jiang Zheng-yu;Tao Lei;Ye Ming;Yang Xi;Wang Ya-jing;Xue Xin;Huang Jing-jie;Gao Yuan;Guo Xiao-ke;Zhang Sheng-lie;Yang Ying-rui;Guo Qing-long;Hu Rong;You Qi-dong
人结直肠癌细胞(HCT116)暴露于亲电体后，通过激活核因子-E2相关因子2(Nrf2)/抗氧化反应元件(ARE)途径来对抗氧化应激。为了寻找新的激活剂，利用荧光素酶报告基因分析筛选了我们实验室的内部数据库，得到了一个新的α-吡喃酮化合物1。2在第一轮构效关系研究中，具有最强的2-氟苯基的ARE诱导活性。生物学研究表明，化合物诱导Nrf2的核转位先于ERK1/2的磷酸化。这些数据鼓励我们使用2作为先导，合成了20个衍生物来讨论更详细的SAR，从而得到更有效的化合物9，它可以作为进一步修饰的起始化合物。
When exposed to electrophiles, human colorectal cancer cells (HCT116) counteract oxidative stress through activating NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway. To identify new activators, luciferase reporter gene assay was used to screen in-house database of our laboratory, leading to a novel α-pyrone compound1as a hit.2with 2-fluoro phenyl group exhibited the strongest ARE inductive activity in the first round structure–activity relationship (SAR) study. Biological studies showed the compound induced nuclear translocation of Nrf2 preceded by phosphorylation of ERK1/2. The data encouraged us to use2as lead and 20 derivatives were synthesized to discuss a more detailed SAR, leading to a more potent compound9, which can be the starting compound for further modification.