3-Aroylmethylene-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-ones as Potent Nrf2/ARE Inducers in Human Cancer Cells and AOM-DSS Treated Mice
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- 作者：Mei-yang Xi ; Jian-min Jia ; Hao-peng Sun ; Zhong-ying Sun ; Jie-wei Jiang ; Ya-jing Wang ; Min-ye Zhang ; Jun-feng Zhu ; Li-li Xu ; Zheng-yu Jiang ; Xin Xue ; Ming Ye ; Xi Yang ; Yuan Gao ; Lei Tao ; Xiao-ke Guo ; Xiao-li Xu ; Qing-long Guo ; Xiao-jin Zhang ; Rong Hu ; Qi-dong You
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：October 24, 2013
- 年：2013
- 卷：56
- 期：20
- 页码：7925-7938
- 全文大小：643K
- 年卷期：v.56,no.20(October 24, 2013)
- ISSN：1520-4804
文摘
Nrf2-mediated activation of ARE regulates expression of cytoprotective enzymes against oxidative stress, inflammation, and carcinogenesis. We have discovered a novel structure (1) as an ARE inducer via luciferase reporter assay to screen the in-house database of our laboratory. The potency of 1 was evaluated by the expression of NQO-1, HO-1, and nuclear translocation of Nrf2 in HCT116 cells. In vivo potency of 1 was studied using AOM-DSS models, showing that the development of colorectal adenomas was significantly inhibited. Administration with 1 lowered the expression of IL-6, IL-1尾, and promoted Nrf2 nuclear translocation. These results indicated that 1 is a potent Nrf2/ARE activator, both in vitro and in vivo. Forty-one derivatives were synthesized for SAR study, and a more potent compound 17 was identified. To our knowledge, this is a potent ARE activator. Besides, its novel structure makes it promising for further optimization.