Original Articles
Jiabing Wang, Lili Huang, Chanchan Cheng, Ge Li, Jingwen Xie, Mengya Shen, Qian Chen, Wulan Li, Wenfei He, Peihong Qiu, Jianzhang Wu. Design, synthesis and biological evaluation of chalcone analogues with novel dual antioxidant mechanisms as potential anti-ischemic stroke agents[J]. Acta Pharmaceutica Sinica B, 2019, 9(2): 335-350

Design, synthesis and biological evaluation of chalcone analogues with novel dual antioxidant mechanisms as potential anti-ischemic stroke agents
Jiabing Wanga,b, Lili Huanga,c, Chanchan Chenga, Ge Lia, Jingwen Xiea, Mengya Shena, Qian Chena, Wulan Lia,d, Wenfei Hea, Peihong Qiua, Jianzhang Wua
a Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China;
b Municipal Hospital Affiliated to Medical School of Taizhou University, Taizhou 318000, China;
c Ningbo Medical Centre Li Huili Hospital, Ningbo 315041, China;
d College of Information Science and Computer Engineering, Wenzhou Medical University, Wenzhou 325035, China
Scavenging reactive oxygen species (ROS) by antioxidants is the important therapy to cerebral ischemia-reperfusion injury (CIRI) in stroke. The antioxidant with novel dual-antioxidant mechanism of directly scavenging ROS and indirectly through antioxidant pathway activation may be a promising CIRI therapeutic strategy. In our study, a series of chalcone analogues were designed and synthesized, and multiple potential chalcone analogues with dual antioxidant mechanisms were screened. Among these compounds, the most active 33 not only conferred cytoprotection of H2O2-induced oxidative damage in PC12 cells through scavenging free radicals directly and activating NRF2/ARE antioxidant pathway at the same time, but also played an important role against ischemia/reperfusion-related brain injury in animals. More importantly, in comparison with mono-antioxidant mechanism compounds, 33 exhibited higher cytoprotective and neuroprotective potential in vitro and in vivo. Overall, our findings showed compound 33 could emerge as a promising anti-ischemic stroke drug candidate and provided novel dual-antioxidant mechanism strategies and concepts for oxidative stress-related diseases treatment.
Key words:    Reactive oxygen species    Cerebral ischemiareperfusion injury    Stroke    Dual-antioxidant mechanism    Chalcones    Antioxidants    Oxidative stress    NRF2/ARE   
Received: 2018-10-29     Revised: 2018-12-03
DOI: 10.1016/j.apsb.2019.01.003
Funds: The work was supported by ZheJiang Province Natural Science Funding of China (Nos. LQ18H280008, Y19B020043, and LY17H160059, China), the National Natural Science Foundation of China (No. 81803580, China), University Students in Zhejiang Science and Technology Innovation Projects (No. 2018R413004, China), National Undergraduate Training Programs for Innovation and Entrepreneurship (No. 201810343025, China) and Granted by the Opening Project of Zhejiang Provincial Top Key Discipline of Pharmaceutical Sciences.
Corresponding author: Peihong Qiu, Jianzhang Wu     Email:wjzwzmc@126.com;wjzwzmu@163.com
Author description:
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Jiabing Wang
Lili Huang
Chanchan Cheng
Ge Li
Jingwen Xie
Mengya Shen
Qian Chen
Wulan Li
Wenfei He
Peihong Qiu
Jianzhang Wu

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