Design, synthesis, and evaluation of NDGA analogues as potential anti-ischemic stroke agents

• Published in: European journal of medicinal chemistry 2018-01, Vol.143, p.1165-1173
• Main Authors: Huang, Lili, Wang, Jiabing, Chen, Liping, Zhu, Min, Wu, Shoubiao, Chu, Shenghui, Zheng, Yuantie, Fan, Ziliang, Zhang, Jiafeng, Li, Wulan, Chen, Dahui, Yang, Xiufei, Wang, Sicen, Qiu, Peihong, Wu, Jianzhang
• Format: Article
• Language: English
• Subjects: Anti-ischemic stroke agent; Keap1/Nrf2/ARE pathway; ROS; Synthesis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.09.028

Exogenous supplementation of antioxidants with ROS scavenging activity would be a potential therapy to cerebral ischemia-reperfusion injury in stroke. In the present study, a series of NDGA analogues with attenuation oxidative stress by directly scavenging ROS and indirectly through keap1/Nrf2/ARE pathway activation were designed and synthesized. All analogues were found to effectively remove ROS directly by DPPH radical scavenging assay, and compound 3a conferred potent protection from the oxidative injury in PC12 cells via promoting Nrf2 to translocate into nucleus and increasing expression of heme oxygenase-1(HO-1), where strongly reduced intracellular ROS level indirectly. More importantly, 3a significantly reduced brain infarction after cerebral ischemia-reperfusion injury in rats subjected to transient middle cerebral artery occlusion (MCAO). Overall, our findings shown compound 3a could serve as a promising compound for the treatment of stroke. [Display omitted] •A series of NDGA derivatives were designed and synthesized base combination principles.•3a could confer cytoprotection by directly scavenging ROS and indirectly through keap1/Nrf2/ARE pathway activation.•The effect of 3a was more pronounced than that of edaravone after MCAO in rats.