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Eur J Med Chem. 2018 Jan 1;143:1165-1173. doi: 10.1016/j.ejmech.2017.09.028. Epub 2017 Oct 16.

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

Author information

1
Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical Universtiy, Wenzhou, Zhejiang 325035, China; Wenzhou Biomedical Innovation Center, Wenzhou University and Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
2
Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical Universtiy, Wenzhou, Zhejiang 325035, China.
3
Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical Universtiy, Wenzhou, Zhejiang 325035, China; Department of Pharmacy, Wenzhou Central Hospital, Wenzhou, Zhejiang 325000, China.
4
Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical Universtiy, Wenzhou, Zhejiang 325035, China; College of Information Science and Computer Engineering, The First Clinical Medical College, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
5
Department of Pharmacy, Wenzhou Central Hospital, Wenzhou, Zhejiang 325000, China.
6
School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shanxi 710049, China.
7
Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical Universtiy, Wenzhou, Zhejiang 325035, China. Electronic address: wjzwzmc@126.com.
8
Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical Universtiy, Wenzhou, Zhejiang 325035, China; Wenzhou Biomedical Innovation Center, Wenzhou University and Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: wjzwzmu@163.com.

Abstract

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.

KEYWORDS:

Anti-ischemic stroke agent; Keap1/Nrf2/ARE pathway; ROS; Synthesis

PMID:
29126723
DOI:
10.1016/j.ejmech.2017.09.028
[Indexed for MEDLINE]

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