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

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.
AuthorsLili Huang, Jiabing Wang, Liping Chen, Min Zhu, Shoubiao Wu, Shenghui Chu, Yuantie Zheng, Ziliang Fan, Jiafeng Zhang, Wulan Li, Dahui Chen, Xiufei Yang, Sicen Wang, Peihong Qiu, Jianzhang Wu
JournalEuropean journal of medicinal chemistry (Eur J Med Chem) Vol. 143 Pg. 1165-1173 (Jan 01 2018) ISSN: 1768-3254 [Electronic] France
PMID29126723 (Publication Type: Journal Article)
CopyrightCopyright © 2017. Published by Elsevier Masson SAS.
Chemical References
  • Neuroprotective Agents
  • Masoprocol
  • Hydrogen Peroxide
Topics
  • Animals
  • Brain Ischemia (drug therapy)
  • Cell Survival (drug effects)
  • Dose-Response Relationship, Drug
  • Drug Design
  • Hydrogen Peroxide (antagonists & inhibitors, pharmacology)
  • Male
  • Masoprocol (chemical synthesis, chemistry, pharmacology)
  • Molecular Structure
  • Neuroprotective Agents (chemistry, pharmacology)
  • PC12 Cells
  • Rats
  • Rats, Sprague-Dawley
  • Stroke (drug therapy)
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

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