Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 157, Issue -, Pages 1376-1394Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.08.071
Keywords
Nrf2 activators; Oxadiazole core; Acute liver injury; Structure-activity relationship; Antioxidant function
Categories
Funding
- National Natural Science Foundation of China [81602948, 81773581, 81773639]
- Natural Science Foundation of Jiangsu Province of China [BK20160746]
- National Major Science and Technology Project of China (Innovation and Development of New Drugs) [2015ZX09101032, 2017ZX09302003, 2018ZX09711002-003-006]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- College Students Innovation Project for the R&D of Novel Drugs [J1310032]
- China Postdoctoral Science Foundation [2017M620232]
- Program for Outstanding Scientific and Technological Innovation Team of Jiangsu Higher Education [YY20180315004]
- Fundamental Research Funds for the Central Universities [2016ZPT005]
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The antioxidant function induced by Nrf2 protects the liver from damage. We found a novel Nrf2 activator named compound 25 via structural modification of compound 1 we previously reported. In vitro, compound 25 induced Nrf2 transport into the nucleus and protected hepatocyte L02 cells from APAP-induced cytotoxicity via activating the Nrf2-ARE signaling pathway. In vivo, 25 exhibited therapeutic effects in a mouse model of acute liver injury induced by acetaminophen (APAP) by up-regulating Nrf2-dependent antioxidases and down-regulating liver injury markers in serum. Together, these results indicated that 25 is a potent Nrf2/ARE activator both in vitro and in vivo. The drug-like properties of compound 25 further revealed its potential for development as a therapeutic drug against acute liver injury. (C) 2018 Elsevier Masson SAS. All rights reserved.
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