Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 24, Issue 16, Pages 3540-3547Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2016.05.056
Keywords
Nrf2 activator; ARE inducers; Oxadiazole core
Funding
- National Natural Science Foundation of China [81230078]
- National Major Science and Technology Project of China (Innovation and Development of New Drugs) [2014ZX09507002-005-015, 2013ZX09402102-001-005]
- Specialized Research Fund for the Doctoral Program of Higher Education (SRFDP) [20130096110002]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- Fundamental Research Funds for the Central Universities [2016ZPY016]
Ask authors/readers for more resources
DDO-7204 is a novel Nrf2 activator first identified through screening of in-house database by ARE-luciferase reporter gene assay. To further optimize this kind of Nrf2 activators efficiently, the hit-based substructure search was applied to screen the Specs database virtually. DDO-7204 contains three rings of A, B, C. SAR results showed that: for ring A, the cyclane substituent is beneficial for ARE inductivity. Enhanced flexibility of linker between ring A and ring B is not preferable for the Nrf2 activity. Ring A replaced by heterocyclic aromatic is beneficial for the Nrf2 activity. The resulting compound 7 was more potent than DDO-7204. Compound 7 can induce Nrf2 translocation into nuclear not only in HCT116 cells, but also in three normal cells such as L02, NCM460 and PC12 cells. The Nrf2-regualted genes, gamma-GCS, NQO1 and HO-1, were up-regulated at a concentration-dependent manner. In addition, compound 7 showed cytoprotective effects on the three normal cells against the damage of H2O2. (C) 2016 Elsevier Ltd. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available