Molecular similarity guided optimization of novel Nrf2 activators with 1,2,4-oxadiazole core.
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, γ-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.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Li-Li
LL
Xu
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Xian
X
Zhang
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: jiangzhengyucpu@163.com.
Zheng-Yu
ZY
Jiang
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: youqidong@gmail.com.
Qi-Dong
QD
You
D000818:Animals; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D006801:Humans; D015394:Molecular Structure; D051267:NF-E2-Related Factor 2 / Q000819:agonists*; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*
D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010069:Oxadiazoles
ARE inducers; Nrf2 activator; Oxadiazole core