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Updated: Mar 19, 2026

Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Molecular similarity guided optimization of novel Nrf2 activators with 1,2,4-oxadiazole core
Li-Li Xu1, Xian Zhang1, Zheng-Yu Jiang2
1State 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.
Abstract:
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.
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