Molecular similarity guided optimization of novel Nrf2 activators with 1,2,4-oxadiazole core |
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| Institution: | 1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China;2. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China;3. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China;1. School of Mechanical Engineering and Automation, Fuzhou University, Fujian 350116, China;2. Department of Medical Oncology, Fujian Provincial Hospital, Fujian 350001, China;1. College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, South Korea;2. College of Pharmacy, Yeungnam University, Gyeongsan 712-749, South Korea;1. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China;2. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China;3. Department of Psychiatry, Ningbo Kangning Hospital, Ningbo, Zhejiang, China;4. Yunnan Key Laboratory of Primate Biomedicine Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan, China;5. Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China;6. Department of Psychiatry, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China;7. Jinhua Second Hospital, Jinhua, Zhejiang, China;8. Wenzhou Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China;9. Hangzhou Seventh People''s Hospital, Hangzhou, Zhejiang, China;10. Institute of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China;11. Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China;12. Department of Bioinformatics, School of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai''an, Shandong, China;1. Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, No. 1 Sec. 1 Jen-Ai Road, Taipei 100, Taiwan;2. Department of Electrical Engineering, College of Electrical and Communication Engineering, Yuan Ze University, Taoyuan, Taiwan;3. Department of Otolaryngology, Far Eastern Memorial Hospital, Taipei, Taiwan;4. Department of Health Care Administration, Oriental Institute of Technology, Taipei, Taiwan;1. Institutes of Biomedical Sciences, Fudan University, Shanghai, China;2. Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China;3. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China;1. School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China;2. Institute of Pharmaceutics, Anhui Academy of Chinese Medicine, Hefei, 230012, China |
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| 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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| Keywords: | Nrf2 activator ARE inducers Oxadiazole core |
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