Novel oxime-bearing coumarin derivatives act as potent Nrf2/ARE activators in vitro and in mouse model
| Autor: | Huang-Hui Chen, Cherng-Chyi Tzeng, Jang Yang Chang, Hsin-Huei Chang, Yu-Tsen Chen, Tai-Chi Wang, Ching-Chuan Kuo, Yeh-Long Chen, Shyh-Chyun Yang, Chuan Shih, Ken-Ming Chang, Chih-Hsiang Huang, I-Li Chen |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Antioxidant Cell Survival NF-E2-Related Factor 2 AKR1C1 medicine.medical_treatment Glutathione reductase In Vitro Techniques Reductase Mice Structure-Activity Relationship Coumarins In vivo Oximes Drug Discovery Tumor Cells Cultured medicine Animals Humans Luciferase Antioxidant Response Elements Luciferases Pharmacology Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry General Medicine Mice Inbred C57BL Heme oxygenase Oxidative Stress Biochemistry Models Animal |
| Zdroj: | European Journal of Medicinal Chemistry. 106:60-74 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2015.10.029 |
| Popis: | We have designed and synthesized certain novel oxime- and amide-bearing coumarin derivatives as nuclear factor erythroid 2 p45-related factor 2 (Nrf2) activators. The potency of these compounds was measured by antioxidant responsive element (ARE)-driven luciferase activity, level of Nrf2-related cytoprotective genes and proteins, and antioxidant activity. Among them, (Z)-3-(2-(hydroxyimino)-2-phenylethoxy)-2H-chromen-2-one (17a) was the most active, and more potent than the positive t-BHQ in the induction of ARE-driven luciferase activity. Exposure of HSC-3 cells to various concentrations of 17a strongly increased Nrf2 nuclear translocation and the expression level of Nrf2-mediated cytoprotective proteins in a concentration-dependent manner. HSC-3 cells pretreated with 17a significantly reduced t-BOOH-induced oxidative stress. In the animal experiment, Nrf2-mediated cytoprotective proteins, such as aldo-keto reductase 1 subunit C-1 (AKR1C1), glutathione reductase (GR), and heme oxygenase (HO-1), were obviously elevated in the liver of 17a-treated mice than that of control. These results suggested that novel oxime-bearing coumarin 17a is able to activate Nrf2/ARE pathway in vivo and are therefore seen as a promising candidate for further investigation. |
| Databáze: | OpenAIRE |
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