title: Novel oxime-bearing coumarin derivatives act as potent Nrf2/ARE activators in vitro and in mouse model.
abstract: 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.
authors.affiliation: School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Ken-Ming
authors.initials: KM
authors.lastname: Chang
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan 350, Taiwan; Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Huang-Hui
authors.initials: HH
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung 907, Taiwan.
authors.forename: Tai-Chi
authors.initials: TC
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung 907, Taiwan.
authors.forename: I-Li
authors.initials: IL
authors.lastname: Chen
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan 350, Taiwan.
authors.forename: Yu-Tsen
authors.initials: YT
authors.lastname: Chen
authors.affiliation: School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Shyh-Chyun
authors.initials: SC
authors.lastname: Yang
authors.affiliation: Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Yeh-Long
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan 350, Taiwan.
authors.forename: Hsin-Huei
authors.initials: HH
authors.lastname: Chang
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan 350, Taiwan.
authors.forename: Chih-Hsiang
authors.initials: CH
authors.lastname: Huang
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan; Institute of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University Medical College, Tainan 704, Taiwan.
authors.forename: Jang-Yang
authors.initials: JY
authors.lastname: Chang
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan 350, Taiwan.
authors.forename: Chuan
authors.initials: C
authors.lastname: Shih
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan 350, Taiwan; Institute of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University Medical College, Tainan 704, Taiwan; Graduate Program for Aging, China Medical University, Taichung 404, Taiwan. Electronic address: cckuo@nhri.org.tw.
authors.forename: Ching-Chuan
authors.initials: CC
authors.lastname: Kuo
authors.affiliation: School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address: tzengch@kmu.edu.tw.
authors.forename: Cherng-Chyi
authors.initials: CC
authors.lastname: Tzeng
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D015394:Molecular Structure; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010091:Oximes / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D003374:Coumarins; D051267:NF-E2-Related Factor 2; D010091:Oximes; C030123:coumarin; D008156:Luciferases
keywords: Antioxidant activity; Cytoprotection; Nrf2/ARE activators; Oxime-bearing coumarins