Novel oxime-bearing coumarin derivatives act as potent Nrf2/ARE activators in vitro and in mouse model

Ken Ming Chang, Huang Hui Chen, Tai Chi Wang, I. Li Chen, Yu Tsen Chen, Shyh Chyun Yang, Yeh Long Chen, Hsin Huei Chang, Chih Hsiang Huang, Jang-Yang Chang, Chuan Shih, Ching Chuan Kuo, Cherng Chyi Tzeng

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)60-74
Number of pages15
JournalEuropean Journal of Medicinal Chemistry
Volume106
DOIs
Publication statusPublished - 2015 Dec 1

Fingerprint

Bearings (structural)
Coumarins
Oximes
Antioxidants
Luciferases
Heme Oxygenase (Decyclizing)
Proteins
Heme Oxygenase-1
Oxidative stress
Glutathione Reductase
Amides
Liver
Animals
Oxidative Stress
In Vitro Techniques
Experiments

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Chang, Ken Ming ; Chen, Huang Hui ; Wang, Tai Chi ; Chen, I. Li ; Chen, Yu Tsen ; Yang, Shyh Chyun ; Chen, Yeh Long ; Chang, Hsin Huei ; Huang, Chih Hsiang ; Chang, Jang-Yang ; Shih, Chuan ; Kuo, Ching Chuan ; Tzeng, Cherng Chyi. / Novel oxime-bearing coumarin derivatives act as potent Nrf2/ARE activators in vitro and in mouse model. In: European Journal of Medicinal Chemistry. 2015 ; Vol. 106. pp. 60-74.
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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.",
author = "Chang, {Ken Ming} and Chen, {Huang Hui} and Wang, {Tai Chi} and Chen, {I. Li} and Chen, {Yu Tsen} and Yang, {Shyh Chyun} and Chen, {Yeh Long} and Chang, {Hsin Huei} and Huang, {Chih Hsiang} and Jang-Yang Chang and Chuan Shih and Kuo, {Ching Chuan} and Tzeng, {Cherng Chyi}",
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Chang, KM, Chen, HH, Wang, TC, Chen, IL, Chen, YT, Yang, SC, Chen, YL, Chang, HH, Huang, CH, Chang, J-Y, Shih, C, Kuo, CC & Tzeng, CC 2015, 'Novel oxime-bearing coumarin derivatives act as potent Nrf2/ARE activators in vitro and in mouse model', European Journal of Medicinal Chemistry, vol. 106, pp. 60-74. https://doi.org/10.1016/j.ejmech.2015.10.029

Novel oxime-bearing coumarin derivatives act as potent Nrf2/ARE activators in vitro and in mouse model. / Chang, Ken Ming; Chen, Huang Hui; Wang, Tai Chi; Chen, I. Li; Chen, Yu Tsen; Yang, Shyh Chyun; Chen, Yeh Long; Chang, Hsin Huei; Huang, Chih Hsiang; Chang, Jang-Yang; Shih, Chuan; Kuo, Ching Chuan; Tzeng, Cherng Chyi.

In: European Journal of Medicinal Chemistry, Vol. 106, 01.12.2015, p. 60-74.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Novel oxime-bearing coumarin derivatives act as potent Nrf2/ARE activators in vitro and in mouse model

AU - Chang, Ken Ming

AU - Chen, Huang Hui

AU - Wang, Tai Chi

AU - Chen, I. Li

AU - Chen, Yu Tsen

AU - Yang, Shyh Chyun

AU - Chen, Yeh Long

AU - Chang, Hsin Huei

AU - Huang, Chih Hsiang

AU - Chang, Jang-Yang

AU - Shih, Chuan

AU - Kuo, Ching Chuan

AU - Tzeng, Cherng Chyi

PY - 2015/12/1

Y1 - 2015/12/1

N2 - 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.

AB - 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.

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DO - 10.1016/j.ejmech.2015.10.029

M3 - Article

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