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Discovery of 4-Anilinoquinolinylchalcone Derivatives as Potential NRF2 Activators
Activation of nuclear factor erythroid-2-related factor 2 (NRF2) has been proven to be an effective means to prevent the development of cancer, and natural curcumin stands out as a potent NRF2 activator and cancer chemopreventive agent. In this study, we have synthesized a series of 4-anilinoquinoli...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396997/ https://www.ncbi.nlm.nih.gov/pubmed/32650607 http://dx.doi.org/10.3390/molecules25143133 |
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author | Kao, Yu-Tse Chen, Yi-Siao Tang, Kai-Wei Lee, Jin-Ching Tseng, Chih-Hua Tzeng, Cherng-Chyi Yen, Chia-Hung Chen, Yeh-Long |
author_facet | Kao, Yu-Tse Chen, Yi-Siao Tang, Kai-Wei Lee, Jin-Ching Tseng, Chih-Hua Tzeng, Cherng-Chyi Yen, Chia-Hung Chen, Yeh-Long |
author_sort | Kao, Yu-Tse |
collection | PubMed |
description | Activation of nuclear factor erythroid-2-related factor 2 (NRF2) has been proven to be an effective means to prevent the development of cancer, and natural curcumin stands out as a potent NRF2 activator and cancer chemopreventive agent. In this study, we have synthesized a series of 4-anilinoquinolinylchalcone derivatives, and used a NRF2 promoter-driven firefly luciferase reporter stable cell line, the HaCaT/ARE cells, to screen a panel of these compounds. Among them, (E)-3-{4-[(4-acetylphenyl)amino]quinolin-2-yl}-1-(4-fluorophenyl)prop-2-en-1-one (13b) significantly increased NRF2 activity in the HaCaT cell with a half maximal effective concentration (EC(50)) value of 1.95 μM. Treatment of compound 13b upregulated HaCaT cell NRF2 expression at the protein level. Moreover, the mRNA level of NRF2 target genes, heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC), and glucose-6-phosphate dehydrogenase (G6PD) were significantly increased in HaCaT cells upon the compound 13b treatment. The molecular docking results exhibited that the small molecule 13b is well accommodated by the bound region of Kelch-like ECH-associated protein 1 (Keap1)-Kelch and NRF2 through stable hydrogen bonds and hydrophobic interaction, which contributed to the enhancement of affinity and stability between the ligand and receptor. Compound 13b has been identified as the lead compound for further structural optimization. |
format | Online Article Text |
id | pubmed-7396997 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-73969972020-08-05 Discovery of 4-Anilinoquinolinylchalcone Derivatives as Potential NRF2 Activators Kao, Yu-Tse Chen, Yi-Siao Tang, Kai-Wei Lee, Jin-Ching Tseng, Chih-Hua Tzeng, Cherng-Chyi Yen, Chia-Hung Chen, Yeh-Long Molecules Article Activation of nuclear factor erythroid-2-related factor 2 (NRF2) has been proven to be an effective means to prevent the development of cancer, and natural curcumin stands out as a potent NRF2 activator and cancer chemopreventive agent. In this study, we have synthesized a series of 4-anilinoquinolinylchalcone derivatives, and used a NRF2 promoter-driven firefly luciferase reporter stable cell line, the HaCaT/ARE cells, to screen a panel of these compounds. Among them, (E)-3-{4-[(4-acetylphenyl)amino]quinolin-2-yl}-1-(4-fluorophenyl)prop-2-en-1-one (13b) significantly increased NRF2 activity in the HaCaT cell with a half maximal effective concentration (EC(50)) value of 1.95 μM. Treatment of compound 13b upregulated HaCaT cell NRF2 expression at the protein level. Moreover, the mRNA level of NRF2 target genes, heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC), and glucose-6-phosphate dehydrogenase (G6PD) were significantly increased in HaCaT cells upon the compound 13b treatment. The molecular docking results exhibited that the small molecule 13b is well accommodated by the bound region of Kelch-like ECH-associated protein 1 (Keap1)-Kelch and NRF2 through stable hydrogen bonds and hydrophobic interaction, which contributed to the enhancement of affinity and stability between the ligand and receptor. Compound 13b has been identified as the lead compound for further structural optimization. MDPI 2020-07-08 /pmc/articles/PMC7396997/ /pubmed/32650607 http://dx.doi.org/10.3390/molecules25143133 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kao, Yu-Tse Chen, Yi-Siao Tang, Kai-Wei Lee, Jin-Ching Tseng, Chih-Hua Tzeng, Cherng-Chyi Yen, Chia-Hung Chen, Yeh-Long Discovery of 4-Anilinoquinolinylchalcone Derivatives as Potential NRF2 Activators |
title | Discovery of 4-Anilinoquinolinylchalcone Derivatives as Potential NRF2 Activators |
title_full | Discovery of 4-Anilinoquinolinylchalcone Derivatives as Potential NRF2 Activators |
title_fullStr | Discovery of 4-Anilinoquinolinylchalcone Derivatives as Potential NRF2 Activators |
title_full_unstemmed | Discovery of 4-Anilinoquinolinylchalcone Derivatives as Potential NRF2 Activators |
title_short | Discovery of 4-Anilinoquinolinylchalcone Derivatives as Potential NRF2 Activators |
title_sort | discovery of 4-anilinoquinolinylchalcone derivatives as potential nrf2 activators |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396997/ https://www.ncbi.nlm.nih.gov/pubmed/32650607 http://dx.doi.org/10.3390/molecules25143133 |
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