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...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-07-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/25/14/3133 |
| _version_ | 1797562930796953600 |
|---|---|
| author | Yu-Tse Kao Yi-Siao Chen Kai-Wei Tang Jin-Ching Lee Chih-Hua Tseng Cherng-Chyi Tzeng Chia-Hung Yen Yeh-Long Chen |
| author_facet | Yu-Tse Kao Yi-Siao Chen Kai-Wei Tang Jin-Ching Lee Chih-Hua Tseng Cherng-Chyi Tzeng Chia-Hung Yen Yeh-Long Chen |
| author_sort | Yu-Tse Kao |
| collection | DOAJ |
| 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, (<i>E</i>)-3-{4-[(4-acetylphenyl)amino]quinolin-2-yl}-1-(4-fluorophenyl)prop-2-en-1-one (<b>13b</b>) significantly increased NRF2 activity in the HaCaT cell with a half maximal effective concentration (EC<sub>50</sub>) value of 1.95 μM. Treatment of compound <b>13b</b> 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 <b>13b</b> treatment. The molecular docking results exhibited that the small molecule <b>13b</b> 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 <b>13b</b> has been identified as the lead compound for further structural optimization. |
| first_indexed | 2024-03-10T18:35:36Z |
| format | Article |
| id | doaj.art-6d65ded367e04782813145cf68477211 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T18:35:36Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-6d65ded367e04782813145cf684772112023-11-20T06:14:00ZengMDPI AGMolecules1420-30492020-07-012514313310.3390/molecules25143133Discovery of 4-Anilinoquinolinylchalcone Derivatives as Potential NRF2 ActivatorsYu-Tse Kao0Yi-Siao Chen1Kai-Wei Tang2Jin-Ching Lee3Chih-Hua Tseng4Cherng-Chyi Tzeng5Chia-Hung Yen6Yeh-Long Chen7Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, TaiwanProgram in Environmental and Occupational Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, TaiwanSchool of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, TaiwanGraduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, TaiwanSchool of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, TaiwanDepartment of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, TaiwanGraduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, TaiwanDepartment of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, TaiwanActivation 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, (<i>E</i>)-3-{4-[(4-acetylphenyl)amino]quinolin-2-yl}-1-(4-fluorophenyl)prop-2-en-1-one (<b>13b</b>) significantly increased NRF2 activity in the HaCaT cell with a half maximal effective concentration (EC<sub>50</sub>) value of 1.95 μM. Treatment of compound <b>13b</b> 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 <b>13b</b> treatment. The molecular docking results exhibited that the small molecule <b>13b</b> 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 <b>13b</b> has been identified as the lead compound for further structural optimization.https://www.mdpi.com/1420-3049/25/14/31334-anilinoquinolinylchalcone derivativesnuclear factor erythroid-2-related factor 2 (NRF2) activatorscancer chemopreventive agent |
| spellingShingle | Yu-Tse Kao Yi-Siao Chen Kai-Wei Tang Jin-Ching Lee Chih-Hua Tseng Cherng-Chyi Tzeng Chia-Hung Yen Yeh-Long Chen Discovery of 4-Anilinoquinolinylchalcone Derivatives as Potential NRF2 Activators Molecules 4-anilinoquinolinylchalcone derivatives nuclear factor erythroid-2-related factor 2 (NRF2) activators cancer chemopreventive agent |
| 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 | 4-anilinoquinolinylchalcone derivatives nuclear factor erythroid-2-related factor 2 (NRF2) activators cancer chemopreventive agent |
| url | https://www.mdpi.com/1420-3049/25/14/3133 |
| work_keys_str_mv | AT yutsekao discoveryof4anilinoquinolinylchalconederivativesaspotentialnrf2activators AT yisiaochen discoveryof4anilinoquinolinylchalconederivativesaspotentialnrf2activators AT kaiweitang discoveryof4anilinoquinolinylchalconederivativesaspotentialnrf2activators AT jinchinglee discoveryof4anilinoquinolinylchalconederivativesaspotentialnrf2activators AT chihhuatseng discoveryof4anilinoquinolinylchalconederivativesaspotentialnrf2activators AT cherngchyitzeng discoveryof4anilinoquinolinylchalconederivativesaspotentialnrf2activators AT chiahungyen discoveryof4anilinoquinolinylchalconederivativesaspotentialnrf2activators AT yehlongchen discoveryof4anilinoquinolinylchalconederivativesaspotentialnrf2activators |