Discovery of 4-Anilinoquinolinylchalcone Derivatives as Potential NRF2 Activators

• Published in: Molecules (Basel, Switzerland) Vol. 25; no. 14; p. 3133
• Main Authors: Kao, Yu-Tse, Chen, Yi-Siao, Tang, Kai-Wei, Lee, Jin-Ching, Tseng, Chih-Hua, Tzeng, Cherng-Chyi, Yen, Chia-Hung, Chen, Yeh-Long
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08-07-2020; MDPI
• Subjects: 4-anilinoquinolinylchalcone derivatives; Antioxidants; cancer chemopreventive agent; Cell Line, Transformed; Chalcones - chemical synthesis; Chalcones - chemistry; Chalcones - pharmacology; Curcumin; Cytotoxicity; Gene expression; Gene Expression Regulation - drug effects; Glucose 6 phosphate dehydrogenase; Glucosephosphate Dehydrogenase; Glutamate-cysteine ligase; Glutamate-Cysteine Ligase - biosynthesis; Heme; Heme oxygenase (decyclizing); Heme Oxygenase-1 - biosynthesis; Humans; Hydrogen bonding; Hydrogen bonds; Hydrophobicity; Kelch-Like ECH-Associated Protein 1 - chemistry; Kelch-Like ECH-Associated Protein 1 - metabolism; Keratinocytes - chemistry; Keratinocytes - metabolism; Kinases; Lead compounds; Molecular docking; Molecular Docking Simulation; mRNA; NF-E2-Related Factor 2 - biosynthesis; NF-E2-Related Factor 2 - genetics; NRF2 protein; nuclear factor erythroid-2-related factor 2 (NRF2) activators; Optimization; Oxidative stress; Oxygenase; Proteins; nuclear factor erythroid-2-related factor 2 (NRF2) activators; 4-anilinoquinolinylchalcone derivatives; cancer chemopreventive agent
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25143133

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, (
)-3-{4-[(4-acetylphenyl)amino]quinolin-2-yl}-1-(4-fluorophenyl)prop-2-en-1-one (
) significantly increased NRF2 activity in the HaCaT cell with a half maximal effective concentration (EC
) value of 1.95 μM. Treatment of compound
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
treatment. The molecular docking results exhibited that the small molecule
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
has been identified as the lead compound for further structural optimization.