Discovery of 4-Anilinoquinolinylchalcone Derivatives as Potential NRF2 Activators

Abstract

<jats:p>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 (EC50) 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.</jats:p>

The Cytoprotective Activity of Nrf2 Is Regulated by Phytochemicals (Sulforaphane, Curcumin, and Silymarin)

“…Additionally, the molecular docking results of some 4-quinolinyn chalcones exhibited that a structurally related small molecule is well-situated by the bound region of Keap1-Kelch and NrF2 through stable hydrogen bonds and the hydrophobic interaction (in a way similar to that depicted in Fig. 8 for silybin), which contributed to high affinity and stability between the ligand and the receptor [179]. The tested compounds are Nrf2 activators in the micromolar concentration.…”

Spongenolactones A–C, Bioactive 5,5,6,6,5-Pentacyclic Spongian Diterpenes from the Red Sea Sponge Spongia sp.

“…In order to discover the biological activity of new metabolites for future medicinal applications, 1 – 3 were tested for their cytotoxic, antibacterial, and anti-inflammatory activities. The cytotoxicity of 1 – 3 against HCC Huh7 cell line was evaluated by the resazurin assay [ 18 , 19 ], and none of the compounds showed notable activity against the growth of this cancer cell line. Furthermore, the assay for the growth inhibition of S. aureus showed that compound 1 exhibited 46%, 47%, and 93% inhibition at 50, 100, and 200 µM, respectively, while 2 displayed 24%, 42%, and 40% inhibition at 50, 100, and 200 µM, respectively.…”

“…The cytotoxicity assay was performed using the methods described previously [ 18 , 19 ]. Huh7 cells were used in resazurin assay (Cayman Chemical) and treated with indicated concentrations (12.5, 50.0, and 200.0 µM) of compounds for 72 h. The DMSO control was assigned 100% of relative cell viability.…”

Natural and Semi-Synthetic Flavonoid Anti-SARS-CoV-2 Agents for the Treatment of Long COVID-19 Disease and Neurodegenerative Disorders of Cognitive Decline

“…HOactivity not only degrades injurious heme, but its effector molecules possess anti-oxidative and anti-inflammatory properties of potential benefit to ARDS patients [352]. 4-Anilinoquinolinyl chalcone upregulates HO-1 expression and has beneficial anti-inflammatory and anti-oxidant properties typical of the chalcone family [353]. Novel chalcones display anti-inflammatory and anti-oxidant effects invitro and after LPS induced acute lung injury [354].…”