Design, synthesis, and biological evaluation of quinolinyl-ureido-phenyl-hydrazide derivatives and quinolinyl-hydrazide derivatives as anticancer agents targeting Nur77-mediated ferroptosis
{"title":"Design, synthesis, and biological evaluation of quinolinyl-ureido-phenyl-hydrazide derivatives and quinolinyl-hydrazide derivatives as anticancer agents targeting Nur77-mediated ferroptosis","authors":"Yan-fang Gao, Yi-jing Yang, Jing-bo Qin, Ming-yue Yu, Sheng-wei Hu, Hao-fan Zhang, Fan-hong Lin, Hong-yu Hu, Mei-juan Fang, Jin-Zhang Zeng","doi":"10.1016/j.ejmech.2025.117559","DOIUrl":null,"url":null,"abstract":"In the recent decade, targeting ferroptosis for cancer therapy has attracted remarkable attention. Interestingly, the transcriptional regulator Nur77, a promising therapeutic target in cancer, has been recently identified as a crucial regulator of ferroptosis. However, no ferroptosis inducer targeting Nur77 has been reported currently. In this study, we built upon our prior research on Nur77 modulator 4-PQBH to design and synthesize four series of new compounds, with the objective of developing novel Nur77-mediated ferroptosis inducers. Among them, compound <strong>8f</strong> exhibited the most potency against the tested cancer cell lines, including human estrogen positive breast cancer and triple-negative breast cancer cell lines, while displaying lower toxicity towards human normal cell lines HaCaT and MCF-10A (IC<sub>50</sub> <em>></em> 50 μM). Furthermore, <strong>8f</strong> demonstrated superior Nur77-binding activity in comparison to the reference compound Csn-B, and it has the capacity to activate the Nur77-driven luciferase activity and increase the protein level of Nur77. Remarkably, <strong>8f</strong> induced an increase in the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and lipid peroxidation, concurrently with a reduction in the expression of GPX4 protein, culminating in the induction of ferroptosis in a Nur77-dependent manner. <em>In vivo</em>, <strong>8f</strong> treatment has been observed to significantly suppress MCF7 xenograft tumor growth. Consequently, a novel ferroptosis inducer targeting Nur77 (<strong>8f</strong>) is first reported as a potent anti-EPBC agent, providing may serve as a promising lead for further drug development targeting Nur77-mediated ferroptosis.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"37 1","pages":""},"PeriodicalIF":6.0000,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ejmech.2025.117559","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
In the recent decade, targeting ferroptosis for cancer therapy has attracted remarkable attention. Interestingly, the transcriptional regulator Nur77, a promising therapeutic target in cancer, has been recently identified as a crucial regulator of ferroptosis. However, no ferroptosis inducer targeting Nur77 has been reported currently. In this study, we built upon our prior research on Nur77 modulator 4-PQBH to design and synthesize four series of new compounds, with the objective of developing novel Nur77-mediated ferroptosis inducers. Among them, compound 8f exhibited the most potency against the tested cancer cell lines, including human estrogen positive breast cancer and triple-negative breast cancer cell lines, while displaying lower toxicity towards human normal cell lines HaCaT and MCF-10A (IC50> 50 μM). Furthermore, 8f demonstrated superior Nur77-binding activity in comparison to the reference compound Csn-B, and it has the capacity to activate the Nur77-driven luciferase activity and increase the protein level of Nur77. Remarkably, 8f induced an increase in the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and lipid peroxidation, concurrently with a reduction in the expression of GPX4 protein, culminating in the induction of ferroptosis in a Nur77-dependent manner. In vivo, 8f treatment has been observed to significantly suppress MCF7 xenograft tumor growth. Consequently, a novel ferroptosis inducer targeting Nur77 (8f) is first reported as a potent anti-EPBC agent, providing may serve as a promising lead for further drug development targeting Nur77-mediated ferroptosis.
期刊介绍:
The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers.
A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.