Design, synthesis, and evaluation of novel benzoylhydrazone derivatives as Nur77 modulators with potent antitumor activity against hepatocellular carcinoma
Nur77 modulators have emerged as a promising therapeutic approach for hepatocellular carcinoma. In this study, a structure-based rational drug design approach was used to design and synthesise a series of 4-((8-hydroxy-2-methylquinolin-4-yl)amino)benzoylhydrazone derivatives based on the binding cha...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2023.2227777 |
| _version_ | 1827123363553738752 |
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| author | Fengming He Jun Chen Taige Zhao Qiaoqiong Wu Na Yin Xiumei Wang Yijing Zhong Xiaodan Guo YingKun Qiu Baicun Li Meijuan Fang Zhen Wu |
| author_facet | Fengming He Jun Chen Taige Zhao Qiaoqiong Wu Na Yin Xiumei Wang Yijing Zhong Xiaodan Guo YingKun Qiu Baicun Li Meijuan Fang Zhen Wu |
| author_sort | Fengming He |
| collection | DOAJ |
| description | Nur77 modulators have emerged as a promising therapeutic approach for hepatocellular carcinoma. In this study, a structure-based rational drug design approach was used to design and synthesise a series of 4-((8-hydroxy-2-methylquinolin-4-yl)amino)benzoylhydrazone derivatives based on the binding characteristics of our previously reported 10g and the native ligand 3NB at the binding Site C of Nur77. Cell-based cytotoxicity assays revealed that compound TMHA37 demonstrated the highest cytotoxicity against all tested cancer cells. The induced fit docking and binding pose metadynamics simulation suggested that TMHA37 was the most promising Nur77 binder at Site C. Molecular dynamics simulation validated the stable binding of TMHA37 to Nur77’s Site C but not to Sites A or B. Specifically, TMHA37 bound strongly to Nur77-LBD (KD = 445.3 nM) and could activate Nur77’s transcriptional activity. Furthermore, TMHA37 exhibited antitumor effects by blocking the cell cycle at G2/M phase and inducing cell apoptosis in a Nur77-dependent manner. |
| first_indexed | 2024-03-09T02:03:05Z |
| format | Article |
| id | doaj.art-ad13e54480a744138d8c675f5f6cad66 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2025-03-20T14:23:44Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-ad13e54480a744138d8c675f5f6cad662024-09-09T17:23:18ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742023-12-0138110.1080/14756366.2023.2227777Design, synthesis, and evaluation of novel benzoylhydrazone derivatives as Nur77 modulators with potent antitumor activity against hepatocellular carcinomaFengming He0Jun Chen1Taige Zhao2Qiaoqiong Wu3Na Yin4Xiumei Wang5Yijing Zhong6Xiaodan Guo7YingKun Qiu8Baicun Li9Meijuan Fang10Zhen Wu11School of Pharmaceutical Sciences, Xiamen University, Xiamen, P.R. ChinaSchool of Pharmaceutical Sciences, Xiamen University, Xiamen, P.R. ChinaSchool of Pharmaceutical Sciences, Xiamen University, Xiamen, P.R. ChinaSchool of Pharmaceutical Sciences, Xiamen University, Xiamen, P.R. ChinaSchool of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, P.R. ChinaSchool of Pharmaceutical Sciences, Xiamen University, Xiamen, P.R. ChinaSchool of Pharmaceutical Sciences, Xiamen University, Xiamen, P.R. ChinaSchool of Pharmaceutical Sciences, Xiamen University, Xiamen, P.R. ChinaSchool of Pharmaceutical Sciences, Xiamen University, Xiamen, P.R. ChinaCenter of Respiratory Medicine, China-Japan Friendship Hospital, National Center for Respiratory Medicine, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, National Clinical Research Center for Respiratory Diseases, Beijing, P.R. ChinaSchool of Pharmaceutical Sciences, Xiamen University, Xiamen, P.R. ChinaSchool of Pharmaceutical Sciences, Xiamen University, Xiamen, P.R. ChinaNur77 modulators have emerged as a promising therapeutic approach for hepatocellular carcinoma. In this study, a structure-based rational drug design approach was used to design and synthesise a series of 4-((8-hydroxy-2-methylquinolin-4-yl)amino)benzoylhydrazone derivatives based on the binding characteristics of our previously reported 10g and the native ligand 3NB at the binding Site C of Nur77. Cell-based cytotoxicity assays revealed that compound TMHA37 demonstrated the highest cytotoxicity against all tested cancer cells. The induced fit docking and binding pose metadynamics simulation suggested that TMHA37 was the most promising Nur77 binder at Site C. Molecular dynamics simulation validated the stable binding of TMHA37 to Nur77’s Site C but not to Sites A or B. Specifically, TMHA37 bound strongly to Nur77-LBD (KD = 445.3 nM) and could activate Nur77’s transcriptional activity. Furthermore, TMHA37 exhibited antitumor effects by blocking the cell cycle at G2/M phase and inducing cell apoptosis in a Nur77-dependent manner.https://www.tandfonline.com/doi/10.1080/14756366.2023.2227777Nur77Benzoylhydrazone derivativeshepatocellular carcinomamolecular dynamics simulationantitumor activity |
| spellingShingle | Fengming He Jun Chen Taige Zhao Qiaoqiong Wu Na Yin Xiumei Wang Yijing Zhong Xiaodan Guo YingKun Qiu Baicun Li Meijuan Fang Zhen Wu Design, synthesis, and evaluation of novel benzoylhydrazone derivatives as Nur77 modulators with potent antitumor activity against hepatocellular carcinoma Journal of Enzyme Inhibition and Medicinal Chemistry Nur77 Benzoylhydrazone derivatives hepatocellular carcinoma molecular dynamics simulation antitumor activity |
| title | Design, synthesis, and evaluation of novel benzoylhydrazone derivatives as Nur77 modulators with potent antitumor activity against hepatocellular carcinoma |
| title_full | Design, synthesis, and evaluation of novel benzoylhydrazone derivatives as Nur77 modulators with potent antitumor activity against hepatocellular carcinoma |
| title_fullStr | Design, synthesis, and evaluation of novel benzoylhydrazone derivatives as Nur77 modulators with potent antitumor activity against hepatocellular carcinoma |
| title_full_unstemmed | Design, synthesis, and evaluation of novel benzoylhydrazone derivatives as Nur77 modulators with potent antitumor activity against hepatocellular carcinoma |
| title_short | Design, synthesis, and evaluation of novel benzoylhydrazone derivatives as Nur77 modulators with potent antitumor activity against hepatocellular carcinoma |
| title_sort | design synthesis and evaluation of novel benzoylhydrazone derivatives as nur77 modulators with potent antitumor activity against hepatocellular carcinoma |
| topic | Nur77 Benzoylhydrazone derivatives hepatocellular carcinoma molecular dynamics simulation antitumor activity |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2023.2227777 |
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