Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 Modulators
Nur77 is an orphan nuclear receptor that participates in the occurrence and development of a variety of tumors. Many agonists of Nur77 have been reported to have significant anticancer effects. Our previous studies have found that the introduction of bicyclic aromatic rings, such as naphthalyl and q...
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MDPI AG
2022-03-01
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| Series: | Molecules |
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| author | Hongyu Hu Jiangang Huang Yin Cao Zhaolin Zhang Fengming He Xianfu Lin Qi Wu Shengxian Zhao |
| author_facet | Hongyu Hu Jiangang Huang Yin Cao Zhaolin Zhang Fengming He Xianfu Lin Qi Wu Shengxian Zhao |
| author_sort | Hongyu Hu |
| collection | DOAJ |
| description | Nur77 is an orphan nuclear receptor that participates in the occurrence and development of a variety of tumors. Many agonists of Nur77 have been reported to have significant anticancer effects. Our previous studies have found that the introduction of bicyclic aromatic rings, such as naphthalyl and quinoline groups, into the <i>N</i>′-methylene position of indoles’ Nur77 modulators can effectively improve the anti-tumor activity of the target compounds. Following our previous studies, a series of novel 1-(2-(6-methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-substituted semicarbazide/thiosemicarbazide derivatives <b>9a</b>–<b>9w</b> were designed and synthesized in four steps from 6-methoxy-2-acetonaphthone and <i>N</i>-dimethylformamide dimethylacetal. All compounds were characterized by <sup>1</sup>H-NMR, <sup>13</sup>C-NMR and HRMS, and their anti-tumor activity on various cancer cell lines such as A549, HepG2, HGC-27, MCF-7 and HeLa are also evaluated. From the series of compounds, <b>9h</b> exhibited the most potent anti-proliferative activity against several cancer cells. Colony formation and cell cycle experiments showed that compound <b>9h</b> inhibited cell growth and arrested the cell cycle. Additionally, <b>9h</b> leads to the cleavage of PARP. We initially explored the mechanism of <b>9h</b>-induced apoptosis and found that compound <b>9h</b> can upregulate Nur77 expression and triggered Nur77 nuclear export, indicating the occurrence of Nur77-mediated apoptosis. These results suggested that <b>9h</b> may be a promising anti-tumor leading compound for the further research. |
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| last_indexed | 2024-03-09T20:28:44Z |
| publishDate | 2022-03-01 |
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| series | Molecules |
| spelling | doaj.art-0114be778b3a466c98f226d1c33d84c42023-11-23T23:28:23ZengMDPI AGMolecules1420-30492022-03-01275169810.3390/molecules27051698Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 ModulatorsHongyu Hu0Jiangang Huang1Yin Cao2Zhaolin Zhang3Fengming He4Xianfu Lin5Qi Wu6Shengxian Zhao7Department of Chemistry, Zhejiang University, Hangzhou 310027, ChinaSchool of Pharmaceutical Sciences, Xiamen University, South Xiang-An Road, Xiamen 361102, ChinaSchool of Pharmaceutical Sciences, Xiamen University, South Xiang-An Road, Xiamen 361102, ChinaXingzhi College, Zhejiang Normal University, Lanxi 321004, ChinaSchool of Pharmaceutical Sciences, Xiamen University, South Xiang-An Road, Xiamen 361102, ChinaDepartment of Chemistry, Zhejiang University, Hangzhou 310027, ChinaDepartment of Chemistry, Zhejiang University, Hangzhou 310027, ChinaCollege of Science and Technology, Ningbo University, Cixi 315302, ChinaNur77 is an orphan nuclear receptor that participates in the occurrence and development of a variety of tumors. Many agonists of Nur77 have been reported to have significant anticancer effects. Our previous studies have found that the introduction of bicyclic aromatic rings, such as naphthalyl and quinoline groups, into the <i>N</i>′-methylene position of indoles’ Nur77 modulators can effectively improve the anti-tumor activity of the target compounds. Following our previous studies, a series of novel 1-(2-(6-methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-substituted semicarbazide/thiosemicarbazide derivatives <b>9a</b>–<b>9w</b> were designed and synthesized in four steps from 6-methoxy-2-acetonaphthone and <i>N</i>-dimethylformamide dimethylacetal. All compounds were characterized by <sup>1</sup>H-NMR, <sup>13</sup>C-NMR and HRMS, and their anti-tumor activity on various cancer cell lines such as A549, HepG2, HGC-27, MCF-7 and HeLa are also evaluated. From the series of compounds, <b>9h</b> exhibited the most potent anti-proliferative activity against several cancer cells. Colony formation and cell cycle experiments showed that compound <b>9h</b> inhibited cell growth and arrested the cell cycle. Additionally, <b>9h</b> leads to the cleavage of PARP. We initially explored the mechanism of <b>9h</b>-induced apoptosis and found that compound <b>9h</b> can upregulate Nur77 expression and triggered Nur77 nuclear export, indicating the occurrence of Nur77-mediated apoptosis. These results suggested that <b>9h</b> may be a promising anti-tumor leading compound for the further research.https://www.mdpi.com/1420-3049/27/5/1698semicarbazidethiosemicarbazideanti-tumor activityNur77apoptosis |
| spellingShingle | Hongyu Hu Jiangang Huang Yin Cao Zhaolin Zhang Fengming He Xianfu Lin Qi Wu Shengxian Zhao Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 Modulators Molecules semicarbazide thiosemicarbazide anti-tumor activity Nur77 apoptosis |
| title | Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 Modulators |
| title_full | Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 Modulators |
| title_fullStr | Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 Modulators |
| title_full_unstemmed | Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 Modulators |
| title_short | Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 Modulators |
| title_sort | synthesis and biological evaluation of 1 2 6 methoxynaphthalen 2 yl 6 methylnicotinoyl 4 substituted semicarbazides thiosemicarbazides as anti tumor nur77 modulators |
| topic | semicarbazide thiosemicarbazide anti-tumor activity Nur77 apoptosis |
| url | https://www.mdpi.com/1420-3049/27/5/1698 |
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