Design, synthesis, and biological evaluation of 5-((8-methoxy-2-methylquinolin-4-yl)amino)-1H-indole-2-carbohydrazide derivatives as novel Nur77 modulators

Li, Baicun; Yao, Jie; Guo, Kaiqiang; He, Fengming; Chen, Kun; Lin, Zongxin; Liu, Shun-Zhi; Huang, Jian‐Gang; Wu, Qiaoqiong; Fang, Meijuan; Zeng, Jin-Zhang; Wu, Zhixian

doi:10.1016/j.ejmech.2020.112608

Cited by 19 publications

(19 citation statements)

References 69 publications

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“…Phosphorylation is currently the most widely known post-translational modi cation [28,32,31]. It is estimated that nearly one-third of the proteins in eukaryotes can be phosphorylated at any time.…”

Section: Discussionmentioning

confidence: 99%

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IFITM3 Regulates NCAPG Through Phosphorylation to Influence the Invasion and Metastasis of HCC

Liu

Zhang

et al. 2020

Preprint

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Background: Several studies have demonstrated that the expression of IFITM3 and NCAPG is closely related to the prognosis of various tumors. However, the mechanism of action of these two is not yet clear. In this study, we have explored the mechanism of action of IFITM3 and NCAPG in the promotion of the invasion and metastasis of hepatocellular carcinoma (HCC). Methods: Specimens of liver cancer and adjacent tissues from 55 HCC patients at the Department of Hepatobiliary Surgery, Second Affiliated Hospital of Nanchang University were collected, and the expression of NCAPG and IFITM3 was determined by qRT-PCR and Western blot. Through the analysis of multiple databases, the relationship between IFITM3 and NCAPG was identified and verified by the CO-IP method. Using SiRNA and plasmids to downregulate and up-regulate IFITM3, we observed the expression of STAT3/CDK1, as well as NCAPG mRNA and protein. After downregulating and up-regulating the expression of IFITM3 and NCAPG, the ability of HCC cells to invade and metastasize was determined using a scratch test and Transwell. After using pathway inhibitors and activators, the expression of NCAPG was observed.Results: According to the database, both IFITM3 and NCAPG were highly expressed in Liver hepatocellular carcinoma. We also confirmed that IFITM3 and NCAPG were up-regulated in HCC tissues and cells. Furthermore, the bioinformatics analysis and CO-IP indicated that there was protein interaction between IFITM3 and NCAPG, and that IFITM3 could regulate NCAPG by phosphorylating it. We further confirmed our observations by retrospective experiments. Reuse of pathway inhibitors and activators indicated that IFITM3 could regulate NCAPG through STAT3/CDK1 to promote the invasion and metastasis of HCC. Finally, animal experiments confirmed that our results were also reproducible in vivo. Conclusion: IFITM3 can regulate NCAPG through STAT3/CDK1 to promote the invasion and metastasis of HCC.

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Section: Discussionmentioning

confidence: 99%

“…STAT3 is a member of the STAT family. It is an important factor that is involved in the modi cation of phosphorylation and is an important nuclear transcription factor [30,31]. STAT3 can also be activated by HBV, HCV, and various oncogene proteins [32].…”

Section: Introductionmentioning

confidence: 99%

IFITM3 Regulates NCAPG Through Phosphorylation to Influence the Invasion and Metastasis of HCC

Liu

Zhang

et al. 2020

Preprint

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show abstract

“…Phosphorylation is currently the most widely known post-translational modi cation [28,30,32]. It is estimated that nearly one-third of the proteins in eukaryotes are phosphorylated at any given point of time.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IFITM3 influences the invasion and metastasis of hepatocellular carcinoma by regulating NCAPG through phosphorylation

Liu

Zhang

et al. 2020

Preprint

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Background:Several studies have demonstrated that the expressions of IFITM3 and NCAPG are closely related to the prognosis of various tumors. However, the mechanism of action of these two is not yet clear. In this study, we have explored the mechanism of action of IFITM3 and NCAPG in the promotion of the invasion and metastasis of hepatocellular carcinoma (HCC). Methods: Specimens of liver cancer and adjacent tissues from 55 HCC patients at the Department of Hepatobiliary Surgery, Second Affiliated Hospital of Nanchang University were collected, and the expressions of NCAPG and IFITM3 were determined by qRT-PCR and Western blotting. Through the analysis of multiple databases, the relationship between IFITM3 and NCAPG was established by the CO-IP method. SiRNA and plasmids were used to downregulate and upregulate IFITM3, and the expression of STAT3/CDK1, NCAPG mRNA, and protein was observed. After downregulating and upregulating the expression of IFITM3 and NCAPG, the ability of HCC cells to invade and metastasize was determined using a scratch test and Transwell assays. After using pathway inhibitors and activators, the expression of NCAPG was observed.Results: According to the database, both IFITM3 and NCAPG were highly expressed in liver hepatocellular carcinoma. We also confirmed that IFITM3 and NCAPG were upregulated in HCC tissues and cells. Furthermore, the bioinformatics analysis and CO-IP indicated that there was a protein interaction between IFITM3 and NCAPG, and that IFITM3 could regulate NCAPG by phosphorylating it. We further confirmed our observations by retrospective experiments. The reuse of pathway inhibitors and activators indicated that IFITM3 could regulate NCAPG through STAT3/CDK1 to promote the invasion and metastasis of HCC. Finally, the animal experiments confirmed that the results were also reproducible in vivo. Conclusion: IFITM3 can regulate NCAPG through STAT3/CDK1 to promote the invasion and metastasis of HCC.

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“…In recent years, our group has studied the anti-tumor activities of a series of indoles derivatives as novel Nur77 regulators on liver cancer cells, lung cancer cells, breast cancer cells and gastric cancer cells [ 18 , 19 , 20 ]. However, currently synthesized small molecule compounds targeting Nur77 are not strong enough in binding, activity and specificity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 Modulators

Huang

Cao

et al. 2022

Molecules

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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 N’-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 9a–9w were designed and synthesized in four steps from 6-methoxy-2-acetonaphthone and N-dimethylformamide dimethylacetal. All compounds were characterized by 1H-NMR, 13C-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, 9h exhibited the most potent anti-proliferative activity against several cancer cells. Colony formation and cell cycle experiments showed that compound 9h inhibited cell growth and arrested the cell cycle. Additionally, 9h leads to the cleavage of PARP. We initially explored the mechanism of 9h-induced apoptosis and found that compound 9h can upregulate Nur77 expression and triggered Nur77 nuclear export, indicating the occurrence of Nur77-mediated apoptosis. These results suggested that 9h may be a promising anti-tumor leading compound for the further research.

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Design, synthesis, and biological evaluation of 5-((8-methoxy-2-methylquinolin-4-yl)amino)-1H-indole-2-carbohydrazide derivatives as novel Nur77 modulators

Cited by 19 publications

References 69 publications

IFITM3 Regulates NCAPG Through Phosphorylation to Influence the Invasion and Metastasis of HCC

IFITM3 Regulates NCAPG Through Phosphorylation to Influence the Invasion and Metastasis of HCC

IFITM3 influences the invasion and metastasis of hepatocellular carcinoma by regulating NCAPG through phosphorylation

Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 Modulators

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