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Design, synthesis, and evaluation of novel benzoylhydrazone derivatives as Nur77 modulators with potent antitumor activity against hepatocellular carcinoma.

ABSTRACT: 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 (K_D = 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.

SUBMITTER: He F

PROVIDER: S-EPMC10294756 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Design, synthesis, and evaluation of novel benzoylhydrazone derivatives as Nur77 modulators with potent antitumor activity against hepatocellular carcinoma.

He Fengming F Chen Jun J Zhao Taige T Wu Qiaoqiong Q Yin Na N Wang Xiumei X Zhong Yijing Y Guo Xiaodan X Qiu YingKun Y Li Baicun B Fang Meijuan M Wu Zhen Z

Journal of enzyme inhibition and medicinal chemistry 20231201 1

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 ...[more]

PMID: 37357764

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Project description:Nitrogen and sulfur glycosylation was carried out via the reaction of rhodanine (1) with α-acetobromoglucose 3 under basic conditions. Deacetylation of the protected nitrogen nucleoside 4 was performed with CH3ONa in CH3OH without cleavage of the rhodanine ring to afford the deprotected nitrogen nucleoside 6. Further, deacetylation of the protected sulfur nucleoside 5 was performed with CH3ONa in CH3OH with the cleavage of the rhodanine ring to give the hydrolysis product 7. The protected nitrogen nucleosides 11a-f were produced by condensing the protected nitrogen nucleoside 4 with the aromatic aldehydes 10a-f in C2H5OH while using morpholine as a secondary amine catalyst. Deacetylation of the protected nitrogen nucleosides 11a-f was performed with NaOCH3/CH3OH without cleavage of the rhodanine ring to afford the deprotected nitrogen nucleosides 12a-f. NMR spectroscopy was used to designate the anomers' configurations. To examine the electrical and geometric properties derived from the stable structure of the examined compounds, molecular modeling and DFT calculations using the B3LYP/6-31+G (d,p) level were carried out. The quantum chemical descriptors and experimental findings showed a strong connection. The IC50 values for most compounds were very encouraging when evaluated against MCF-7, HepG2, and A549 cancer cells. Interestingly, IC50 values for 11a, 12b, and 12f were much lower than those for Doxorubicin (7.67, 8.28, 6.62 μM): (3.7, 8.2, 9.8 μM), (3.1, 13.7, 21.8 μM), and (7.17, 2.2, 4.5 μM), respectively. Against Topo II inhibition and DNA intercalation, when compared to Dox (IC50 = 9.65 and 31.27 μM), compound 12f showed IC50 values of 7.3 and 18.2 μM, respectively. In addition, compound 12f induced a 65.6-fold increase in the rate of apoptotic cell death in HepG2 cells, with the cell cycle being arrested in the G2/M phase as a result. Additionally, it upregulated the apoptosis-mediated genes of P53, Bax, and caspase-3,8,9 by 9.53, 8.9, 4.16, 1.13, and 8.4-fold change, while it downregulated the Bcl-2 expression by 0.13-fold. Therefore, glucosylated Rhodanines may be useful as potential therapeutic candidates against cancer because of their topoisomerase II and DNA intercalation activity.

Dataset Information

Design, synthesis, and evaluation of novel benzoylhydrazone derivatives as Nur77 modulators with potent antitumor activity against hepatocellular carcinoma.

Publications

Design, synthesis, and evaluation of novel benzoylhydrazone derivatives as Nur77 modulators with potent antitumor activity against hepatocellular carcinoma.

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