Department of Chemistry, Zhejiang University, Hangzhou 310027, China.
College of Science and Technology, Ningbo University, Cixi 315302, China.
Molecules. 2022 Mar 4;27(5):1698. doi: 10.3390/molecules27051698.
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 '-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 - were designed and synthesized in four steps from 6-methoxy-2-acetonaphthone and -dimethylformamide dimethylacetal. All compounds were characterized by H-NMR, 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, exhibited the most potent anti-proliferative activity against several cancer cells. Colony formation and cell cycle experiments showed that compound inhibited cell growth and arrested the cell cycle. Additionally, leads to the cleavage of PARP. We initially explored the mechanism of -induced apoptosis and found that compound can upregulate Nur77 expression and triggered Nur77 nuclear export, indicating the occurrence of Nur77-mediated apoptosis. These results suggested that may be a promising anti-tumor leading compound for the further research.
Nur77 是一种孤儿核受体，参与多种肿瘤的发生和发展。许多 Nur77 的激动剂已被报道具有显著的抗癌作用。我们之前的研究发现，将双环芳烃环（如萘基和喹啉基）引入吲哚的‘-亚甲基位置’Nur77 调节剂中，可以有效地提高目标化合物的抗癌活性。在我们之前的研究基础上，我们设计并合成了一系列新型的 1-(2-(6-甲氧基萘-2-基)-6-甲基烟酰基)-4-取代的半脒/硫代半脒衍生物，从 6-甲氧基-2-乙酰萘和二甲基甲酰胺二甲缩醛出发，经过四步反应得到。所有化合物均通过 1H-NMR、13C-NMR 和高分辨质谱（HRMS）进行了表征，并评估了它们对多种癌细胞系（如 A549、HepG2、HGC-27、MCF-7 和 HeLa）的抗肿瘤活性。在所合成的化合物中，化合物 对多种癌细胞表现出最强的增殖抑制活性。集落形成和细胞周期实验表明，化合物 能够抑制细胞生长并使细胞周期停滞。此外， 导致 PARP 的裂解。我们初步探讨了 诱导细胞凋亡的机制，发现化合物 可以上调 Nur77 的表达并触发 Nur77 的核输出，表明发生了 Nur77 介导的细胞凋亡。这些结果表明，化合物 可能是一种很有前途的抗肿瘤先导化合物，值得进一步研究。
