Design, synthesis, and biological evaluation of 5-((8-methoxy-2-methylquinolin-4-yl)amino)-1H-indole-2-carbohydrazide derivatives as novel Nur77 modulators
Design, synthesis, and biological evaluation of 5-((8-methoxy-2-methylquinolin-4-yl)amino)-1H-indole-2-carbohydrazide derivatives as novel Nur77 modulators
复制标题
作为新型 Nur77 调节剂的 5-((8-甲氧基-2-甲基喹啉-4-基)氨基)-1H-吲哚-2-碳酰肼衍生物的设计、合成和生物学评价
DOI：
10.1016/j.ejmech.2020.112608
复制
发表时间：
2020-10-15
影响因子：
6.7
通讯作者：
Wu, Zhen
中科院分区：
文献类型：
--
作者：
Li, Baicun;Yao, Jie;Wu, Zhen
Nur 77是治疗癌症如HCC的潜在靶点。在此，我们详细地发现了一系列新的5-（（8-甲氧基-2-甲基喹啉-4-基）氨基）-1H-吲哚-2-碳酰肼衍生物作为潜在的Nur 77调节剂。对目标化合物的抗增殖活性和Nur 77结合亲和力的研究导致发现了一种先导候选物（10 g），其是一种良好的Nur 77结合剂（KD = 3.58 +/- 0.16 μ M），对所有测试的肝癌细胞具有广谱抗增殖活性（IC 50 < 2.0 μ M），并且对正常LO 2细胞具有低毒性。10 g可上调Nur 77的表达并介导Nur 77的亚细胞定位，诱导肝癌细胞凋亡，其机制依赖于10 g诱导Nur 77依赖的自噬和内质网应激作为凋亡的上游。此外，体内测定证实10 g显著抑制异种移植肿瘤生长。这些结果表明，10 g具有开发为新型Nur 77靶向抗肝癌药物的潜力。(C)2020 Elsevier Masson SAS。All rights reserved.
Nur77 is a potential target for the treatment of cancer such as HCC. Herein, we detailed the discovery of a novel series of 5-((8-methoxy-2-methylquinolin-4-yl)amino)-1H-indole-2-carbohydrazide derivatives as potential Nur77 modulators. The studies of antiproliferative activity and Nur77-binding affinity of target compounds resulted in the discovery of a lead candidate (10g), which was a good Nur77 binder (K-D = 3.58 +/- 0.16 mu M) with a broad-spectrum antiproliferative activity against all tested hepatoma cells (IC50 < 2.0 mu M) and was low toxic to normal LO2 cells. 10g could up-regulate Nur77 expression and mediate sub-cellular localization of Nur77 to induce apoptosis in hepatocellular carcinoma cell lines, which relied on 10g inducing Nur77-dependent autophagy and endoplasmic reticulum stress as the upstream of apoptosis. Moreover, the in vivo assays verified that 10g significantly inhibited xenograft tumor growth. These results indicate that 10g has the potential to be developed as a novel Nur77-targeting anti-hepatoma drug. (C) 2020 Elsevier Masson SAS. All rights reserved.