当前位置: X-MOL 学术Eur. J. Med. Chem. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
2-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[3.2.1]octan-3-one derivatives: simplification and modification of aconitine scaffold for the discovery of novel anticancer agents
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-11-05 , DOI: 10.1016/j.ejmech.2020.112988
Yi Zhang , Ting-jian Zhang , Xin-yang Li , Jing-wei Liang , Shun Tu , Hai-li Xu , Wen-han Xue , Xin-hua Qian , Zhen-hao Zhang , Xu Zhang , Fan-hao Meng

The molecular chaperone heat shock protein 90 (Hsp90) is a promising target for cancer therapy. Natural product aconitine is a potential Hsp90 inhibitor reported in our previous work. In this study, we designed and synthesized a series of 2-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[3.2.1]octan-3-one derivatives as potent Hsp90 inhibitors by simplifying and modifying aconitine scaffold. Among these compounds, 14t exhibited an excellent antiproliferative activity against LoVo cells with an IC50 value of 0.02 μM and a significant Hsp90α inhibitory activity with an IC50 value of 0.71 nM. Molecular docking studies provided a rational binding model of 14t in complex with Hsp90α. The following cell cycle and apoptosis assays revealed that compound 14t could arrest cell cycle at G1/S phase and induce cell apoptosis via up-regulation of bax and cleaved-caspase 3 protein expressions while inhibiting the expressions of bcl-2. Moreover, 14t could inhibit cell migration in LoVo and SW620 cell lines. Consistent with in vitro results, 14t significantly repressed tumor growth in the SW620 xenograft mouse model.



中文翻译:

2-(((1-苯基-1 H -1,2,3-三唑-4-基)甲基)-2-氮杂双环[3.2.1] octan-3-one衍生物:乌头碱支架的简化和修饰新型抗癌药

分子伴侣热激蛋白90(Hsp90)是癌症治疗的有希望的目标。天然产物乌头碱是我们先前工作中报道的潜在Hsp90抑制剂。在这项研究中,我们设计和合成了一系列的2-((1-苯基-1 H -1,2,3-三唑-4-基)甲基)-2-氮杂双环[3.2.1] octan-3-one通过简化和修饰乌头碱支架,将其衍生物作为有效的Hsp90抑制剂。在这些化合物中,14t对LoVo细胞表现出优异的抗增殖活性,IC 50值为0.02μM,Hsp90α抑制活性很强,IC 50值为0.71 nM。分子对接研究提供了14t的合理结合模型与Hsp90α复合。随后的细胞周期和凋亡测定表明,化合物14t可以通过上调bax和半胱天冬酶3的表达,同时抑制bcl-2的表达,从而使细胞周期停留在G1 / S期并诱导细胞凋亡。而且,14t可以抑制LoVo和SW620细胞系中的细胞迁移。与体外结果一致,SW620异种移植小鼠模型中14t显着抑制了肿瘤的生长。

更新日期:2020-11-06
down
wechat
bug