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Development of triazolothiadiazine derivatives as highly potent tubulin polymerization inhibitors: structure-activity relationship, in vitro and in vivo study
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-09-18 , DOI: 10.1016/j.ejmech.2020.112847
Weifeng Ma , Peng Chen , Xiansen Huo , Yufeng Ma , Yanhong Li , Pengcheng Diao , Fang Yang , Shengquan Zheng , Mengjin Hu , Wenwei You , Peiliang Zhao

Based on our prior work, we reported the design, synthesis, and biological evaluation of fifty-two new triazolothiadiazine-based analogues of CA-4 and their preliminary structure-activity relationship. Among synthesized compounds, Iab was found to be the most potent derivative possessing IC50 values ranging from single-to double-digit nanomolar in vitro, and also exhibited excellent selectivity over the normal human embryonic kidney HEK-293 cells (IC50 > 100 μM). Further mechanistic studies revealed that Iab significantly blocked tubulin polymerization and disrupted the intracellular microtubule network of A549 cells. Moreover, Iab induced G2/M cell cycle arrest by regulation of p-cdc2 and cyclin B1 expressions, and caused cell apoptosis through up-regulating cleaved PARP and cleaved caspase-3 expressions, and down-regulating of Bcl-2. Importantly, in vivo, Iab effectively suppressed tumor growth of A549 lung cancers in a xenograft mouse model without obvious signs of toxicity, confirming its potential as a promising candidate for cancer treatment.



中文翻译:

triazolothiadiazine衍生物的发展为高度有效的微管蛋白聚合抑制剂:结构-活性关系,在体外体内研究

基于我们先前的工作,我们报道了CA-4的52种新的基于三唑并噻二嗪的类似物的设计,合成和生物学评估,以及它们的初步结构-活性关系。在合成的化合物中,Iab被发现是最有效的衍生物,在体外具有IC 50值(从几位数到几位数纳摩尔,并且对正常人胚胎肾HEK-293细胞也表现出优异的选择性(IC 50 > 100μM )。进一步的机理研究表明,Iab显着阻断微管蛋白聚合并破坏A549细胞的细胞内微管网络。此外,艾伯通过调节p-cdc2和cyclin B1的表达诱导G2 / M细胞周期阻滞,并通过上调裂解的PARP和caspase-3的表达以及下调Bcl-2引起细胞凋亡。重要的是,在体内Iab有效抑制异种移植小鼠模型中A549肺癌的肿瘤生长,而没有明显的毒性迹象,从而证实了其作为有望用于癌症治疗的潜力。

更新日期:2020-09-20
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