The discovery of novel indazole derivatives as tubulin colchicine site binding agents that displayed potent antitumor activity both in vitro and in vivo
The discovery of novel indazole derivatives as tubulin colchicine site binding agents that displayed potent antitumor activity both in vitro and in vivo
复制标题
发现新型吲唑衍生物作为微管蛋白秋水仙碱位点结合剂，在体外和体内均表现出有效的抗肿瘤活性
DOI：
10.1016/j.ejmech.2019.111968
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发表时间：
2020-02-01
影响因子：
6.7
通讯作者：
Liu, Zhao-Peng
中科院分区：
文献类型：
--
作者：
Cui, Ying-Jie;Ma, Chen-Chen;Liu, Zhao-Peng
结合秋水仙碱位点的微管蛋白抑制剂是被广泛研究的抗癌药物。在我们的持续研究中，我们设计了一系列新的茚唑衍生物作为微管靶向药物（mta）。结构-活性关系（SARs）研究表明，3,4,5-三甲氧基苯基片段和甲基或甲氧基取代具有较好的抗增殖活性。茚唑衍生物3c和3f对HepG2、HCT116、SW620、HT29和A549肿瘤细胞表现出明显的低纳摩尔效价。在机制研究中，3c和3f被证明靶向秋水仙碱位点，抑制微管蛋白聚合，破坏细胞微管网络，使HCT116细胞处于G2/M期，并诱导细胞凋亡。在HCT116异种移植小鼠模型中，口服剂量为25 mg/kg的3c和3f对肿瘤生长的抑制作用分别为45.3%和58.9%，且未引起明显的体重减轻。吲哚唑3f可作为结直肠癌治疗的良好先导物或候选药物。(C) 2019 Elsevier Masson SAS。版权所有。
Tubulin inhibitors that bind to the colchicine site are widely studied anticancer agents. In continuous our researches, we designed a series of novel indazole derivatives as microtubule-targeting agents (MTAs). The structure-activity relationships (SARs) investigations indicated that a 3,4,5-trimethoxyphenyl moiety and a methyl or methoxy substitution were preferred for the better antiproliferative activity. The indazole derivatives 3c and 3f showed noteworthy low nanomolar potency against HepG2, HCT116, SW620, HT29 and A549 tumor cells. In mechanism studies, 3c and 3f were proved to target the colchicine site, inhibited tubulin polymerization and disrupted cellular microtubule networks, arrested HCT116 cell in G2/M phase and induced cell apoptosis. In the HCT116 xenografts mouse model, 3c and 3f suppressed tumor growth by 45.3% and 58.9% at an orally dose of 25 mg/kg without causing obvious weight loss. The indazole 3f may serve as a good lead or drug candidate for colorectal cancer therapy. (C) 2019 Elsevier Masson SAS. All rights reserved.