Synthesis, Evaluation, and Mechanism Study of Novel Indole-Chalcone Derivatives Exerting Effective Antitumor Activity Through Microtubule Destabilization in Vitro and in Vivo
Synthesis, Evaluation, and Mechanism Study of Novel Indole-Chalcone Derivatives Exerting Effective Antitumor Activity Through Microtubule Destabilization in Vitro and in Vivo
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DOI：
10.1021/acs.jmedchem.6b00021
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发表时间：
2016-06-09
影响因子：
7.3
通讯作者：
Li, Xingshu
中科院分区：
文献类型：
--
作者：
Yan, Jun;Chen, Jie;Li, Xingshu
合成了29个新的吲哚-查耳酮衍生物，并对其抗增殖活性进行了评价。其中，14 k表现出最有效的活性，对6种癌细胞的IC 50值为3-9 nM，与化合物2相比，其活性增加了3.8-8.7倍。进一步的研究表明14 k是一种新的微管蛋白聚合抑制剂，与秋水仙碱位点结合。它对正常人类细胞的低细胞毒性和对耐药细胞几乎同样有效的活性揭示了癌症治疗的可能性。细胞机制研究表明，14 k使细胞周期阻滞于G（2）/M期，并伴随着线粒体膜电位的降低而沿着诱导细胞凋亡。此外，在小鼠肝微粒体中观察到14 k的良好代谢稳定性。重要的是，14 k及其磷酸盐14 k-P在体内抑制异种移植模型中的肿瘤生长而没有明显的毒性，这优于参比化合物CA-4P和2.总之，14 k值得考虑用于癌症治疗。
Twenty-nine novel indole-chalcone derivatives were synthesized and evaluated for antiproliferative activity. Among them, 14k exhibited most potent activity, with IC50 values of 3-9 nM against six cancer cells, which displayed a 3.8-8.7-fold increase in activity when compare with compound 2. Further investigation revealed 14k was a novel tubulin polymerization inhibitor binding to the colchicine site. Its low cytotoxicity toward normal human cells and nearly equally potent activity against drug resistant cells revealed the possibility for cancer therapy. Cellular mechanism studies elucidated 14k arrests cell cycle at G(2)/M phase and induces apoptosis along with the decrease of mitochondrial membrane potential. Furthermore, good metabolic stability of 14k was observed in mouse liver microsomes. Importantly, 14k and its phosphate salt 14k-P inhibited tumor growth in xenograft models in vivo without apparent toxicity, which was better than the reference compound CA-4P and 2. In summary, 14k deserves consideration for cancer therapy.