Identification of novel non-toxic and anti-angiogenic α-fluorinated chalcones as potent colchicine binding site inhibitors.
Identification of novel non-toxic and anti-angiogenic α-fluorinated chalcones as potent colchicine binding site inhibitors.
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鉴定新型无毒且抗血管生成的α-氟化查耳酮作为有效的秋水仙碱结合位点抑制剂
DOI：
10.1080/14756366.2021.2014831
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发表时间：
2022-12
影响因子：
5.6
通讯作者：
Yao Y
中科院分区：
文献类型：
--
作者：
Sun M;Yuan M;Kang Y;Qin J;Zhang Y;Duan Y;Wang L;Yao Y
制备了α-氟代查尔酮，并评价了它们对6种人癌细胞系的细胞生长抑制特性。最有效的查耳酮4c表现出对癌细胞相对于正常人细胞的优异选择性毒性，其IC 50值在纳摩尔浓度范围内对5种癌细胞系。进一步的研究表明，4c可以结合到微管蛋白的秋水仙碱位点，破坏细胞微管网络，并有效地抑制微管蛋白聚合。细胞机制研究表明，4c使MGC-803细胞周期阻滞于G2/M期。此外，4c剂量依赖性地通过线粒体功能障碍引起MGC-803细胞凋亡。值得注意的是，发现化合物4c在体外抑制HUVECs管形成、迁移和侵袭。此外，我们的数据表明，用4c处理显著降低MGC-803细胞的体外转移和增殖。总之，这项工作表明查耳酮杂合物4c是微管蛋白组装的有效抑制剂，具有显著的抗血管生成和抗癌特性。
α-Fluorinated chalcones were prepared and evaluated for their cell growth inhibitory properties against six human cancer cell lines. The most potent chalcone 4c demonstrated excellent selective toxicity against cancer cells versus normal human cells, with IC50 values at nanomolar concentration ranges against 5 cancer cell lines. A further study revealed that 4c could bind to the colchicine site of tubulin, disrupt the cell microtubule networks, and effectively inhibit tubulin polymerisation. Cellular-based mechanism studies elucidated that 4c arrested MGC-803 cell cycle at G2/M phase. In addition, 4c dose-dependently caused Caspase-induced apoptosis of MGC-803 cells through mitochondrial dysfunction. Notably, compound 4c was found to inhibit the HUVECs tube formation, migration, and invasion in vitro. Furthermore, our data suggested that treatment with 4c significantly reduced MGC-803 cells metastasis and proliferation in vitro. Overall, this work showed that chalcone hybrid 4c is a potent inhibitor of tubulin assembly with prominent anti-angiogenesis and anti-cancer properties.
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