Discovery of a Series of Thiazole Derivatives as Novel Inhibitors of Metastatic Cancer Cell Migration and Invasion.
Discovery of a Series of Thiazole Derivatives as Novel Inhibitors of Metastatic Cancer Cell Migration and Invasion.
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DOI：
10.1021/ml300322n
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发表时间：
2013-02-14
影响因子：
4.2
通讯作者：
Wang, Guangdi
中科院分区：
文献类型：
--
作者：
Zheng, Shilong;Zhong, Qiu;Jiang, Quan;Mottamal, Madhusoodanan;Zhang, Qiang;Zhu, Naijue;Burow, Matthew E.;Worthylake, Rebecca A.;Wang, Guangdi
癌细胞迁移和侵袭的有效抑制剂可以潜在地导致作为阻断肿瘤转移的疗法的临床应用，肿瘤转移是癌症患者死亡的主要原因。为此，我们设计并合成了一系列噻唑衍生物，这些衍生物对转移性癌细胞的细胞迁移和侵袭表现出有效的功效。在MDA-MB-231细胞的剂量依赖性transwell迁移试验中，发现最有效的化合物5 k的IC 50值为176 nM。在10 μM剂量下，5 k对HeLa和A549细胞的迁移抑制率约为80%，对MDA-MB-231细胞的侵袭抑制率约为60%。重要的是，大多数衍生物在克隆形成试验中没有表现出明显的细胞毒性。对细胞增殖的低至可忽略的抑制是这些抗迁移衍生物的期望性质，因为它们作为潜在的治疗剂对健康细胞具有低毒性的希望。通过显微镜分析肌动蛋白细胞骨架的机制研究表明，化合物5 k基本上减少了细胞f-肌动蛋白，并阻止了肌成束蛋白定位于富含肌动蛋白的膜突起。这些结果表明，抗迁移活性可能是由于受损的肌动蛋白结构的突起，是必要的驱动迁移。
Effective inhibitors of cancer cell migration and invasion can potentially lead to clinical applications as therapy to block tumor metastasis, the primary cause of death in cancer patients. To this end we have designed and synthesized a series of thiazole derivatives that showed potent efficacy against cell migration and invasion in metastatic cancer cells. The most effective compound, 5k, was found to have an IC50 value of 176 nM in the dose-dependent transwell migration assays in MDA-MB-231cells. At the dose of 10 μM, 5k also blocked about 80% of migration in HeLa and A549 cells and 60% of invasion of MDA-MB-231 cells. Importantly, the majority of the derivatives exhibited no apparent cytotoxicity in the clonogenic assays. The low to negligible inhibition of cell proliferation is a desirable property of these anti-migration derivatives because they hold promise of low toxicity to healthy cells as potential therapeutic agents. Mechanistic studies analyzing the actin cytoskeleton by microscopy demonstrate that compound 5k substantially reduced cellular f-actin, and prevented localization of fascin to actin-rich membrane protrusions. These results suggest that the anti-migration activity may result from impaired actin structures in protrusions that are necessary to drive migration.
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影响因子：
7.3
作者：
Romagnoli, Romeo;Baraldi, Pier Giovanni;Brancale, Andrea;Ricci, Antonio;Hamel, Ernest;Bortolozzi, Roberta;Basso, Giuseppe;Viola, Giampietro
通讯作者：
Viola, Giampietro
DOI：
10.1016/j.biocel.2010.06.019
发表时间：
2010-10-01
影响因子：
4
作者：
Jayo, Asier;Parsons, Maddy
通讯作者：
Parsons, Maddy
影响因子：
5.7
作者：
D'Alise, Anna Morena;Amabile, Giovanni;Cortese, Riccardo
通讯作者：
Cortese, Riccardo
影响因子：
11.5
作者：
Epstein, RJ
通讯作者：
Epstein, RJ
影响因子：
7.3
作者：
Li, Wei-Wei;Wang, Xiao-Yan;Yang, Sheng-Yong
通讯作者：
Yang, Sheng-Yong