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Design, synthesis and biological evaluation of novel thiosemicarbazone-indole derivatives targeting prostate cancer cells
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-10-29 , DOI: 10.1016/j.ejmech.2020.112970
Zhang-Xu He , Jin-Ling Huo , Yun-Peng Gong , Qi An , Xin Zhang , Hui Qiao , Fei-Fei Yang , Xin-Hui Zhang , Le-Min Jiao , Hong-Min Liu , Li-Ying Ma , Wen Zhao

To discover novel anticancer agents with potent and low toxicity, we designed and synthesized a range of new thiosemicarbazone-indole analogues based on lead compound 4 we reported previously. Most compounds displayed moderate to high anticancer activities against five tested tumor cells (PC3, EC109, DU-145, MGC803, MCF-7). Specifically, the represented compound 16f possessed strong antiproliferative potency and high selectivity toward PC3 cells with the IC50 value of 0.054 μM, compared with normal WPMY-1 cells with the IC50 value of 19.470 μM. Preliminary mechanism research indicated that compound 16f could significantly suppress prostate cancer cells (PC3, DU-145) growth and colony formation in a dose-dependent manner. Besides, derivative 16f induced G1/S cycle arrest and apoptosis, which may be related to ROS accumulation due to the activation of MAPK signaling pathway. Furthermore, molecule 16f could effectively inhibit tumor growth through a xenograft model bearing PC3 cells and had no evident toxicity in vivo. Overall, based on the biological activity evaluation, analogue 16f can be viewed as a potential lead compound for further development of novel anti-prostate cancer drug.



中文翻译:

靶向前列腺癌细胞的新型硫半脲酮吲哚衍生物的设计,合成和生物学评价

为了发现具有强效和低毒性的新型抗癌药,我们基于先前报道的铅化合物4设计并合成了一系列新的硫代半碳酰胺-吲哚类似物。大多数化合物对五个测试的肿瘤细胞(PC3,EC109,DU-145,MGC803,MCF-7)显示出中度到高度的抗癌活性。具体地说,所表示的化合物16F具有强抗增殖效力和朝向PC3细胞与IC高选择性50 0.054μM的值,与正常WPMY-1细胞与IC相比50 19.470μM的值。初步机理研究表明,化合物16f可以剂量依赖性方式显着抑制前列腺癌细胞(PC3,DU-145)的生长和集落形成。此外,衍生物16f诱导G1 / S周期阻滞和凋亡,可能是由于MAPK信号通路的激活与ROS的积累有关。此外,分子16f可通过带有PC3细胞的异种移植模型有效抑制肿瘤生长,并且在体内没有明显的毒性。总体而言,基于生物学活性评估,类似物16f可被视为进一步开发新型抗前列腺癌药物的潜在先导化合物。

更新日期:2020-10-30
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