Design, synthesis and biological evaluation of novel thiosemicarbazone-indole derivatives targeting prostate cancer cells
Design, synthesis and biological evaluation of novel thiosemicarbazone-indole derivatives targeting prostate cancer cells
复制标题
针对前列腺癌细胞的新型缩氨基硫脲-吲哚衍生物的设计、合成和生物学评价。
DOI：
10.1016/j.ejmech.2020.112970
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发表时间：
2021-01-15
影响因子：
6.7
通讯作者：
Zhao, Wen
中科院分区：
文献类型：
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作者：
He, Zhang-Xu;Huo, Jin-Ling;Zhao, Wen
为了发现高效低毒的新型抗癌药物，我们以前文报道的先导化合物4为基础，设计并合成了一系列新的硫代氨基脲-吲哚类似物。大多数化合物对5种肿瘤细胞（PC3、EC109、DU-145、MGC803、MCF-7）显示出中高的抗癌活性。其中，所代表的化合物16f对PC3细胞具有较强的抗增殖能力和高选择性，IC50值为0.054 μ M，而WPMY-1正常细胞的IC50值为19.470 μ M。初步机制研究表明，化合物16f可显著抑制前列腺癌细胞（PC3、DU-145）的生长和集落形成，并呈剂量依赖性。此外，衍生物16f诱导G1/S周期阻滞和细胞凋亡，这可能与MAPK信号通路激活导致ROS积累有关。此外，分子16f可以通过携带PC3细胞的异种移植模型有效抑制肿瘤生长，并且在体内无明显毒性。综上所述，基于生物活性评价，类似物16f可作为进一步开发新型抗前列腺癌药物的潜在先导化合物。(C) 2020 Elsevier Masson SAS。版权所有。
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 mu M, compared with normal WPMY-1 cells with the IC50 value of 19.470 mu M. 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. (C) 2020 Elsevier Masson SAS. All rights reserved.