State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, PR China.
State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, PR China.
Eur J Med Chem. 2021 Jan 15;210:112970. doi: 10.1016/j.ejmech.2020.112970. Epub 2020 Oct 29.
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 IC value of 0.054 μM, compared with normal WPMY-1 cells with the IC 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.
为了发现具有高效低毒的新型抗癌剂，我们设计并合成了一系列基于我们之前报道的先导化合物 4 的新型硫代缩氨基脲-吲哚类似物。大多数化合物对 5 种测试的肿瘤细胞（PC3、EC109、DU-145、MGC803、MCF-7）表现出中等至高度的抗癌活性。具体来说，代表性化合物 16f 对 PC3 细胞具有很强的增殖抑制活性和高选择性，IC 值为 0.054 μM，而对正常的 WPMY-1 细胞，IC 值为 19.470 μM。初步的机制研究表明，化合物 16f 能显著抑制前列腺癌细胞（PC3、DU-145）的生长和集落形成，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 信号通路的激活导致 ROS 积累有关。此外，分子 16f 能够通过携带 PC3 细胞的异种移植模型有效抑制肿瘤生长，且在体内无明显毒性。总体而言，基于生物活性评价，类似物 16f 可视为进一步开发新型抗前列腺癌药物的潜在先导化合物。
