State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou, Henan, 450001, PR China.
State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou, Henan, 450001, PR China.
Eur J Med Chem. 2020 Dec 15;208:112789. doi: 10.1016/j.ejmech.2020.112789. Epub 2020 Aug 31.
As our research focuses on anticancer drugs, a series of novel derivatives of flexicaulin A (FA), an ent-kaurene diterpene, condensed with an aromatic ring were synthesized, and their antiproliferative activities against four human cancer cell lines (TE-1, EC109, MCF-7, and MGC-803) were evaluated. The activities of most of the new compounds were better than those of FA. Compound 2y exhibited the best activity with an IC50 value reaching 0.13 μM against oesophageal cancer cells (EC109 cells). The IC50 values for 2y in normal cells (GES-1 cells and HUVECs) were 0.52 μM and 0.49 μM, respectively. Subsequent mechanistic investigations found that compound 2y can inhibit the proliferation of cancer cells and cell cloning. In addition, 2y could reduce the mitochondrial membrane potential, increase the apoptosis rate, and increase the ROS level in EC109 cells. Moreover, 2y can upregulate the expression of ROS/JNK pathway-related proteins (p-ASK1, p-MKK4, p-JNK, and p-Cjun (ser63)) and pro-apoptotic proteins (Bax, Bad, and Bim). In vivo experiments showed that 2y can inhibit tumour growth in nude mice. The mechanism involves an increase in protein expression in the ROS pathway, leading to changes in apoptosis-related proteins. In addition, compound 2y shows low toxicity. These results indicate that compound 2y holds promising potential as an antiproliferative agent.
由于我们的研究重点是抗癌药物，因此合成了一系列新型的 flexicaulin A（FA）衍生物，FA 是一种贝壳杉烷二萜，与芳环缩合。评估了它们对四种人癌细胞系（TE-1、EC109、MCF-7 和 MGC-803）的增殖活性。大多数新化合物的活性均优于 FA。化合物 2y 对食道癌细胞（EC109 细胞）表现出最佳活性，IC50 值达到 0.13 μM。2y 在正常细胞（GES-1 细胞和 HUVECs）中的 IC50 值分别为 0.52 μM 和 0.49 μM。随后的机制研究发现，化合物 2y 可以抑制癌细胞的增殖和细胞克隆。此外，2y 可以降低线粒体膜电位，增加 EC109 细胞的凋亡率和 ROS 水平。此外，2y 可以上调 ROS/JNK 通路相关蛋白（p-ASK1、p-MKK4、p-JNK 和 p-Cjun（ser63））和促凋亡蛋白（Bax、Bad 和 Bim）的表达。体内实验表明，2y 可以抑制裸鼠肿瘤生长。其机制涉及 ROS 通路中蛋白表达的增加，导致凋亡相关蛋白的变化。此外，化合物 2y 显示出低毒性。这些结果表明，化合物 2y 具有作为增殖抑制剂的潜力。
