School of Life Science and Engineering, Southwest University of Science and Technology, No. 59, Middle Section of Qinglong Avenue, Mianyang 621010, China; Institute of Materials, China Academy of Engineering Physics, Jiangyou 621907, China.
School of Life Science and Engineering, Southwest University of Science and Technology, No. 59, Middle Section of Qinglong Avenue, Mianyang 621010, China; Marine College, Shandong University at Weihai, No. 180, Wenhua West Road, Weihai 264209, China.
Bioorg Chem. 2021 Jan;106:104496. doi: 10.1016/j.bioorg.2020.104496. Epub 2020 Nov 24.
Many artemisinin derivatives have good inhibitory effects on malignant tumors. In this work, a novel series of artemisinin derivatives containing piperazine and fluorine groups were designed and synthesized and their structures were confirmed by H NMR, C NMR and HRMS technologies. The in vitro cytotoxicity against various cancer cell lines was evaluated. Among the derivatives, compound 12h was found to exhibit not only the best activity against HCT-116 cells (IC = 0.12 ± 0.05 μM), but also low toxicity against normal cell line L02 (IC = 12.46 ± 0.10 μM). The mechanisms study revealed that compound 12h caused the cell cycle arrest in G1 phase, induced apoptosis in a concentration-dependent manner, significantly reduced mitochondrial membrane potential, increased intracellular ROS and Ca levels, up-regulated the expression of Bax, cleaved caspase-9, cleaved caspase-3, and down-regulated the expression of Bcl-2 protein. A series of analyses confirmed that 12h can inhibit HCT-116 cells migration and induce apoptosis by a mechanism of the mitochondria-mediated pathway in the HCT-116 cell line. The present work indicates that compound 12h may merit further investigation as a potential therapeutic agent for colorectal cancer.
许多青蒿素衍生物对恶性肿瘤具有良好的抑制作用。在这项工作中，设计并合成了一系列新型含哌嗪和氟基团的青蒿素衍生物，并通过 1 H NMR、 13 C NMR 和 HRMS 技术确证了它们的结构。评估了它们对各种癌细胞系的体外细胞毒性。在这些衍生物中，化合物 12h 不仅对 HCT-116 细胞表现出最佳的活性（IC 50 = 0.12 ± 0.05 μM），而且对正常细胞系 L02 的毒性也很低（IC 50 = 12.46 ± 0.10 μM）。机制研究表明，化合物 12h 导致细胞周期停滞在 G1 期，呈浓度依赖性诱导细胞凋亡，显著降低线粒体膜电位，增加细胞内 ROS 和 Ca 水平，上调 Bax 表达，裂解 caspase-9 和 caspase-3，下调 Bcl-2 蛋白表达。一系列分析证实，12h 可以通过线粒体介导的途径抑制 HCT-116 细胞迁移并诱导细胞凋亡。本工作表明，化合物 12h 可能值得进一步研究，作为结直肠癌的潜在治疗剂。
