State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
Bioorg Chem. 2021 Jun;111:104903. doi: 10.1016/j.bioorg.2021.104903. Epub 2021 Apr 20.
A series of dihydroartemisinin-cinnamic acid hybrids were designed, synthesized and evaluated. Most of the tested compounds showed enhanced anti-proliferative activities than artemisinin and dihydroartemisinin, among which 16 g had the superior potency with IC values ranging from 5.07 μM to 7.88 μM against four tested cancer cell lines. The cell cycle arrest revealed that 16 g induced A549 cell cycle arrest at G0/G1 phase via regulation of G1-related protein expression (Cdk4). Further mechanism studies reveal that 16 g induced A549 cells apoptosis via inhibiting Akt/Bad pathway. Moreover, 16 g depolarized the mitochondria membrane potentials and induced ROS generation in A549. Additionally, 16 g blocked migration of A549 cells in a concentration-dependent manner. What's more, 16 g is barely nontoxic to zebrafish embryos. Overall, the cell cycle arrest, inhibition of Akt/Bad signal pathway, ROS generation and migration blocked might explain the potent anti-proliferative activities of these compounds.
设计、合成并评价了一系列二氢青蒿素-肉桂酸杂合体。大多数测试化合物的抗增殖活性均优于青蒿素和双氢青蒿素，其中 16g 对四种测试的癌细胞系的活性最强，IC 值范围为 5.07μM 至 7.88μM。细胞周期阻滞显示，16g 通过调节 G1 相关蛋白表达（Cdk4）将 A549 细胞周期阻滞在 G0/G1 期。进一步的机制研究表明，16g 通过抑制 Akt/Bad 通路诱导 A549 细胞凋亡。此外，16g 使 A549 细胞的线粒体膜电位去极化并诱导 ROS 的产生。此外，16g 以浓度依赖的方式阻断 A549 细胞的迁移。更重要的是，16g 对斑马鱼胚胎几乎没有毒性。总的来说，细胞周期阻滞、抑制 Akt/Bad 信号通路、ROS 的产生和迁移的阻断可能解释了这些化合物的强大的抗增殖活性。
