Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, China.
Department of Pharmacology, College of Medicine, Yanbian University, Yanji 133002, China.
Molecules. 2018 Dec 30;24(1):121. doi: 10.3390/molecules24010121.
Six series of novel isosteviol derivatives; modified in the C-19 position; were synthesized; and their antiproliferative activity was evaluated against three human cancer cell lines (HCT-116; BEL-7402; HepG2) and the human L02 normal cell line in vitro. Most of the derivatives tested here exhibited improved antiproliferative activity with high selectivity when compared with the parent compound isosteviol and the positive control drug 5-fluorouracil. Among these derivatives; compound exhibited the most potent antiproliferative activity and commendable selectivity between cancer and normal cells. In addition; compound inhibited the colony formation of HCT-116 cells in a concentration-dependent manner. Further studies revealed that compound arrested the HCT-116 cell cycle in the S phase; and western blot analysis demonstrated the mechanism may be correlated with a change in the expression of cyclin A; cyclin B1; and cyclin E1. Furthermore; the results of a docking study that involved placing compound into the CDK2/cyclin A binding site revealed that its mode of action was possibly as a CDK2/cyclin A inhibitor.
合成了六个系列的新型甜菊醇衍生物，对 C-19 位进行了修饰，并对其体外抗三种人癌细胞系（HCT-116、BEL-7402、HepG2）和人正常细胞系 L02 的增殖活性进行了评价。与母体化合物甜菊醇和阳性对照药物 5-氟尿嘧啶相比，大多数测试的衍生物表现出更好的增殖抑制活性和高选择性。在这些衍生物中，化合物 表现出最强的增殖抑制活性和在癌细胞与正常细胞之间的良好选择性。此外，化合物 以浓度依赖性方式抑制 HCT-116 细胞集落形成。进一步的研究表明，化合物 使 HCT-116 细胞周期停滞在 S 期；Western blot 分析表明，其机制可能与细胞周期蛋白 A、B1 和 E1 的表达变化有关。此外，将化合物 放入 CDK2/细胞周期蛋白 A 结合位点的对接研究结果表明，其作用模式可能是作为 CDK2/细胞周期蛋白 A 抑制剂。
