Sang Chun-Yan, Tian Heng-Zhi, Chen Yue, Liu Jian-Fei, Chen Shi-Wu, Hui Ling
School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
College of Life Science, Northwest Normal University, Lanzhou 730070, China.
Bioorg Med Chem Lett. 2018 Jan 15;28(2):71-76. doi: 10.1016/j.bmcl.2017.12.012. Epub 2017 Dec 7.
A series of 4β-(thiazol-2-yl)amino-4'-O-demethyl-4-deoxypodophyllotoxins were synthesized, and their cytotoxicities were evaluated against four human cancer cell lines (A549, HepG2, HeLa, and LOVO cells) and normal human diploid fibroblast line WI-38. Some of the compounds exhibited promising antitumor activity and less toxicity than the anticancer drug etoposide. Among them, compounds 15 and 17 were found to be the most potent synthetic derivatives as topo-II inhibitors, and induced DNA double-strand breaks via the p73/ATM pathway as well as the H2AX phosphorylation in A549 cells. These compounds also arrested A549 cells cycle in G2/M phase by regulating cyclinB1/cdc2(p34). Taken together, these results show that a series of compounds are potential anticancer agents.
合成了一系列4β-(噻唑-2-基)氨基-4'-O-去甲基-4-脱氧鬼臼毒素，并评估了它们对四种人类癌细胞系（A549、HepG2、HeLa和LOVO细胞）以及正常人二倍体成纤维细胞系WI-38的细胞毒性。一些化合物表现出有前景的抗肿瘤活性，且毒性比抗癌药物依托泊苷小。其中，化合物15和17被发现是作为拓扑异构酶II抑制剂最有效的合成衍生物，并通过p73/ATM途径以及A549细胞中的H2AX磷酸化诱导DNA双链断裂。这些化合物还通过调节细胞周期蛋白B1/细胞周期蛋白依赖性激酶2(p34)使A549细胞周期停滞在G2/M期。综上所述，这些结果表明这一系列化合物是潜在的抗癌剂。
