Zhang Lidan, Ren Wen, Wang Xiaoyan, Zhang Jiaying, Liu Jie, Zhao Lifeng, Zhang Xia
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
Analytical & Testing Center, Sichuan University, Chengdu 610064, China.
Eur J Med Chem. 2017 Jan 27;126:1071-1082. doi: 10.1016/j.ejmech.2016.12.021. Epub 2016 Dec 14.
A series of novel polycyclic spiro-fused carbocyclicoxindoles were synthesized and investigated for their in vitro antiproliferative activities against nine human cancer cell lines. Five compounds (10i, 10l, 10n, 10p, and 10r) demonstrated anticancer activities against A2780s cells with IC values of less than 30 μM. In particular, compound 10i showed anticancer activities against seven cancer cell lines and stronger activities than cisplatin in A2780s, A2780T, CT26, and HCT116 cells. Further studies illustrated that compound 10i arrested cell cycle in G1 phase and induced apoptosis of HCT116 cells. This compound also effectively increased the protein levels of cleaved caspase-3, p53, and MDM2. Molecular docking results revealed that compound 10i could bind well to the p53-binding site on MDM2, indicating that it might work by blocking the MDM2-p53 interactions.
合成了一系列新型多环螺稠合碳环氧化吲哚，并研究了它们对九种人类癌细胞系的体外抗增殖活性。五种化合物（10i、10l、10n、10p和10r）对A2780s细胞表现出抗癌活性，IC值小于30μM。特别是，化合物10i对七种癌细胞系表现出抗癌活性，并且在A2780s、A2780T、CT26和HCT116细胞中比顺铂具有更强的活性。进一步的研究表明，化合物10i使细胞周期停滞在G1期并诱导HCT116细胞凋亡。该化合物还有效提高了裂解的caspase-3、p53和MDM2的蛋白质水平。分子对接结果表明，化合物10i可以与MDM2上的p53结合位点良好结合，表明它可能通过阻断MDM2-p53相互作用发挥作用。
