Li You-Shan, Peng Bin, Ma Li, Cao Sheng-Li, Bai Lu-Lu, Yang Chao-Rui, Wan Chong-Qing, Yan Hao-Jie, Ding Pan-Pan, Li Zhong-Feng, Liao Ji, Meng Ying-Ying, Wang Hai-Long, Li Jing, Xu Xingzhi
Department of Chemistry, Capital Normal University, Beijing 100048, PR China.
School of Medicine, Shenzhen University, Shenzhen, Guangdong 518060, PR China; Beijing Key Laboratory of DNA Damage Response, College of Life Science, Capital Normal University, Beijing 100048, PR China.
Eur J Med Chem. 2017 Feb 15;127:137-146. doi: 10.1016/j.ejmech.2016.12.050. Epub 2016 Dec 26.
Two new platinum(II) complexes 7a and 7b with methyl hydrazinecarbodithioate derivatives of indolin-2-one have been prepared and characterized by single-crystal X-ray diffraction, NMR spectroscopy and mass spectrometry. Antiproliferative activity of the two complexes and their ligands 6a and 6b against HCT-116, MCF-7 and MDA-MB-231 cell lines was determined by the MTS assay. Complexes 7a and 7b exhibited stronger antiproliferative activity against three cell lines than compounds 6a and 6b (IC, 1.89-5.60 versus 6.52-35.13 μM). Moreover, treatment of HCT-116 cells with the complexes resulted in an obvious sub-G1 peak by cell cycle profile analysis, and an increase of cleaved PARP1 and caspases 3, 7, and 9 by immunoblotting analysis. Live cell imaging showed that nucleus shrinkage and condensation started to appear when MCF-7 cells were treated with 7a for 8 h. Fluorescent spectrophotometric analysis revealed that the complexes physically associated with calf thymus DNA. Competitive DNA binding assays uncovered that the complexes non-covalently bind to DNA. Taken together, our results indicated that the two new platinum(II) complexes 7a and 7b non-covalently bind to DNA with high affinity and exhibit cytotoxicity against cancer cells by inducing apoptosis.
已制备出两种含吲哚啉 - 2 - 酮甲基肼基二硫代甲酸酯衍生物的新型铂（II）配合物7a和7b，并通过单晶X射线衍射、核磁共振光谱和质谱对其进行了表征。通过MTS法测定了这两种配合物及其配体6a和6b对HCT - 116、MCF - 7和MDA - MB - 231细胞系的抗增殖活性。配合物7a和7b对三种细胞系表现出比化合物6a和6b更强的抗增殖活性（IC，1.89 - 5.60对6.52 - 35.13 μM）。此外，通过细胞周期分析，用这些配合物处理HCT - 116细胞导致明显的亚G1峰，通过免疫印迹分析导致裂解的PARP1以及半胱天冬酶3、7和9增加。活细胞成像显示，当用7a处理MCF - 7细胞8小时时，细胞核开始出现收缩和凝聚。荧光分光光度分析表明，这些配合物与小牛胸腺DNA发生物理缔合。竞争性DNA结合试验表明，这些配合物与DNA非共价结合。综上所述，我们的结果表明，两种新型铂（II）配合物7a和7b以高亲和力与DNA非共价结合，并通过诱导凋亡对癌细胞表现出细胞毒性。
