Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, and National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Huaiyin Institute of Technology, Huaian 223003, China; State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, China.
Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
Bioorg Chem. 2020 Dec;105:104430. doi: 10.1016/j.bioorg.2020.104430. Epub 2020 Oct 27.
For the sake to develop novel platinum(IV) complexes to reverse cisplatin (CDDP) resistence, four multifunctional platinum(IV) prodrugs via conjugating chalcones with the related platinum(IV) complexes derived from cisplatin were designed and evaluated for anti-tumor actyivities in vitro and in vivo. Among them, complex 9 exhibited excellent anticancer activities in vitro with IC values at the submicromolar level against the tested human cancer cells, whereas showed low cytotoxicity towards human normal liver cells HL-7702. Further mechanistic studies indicated that complex 9 induced G2/M phase arrest and apoptosis in A549 cells, which was associated with a collapse of the mitochondrial membrane potential (MMP), alterations in the expression of some apoptosis-related proteins, and enhanced level of the intracellular reactive oxygen species (ROS). More importantly, complex 9 significantly suppressed the tumor growth in the A549 xenograft model without obvious hints of toxicity.
为了开发新型铂（IV）配合物以逆转顺铂（CDDP）耐药性，设计并评价了通过将查耳酮与源自顺铂的相关铂（IV）配合物连接而得到的四种多功能铂（IV）前药的体外和体内抗肿瘤活性。其中，配合物 9 表现出优异的体外抗癌活性，对测试的人癌细胞的 IC 值达到亚微摩尔水平，而对人正常肝细胞 HL-7702 的细胞毒性较低。进一步的机制研究表明，配合物 9 诱导 A549 细胞中的 G2/M 期阻滞和细胞凋亡，这与线粒体膜电位（MMP）的崩溃、一些凋亡相关蛋白表达的改变以及细胞内活性氧（ROS）水平的增强有关。更重要的是，配合物 9 显著抑制了 A549 异种移植模型中的肿瘤生长，而没有明显的毒性迹象。
