使用二氯乙酸轴向配体的双靶向策略提高铂（IV）前药的抗癌活性。

Improving the anticancer activity of platinum(iv) prodrugs using a dual-targeting strategy with a dichloroacetate axial ligand.

作者信息

Liu Fengfan, Dong Xiaomei, Shi Qiwen, Chen Jianli, Su Weike

机构信息

National Engineering Research Center for Process Decelopment of Active Pharmaceutial Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology Hangzhou P. R. China

College of Pharmaceutical Sciences, Zhejiang University of Technology Hangzhou P. R. China.

出版信息

RSC Adv. 2019 Jul 17;9(39):22240-22247. doi: 10.1039/c9ra03690c.

Four novel platinum(iv) complexes, characteristic of DCA/TFA and with chloride ions as axial ligands, were designed and synthesized. This type of platinum(iv) complexes 1a-2b exhibited significant cytotoxic activity, and the cytotoxicity of 1b was the greatest among these four complexes, which was 20.61 fold and 7.65 fold higher than that of cisplatin against HepG-2 and NCI-H460 cancer cells, respectively. The result from the apoptosis assay of 1b was consistent with the result from the cytotoxicity assay. In addition, complexes 1a and 1b induced cell cycle arrest at the S phase on HepG-2 cells. Taken together, our data showed that Pt(iv) complex 1b released the corresponding Pt(ii) complex and DCA, and induced apoptosis as well as disruption of the mitochondrial membrane potential, establishing Pt(iv) complex 1b as a potential dual-targeting anticancer agent.

设计并合成了四种新型的以二氯乙酸/三氟乙酸为特征且以氯离子作为轴向配体的铂（IV）配合物。这类铂（IV）配合物1a - 2b表现出显著的细胞毒性活性，其中1b的细胞毒性在这四种配合物中最大，分别比顺铂对HepG - 2和NCI - H460癌细胞的细胞毒性高20.61倍和7.65倍。1b的凋亡检测结果与细胞毒性检测结果一致。此外，配合物1a和1b使HepG - 2细胞的细胞周期阻滞于S期。综上所述，我们的数据表明Pt（IV）配合物1b释放出相应的Pt（II）配合物和二氯乙酸，并诱导细胞凋亡以及线粒体膜电位的破坏，确立了Pt（IV）配合物1b作为一种潜在的双靶点抗癌剂。