Designing anticancer copper(II) complexes by optimizing 2-pyridine-thiosemicarbazone ligands
Designing anticancer copper(II) complexes by optimizing 2-pyridine-thiosemicarbazone ligands
复制标题
通过优化 2-吡啶-缩氨基硫脲配体设计抗癌铜 (II) 配合物
DOI：
10.1016/j.ejmech.2018.09.020
复制
发表时间：
2018-10-05
影响因子：
6.7
通讯作者：
Yang, Feng
中科院分区：
文献类型：
--
作者：
Deng, Jungang;Yu, Ping;Yang, Feng
为了开发潜在的下一代金属抗癌药物，我们通过修饰配体N-4位的氢原子，设计并合成了5种Cu(II) 2-吡啶-硫代氨基脲配合物，并研究了它们的构效关系和抗癌机制。不同组对N-4位点的修饰导致细胞摄取有显著差异，并产生较好的抗肿瘤活性。Cu复合物将细胞周期阻滞在S期，导致细胞周期蛋白和细胞周期蛋白依赖激酶水平下调，细胞周期蛋白依赖激酶抑制剂表达上调。Cu络合物通过激活p53和诱导活性氧的产生来调节b细胞淋巴瘤-2家族蛋白的表达，引起线粒体膜电位的改变和细胞色素c的释放，与凋亡蛋白酶激活因子-1形成二聚体，从而激活caspase-9/3，诱导细胞凋亡，发挥化疗作用。此外，Cu复合物通过下调c-myc调控基因和人端粒酶逆转录酶的表达来抑制端粒酶。(C) 2018 Elsevier Masson SAS。版权所有。
To develop potential next-generation metal anticancer agents, we designed and synthesised five Cu(II) 2-pyridine-thiosemicarbazone complexes by modifying the hydrogen atom at the N-4 position of ligands, and then investigated their structure-activity relationships and anticancer mechanisms. Modification of the N-4 position with different groups caused significant differences in cellular uptake and produced superior antitumor activity. Cu complexes arrested the cell cycle at S phase, leading to down-regulation of levels of cyclin and cyclin-dependent kinases and up-regulation of expression of cyclin-dependent kinase inhibitors. Cu complexes exerted chemotherapeutic effects via activating p53 and inducing production of reactive oxygen species to regulate expression of the B-cell lymphoma-2 family of proteins, causing a change in the mitochondrial membrane potential and release of cytochrome c to form a dimer with apoptosis protease activating factor-1, resulting in activation of caspase-9/3 to induce apoptosis. In addition, Cu complexes inhibited telomerase by down-regulating the c-myc regulator gene and expression of the human telomerase reverse transcriptase. (C) 2018 Elsevier Masson SAS. All rights reserved.