Departamento de Química Inorgánica, Instituto de Síntesis Química y Catálisis Homogénea-ISQCH, Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain.
Departamento de Farmacología y Fisiología, Unidad de Fisiología. and CIBERobn, IIS Aragón, IA2, Universidad de Zaragoza, 50013 Zaragoza, Spain.
Inorg Chem. 2020 Dec 7;59(23):17732-17745. doi: 10.1021/acs.inorgchem.0c02922. Epub 2020 Nov 18.
A series of gold(I) and silver(I) derivatives with N- or S-donor ligands derived from 2-anilinopyridine has been synthesized and characterized. The mononuclear structure of Au(L1)(PPh) () and Au(L2)(PPh) () was confirmed by X-ray diffraction studies, as well as the dinuclear structure in the case of [Ag(TfO)(L1)] (). Most of the complexes are cytotoxic against a model of colorectal adenocarcinoma (Caco-2 cell line) and breast adenocarcinoma cancer cell lines (MCF-7). Au(L1)(PPh) () was able to induce caspases 8 and 3 activation, loss of mitochondrial membrane potential, and reactive oxygen species (ROS)-dependent cell death on Caco-2 cells upon 24 h incubation. In addition, the gold complex produced a significant inhibition of the redox enzyme thioredoxin reductase as well as 20S proteasome. However, the silver(I) analogue, [Ag(TfO)(L1)(PPh)] (), induced cell death independent of inhibition of thioredoxin reductase and 20S proteasome, triggered ROS-independent apoptosis mediated by caspase 8 and 3 activation, and loss of mitochondrial membrane potential, which points to a different mechanism of action for both derivatives, dependent on the metal center.
已合成并表征了一系列具有 N 或 S 供体配体的金（I）和银（I）衍生物，这些配体来自 2- 苯胺吡啶。单核结构Au(L1)(PPh)()和Au(L2)(PPh)()通过 X 射线衍射研究得到了证实，而对于Ag(TfO)(L1)则为双核结构。大多数配合物对结直肠腺癌（Caco-2 细胞系）和乳腺癌腺癌细胞系（MCF-7）具有细胞毒性。Au(L1)(PPh)()在孵育 24 小时后能够诱导 Caco-2 细胞中半胱天冬酶 8 和 3 的激活、线粒体膜电位丧失和依赖活性氧物种 (ROS)的细胞死亡。此外，金配合物产生了对氧化还原酶硫氧还蛋白还原酶以及 20S 蛋白酶体的显著抑制。然而，银（I）类似物Ag(TfO)(L1)(PPh)诱导的细胞死亡不依赖于硫氧还蛋白还原酶和 20S 蛋白酶体的抑制，通过半胱天冬酶 8 和 3 的激活以及线粒体膜电位丧失引发 ROS 非依赖性细胞凋亡，这表明两种衍生物的作用机制不同，取决于金属中心。
