化学
药效团
硫氧还蛋白还原酶
雌激素受体
三苯氧胺
活性氧
细胞内
配体(生物化学)
细胞毒性
体外
生物化学
线粒体
癌细胞
酶
药理学
硫氧还蛋白
受体
癌症
乳腺癌
内科学
医学
作者
Valeria Scalcon,Riccardo Bonsignore,Jana Aupič,Sophie Thomas,Alessandra Folda,Alexandra A. Heidecker,Alexander Pöthig,Alessandra Magistrato,Angela Casini,Maria Pia Rigobello
标识
DOI:10.1021/acs.jmedchem.3c00617
摘要
Two new ‘hybrid’ metallodrugs of Au(III) (AuTAML) and Cu(II) (CuTAML) were designed featuring a tamoxifen-derived pharmacophore to ideally synergize the anticancer activity of both the metal center and the organic ligand. The compounds have antiproliferative effects against human MCF-7 and MDA-MB 231 breast cancer cells. Molecular dynamics studies suggest that the compounds retain the binding activity to estrogen receptor (ERα). In vitro and in silico studies showed that the Au(III) derivative is an inhibitor of the seleno-enzyme thioredoxin reductase, while the Cu(II) complex may act as an oxidant of different intracellular thiols. In breast cancer cells treated with the compounds, a redox imbalance characterized by a decrease in total thiols and increased reactive oxygen species production was detected. Despite their different reactivities and cytotoxic potencies, a great capacity of the metal complexes to induce mitochondrial damage was observed as shown by their effects on mitochondrial respiration, membrane potential, and morphology.
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