新型的钌配合物具有氯辅糖装饰配体的增强的DNA损伤和抗增殖活性
Enhanced DNA damage and anti-proliferative activity of a novel ruthenium complex with a chlorambucil-decorated ligand
影响因子:3.20000
分区:化学2区 / 无机化学与核化学1区 生化与分子生物学3区
发表日期:2024 Nov
作者:
Alberto Gobbo, Feihong Chen, Stefano Zacchini, Shaohua Gou, Fabio Marchetti
摘要
三苯基膦的取代反应[RUCL（PPH3）2（TPM）] Cl，1，具有Tris（吡唑基）甲烷（TPM）作为配体的特征，与氯氨基糖含量的吡啶吡啶配体Pyca，3-氨基氨基肾上腺素（Pynh2）和4-吡啶甲烷（Pyrididinemenemethanh2）高产2-4。 PYCA是通过与氯氨基糖酯化4-吡啶甲醇的酯化初步获得的。新化合物PYCA和2-3的特征是IR和多核NMR光谱。另外，通过单晶X射线衍射确定3的结构。 2-4和PYCA的体外抗增殖活性是针对癌细胞系的小组确定的，将2概述为表现最多的化合物。随后使用2进行了靶向研究，以阐明机械方面，包括评估细胞摄取，细胞周期停滞，产生活性氧（ROS），蛋白质印迹和DNA损伤（彗星测试）。总体而言，数据强调，2提供的抗癌活性主要影响线粒体途径，并可能对DNA损伤产生额外的贡献。
Abstract
Triphenylphosphine substitution reactions of [RuCl(PPh3)2(tpm)]Cl, 1, featuring tris(pyrazolyl)methane (tpm) as ligand, with the chlorambucil-decorated pyridine ligand PyCA, 3-aminopyridine (PyNH2) and 4-pyridinemethanol (PyOH) afforded the corresponding pyridine complexes 2-4 in high yields. PyCA was preliminarily obtained via esterification of 4-pyridinemethanol with chlorambucil. The new compounds PyCA and 2-3 were characterized by IR and multinuclear NMR spectroscopy. Additionally, the structure of 3 was ascertained by single crystal X-ray diffraction. The in vitro anti-proliferative activity of 2-4 and PyCA was determined against a panel of cancer cell lines, outlining 2 as the most performing compound. Targeted studies were subsequently undertaken using 2 to elucidate mechanistic aspects, including the assessment of ruthenium cellular uptake, cell cycle arrest, production of reactive oxygen species (ROS), western blotting and DNA damage (comet test). Overall, data highlight that the anticancer activity provided by 2 primarily affects the mitochondria pathway with a potential additional contribution from DNA damage.