一款新型钌配合氯布硼嗪配体的复合物增强DNA损伤及抗增殖活性
Enhanced DNA damage and anti-proliferative activity of a novel ruthenium complex with a chlorambucil-decorated ligand
DOI 原文链接
用sci-hub下载
如无法下载，请从 Sci-Hub 选择可用站点尝试。
影响因子:3.2
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
DOI:
10.1016/j.jinorgbio.2024.112703
摘要
以三苯基膦取代反应合成的[RuCl(PPh3)2(tpm)]Cl（1）中，配体为三(吡唑基)甲烷（tpm），与氯布硼嗪修饰的吡啶配体PyCA、3-氨基吡啶（PyNH2）以及4-吡啶甲醇（PyOH）反应，获得了对应的吡啶配合物2-4，产率高。PyCA通过4-吡啶甲醇与氯布硼嗪的酯化反应获得。新化合物PyCA及2-3通过红外光谱和多核核磁共振（NMR）鉴定，单晶X射线衍射确认了3的结构。体外抗增殖活性在一系列癌细胞系中进行检测，其中2表现最优。随后，使用2进行机制研究，包括钌的细胞摄取、细胞周期阻滞、活性氧（ROS）产生、西方印迹分析和DNA损伤（彗星试验）。总体数据显示，2的抗癌活性主要通过线粒体途径发挥作用，并可能伴有DNA损伤的额外贡献。
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.