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结构多样的锌 (II) 配合物含有三足四齿酚氧化胺,具有良好的抗增殖作用。

Structurally diverse zinc(II) complexes containing tripodal tetradentate phenoxido-amines with promising antiproliferative effects.

发表日期:2024 Jul 09
作者: Salah S Massoud, Franz A Mautner, Febee R Louka, Nahed M H Salem, Roland C Fischer, Ana Torvisco, Ján Vančo, Jan Belza, Zdeněk Dvořák, Zdeněk Trávníček
来源: ANTIOXIDANTS & REDOX SIGNALING

摘要:

合成了具有酚和胺部分中可变取代基的三足四齿酚胺的结构多样的锌(II)配合物,并进行了彻底的表征。两个双核 [Zn2(L1)2](ClO4)2·MeOH (1)、[Zn2(L2)2](ClO4)2 (2) 和四个单核 [Zn(L3)(H2O)]·MeOH ( 3)、[Zn(L4)] (4)、[Zn(L5)] (5) 和 [Zn(L6)] (6) 配合物显示出扭曲的八面体、三角双锥体或四面体几何形状。评估游离 HL1 和 H2L3-6 配体以及复合物 1-6 对人类癌细胞系(A2780、A2780R、PC-3 和 22Rv1)和正常健康 MRC-5 细胞的体外细胞毒性。总体结果显示出高至中度的细胞毒性(复合物 6 的最佳 IC50 值范围为 2.4 至 4.5 μM),但明显高于参考药物顺铂。中等活性的复合物 1-4 对 A2780 细胞表现出比 MRC-5 细胞更高的选择性(IC50 ≈ 16.3-19.5 μM)(1、2 和 4 的 IC50 >50 μM,3 的 IC50 >25 μM)。选择配合物1、2和6以及配体H2L6进行后续更深入的生物学评估。研究了它们在 A2780 细胞中的时间分辨细胞摄取和其他细胞效应,例如细胞周期概况、细胞内 ROS 产生、诱导细胞凋亡和激活 caspase 3/7。复合物 1 和 2 在 A2780 细胞中引起显着的 G0/G1 细胞周期停滞,并在正常条件下产生抗氧化作用。它们对与细胞毒性相关的细胞过程仅表现出有限的影响,即诱导细胞凋亡、线粒体膜电位耗竭和自噬。这些发现至少部分归因于复合物进入 A2780 细胞的能力较低以及靶癌细胞代谢活性的抑制。
Structurally diverse zinc(II) complexes with tripodal tetradentate phenolic-amines of variable substituents in the phenol and amine moieties were synthesized and thoroughly characterized. The two dinuclear [Zn2(L1)2](ClO4)2·MeOH (1), [Zn2(L2)2](ClO4)2 (2), and four mononuclear [Zn(L3)(H2O)]·MeOH (3), [Zn(L4)] (4), [Zn(L5)] (5) and [Zn(L6)] (6) complexes revealed distorted octahedral, trigonal-bipyramidal or tetrahedral geometries. The free HL1 and H2L3-6 ligands, and complexes 1-6 were evaluated for in vitro cytotoxicity against human cancer cell lines (A2780, A2780R, PC-3 and 22Rv1) and normal healthy MRC-5 cells. Overall results revealed high-to-moderate cytotoxicity (with the best IC50 values for complex 6 ranging from 2.4 to 4.5 μM), which is however, significantly higher than that of the reference drug cisplatin. The moderately active complexes 1-4 showed considerable selectivity on A2780 cells (IC50 ≈ 16.3-19.5 μM) over MRC-5 ones (with IC50 >50 μM for 1, 2 and 4, and with IC50 >25 μM for 3). The complexes 1, 2, and 6 and the ligand H2L6 were chosen for subsequent deeper biological evaluations. Their time-resolved cellular uptake and other cellular effects in A2780 cells were studied, such as cell cycle profile, intracellular ROS production, induction of apoptosis and activation of caspases 3/7. Complexes 1 and 2 caused significant G0/G1 cell cycle arrest in A2780 cells and antioxidant effects at normal conditions. They showed only limited effects on cellular processes connected with cytotoxicity, i.e. induction of apoptosis, depletion of mitochondrial membrane potential, and autophagy. These findings can be at least partly attributed to the low ability of the complexes to enter the A2780 cells and the depression of metabolic activity of the target cancer cells.