Department of Chemistry, University of Isfahan, Isfahan 81746-73441, Iran.
Dalton Trans. 2021 Mar 21;50(11):3990-4007. doi: 10.1039/d0dt03962d. Epub 2021 Mar 2.
To investigate the effect of different halogen substituents and leaving groups and the flexibility of ligands on the anticancer activity of copper complexes, sixteen copper(ii) complexes with eight different tridentate Schiff-base ligands containing pyridine and 3,5-halogen-substituted phenol moieties were synthesized and characterized by spectroscopic methods. Four of these complexes were also characterized by X-ray crystallography. The cytotoxicity of the complexes was determined in three different tumor cell lines (i.e. the A2780 ovarian, HCT116 colorectal and MCF7 breast cancer cell line) and in a normal primary fibroblast cell line. Complexes were demonstrated to induce a higher loss of cell viability in the ovarian carcinoma cell line (A2780) with respect to the other two tumor cell lines, and therefore the biological mechanisms underlying this loss of viability were further investigated. Complexes with ligand L (containing a 2-pycolylamine-type motif) were more cytotoxic than complexes with L (containing a 2-(2-pyridyl)ethylamine-type motif). The loss of cell viability in A2780 tumor cells was observed in the order Cu(Cl-L)NO > Cu(Cl-L)Cl > Cu(Br-L)Cl > Cu(BrCl-L)Cl. All complexes were able to induce reactive oxygen species (ROS) that could be related to the loss of cell viability. Complexes Cu(BrCl-L)Cl and Cu(Cl-L)NO were able to promote A2780 cell apoptosis and autophagy and for complex Cu(BrCl-L)Cl the increase in apoptosis was due to the intrinsic pathway. Cu(Cl-L)Cl and Cu(Br-L)Cl complexes lead to cellular detachment allowing to correlate with the results of loss of cell viability. Despite the ability of the Cu(BrCl-L)Cl complex to induce programmed cell death in A2780 cells, its therapeutic window turned out to be low making the Cu(Cl-L)NO complex the most promising candidate for additional biological applications.
为了研究不同卤素取代基和离去基团以及配体的灵活性对铜配合物抗癌活性的影响，合成并通过光谱方法表征了十六个含有吡啶和 3,5-卤素取代苯酚部分的八元三齿席夫碱配体的铜（ii）配合物。其中四个配合物还通过 X 射线晶体学进行了表征。在三种不同的肿瘤细胞系（即 A2780 卵巢癌、HCT116 结直肠癌和 MCF7 乳腺癌细胞系）和正常原代成纤维细胞系中测定了配合物的细胞毒性。结果表明，配合物在卵巢癌细胞系（A2780）中诱导细胞活力丧失的程度高于其他两种肿瘤细胞系，因此进一步研究了导致这种活力丧失的生物学机制。含有配体 L（含有 2-吡啶基乙胺型结构单元）的配合物比含有配体 L（含有 2-（2-吡啶基）乙胺型结构单元）的配合物更具细胞毒性。在 A2780 肿瘤细胞中，细胞活力丧失的顺序为 Cu(Cl-L)NO > Cu(Cl-L)Cl > Cu(Br-L)Cl > Cu(BrCl-L)Cl。所有配合物都能够诱导活性氧物种（ROS），这可能与细胞活力丧失有关。配合物 Cu(BrCl-L)Cl 和 Cu(Cl-L)NO 能够促进 A2780 细胞凋亡和自噬，而对于配合物 Cu(BrCl-L)Cl，凋亡的增加是由于内在途径。Cu(Cl-L)Cl 和 Cu(Br-L)Cl 配合物导致细胞脱落，这与细胞活力丧失的结果相关。尽管 Cu(BrCl-L)Cl 配合物能够诱导 A2780 细胞程序性细胞死亡，但它的治疗窗口较低，使得 Cu(Cl-L)NO 配合物成为具有进一步生物学应用的最有前途的候选物。
