Copper(I) Complexes With Phenanthroline-Functionalized NHC Ligands Achieve Effective Anticancer Activity via Mitochondrial and Endoplasmic Reticulum Stress

IF 3.7 2区化学 Q2 CHEMISTRY, APPLIED

Applied Organometallic Chemistry Pub Date : 2024-09-17 DOI:10.1002/aoc.7756

Chao Chen, Yilun Zheng, Hong Rao, Fan Huang, Chao Shen, Chunxin Lu

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Abstract

Copper complexes exhibit promising anticancer properties, which can be further promoted by suitable ligands. In this study, we synthesized and investigated the anticancer effects of three copper(I) complexes with N-heterocyclic carbene (NHC) ligands derived from phenanthroline-functionalized imidazole salts. The synthesis of these NHC-copper(I) complexes (Cu1-Cu3) was meticulously characterized using NMR and elemental analysis; their crystal structures were further delineated by X-ray diffraction. Our findings illustrate the unique geometric configurations of these complexes: Cu1 features a dinuclear arrangement with off-linear geometry; Cu2 and Cu3 are characterized by a bi-copper core stabilized by two phenanthroline-modified carbene ligands. Crucially, in vitro cytotoxic evaluations revealed that these complexes possess suitability anticancer activity. Among them, Cu2 exhibited enhanced cytotoxicity activity, achieving a half-maximal inhibitory concentration (IC₅₀) of 4.36 ± 0.25 μM in colon cancer cell line HCT-116, markedly surpassing the efficacy of cisplatin. Subsequent investigations elucidated that Cu2 notably increases intracellular reactive oxygen species (ROS) levels and induces mitochondrial membrane depolarization and endoplasmic reticulum stress, leading to oxidative stress-mediated apoptosis of colon cancer cells.

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具有菲罗啉功能化 NHC 配体的铜(I)配合物通过线粒体和内质网应激实现有效的抗癌活性

铜配合物具有良好的抗癌特性，合适的配体可进一步促进其抗癌作用。在本研究中，我们合成了三种铜（I）配合物，并研究了它们的抗癌作用，这些配合物的N-杂环碳烯（NHC）配体来自菲罗啉功能化咪唑盐。我们利用核磁共振和元素分析对这些 NHC-铜(I)配合物（Cu1-Cu3）的合成进行了细致的表征，并通过 X 射线衍射进一步划分了它们的晶体结构。我们的研究结果表明了这些配合物独特的几何构型：Cu1 具有非线性几何的双核排列；Cu2 和 Cu3 的特征是由两个菲罗啉修饰的碳烯配体稳定的双铜核。重要的是，体外细胞毒性评估显示，这些复合物具有适当的抗癌活性。其中，Cu2 表现出更强的细胞毒性活性，在结肠癌细胞系 HCT-116 中的半数最大抑制浓度（IC50）为 4.36 ± 0.25 μM，明显超过顺铂的疗效。随后的研究阐明，Cu2 显著增加细胞内活性氧（ROS）水平，诱导线粒体膜去极化和内质网应激，导致氧化应激介导的结肠癌细胞凋亡。

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来源期刊

Applied Organometallic Chemistry 化学-无机化学与核化学

CiteScore

7.80

自引率

10.30%

发文量

408

审稿时长

2.2 months

期刊介绍： All new compounds should be satisfactorily identified and proof of their structure given according to generally accepted standards. Structural reports, such as papers exclusively dealing with synthesis and characterization, analytical techniques, or X-ray diffraction studies of metal-organic or organometallic compounds will not be considered. The editors reserve the right to refuse without peer review any manuscript that does not comply with the aims and scope of the journal. Applied Organometallic Chemistry publishes Full Papers, Reviews, Mini Reviews and Communications of scientific research in all areas of organometallic and metal-organic chemistry involving main group metals, transition metals, lanthanides and actinides. All contributions should contain an explicit application of novel compounds, for instance in materials science, nano science, catalysis, chemical vapour deposition, metal-mediated organic synthesis, polymers, bio-organometallics, metallo-therapy, metallo-diagnostics and medicine. Reviews of books covering aspects of the fields of focus are also published.