DNA Interaction and Antitumor Activity of A Copper(II) Complex Containing Sparfloxacin and Triazine Derivatives

doi:10.6023/A19110403

Acta Chimica Sinica ›› 2020, Vol. 78 ›› Issue (3): 263-270.DOI: 10.6023/A19110403 Previous Articles Next Articles

Special Issue: 分子探针、纳米生物学与生命分析化学

Article

司帕沙星及均三嗪衍生物铜(II)配合物与DNA作用及其抗肿瘤活性

刘启雁, 蔡戴宏, 戚永育, 乐学义

华南农业大学应用化学系广州 510642

投稿日期:2019-11-13 发布日期:2020-02-24
通讯作者: 乐学义 E-mail:lexyfu@163.com
基金资助:
项目受广东省自然科学基金（No.2015A030313423）资助.

DNA Interaction and Antitumor Activity of A Copper(II) Complex Containing Sparfloxacin and Triazine Derivatives

Liu Qiyan, Cai Daihong, Qi Yongyu, Le Xueyi

Department of Applied Chemistry, South China Agricultural University, Guangzhou 510642

Received:2019-11-13 Published:2020-02-24
Supported by:
Project supported by the Natural Science Foundation of Guangdong Province (No. 2015A030313423).

DNA is an important target for antitumor drugs, hence investigation of the interaction between drug molecules and DNA can help to design targeted DNA antitumor drugs. New ternary copper(II) complex[Cu(Sf)(PyTA)(H₂O)]·ClO₄· 3.5H₂O[Sf=sparfloxacin, 5-amino-1-cyclopropyl-7-(cis-3,5-dimethyl-1-piperazinyl)-6,8-difluoro-1,4-dihydro-4-oxoquino-line-3-carboxylic acid, PyTA=2,4-diamino-6-(2'-pyridyl)-1,3,5-triazine] was synthesized and characterized by elemental analyses, molar conductivity measurement and various spectroscopic techniques such as infrared, ultraviolet-visible, and electrospray ionization mass spectra. The interaction of the complex with DNA was investigated using electronic absorption spectroscopy, KI fluorescence quench, viscosity measurement and molecular docking techniques. It was found that the complex could bind to DNA through an intercalation mode being related with the quinoline ring of ligand Sf, and the corresponding binding constant K_b is 1.23×10⁴ L/mol. Moreover, the antitumor activity of the complex was evaluated using the MTT[3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide] method, revealing that the complex displayed favorable cytotoxic effects[IC₅₀=(57.0±1.6)~(77.6±1.4) μmol/L] toward cancer cells (A549, Bel-7402 and Eca-109) and less toxic towards normal cells (3T3). Most importantly, the cytotoxic mechanism of the complex towards Eca-109 cells was explored by single cell gel electrophoresis assay, Hoechst 33342 staining, Annexin V-FITC/PI double dye flow cytometry, measurement of mitochondrial membrane potential change, detection of intracellular cytochrome C and Ca²⁺ levels, and test of cell cycle arrest. Single cell gel electrophoresis assay (comet assays) demonstrated that the complex could damage DNA and cause apoptosis. Double staining analysis showed that the complex could induce apoptosis in Eca-109 cells. Cell cycle arrest studies revealed the cell growth arrest at S and G2/M phases. The complex also could induce a reduction in the mitochondrial membrane potential and release of the cytochrome C, and increase the intracellular Ca²⁺ level. The results demonstrated that the complex could induce apoptosis in Eca-109 cells through DNA-binding mitochondrial dysfunctional pathways, which was accompanied by the cell growth arrest at S and G2/M phases and damage of DNA.

Key words: copper(II) complex, sparfloxacin, DNA, antitumor activity

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Liu Qiyan, Cai Daihong, Qi Yongyu, Le Xueyi. DNA Interaction and Antitumor Activity of A Copper(II) Complex Containing Sparfloxacin and Triazine Derivatives[J]. Acta Chimica Sinica, 2020, 78(3): 263-270.

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司帕沙星及均三嗪衍生物铜(II)配合物与DNA作用及其抗肿瘤活性

DNA Interaction and Antitumor Activity of A Copper(II) Complex Containing Sparfloxacin and Triazine Derivatives

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