Citation: 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. doi: 10.6023/A19110403 shu

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

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

Corresponding author: Le Xueyi, lexyfu@163.com
Received Date: 13 November 2019
Available Online: 21 February 2020
Fund Project: Project supported by the Natural Science Foundation of Guangdong Province (No. 2015A030313423)the Natural Science Foundation of Guangdong Province 2015A030313423

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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.
- copper(Ⅱ) complex,
- sparfloxacin,
- DNA,
- antitumor activity
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