SIOC 中文
ACS
Adv search

Acta Chimica Sinica >

2020 , Vol. 78 >Issue 3: 263 - 270

DOI: https://doi.org/10.6023/A19110403

Article

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

  • Liu Qiyan ,
  • Cai Daihong ,
  • Qi Yongyu ,
  • Le Xueyi
Expand
  • Department of Applied Chemistry, South China Agricultural University, Guangzhou 510642

Received date: 2019-11-13

  Online published: 2020-02-24

Supported by

Project supported by the Natural Science Foundation of Guangdong Province (No. 2015A030313423).

Fold

Abstract

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 Kb 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

Cite this article

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

References

[1] Rehman, S. U.; Sarwar, T.; Mohammed, A. H.; Hassan, M. I.; Mohammad, T. Arch. Biochem. Biophys. 2015, 576, 49.
[2] Santini, C.; Pellei, M.; Gandin, V.; Porchia, M.; Tisato, F.; Marzano, C. Chem. Rev. 2014, 114, 815.
[3] Tardito, S.; Bassanetti, I.; Bignardi, C.; Elviri, L.; Tegoni, M.; Mucchino, C.; Bussolati, O.; Franchi-Gazzola, R.; Marchiò, L. J. Am. Chem. Soc. 2011, 133, 6235.
[4] Qi, Y. Y.; Gan, Q.; Liu, Y. X.; Xiong, Y. H.; Mao, Z. W.; Le, X. Y. Eur. J. Med. Chem. 2018, 154, 220.
[5] Shi, X. C.; Fang, H. B.; Guo, Y.; Yuan, H.; Guo, Z. J.; Wang, X. Y. J. Inorg. Biochem. 2019, 190, 38.
[6] Turel, I. Coord. Chem. Rev. 2002, 232, 27.
[7] Dorotíková, S.; Kožíšková, J.; Malček, M.; Jomová, K.; Herich, P.; Plevová, K.; Briestenská, K.; Chalupková, A.; Mistríková, J.; Milata, V.; Dvoranová, D.; Bučinský, L. J. Inorg. Biochem. 2015, 150, 160.
[8] Akhtar, J.; Khan, A. A.; Ali, Z.; Haider, R.; Yar, M. S. Eur. J. Med. Chem. 2017, 125, 143.
[9] Xiao, Y.; Wang, Q.; Huang, Y. M.; Ma, X. L.; Xiong, X. N.; Li, H. Dalton Trans. 2016, 45, 10928.
[10] Geary, W. J. Coord. Chem. Rev. 1971, 7, 81.
[11] Efthimiadou, E. K.; Katsarou, M. E.; Karaliota, A.; Psomas, G. J. Inorg. Biochem. 2008, 102, 910.
[12] Guo, Q.; Li, L. Z.; Dong, J. F.; Liu, H. Y.; Xue, Z. C.; Xu, T. Acta Chim. Sinica 2012, 70, 1617. (郭琼, 李连之, 董建方, 刘鸿雁, 薛泽春, 许涛, 化学学报, 2012, 70, 1617.)
[13] Fu, X. B.; Liu, D. D.; Lin, Y.; Hu, W.; Mao, Z. W.; Le, X. Y. Dalton Trans. 2014, 43, 8721.
[14] Fu, X. B.; Zhang, J. J.; Liu, D. D.; Gan, Q.; Gao, H. W.; Mao, Z. W.; Le, X. Y. J. Inorg. Biochem. 2015, 143, 77.
[15] Trott, O.; Olson, A. J. J. Comput. Chem. 2010, 31, 455.
[16] Chen, J. J.; Ye, H. N.; Zhang, M. J.; Li, J. Y.; Liu, J. Y.; Xue, J. P. Chin. J. Chem. 2016, 34, 983.
[17] Feng, C. G.; Gan, Q.; Liu, X.; He, H. Y. Chin. J. Chem. 2012, 30, 1589.
[18] Hong, X. L.; Zhou, Y. H.; Zeng, C. C.; Wu, X. C.; Liu, Y. J. J. Organomet. Chem. 2017, 846, 312.
[19] Weng, H.; Tan, Z. J.; Hu, Y. P.; Shu, Y. J.; Bao, R. F.; Jiang, L.; Wu, X. S.; Li, M. L.; Ding, Q.; Wang, X. A.; Xiang, S. S.; Li, H. F.; Cao, Y.; Tao, F.; Liu, Y. B. Cancer Cell Int. 2014, 14, 96.
[20] Huang, H. Y.; Zhang, P. Y.; Yu, B. L.; Chen, Y.; Wang, J. Q.; Ji, L. N.; Chao, H. J. Med. Chem. 2014, 57, 8971.
[21] Tang, B.; Wan, D.; Lai, S. H.; Yang, H. H.; Zhang, C.; Wang, X. Z.; Zeng, C. C.; Liu, Y. J. J. Inorg. Biochem. 2017, 173, 93.
[22] Wan. D.; Tang, B.; Wang, Y. J.; Guo, B. H.; Yin, H.; Yi, Q. Y.; Liu, Y. J. Eur. J. Med. Chem. 2017, 139, 180.
[23] Min, X.; Heng, H.; Yu, H. L.; Dan, M.; Jie, C.; Zeng, Y.; Ning, H.; Liu, Z. G.; Wang, Z. Y.; Lin, W. Oncology Lett. 2018, 15, 2459.
[24] Clapham, D. E. Cell 2007, 131, 1047.
[25] Kar, P.; Samanta, K.; Shaikh, S.; Chowdhury, A.; Chakraborti, T.; Chakraborti, S. Arch. Biochem. Biophys. 2010, 495, 1.
[26] Zou, H. H.; Wang, L.; Long, Z. X.; Qin, Q. P.; Song, Z. K.; Xie, T.; Zhang, S. H.; Liu, Y. C.; Lin, B.; Chen, Z. F. Eur. J. Med. Chem. 2016, 108, 1.
[27] Liu, Y.; Chen, X. M.; Zhang, L. Q.; Sun, D. D.; Zhou, Y. H.; Chen, L. M.; Liu, J. Acta Chim. Sinica 2014, 72, 473. (刘莹, 陈小曼, 张朗棋, 孙冬冬, 周艳晖, 陈兰美, 刘杰, 化学学报, 2014, 72, 473.)
[28] Zhao, Q. H.; Fan, A. L.; Li, L. N.; Xie, M. J. Acta Crystallogr. Sect. E Struct. Rep. Online 2009, 65, M622.
[29] Waring, M. J. J. Mol. Biol. 1965, 13, 269.
[30] Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, 154104.
Options
Outlines

/

〈 〉