Abstract
Five new ruthenium(II) polypyridyl complexes [Ru(N–N)2(BTCP)](ClO4)2 (BTCP = 2-(bicyclo[2.2.1]hept-5-en-2-yl)-1H-imidazo[4,5-f][1,10]phenanthroline; N–N = dmb: 4,4′-dimethyl-2,2′-bipyridine, 1; bpy: 2,2′-bipyridine 2; ttbpy: ditertairy-butyl-2,2′-bipyridine 3; phen: 1,10-phenanthroline 4; dmp: 2,9-dimethyl-1,10-phenanthroline 5) were synthesized and characterized by elemental analysis, IR, ESI-MS, 1H NMR and 13C NMR. The DNA-binding behaviors were studied by electronic absorption titration, viscosity measurements and molecular docking. The results show that complexes 1–4 interact with CT-DNA through intercalative modes, whereas complex 5 interacts through a partial intercalative mode. The DNA-binding constants follow the order of 3 > 4 > 1 > 2 > 5. The cytotoxic activity of the complexes against SGC-7901, PC-12, SiHa, HepG2, BEL-7402, A549 and HeLa cancer cell lines was evaluated by MTT method. The complexes display moderate cytotoxic activity toward BEL-7402 cells with an IC50 value of 25.5 ± 1.3 µM for 1, 45.7 ± 4.2 µM for 2, 6.5 ± 0.4 µM for 3, 13.2 ± 1.2 µM for 4 and 9.1 ± 1.1 µM for 5, respectively. Complex 5 exhibits the highest cytotoxic effect on the cell growth in SGC-7901, HepG2 and A549 cells among the complexes. The cytotoxic activity of the complexes is not consistent with the order of their DNA-binding constants. The apoptosis of BEL-7402 cells was studied under a fluorescent microscope and by flow cytometry. Measurements of reactive oxygen species, mitochondrial membrane potential and comet assays were carried out. The cell cycle arrest was investigated by flow cytometry, and the results demonstrate that complexes 1, 2, 4 and 5 inhibit the cell growth at G0/G1 phase and complex 3 induces cell cycle arrest at G2/M phase in BEL-7402 cells. The expression of Bcl-2 family induced by the complexes was studied by western blot. The results obtained show that complexes induce apoptosis in BEL-7402 cells through action of DNA and ROS-mediated mitochondrial dysfunction pathways.
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This work was supported by the Natural Science Foundation of Guangdong Province (No. 2016A030313728).
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Huang, HL., Tang, B., Yi, QY. et al. Synthesis, DNA-binding, molecular docking and cytotoxic activity in vitro evaluation of ruthenium(II) complexes. Transit Met Chem 44, 11–24 (2019). https://doi.org/10.1007/s11243-018-0264-y
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DOI: https://doi.org/10.1007/s11243-018-0264-y