Nuclei DNA and mitochondria dual damages induced by thiosemicarbazone tripyridyl copper complexes with potential anti-tumor activity

摘要

In this study, we synthesised and characterised a di-nuclear complex, [Cu-2(dppco)Br-3] (1), and a mononuclear complex, [Cu(dppc)Br] (2), with the thiosemicarbazone tripyridyl ligand dppc = 2-(di(pyridin-2)-yl) methylene)-N-(pyridin-2-yl)hydrazine-1-carbothio-amide. The S atom of the ligand in complex 1 was replaced by an O atom in the solvothermal reaction, while only the ligand in complex 2 contains an S tom (it is therefore a thiosemicarbazone). Compared to complex 1, complex 2 has a stronger inhibitory effect on the colon cancer cell line (HCT116), human breast cancer cell line (CAOV-3) and liver cancer cell line (SMMC7721), especially being more sensitive to HCT116 cells. Fluorescence, circular dichroism and DNA cleavage experiments showed that complexes 1 and 2 have an excellent DNA binding ability, mostly binding to DNA by the intercalation mode. In contrast, the thiosemicarbazone-based complex 2 has a stronger cell uptake ability, which triggered more prominent cellular apoptosis and cell cycle arrest. Further mechanism studies revealed that complex 2 caused more serious mitochondrial damage than that for complex 1, including an increased level of reactive oxygen species (ROS) and Ca2+, decreased ATP content and mitochondrial membrane potential (Delta psi(m)), and significantly transformed the mitochondrial morphology.

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