Sparfloxacin - Cu(II) - aromatic heterocyclic complexes: synthesis, characterization and in vitro anticancer evaluation

Two new copper(II) complexes of sparfloxacin (sf), [Cu(Hsf)(HPB)(H2O)](ClO4)(2) (1) and [Cu(Hsf)(PBT)(H2O)](ClO4)(2) (2) (where HPB = 2-(2'-pyridyl)benzimidazole and PBT = 2-(4'-pyridyl) benzothiazole), have been synthesized and characterized by physicochemical and spectroscopic techniques. The oil water partition coefficient (log P) values of complexes 1 and 2 were 1.47 and 171, respectively. By studying the interaction between the complexes and DNA, it was found that the complexes could bind to DNA through an intercalation mode. Moreover, both complexes were evaluated for antitumor activity, revealing that the complexes displayed good inhibitory activity toward the tested cancer cell lines (human lung carcinoma A549 cells, human hepatocellular carcinoma Bel-7402 cells and human esophageal carcinoma Eca-109 cells), but showed relatively low toxicity against normal human hepatic LO2 cells. In particular, the antitumor mechanism of the complexes on Eca-109 cells was investigated by morphological analysis, apoptosis analysis and determination of cell cycle arrest, mitochondrial membrane potential, reactive oxygen species (ROS) levels, and release of cytochrome c and Ca2+. The results demonstrated that the complexes could induce loss of intracellular mitochondrial functions and increase of ROS levels, which led to an increase of Ca2+ levels and the release of cytochrome c into the cytoplasm. In addition, the cell cycle was arrested in the G2/M phase, and western blot analysis showed that the caspase family was activated. These results fully proved that the complexes could induce apoptosis through DNA damage and loss of mitochondrial functions, accompanied by the regulation of endogenous proteins.

Automated summary

Two new copper(II) complexes of sparfloxacin were synthesized and displayed good antitumor activity by inducing apoptosis through DNA damage and loss of mitochondrial functions.