Synthesis, crystal structure, cytotoxicity and cell apoptosis induction of a copper(II)-based Schiff base complex

• A Schiff base HClQP was not cytotoxic to both tumor cells and normal liver cells.
• A copper(II) complex of HClQP showed high cytotoxicity to four tumor cell lines.
• The complex showed no obvious cytotoxicity to HL-7702 normal liver cell line.
• The complex induced mitochondria-mediated cell apoptosis by S phase arrest.

A new copper(II) complex, [CuII(ClQP)(NO3)(H2O)] (1), bearing with 4-Chloro-2-(quinolin-8-yliminomethyl)-phenol (HClQP) as Schiff base ligand, was synthesized and structurally characterized by IR, elemental analysis, ESI-MS and single crystal X-ray diffraction analysis. The crystal structure revealed that complex 1 was five coordinated by one N,N,O-tridentated ClQP, one H2O and one nitrate anion, respectively, to form a pyramidal coordinating geometry. The antitumor activity of complex 1 against HepG2, BEL-7404, MGC80-3 and NCI-H460 tumor cell lines were screened by MTT assay. The IC50 values were in the range of 6.53–23.62 μM, in which HepG2 cell line showed the highest sensitivity to complex 1. It is worth noting that complex 1 did not show cytotoxicity to human normal liver cell line HL-7702, suggesting its cytotoxic selectivity on these tumor cell lines. Towards the most sensitive HepG2 cell line, complex 1 significantly induced S phase cell cycle arrest, probably due to its intercalative binding with DNA based on its rigid planar structure as well as the planar aromatic groups of HClQP ligand. Furthermore, the HepG2 cells treated with 1 showed typical cell apoptosis in dose-dependent manner visualized by Hoechst 33258 staining. And the cell apoptosis in the HepG2 cells induced by 1 was further confirmed by the loss of mitochondrial membrane potential visualized by JC-1 staining in cells. The detailed flow cytometric assay revealed that complex 1 could up-regulate the expression of the caspase-3. From these results, it can be concluded that complex 1 induced the mitochondrion-mediated cell apoptosis by caspase-3 activation, most probably due to the S phase cell cycle arrest in HepG2 cells owing to the DNA binding affinity of 1via intercalative binding mode.

A new copper(II) complex, [CuII(ClQP)(NO3)(H2O)]·0.5H2O (1), bearing Schiff base ligand, was synthesized and structurally characterized by IR, elemental analysis, ESI-MS and single crystal X-ray diffraction analysis. Although the HClQP ligand did not show cytotoxicity to all the tested cell lines, the complex 1 showed significant growth inhibition on the HepG2, BEL-7404, MGC80-3 and NCI-H460 tumor cell lines. Furthermore, complex 1 did not show cytotoxicity to the normal liver cell line HL-7702, suggesting its potential cytotoxic selectivity on the tumor cell lines. Complex 1 induced significant cell apoptosis in HepG2 cells via S phase cell cycle arrest, which was most probably mediated by intrinsic mitochondrial apoptotic pathway owing to the activation of caspase-3. Considering the S phase cell cycle arrest was generally regarded to be closely related with the blocking on DNA replication, the rigid aromatic planar structure of complex 1 with suggested DNA intercalative binding ability should be attributed for its antitumor mechanism.Figure optionsDownload as PowerPoint slide