DNA binding, cytotoxicity and mitochondria-mediated cell apoptosis induction of a new zinc(II) complex of 5-chloro-8-hydroxylquinoline

Abstract

A new zinc(II) complex (<strong>1</strong>) of 5-chloro-8-hydroxylquinoline (HClQ) has been synthesized and characterized by IR spectroscopy, ESI-MS spectrometry, elemental analysis and single crystal X-ray diffraction analysis. The DNA binding property of complex (<strong>1</strong>) has been investigated by UV-vis spectroscopy, circular dichroism spectroscopy and agarose gel electrophoresis. The results indicate that complex (<strong>1</strong>) binds with ct-DNA via an intercalative mode, and also exhibits DNA cleavage activity. The <em>in vitro</em> cytotoxicity of complex (<strong>1</strong>) has been screened by MTT assay against a series of tumor cell lines as well as HL-7702 normal liver cell line and, compared with that of cisplatin. Complex (<strong>1</strong>) shows lower cytotoxicity than cisplatin towards both the tumor cell lines and the normal liver cell line, except the BEL-7404 liver tumor cell line. The IC₅₀ value of (<strong>1</strong>) towards BEL-7404 is 7.04&plusmn;0.06 &mu;<em>M</em>, which is lower than that of cisplatin (25.08&plusmn;0.12 &mu;<em>M</em>). This suggests that BEL-7404 is the most sensitive tumor cell line for (<strong>1</strong>). Complex (<strong>1</strong>) is found to induce cell apoptosis in the BEL-7404 cells by arresting the cell cycle at the S phase. The antitumor mechanism of (<strong>1</strong>) involves targeting the mitochondria-mediated pathway, since the ROS release and the cytoplasmic [Ca²⁺]_c increase in the tested tumor cells after incubation with (<strong>1</strong>). Flow cytometry assay on the cellular level confirms that the dysfunction of the mitochondria (indicated by the loss of mitochondrial membrane potential) and the release of ROS and Ca²⁺, directly cause the activation of caspase cascade, including caspase-9 as the initiator and caspase-3 as the executor. These results strongly suggest that the central Zn(II) as the coordinating centre plays the key role in enhancing the antitumor activity and actuating the potential apoptotic pathway for this kind of halogenated quinoline derivatives.