Cytotoxicity of cyclometalated platinum complexes based on tridentate NCN and CNN-coordinating ligands: Remarkable coordination dependence

• Higher anticancer activity of (N^C^N)PtCl than that of cisplatin
• Drastic difference in cytotoxicity displayed by (N^C^N)PtCl and (C^N^N)PtCl
• Potentially important role of trans effect in higher cytotoxicity of (N^C^N)PtCl
• Activation of PARP via caspase 7 observed in the cell apoptosis.

A series of cyclometalated platinum complexes with diverse coordination patterns and geometries were screened for their anticancer activity. It was discovered that the N^C^N-coordinated platinum complex based on 1,3-di(pyridyl)benzene displayed much higher cytotoxicity against human lung cancer cells NCI-H522, HCC827, and NCI-H1299, and human prostate cancer cell RV1 than cisplatin. In a sharp contrast, the C^N^N-coordinated platinum complex based on 6-phenyl-2,2′-bipyridine was ineffective on these cancer cells. This remarkable difference in cytotoxicity displayed by N^C^N- and C^N^N-coordinated platinum complexes was related to the trans effect of the carbon donor in the cyclometalated platinum complexes, which played a crucial role in facilitating the dissociation of the chloride ligand to create an active binding site. The DNA binding was studied for the N^C^N-coordinated platinum complex using electrophoresis and emission titration. The cellular uptake observed by fluorescent microscope showed that the complex is largely concentrated in the cytoplasm. The possible pathways for the cell apoptosis were studied by western blot analysis and the activation of PARP via caspase 7 was observed.

Drastic difference in cytotoxicity was found between isomeric platinum complexes (N^C^N)PtCl and (C^N^N)PtCl. The N^C^N-coordinated Pt complex demonstrated remarkably higher t against a series of human lung cancer cells and a prostate cancer cell, which was attributed to the trans effect of the carbon donor in N^C^N-coordinated complex.Figure optionsDownload as PowerPoint slide