Synthesis and anticancer evaluation of copper(II)- and manganese(II)-theophylline mixed ligand complexes

Metals complexed to organic ligands have attracted much attention as potential treatments for cancer. In this paper we present the synthesis and anticancer activity of four metal complexes [Cu(theo)(2)(H2O)(3)]'2H(2)O (1), Cu (theo)(2)bpy(H2O)'4H(2)O (2), Cu(theo)(2)phen(H2O)'5H(2)O (3), and [Mn(theo)(2)(H2O)(4)] (4) (Theo = theophylline; Bpy = 1,2-bipyridine; Phen = 1,10-phenanthroline). The compounds were characterized by Single Crystal X-ray diffraction (SC-XRD), UV-Vis diffuse reflectance spectroscopy (UV-Vis-DRS), Fourier-transform infrared spectroscopy (FT-IR) and Thermogravimetry-Differential Scanning Calorimetry (TGA-DSC). Based on crystal data, copper(II) and manganese(II) complexes exhibited square pyramidal and octahedral configurations, respectively. The complexes were assessed for anticancer activity against a panel of cell lines, representing breast-, lung-, colorectal-, and pancreatic cancer, as well glioblastoma and neuroblastoma; cancers of the central nervous system. Cu(theo)(2)phen(H2O)'5H(2)O (complex 3) showed superior and broad spectrum antitumor activity compared to complexes 1, 2 and 4. The IC50 values of complex 3 ranged between 1.5 and 5 mu M making it a promising lead compound. Complex 3 showed similar or better activity to doxorubicin on the panel of cell lines evaluated. An evaluation of the ligands, 1,2-theophylline and 1,10-phenanthroline showed that theophylline did not contribute to the cytotoxic effect of the complexes. In contrast, 1,10-phenanthroline showed poor cytotoxic activity at a concentration of 5 mu M but caused significant cytotoxicity at 50 mu M. Preliminary analysis of the effect of the complexes on cell morphology indicates the absence of necrotic cell death. Formation of cytoplasmic vacuoles, indicative of paraptosis was commonly observed. Complex 3 decreased the binding of Hoechst 33342 to some cells and changed the appearance of the nuclei. Molecular modelling of the complex supports the notion that the complex is able to bind to DNA. The formation of apoptotic nuclei was observed for all cell lines, whilst overt apoptosis was evident in the glioblastoma cell line. The data presented here indicates that complex 3 is worthy of further evaluation as a potential anticancer agent.