New platinum(II) and palladium(II) complexes with substituted terpyridine ligands: synthesis and characterization, cytotoxicity and reactivity towards biomolecules

A series of palladium(II) (1-3) and platinum(II) chloride complexes (4 and 5) with 2,2:6,2-terpyridine (terpy) derivatives substituted at the 4 position, was synthesized and fully characterized. Single crystal X-ray diffraction analysis of complexes 2, 3 and 5 showed tridentate coordination of the 4-substituted terpyridine (terpy) ligands to the metal center. Moreover, in vitro cytotoxic activity of these complexes toward a panel of human cancer cell lines (lung cancer A549, colorectal cancer HCT116, ovarian cancer IGROV-1) and toward normal cell line HDF (dermal fibroblast) was determined by Trypan Blue exclusion assay. Overall, the tested compounds manifested a relevant cytotoxicity for the selected cancer cell lines with complex 4 also showing a modest cytotoxicity on the normal cell lines. To better understand the mode of action of these metal complexes, their reactivity with three model proteins, i.e. hen egg white lysozyme (HEWL), cytochrome c (cyt c) and ribonuclease A (RNase A) were comparatively investigated through ESI-MS analysis. The results highlighted a different behavior between the two series of complexes being platinum compounds more reactive toward RNase and cyt c than palladium compounds. Based on the obtained results, it is proposed that in presence of RNase A and cyt c, the platinum complexes undergo activation through release of labile ligands followed by binding to the protein. In contrast, palladium complexes revealed a far lower reactivity implying the likely occurrence of a different mechanism of action.