Theoretical and experimental study of gold(III), palladium(II), and platinum (II) complexes with 3-((4-nitrophenyl)thio)phenylcyanamide and 2,2′-bipyridine ligands: cytotoxic activity and interaction with 9-methylguanine

Abstract The new gold(III), palladium(II), and platinum(II) complexes with 3-((4-nitrophenyl)thio)phenylcyanamide (HL) and 2,2′-bipyridine (bpy) ligands of formula [M(bpy)LCl] (M = Pd(II),1, Pt(II), 2) or [Au(bpy)LCl]Cl, 3, have been synthesized and fully characterized. The cytotoxicity of free ligands and complexes 1-3 were evaluated against HT-29 (colorectal adenocarcinoma), MCF-7 (breast), and HeLa (human squamous cervical adenocarcinoma) cancer cell lines along with MRC-5 non-tumorigenic cells (human lung fibroblasts) and their activity has been compared to the familiar platinum-based anticancer agent cisplatin. The free ligands bpy and HL were ineffective against the cancer cell lines. However, the complexes 1-3 showed a significant in vitro antitumor activity with IC50 values in the low micromolar. The complexes 1-3 were revealed to produce cellular reactive oxygen species (ROS). The most potent ROS producer, complex 3, also elicited the highest cytotoxicity. The interaction of 9-methylguanine (9-MeG-N7) with complexes 1-3 was studied by 1H NMR and mass spectroscopy. Furthermore, DFT calculations have been performed on complexes 1-3 and also [M(bpy)(L)(9-MeG-N7)](NO3)(M = Pd(II), 4, Pt(II), 5) or [Au(bpy)(L)(9-MeG-N7)](NO3)2, 6, using the BP86-D and B3LYP* functionals to provide a complete rationalization of their structures and to describe their electronic structures. The energy decomposition analysis (EDA) gave a clear understanding of the bonding for all complexes 1-6 showing that the interactions are mostly governed by electrostatic ones. Strong interactions occurred between the chlorine anion and the metallic fragment, but weakened between 9-methylguanine and the metallic fragment, in agreement with the electron transfers and the interaction energies.