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.