Platinum(II) coordination compounds with 4'-pyridyl functionalized 2,2':6',2″-terpyridines as an alternative to enhanced chemotherapy efficacy and reduced side-effects

Abstract

Two platinum(II) coordination compounds, [PtCl(4'-R¹-terpy)](SO₃CF₃) (1) and [PtCl(4'-R²-terpy)](SO₃CF₃) (2), with 4'-(2-pyridyl)-2,2':6',2″-terpyridine (4'-R¹-terpy) or 4'-(3-pyridyl)-2,2':6',2″-terpyridine (4'-R²-terpy) were synthesized and the impact of the pendant pyridyl ring on the structure and cytotoxic activity of Pt(II)-terpyridine complexes was explored. The single-crystal X-ray diffraction analysis confirmed square planar coordination of the cations [PtCl(4'-Rⁿ-terpy)]⁺. The mode of binding of 1 and 2 to calf thymus DNA was examined by UV-Vis absorption titration, ethidium displacement assay and reaction with 9-ethylguanine, and the mixed covalent-intercalative mode was demonstrated. The cytotoxicity of the Pt(II) complexes against six cancer cell lines and three normal ones was determined using MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay and compared to cisplatin. The IC₅₀ values for the compound 2 towards the cancer cell lines are in the low micromolar range. Most remarkably, 2 was over 4 times more effective than 1 and cisplatin against non-small lung adenocarcinoma (A549), and its selectivity index was ~60-80 times higher than that for 1 and cisplatin. The mechanisms underlying the loss of viability under treatment of 2 was further investigated including F-actin staining, mitotic index analysis, cytometric cell cycle analysis, Fluorescein isothiocyanate (FITC) -conjugated Annexin V antibody and propidium iodide (PI) staining, measurements of reactive oxygen species (ROS) in cells, analysis of changes in the mitochondrial mass and potential and quantitative real time polymerase chain reaction (qRT-PCR) genes analysis. The compound 2 was found to have a pro-oxidative effect by strong stimulation of cells for the production of reactive oxygen species and cytostatic effect through cell cycle arrest.

Keywords: 4′-functionalized 2,2′:6′,2″-terpyridines; Apoptosis; Cytotoxicity; DNA-binding; Platinum(II) complexes; qRT-PCR.