Exploring heterometallic bridged Pt(II)-Zn(II) complexes as potential antitumor agents

Abstract

The four novel complexes [{cis-PtCl(NH₃)₂(μ-4,4'-bipyridyl)ZnCl(terpy)}](ClO₄)₂ (C1), [{trans-PtCl(NH₃)₂(μ-4,4'-bipyridyl)ZnCl(terpy)}](ClO₄)₂ (C2), [{cis-PtCl(NH₃)₂(μ-pyrazine)ZnCl(terpy)}](ClO₄)₂ (C3) and [{trans-PtCl(NH₃)₂(μ-pyrazine)ZnCl(terpy)}](ClO₄)₂ (C4) (where terpy = 2,2':6',2''-terpyridine) were synthesized and characterized. Acid-base titrations and concentration dependent kinetic measurements for the reactions with biologically relevant ligands such as guanosine-5'-monophosphate (5'-GMP), inosine-5'-monophosphate (5'-IMP) and glutathione (GSH), were studied at pH 7.4 and 37 °C. The binding of the heterometallic bridged cis- or trans-Pt(II)-Zn(II) complexes to calf thymus DNA (CT-DNA) was studied by UV absorption and fluorescence emission spectroscopy and molecular docking. The results indicated that the complexes bind strongly to DNA, through groove binding, hydrogen bonds, and hydrophobic or electrostatic interaction. The possible in vitro DNA protective effect of cis- and trans-Pt-L-Zn complexes has shown that C3 had significant dose-dependent DNA-protective effect and the same ability to inhibit peroxyl as well as hydroxyl radicals. Antiproliferative effect of the complexes, mRNA expression of apoptosis and repair-related genes after treatment in cancer cells indicated that newly synthesized C2 exhibited highly selective cytotoxicity toward colon carcinoma HCT116 cells. Only treatment with trans analog C2 induced effect similar to the typical DNA damaging agent such as cisplatin, characterized by p53 mediated cell response, cell cycle arrest and certain induction of apoptotic related genes. Both cis- and trans-isomers C1 and C2 showed potency to elicit expression of PARP1 mRNA and in vitro DNA binding.

Keywords: Antitumor agents; Heterometallic complexes; Structure-reactivity correlation.