Insights into the binding of half-sandwich phosphino Ir(III) and Ru(II) complexes to deoxyribonucleic acid, albumin and apo-transferrin: Experimental and theoretical investigation

Abstract

A group of cytotoxic half-sandwich iridium(III) (Ir(η5-Cp*)Cl2PPh2CH2OH (IrPOH)), (Ir(η5-Cp*)Cl2P(p-OCH3Ph)2CH2OH (IrMPOH)), and ruthenium(II) (Ru(η6-p-cymene)Cl2PPh2CH2OH (RuPOH), Ru(η6-p-cymene)Cl2P(p-OCH3Ph)2CH2OH (RuMPOH)) complexes with phosphine ligands exhibit the ability to (i) slow hydrolysis which is reversed by adding a high NaCl concentration; (ii) oxidation of NADH to NAD+; (iii) induction of cytotoxicity towards various cancer cell lines. Furthermore, we found that RuPOH and RuMPOH selectively inhibit the proliferation of skin cancer cells (WM266-4) while Ir(III) complexes were found to be moderate against prostate cancer cells (DU-145). Herein, to elucidate the cytotoxic effects, we investigated the interaction of these complexes with DNA and serum proteins by gel electrophoresis, fluorescence spectroscopy, and molecular docking studies. Fluorescence spectroscopic data (calf thymus DNA: CT-DNA titration), together with analysis of DNA fragmentation (gel electrophoresis) and molecular docking provided evidence for the multimodal interaction of Ir(III) and Ru(III) complexes with DNA with predominance of intercalation and minor groove binding. All examined complexes caused single-stranded cleavage of the sugar–phosphate backbone of plasmid DNA. The affinity of the complexes for apo-transferrin (apo-Tf) and human serum albumin (HSA) was evaluated by fluorescence emission spectroscopy to calculate the binding constants which suggested a tight and reversible binding. Moreover, ruthenium complexes can mimic the binding of iron compounds to specific biomolecules such as albumin and transferrin better than iridium complexes. In silico study indicate that complexes mostly bind to (i) apo-Tf with a preference for a single binding site and/or (ii) to dock within all the four predicted binding sites of HSA with the predominance of site I which include tryptophan residues of HSA. This class of ruthenium(II) and iridium(III) complexes has unusual features worthy of further exploration in the design of novel anticancer drugs.