Polypyridyl Ruthenium Complexes: Novel DNA-Intercalating Agents against Human Breast Tumor

João Barolli,Márcia Cominetti,Javier Ellena,Juliana Ribeiro,Fabio Miranda,Alzir Batista,Virtudes Moreno,Rodrigo Corrêa,Carlos Bloch Jr

doi:10.21577/0103-5053.20170019

Abstract

This paper describes a new series of four DNA-intercalating agents with promising anticancer activities, based on ruthenium(II) with the planar ligand dpqQX (dpqQX = dipyrido[3,2-a:2',3'-c]quinoxaline[2,3-b]quinoxaline). The complexes identified as trans-[RuCl2(dppb)(dpqQX)], cis-[RuCl2(dppb)(dpqQX)], ct-[RuCl(CO)(dppb)(dpqQX)]PF6 and ct-[RuCl2(PPh3)2(dpqQX)] (dppb = 1,4-bis(diphenylphosphine)butane and PPh3 = triphenylphosphine) were characterized by 31P{1H} nuclear magnetic resonance (NMR) and infrared spectroscopies, cyclic voltammetry, molar conductance measurements, elemental analysis, mass spectrometry and X-ray diffraction analysis for complex ct-[RuCl2(PPh3)2(dpqQX)]. Their in vitro cytotoxic activities against MDA-MB-213 and MCF-7 breast cancer cells were evaluated and compared with normal L-929 cells. Low drug concentration at which 50% of the cells are viable relative to the control (IC50) values were obtained for all four complexes compared with a reference metallodrug, cisplatin. In addition, DNA affinity studies from titrations, as well as the images obtained by atomic force microscopy (AFM) involving pBR322 plasmid DNA, suggest interactions between the metal complexes and the DNA macromolecule, in which they act as intercalating agents. The intercalation of the complexes with DNA was confirmed by viscosity measurements.

Highlights

Metal complexes containing a planar polypyridyl ligand obtained from 1,10-phenanthroline have been extensively studied in the last decades due to their DNA binding ability.1-3 ruthenium(II) complexes coordinated with phenazine and quinoxaline derivatives can bind to DNA through intermolecular forces
The purity of the complexes was confirmed by elemental analysis and 31P{1H} nuclear magnetic resonance (NMR) spectra suggesting the formation of trans-[RuCl2(dppb)(dpqQX)] [1], cis-[RuCl2(dppb)] [2], ct-[RuCl(CO)(dppb)(dpqQX)]PF6 [3] and ct-[RuCl2(PPh3)2(dpqQX)] [4] compounds
Antitumoral activity The new ruthenium complexes were submitted to cytotoxic assays to study the effects of the complexes on the viability of invasive and non-invasive human breast tumor cells, MDA-MB-231 and MCF-7, respectively, in vitro, by the MTT method

Summary

Introduction

Metal complexes containing a planar polypyridyl ligand obtained from 1,10-phenanthroline have been extensively studied in the last decades due to their DNA binding ability.1-3 ruthenium(II) complexes coordinated with phenazine and quinoxaline derivatives can bind to DNA through intermolecular forces. All complexes were characterized and their biological properties such as cytotoxicity against invasive MDA-MB 231 and non-invasive MCF-7 tumor cells lines were evaluated, including their interaction with the DNA molecule.

Results

Conclusion