Ruthenium(II) Complexes Containing Anti-Inflammatory Drugs as Ligands: Synthesis, Characterization andin vitroCytotoxicity Activities on Cancer Cell Lines

Junai C S Lopes,Norberto P Lopes,Marcos Pivatto,Denise C Tavares,Jaqueline L Damasceno,Alzir A Batista,Adriana P M Guedes,Victor M Deflon,Pollyanna F Oliveira,Gustavo Von Poelhsitz,Pedro I S Maia

doi:10.5935/0103-5053.20150161

Abstract

The synthesis, characterization and cytotoxic activity of cis-[Ru(dicl)(dppm)2]PF6 and cis-[Ru(ibu)(dppm)2]PF6, (dppm = 1,1-bis(diphenylphosphine)methane; dicl = diclofenac anion and ibu = ibuprofen anion), are described in this work. Complexes were characterized by elemental analysis, Fourier transform infrared spectroscopy (FTIR), UV-Vis, 31P{1H} nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRESIMS). X-ray structure of cis-[Ru(ibu)(dppm)2]PF6 is also described. Preliminary calf thymus DNA (ct-DNA) binding studies were carried out by UV-Vis and viscosity experiments, with results suggesting the existence of electrostatic interactions between ruthenium complexes and ct-DNA. Cytotoxicity assays were carried out on a panel of human cancer cell lines and a human normal cell line. Complexes displayed a high to moderate cytotoxicity with IC50 ranging from 5 to 47 µmol L-1. cis-[Ru(ibu) (dppm)2]PF6 was found to be the most active, with IC50 values lower than cisplatin. The degree of cytotoxicity was maintained for the normal cell line, although cis-[Ru(ibu)(dppm)2]PF6 exhibited a similar selectivity to that of cisplatin but with a higher activity for at least two tumor cell lines which evidences a promising anticancer candidate and selects this complex for further experiments.

Highlights

The disseminated use of cisplatin and other platinum based metallodrugs as chemotherapeutic agents against ovarian, bladder and testicular cancers, among others, is still a key aspect for the development of the medicinal inorganic chemistry.[1,2,3,4,5,6] In the search for coordination compounds which are active against tumors and less toxic than cisplatin, ruthenium compounds emerge as the most promisingVol 26, No 9, 2015 NH Cl Cl O N Cl RuIII Cl S CH3 CH3 HN NH Cl HN NH N Cl RuI II
The spectroscopic analyses are in agreement with a chelated coordination through the carboxylate group, for the diclofenac and ibuprofen ligands
Viscosity experiments suggest an electrostatic interaction between calf thymus DNA (ct-DNA) and complexes 1 and 2

Summary

Introduction

A previous work from our group presented biological results from the diphosphinic ruthenium(II) precursor cis-[RuCl2(dppm)2] and its derivative with 2-pyridinecarboxylic acid anion (pic−), the complex [Ru(pic)(dppm)2]PF6, where the pic− ligand coordinates on N,O-bidentate mode. The reaction of sodium salts of diclofenac and ibuprofen with the ruthenium(II) diphosphine precursor complex cis[RuCl2(dppm)2] resulted in the products 1 and 2 by chlorido exchange under mild conditions as showed in Scheme 1.

Results

Conclusion