Mixed Ternary Mononuclear Copper(II) Complexes Based on Valproic Acid with 1,10-Phenanthroline and 2,2’-Bipyridine Ligands: DNA Interaction and Cytotoxicity in V79 Cells

Claus Pich,Miriana Machado,Mariana Roesch-Ely,Iuri De Oliveira,João Henriques,Sidnei Moura,Nour Ghermani,Françoise Dumas,Marilda Chiarello,Bárbara Soares,Hernan Terenzi,Tatiana Fortunato,Paulo Dos Santos

doi:10.21577/0103-5053.20180229

Abstract

This paper reports the DNA interaction and cytotoxicity of binary and ternary copper(II) complexes of valproic acid with phenanthroline or bipyridine and the complementary characterization of Cu(Valp)2Bipy by crystallography. Circular dichroism, plasmid and oligonucleotide assays have shown that the complexes interact with DNA in different manners and are able to cleave plasmid DNA and oligonucleotides at concentrations from 10 to 1000 mol L-1. The plasmid DNA cleavage is enhanced 650, 375 and 285 times by photo activation with UVB light for the complexes Cu(Valp)2Phen, Cu(Valp)2Bipy and Cu2(Valp)4, respectively. Cytotoxicity assays demonstrated that V79 cells were more sensitive to CuII derivatives than sodium valproate as evaluated by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) and clonogenic assays, where the cytotoxic profile of the compounds was: Cu(Valp)2Phen higher than Cu(Valp)2Bipy, higher than Cu2(Valp)4. Therefore, we report two copper complexes, which interact with DNA and promote its cleavage, leading to an enhanced cytotoxicity when compared to valproic acid.

Highlights

The research on metals coordinated with organic molecules regularly used as drugs has increased in latestMixed Ternary Mononuclear Copper(II) Complexes Based on Valproic AcidJ
Searching for new active and secure drugs, this study aims the characterization of deoxyribonucleic acid (DNA) interaction ability of the three valproic acid (VPA) related complexes, their nuclease activity and the cytotoxicity in mammalian cells in vitro as preliminary studies for the development of a new series of molecules
The VPA used in seizure, bipolar disorder and migraine headaches therapy has been reported in the last years as a drug candidate to be used in cancer therapy, alone or as an adjuvant

Summary

Introduction

The research on metals coordinated with organic molecules regularly used as drugs has increased in latestMixed Ternary Mononuclear Copper(II) Complexes Based on Valproic AcidJ. Mixed Ternary Mononuclear Copper(II) Complexes Based on Valproic Acid For this purpose, transition metal ions are some of the most important ions due to their role in various pathways as catalytic centers in enzymes and transition metal complexes, especially iron and copper. Transition metal ions are some of the most important ions due to their role in various pathways as catalytic centers in enzymes and transition metal complexes, especially iron and copper In their reduced oxidation state, transition metal ions can promote the formation of free radicals through Haber-Weiss or Fenton reactions.[5] The copper(II) is a Lewis acid and is one of the metals acting as an essential trace element involved in cellular respiration, antioxidant defense, neurotransmission, connective tissue biosynthesis and cellular iron metabolism.[6,7] Copper-based complexes have been investigated on the assumption that endogenous metals may be less toxic for normal cells than for cancer cells. The redox activity and affinity for binding sites that should be occupied by other metals makes copper to be toxic in some situations.[8]

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