A Switch between Antioxidant and Prooxidant Properties of the Phenolic Compounds Myricetin, Morin, 3',4'-Dihydroxyflavone, Taxifolin and 4-Hydroxy-Coumarin in the Presence of Copper(II) Ions: A Spectroscopic, Absorption Titration and DNA Damage Study.

Klaudia Jomová,Peter Lauro,Marian Valko,Ibrahim M Alhazza,Saleh H Alwasel,Lenka Hudecova,Miriama Simunkova

doi:10.3390/molecules24234335

Abstract

The beneficial effects of polyphenols, predominantly in the context of oxidative stress-related diseases such as cancer, cardiovascular diseases and neurological conditions including Alzheimer’s and Parkinson’s diseases, have been documented by a number of papers and reviews. The antioxidant/prooxidant properties of phenolic compounds are related mainly to the number and positions of hydroxyl groups and to their redox metal (Cu, Fe) chelating capacity. In this work we studied structurally distinct phenolic molecules such as myricetin, morin, 3′,4′-dihydroxy-flavone, taxifolin and 4-hydroxycoumarin, either alone or as interacting with Cu2+ ions. EPR and UV-Vis spectroscopy confirmed that the effective binding of cupric ions to phenolic compounds requires the presence of the 3-OH and 4-CO groups on the flavonoid C ring and unsaturated C2-C3 bond of the C-ring, which permits through-conjugation with the B-ring. An ABTS assay revealed that radical scavenging activities of phenolic compounds are related to their number of hydroxyl groups, planarity of the molecular skeleton, extent of delocalization and they decrease in the order: myricetin > morin > 3′,4′-dihydroxyflavone ~ 4-hydroxy coumarin > taxifolin. Absorption titrations indicate that copper ions can modulate the DNA binding affinity of flavonoids via the formation of their Cu-chelates. Gel electrophoresis measurements indicated that the protective effect of the phenolic compounds decreases in the order: 3′,4′-dihydroxyflavone > 4-OH coumarin > morin > taxifolin ~ myricetin. This can be explained by the fact that myricetin, taxifolin and morin form stable Cu(II) complexes capable of causing DNA damage via interaction with DNA and ROS formation via the Fenton reaction. Application of ROS scavengers revealed the formation of singlet oxygen, superoxide and hydroxyl radicals and their concerted synergistic effect on the DNA. The overall results suggest that the most pronounced DNA damage has been observed for flavonoids containing higher number of hydroxyl groups (including 3-OH group of the C ring), such as myricetin (six hydroxyl groups), morin and taxifolin (five hydroxyl groups) in the presence of Cu(II) ions. The proposed mechanism of action by which Cu(II) complexes of myricetin, morin and taxifolin interact with DNA predispose these substances to act as potential anticancer agents. The anticancer activity of phenolic compounds can be explained by their moderate prooxidant properties, which can boost ROS formation and kill cancer cells. Alternatively, slight prooxidant properties may activate antioxidant systems, including antioxidant enzymes and low molecular antioxidants such as glutathione and thus act as preventive anticancer agents.

Highlights

OwingOwing to to their their potential potential beneficial beneficial health health effects, effects, polyphenolic polyphenolic compounds compounds have have attracted attracted significant significant attention attention during during the the past past two two decades decades [1].Nature is is the the flavonoids.flavonoids
The results further indicate that the tight interaction between phenolic compounds and cupric ions via the 3-OH and 4-CO groups is only achieved if the unsaturated C2-C3 bond of the
We propose that the formation of dimeric or even polymeric species of cupric ions (Cu):myricetin complex, as documented by the EPR spectroscopic measurements and hyperchromism observed in the absorption titrations, point to the complex mechanism of action of the Cu(myricetin)2 complex causing significant DNA damage

Summary

Introduction

OwingOwing to to their their potential potential beneficial beneficial health health effects, effects, polyphenolic polyphenolic compounds compounds have have attracted attracted significant significant attention attention during during the the past past two two decades decades [1].Nature is is the the flavonoids.flavonoids. Owing to to their their potential potential beneficial beneficial health health effects, effects, polyphenolic polyphenolic compounds compounds have have attracted attracted significant significant attention attention during during the the past past two two decades decades [1]. Flavonoid biosynthesis biosynthesis is is stimulated stimulated by by light light and and these compounds accumulate mainly in the peel and bark of plants, and in their seeds these compounds accumulate mainly in the peel and bark of plants, and in their seeds and and flowers. The primary function of flavonoids is to to provide provide protection protection against against reactive reactive oxygen oxygen species species (ROS). The. The beneficial beneficial health health effects effects of of flavonoids flavonoids have have been been associated associated with with their their ability ability to to prevent prevent oxidative damage to toliving livingorganisms, organisms,caused caused.

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