Iron Complexes of Flavonoids-Antioxidant Capacity and Beyond

Kejík, Zdeněk; Kaplánek, Robert; Masařík, Michal; Babula, Petr; Matkowski, Adam; Filipenský, Petr; Veselá, Kateřina; Gburek, Jakub; Sýkora, David; Martásek, Pavel; Jakubek, Milan

doi:10.3390/ijms22020646

Cited by 68 publications

(38 citation statements)

References 141 publications

(201 reference statements)

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“…Previous studies have shown that the dietary administration of high doses of quercetin to patients suffering from neurological disorders, resulted in improvements to their cognitive functions [60]. Optimization of the necessary dose size and establishment of the critical age of the patient, at which to start kaempferol and other flavonoids supplementation for preventative therapy and/or treatment, are important issues for further investigation [61][62][63][64][65][66][67][68][69][70]. It is probable that such an optimized long-term preventive supplementation strategy may reduce the occurrence and delay the incidence of redox metal/oxidative stress-related diseases such as neurological disorders with disturbed metabolism of redox metals.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant vs. Prooxidant Properties of the Flavonoid, Kaempferol, in the Presence of Cu(II) Ions: A ROS-Scavenging Activity, Fenton Reaction and DNA Damage Study

Šimunková

Barbieriková

Jomová

et al. 2021

IJMS

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Kaempferol is a flavonoid that occurs in tea and in many vegetables and fruits, including broccoli, cabbage, beans, grapes, apples, and strawberries. The efficacy of Kaempferol has been demonstrated in the treatment of breast, esophageal, cervical, ovarian, and liver cancers and leukemia, which very likely arises from its prooxidant properties and the activation of pro-apoptotic pathways. Indeed, this matter has already been the focus of a number of published studies and reviews. The aim of the present study was to elucidate the antioxidant vs. prooxidant properties of flavonoids in the presence of the redox-active metal, copper (II) ion, by means of the Fenton reaction. The specific motivation of this work is that, since an increased level of Cu(II) ions is known to be associated with many disease states such as neurological conditions (Alzheimer’s disease) and cancer, any interaction between these ions and flavonoids might affect the outcome of therapeutic uses of the latter. The structure of the Cu-kaempferol complex in DMSO was investigated by means of low temperature EPR spectroscopy, which confirmed the existence of at least two distinct coordination environments around the copper (II) ion. UV vis-spectra of kaempferol and its Cu(II) complex in DMSO revealed an interaction between the 5-OH (A ring) group and the 4-CO (C ring) group of kaempferol with Cu(II) ions. An ABTS assay confirmed that kaempferol acted as an effective radical scavenger, and that this effect was further enhanced in the form of the Cu(II)-kaempferol complex. Quantitative EPR spin trapping experiments, using DMPO as the spin trap, confirmed suppression of the formation of a mixture of hydroxyl, superoxide, and methyl radicals, in a Fenton reaction system, upon coordination of kaempferol to the redox-active Cu(II) ions, by 80% with respect to the free Cu(II) ions. A viscometric study revealed a better DNA-intercalating ability of the Cu-kaempferol complex than for free kaempferol, essential for conferring anticancer activity of these substances. The results of the viscometric measurements were compared with those from a DNA damage study of Cu-kaempferol complexes in a Fenton reaction system, using gel electrophoresis. At low concentrations of kaempferol (Cu–kaempferol ratios of 1:1 and 1:2), a very weak protective effect on DNA was noted, whereas when kaempferol was present in excess, a significant DNA-protective effect was found. This can be explained if the weakly intercalated kaempferol molecules present at the surface of DNA provide protection against attack by ROS that originate from the Fenton reaction involving intercalated Cu(II)-kaempferol complexes. Following the application of ROS scavengers, L-histidine, DMSO, and SOD, gel electrophoresis confirmed the formation of singlet oxygen, hydroxyl radicals, and superoxide radical anions, respectively. We propose that the prooxidant properties of Cu-kaempferol complexes may provide anticancer activity of these substances. When present in excess, kaempferol displays antioxidant properties under Cu-Fenton conditions. This suggests that kaempferol might prove a suitable candidate for the prevention or treatment of oxidative stress related medical conditions that involve a disturbed metabolism of redox metals such as copper, for example, Menkes disease, and neurological disorders, including Alzheimer’s disease. For the potential use of kaempferol in clinical practice, it will be necessary to optimize the dose size and critical age of the patient so that this flavonoid may be beneficial as a preventive drug against cancer and neurological disorders.

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Section: Discussionmentioning

confidence: 99%

Antioxidant vs. Prooxidant Properties of the Flavonoid, Kaempferol, in the Presence of Cu(II) Ions: A ROS-Scavenging Activity, Fenton Reaction and DNA Damage Study

Šimunková

Barbieriková

Jomová

et al. 2021

IJMS

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“…Data on the complexation behavior of Que and Lut by Al(III) and Fe(III) ions come from several studies [ 26 , 33 , 64 , 65 ], some of which combine experimental and computational approaches [ 31 , 34 ]; others have reported the calculated structures of the complexes optimized under physiological conditions [ 51 ] while others have focused on their spectroscopic characterization [ 26 , 55 , 56 ].…”

Section: Discussionmentioning

confidence: 99%

A Review on Coordination Properties of Al(III) and Fe(III) toward Natural Antioxidant Molecules: Experimental and Theoretical Insights

et al. 2021

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This review focuses on the ability of some natural antioxidant molecules (i.e., hydroxycinnamic acids, coumarin-3-carboxylic acid, quercetin, luteolin and curcumin) to form Al(III)- and Fe(III)-complexes with the aim of evaluating the coordination properties from a combined experimental and theoretical point of view. Despite the contributions of previous studies on the chemical properties and biological activity of these metal complexes involving such natural antioxidants, further detailed relationships between the structure and properties are still required. In this context, the investigation on the coordination properties of Al(III) and Fe(III) toward these natural antioxidant molecules might deserve high interest to design water soluble molecule-based metal carriers that can improve the metal’s intake and/or its removal in living organisms.

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“…Flavonoids are also known to chelate various transition metal cations commonly encountered in cells such as iron, copper, and others and can generate ROS such as H 2 O 2 and flavonoid quinone products [ 97 , 98 ]. Halliwell and colleagues demonstrated that EGCG and other flavonoids can rapidly generate cytotoxic concentrations of H 2 O 2 in cell culture media, and it is likely that this phenomenon depends on flavonoid-metal ion complexes [ 20 , 99 ].…”

Section: Chemistry Of Flavonoids In Aqueous Solutionsmentioning

confidence: 99%

Protein Adducts and Protein Oxidation as Molecular Mechanisms of Flavonoid Bioactivity

Joyner

2021

Molecules

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There are tens of thousands of scientific papers about flavonoids and their impacts on human health. However, despite the vast amount of energy that has been put toward studying these compounds, a unified molecular mechanism that explains their bioactivity remains elusive. One contributing factor to the absence of a general mechanistic explanation of their bioactivity is the complexity of flavonoid chemistry in aqueous solutions at neutral pH. Flavonoids have acidic protons, are redox active, and frequently auto-oxidize to produce an array of degradation products including electrophilic quinones. Flavonoids are also known to interact with specificity and high affinity with a variety of proteins, and there is evidence that some of these interactions may be covalent. This review summarizes the mechanisms of flavonoid oxidation in aqueous solutions at neutral pH and proposes the formation of protein-flavonoid adducts or flavonoid-induced protein oxidation as putative mechanisms of flavonoid bioactivity in cells. Nucleophilic residues in proteins may be able to form covalent bonds with flavonoid quinones; alternatively, specific amino acid residues such as cysteine, methionine, or tyrosine in proteins could be oxidized by flavonoids. In either case, these protein-flavonoid interactions would likely occur at specific binding sites and the formation of these types of products could effectively explain how flavonoids modify proteins in cells to induce downstream biochemical and cellular changes.

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Iron Complexes of Flavonoids-Antioxidant Capacity and Beyond

Cited by 68 publications

References 141 publications

Antioxidant vs. Prooxidant Properties of the Flavonoid, Kaempferol, in the Presence of Cu(II) Ions: A ROS-Scavenging Activity, Fenton Reaction and DNA Damage Study

Antioxidant vs. Prooxidant Properties of the Flavonoid, Kaempferol, in the Presence of Cu(II) Ions: A ROS-Scavenging Activity, Fenton Reaction and DNA Damage Study

A Review on Coordination Properties of Al(III) and Fe(III) toward Natural Antioxidant Molecules: Experimental and Theoretical Insights

Protein Adducts and Protein Oxidation as Molecular Mechanisms of Flavonoid Bioactivity

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