Cobalt intoxication can occur after its release from metal-based prostheses, which is generally clinically severe. Therefore, there is a need for the development of a cobalt chelator since there are currently no approved drugs for cobalt intoxication. As flavonoids are known for their metal chelating properties and safety, the screening of cobalt chelating properties was performed in a total of 23 flavonoids by our recently developed new spectrophotometric assay. Further assessment of positive or negative consequences of cobalt chelation was performed both in vitro and ex vivo. Six and thirteen flavonoids significantly chelated cobalt ions at pH 7.5 and 6.8, respectively. Baicalein demonstrated a significant activity even at pH 5.5; however, none of the flavonoids showed chelation at pH 4.5. In general, baicalein and 3-hydroxyflavone were the most active. They also mildly decreased the cobalt-triggered Fenton reaction, but baicalein toxicity toward red blood cells was strongly increased by the addition of cobalt. Quercetin, tested as an example of flavonoid unable to chelate cobalt ions significantly, stimulated both the cobalt-based Fenton reaction and the lysis of erythrocytes in the presence of cobalt. Therefore, 3-hydroxyflavone can serve as a potential template for the development of novel cobalt chelators.

• Publication type
• Journal Article MeSH

Data on alkaloid interactions with the physiologically important transition metals, iron and copper, are mostly lacking in the literature. However, these interactions can have important consequences in the treatment of both Alzheimer's disease and cancer. As isoquinoline alkaloids include galanthamine, an approved drug for Alzheimer's disease, as well as some potentially useful compounds with cytostatic potential, 28 members from this category of alkaloids were selected for a complex screening of interactions with iron and copper at four pathophysiologically relevant pH and in non-buffered conditions (dimethyl sulfoxide) by spectrophotometric methods in vitro. With the exception of the salts, all the alkaloids were able to chelate ferrous and ferric ions in non-buffered conditions, but only five of them (galanthine, glaucine, corydine, corydaline and tetrahydropalmatine) evoked some significant chelation at pH 7.5 and only the first two were also active at pH 6.8. By contrast, none of the tested alkaloids chelated cuprous or cupric ions. All the alkaloids, with the exception of the protopines, significantly reduced the ferric and cupric ions, with stronger effects on the latter. These effects were mostly dependent on the number of free aromatic hydroxyls, but not other hydroxyl groups. The most potent reductant was boldine. As most of the alkaloids chelated and reduced the ferric ions, additional experimental studies are needed to elucidate the biological relevance of these results, as chelation is expected to block reactive oxygen species formation, while reduction could have the opposite effect.

• Keywords
• alkaloid, chelation, copper, iron, reduction,
• MeSH
• Alzheimer Disease * MeSH
• Chelating Agents chemistry   MeSH
• Cytostatic Agents * MeSH
• Dimethyl Sulfoxide MeSH
• Galantamine MeSH
• Hydroxyl Radical MeSH
• Isoquinolines pharmacology   MeSH
• Humans MeSH
• Copper chemistry   MeSH
• Reactive Oxygen Species MeSH
• Reducing Agents MeSH
• Salts MeSH
• Iron chemistry   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Chelating Agents MeSH
• Cytostatic Agents * MeSH
• Dimethyl Sulfoxide MeSH
• Galantamine MeSH
• Hydroxyl Radical MeSH
• Isoquinolines MeSH
• Copper MeSH
• Reactive Oxygen Species MeSH
• Reducing Agents MeSH
• Salts MeSH
• Iron MeSH

Flavonoids are common plant natural products able to suppress ROS-related damage and alleviate oxidative stress. One of key mechanisms, involved in this phenomenon is chelation of transition metal ions. From a physiological perspective, iron is the most significant transition metal, because of its abundance in living organisms and ubiquitous involvement in redox processes. The chemical, pharmaceutical, and biological properties of flavonoids can be significantly affected by their interaction with transition metal ions, mainly iron. In this review, we explain the interaction of various flavonoid structures with Fe(II) and Fe(III) ions and critically discuss the influence of chelated ions on the flavonoid biochemical properties. In addition, specific biological effects of their iron metallocomplexes, such as the inhibition of iron-containing enzymes, have been included in this review.

• Keywords
• flavonoids, iron ions, metallocomplexes,
• MeSH
• Antioxidants chemistry   pharmacology   MeSH
• Chelating Agents chemistry   pharmacology   MeSH
• Flavonoids chemistry   MeSH
• Heme chemistry   MeSH
• Ions chemistry   metabolism   MeSH
• Coordination Complexes chemistry   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Protein Binding MeSH
• Structure-Activity Relationship MeSH
• Iron chemistry   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Antioxidants MeSH
• Chelating Agents MeSH
• Flavonoids MeSH
• Heme MeSH
• Ions MeSH
• Coordination Complexes MeSH
• Iron MeSH

Interaction of flavonoids with transition metals can be partially responsible for their impact on humans. Stoichiometry of the iron/copper complex with a flavonoid glycoside isoquercitrin, a frequent component of food supplements, was assessed using competitive and non-competitive methods in four (patho)physiologically-relevant pH values (4.5. 5.5, 6.8, and 7.5). Isoquercitrin chelated all tested ions (Fe2+, Fe3+, Cu2+, and Cu⁺) but its affinity for Cu⁺ ions proved to be very low. In general, the chelation potency dropped with pH lowering. Metal complexes of 1:1 stoichiometry were mostly formed, however, they were not stable and the stoichiometry changed depending on conditions. Isoquercitrin was able to reduce both Cu2+ and Fe3+ ions at low ratios, but its reducing potential was diminished at higher ratios (isoquercitrin to metal) due to the metal chelation. In conclusion, this study emphasizes the need of using multiple different methods for the assessment of chelation potential in moderately-active metal chelators, like flavonoids.

• Keywords
• Job’s method, chelator, copper, iron, quercetin-3-O-β-glucopyranoside, reduction, stoichiometry,
• MeSH
• Chelating Agents chemistry   MeSH
• Flavonoids chemistry   MeSH
• Hydrogen-Ion Concentration MeSH
• Copper chemistry   MeSH
• Quercetin analogs & derivatives   chemistry   MeSH
• Iron chemistry   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Chelating Agents MeSH
• Flavonoids MeSH
• isoquercitrin MeSH Browser
• Copper MeSH
• Quercetin MeSH
• Iron MeSH

OBJECTIVES: Rutin, quercetin-3-O-rutinoside, a natural flavonol glycoside, has shown various in vitro benefits with potential use treating human diseases, especially cardiovascular system disorders. Antioxidant properties are assumed to underlie the majority of these benefits. Yet rutin pro-oxidant properties have been reported as well. Our research group has recently shown aggravating effects on isoprenaline (ISO)-induced cardiotoxicity in Wistar:Han rats after 24 hours. METHODS: This study was designed to examine in more detail the reasons for the negative effects of rutin (11.5 and 46 mg/kg, i.v.) after administration of ISO (100 mg/kg, s.c.) in rats within 2 hours of continuous experiment and in the H9c2 cardiomyoblast-derived cell line. RESULTS: Like our previous findings, rutin did not (11.5 or 46 mg/kg, i.v.) reduce the ISO-induced mortality within 2 hours although the lower dose significantly reduced cardiac troponin T (cTnT) and partly improved the histological findings. In contrast, the higher dose increased the mortality in comparison with solvent (1.26% w/v sodium bicarbonate). This was not caused by any specific haemodynamic disturbances. It appears to be associated with oxidative stress as rutin enhanced intracellular reactive oxygen species formation in vitro and had the tendency to increase it in vivo. CONCLUSIONS: Rutin, likely due to its pro-oxidative effects, can exacerbate catecholamine cardiotoxicity depending on the dose used.

• Keywords
• Catecholamine, Flavonoid, H9c2 cell line, Isoprenaline, Reactive oxygen species, Rutin, Wistar rat,
• MeSH
• Cell Line MeSH
• Dinoprost analogs & derivatives   blood   MeSH
• Electrocardiography MeSH
• Glutathione blood   MeSH
• Injections, Intravenous MeSH
• Isoproterenol adverse effects   MeSH
• Kaplan-Meier Estimate MeSH
• Cardiotoxicity etiology   mortality   MeSH
• Myocardium pathology   MeSH
• Rats, Wistar MeSH
• Reactive Oxygen Species metabolism   MeSH
• Rutin administration & dosage   adverse effects   pharmacokinetics   MeSH
• Heart drug effects   MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 8-epi-prostaglandin F2alpha MeSH Browser
• Dinoprost MeSH
• Glutathione MeSH
• Isoproterenol MeSH
• Reactive Oxygen Species MeSH
• Rutin MeSH

Isoflavones are commonly consumed in many Asian countries and have potentially positive effects on human being. Only a few and rather controversial data on their interactions with copper and iron are available to date. 13 structurally related isoflavones were tested in the competitive manner for their Cu/Fe-chelating/reducing properties. Notwithstanding the 5-hydroxy-4-keto chelation site was associated with ferric, ferrous, and cupric chelation, the chelation potential of isoflavones was low and no cuprous chelation was observed. None of isoflavones was able to substantially reduce ferric ions, but the vast majority reduced cupric ions. The most important feature for cupric reduction was the presence of an unsubstituted 4'-hydroxyl; contrarily the presence of a free 5-hydroxyl decreased or abolished the reduction due to chelation of cupric ions. The results from this study may enable additional experiments which might clarify the effects of isoflavones on human being and/or mechanisms of copper absorption.

• MeSH
• Isoflavones metabolism   MeSH
• Humans MeSH
• Copper metabolism   MeSH
• In Vitro Techniques MeSH
• Iron metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Isoflavones MeSH
• Copper MeSH
• Iron MeSH