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

2,3-Dehydrosilybin (DHS) was previously shown to chelate and reduce both copper and iron ions. In this study, similar experiments with 2,3-dehydrosilychristin (DHSCH) showed that this congener of DHS also chelates and reduces both metals. Statistical analysis pointed to some differences between both compounds: in general, DHS appeared to be a more potent iron and copper chelator, and a copper reducing agent under acidic conditions, while DHSCH was a more potent copper reducing agent under neutral conditions. In the next step, both DHS and DHSCH were tested for metal-based Fenton chemistry in vitro using HPLC with coulometric detection. Neither of these compounds were able to block the iron-based Fenton reaction and, in addition, they mostly intensified hydroxyl radical production. In the copper-based Fenton reaction, the effect of DHSCH was again prooxidant or neutral, while the effect of DHS was profoundly condition-dependent. DHS was even able to attenuate the reaction under some conditions. Interestingly, both compounds were strongly protective against the copper-triggered lysis of red blood cells, with DHSCH being more potent. The results from this study indicated that, notwithstanding the prooxidative effects of both dehydroflavonolignans, their in vivo effect could be protective.

• Keywords
• copper, dehydroflavonolignans, dehydrosilybin, dehydrosilychristin, flavonolignans, hydroxyl radical, iron, milk thistle, prooxidation, silymarin,
• Publication type
• Journal Article 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

Iron and copper release participates in the myocardial injury under ischemic conditions and hence protection might be achieved by iron chelators. Data on copper chelation are, however, sparse. The effect of the clinically used copper chelator D-penicillamine in the catecholamine model of acute myocardial injury was tested in cardiomyoblast cell line H9c2 and in Wistar Han rats. D-Penicillamine had a protective effect against catecholamine-induced injury both in vitro and in vivo. It protected H9c2 cells against the catecholamine-induced viability loss in a dose-dependent manner. In animals, both intravenous D-penicillamine doses of 11 (low) and 44 mg/kg (high) decreased the mortality caused by s.c. isoprenaline (100 mg/kg) from 36% to 14% and 22%, respectively. However, whereas the low D-penicillamine dose decreased the release of cardiac troponin T (specific marker of myocardial injury), the high dose resulted in an increase. Interestingly, the high dose led to a marked elevation in plasma vitamin C. This might be related to potentiation of oxidative stress, as suggested by additional in vitro experiments with D-penicillamine (iron reduction and the Fenton reaction). In conclusion, D-penicillamine has protective potential against catecholamine-induced cardiotoxicity; however the optimal dose selection seems to be crucial for further application.

• MeSH
• Cell Line MeSH
• Iron Chelating Agents pharmacology   MeSH
• Deferoxamine pharmacology   MeSH
• Ions MeSH
• Cardiotonic Agents chemistry   pharmacology   MeSH
• Catecholamines MeSH
• Hydrogen-Ion Concentration MeSH
• Myocardium pathology   MeSH
• Penicillamine chemistry   pharmacology   MeSH
• Rats, Wistar MeSH
• Troponin T metabolism   MeSH
• Cell Survival drug effects   MeSH
• Iron metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Iron Chelating Agents MeSH
• Deferoxamine MeSH
• Ions MeSH
• Cardiotonic Agents MeSH
• Catecholamines MeSH
• Penicillamine MeSH
• Troponin T MeSH
• Iron MeSH

OBJECTIVES: This study is an extension to our finding of direct anti-oxidant activities of lanthanide(III) complexes with the heterocyclic compound, 5-aminoorotic acid (AOA). In this experiment, we used AOA and coumarin-3-carboxylic acid as the two heterocyclic compounds with anti-oxidant potential, to produce the complexes with different lanthanides. METHODS: Lanthanide(III) complexes were tested on the iron-driven Fenton reaction. The product of this reaction, the hydroxyl radical, was detected by HPLC. RESULTS: All complexes as well as their ligands had positive or neutral effect on the Fenton reaction but their behavior was different. Both pure ligands in low concentration ratio to iron were inefficient in contrast to some of their complexes. Complexes of neodymium, samarium, gadolinium, and partly of cerium blocked the Fenton reaction at very low ratios (in relation to iron) but the effect disappeared at higher ratios. In contrast, lanthanum complexes appeared to be the most promising. Both blocked the Fenton reaction in a dose-dependent manner. CONCLUSION: Lanthanide(III) complexes were proven to block the iron-driven production of the hydroxyl radical. Second, the lanthanide(III) element appears to be crucial for the anti-oxidant effect. Overall, lanthanum complexes may be promising direct anti-oxidants for future testing.

• Keywords
• 5-Aminoorotic acid, Anti-oxidant, Coumarin-3-carboxylic acid, Iron, Lanthanide(III),
• MeSH
• Antioxidants MeSH
• Coumarins chemistry   MeSH
• Orotic Acid analogs & derivatives   chemistry   MeSH
• Lanthanoid Series Elements chemistry   MeSH
• Ligands MeSH
• Hydrogen Peroxide chemistry   MeSH
• Iron chemistry   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 5-aminoorotic acid MeSH Browser
• Antioxidants MeSH
• coumarin-3-carboxylic acid MeSH Browser
• Fenton's reagent MeSH Browser
• Coumarins MeSH
• Orotic Acid MeSH
• Lanthanoid Series Elements MeSH
• Ligands MeSH
• Hydrogen Peroxide MeSH
• Iron 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