Transferrin iron, chelatable iron and ferritin in idiopathic haemochromatosis.
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Adult↗
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Desferrioxamine-chelatable iron (DCI), a component of serum non-transferrin-bound iron (NTBI) used for assessing iron chelation therapy.
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Chelating Agents↗
Design, synthesis and antimalarial activity of a new class of iron chelators.
Iron is crucial for many biochemical reactions involved in the growth and multiplication of the malaria parasite Plasmodium falciparum. There are many reports indicating that the iron chelators have antimalarial activity in vitro, in vivo and in human studies. However, these compounds suffer from a number of serious problems such as limited membrane permeability, short half-life and require long subcutaneous infusions. To circumvent these drawbacks we have designed a new class of iron chelators, wherein EDTA is tethered to 4-aminoquinoline. Here 4-aminoquinoline scaffold is used as a carrier to penetrate biological membrane and facilitate targetting the compounds to acidic food vacuole of the parasite. This study describes the synthesis of novel iron chelators and their in vitro antimalarial activity against P. falciparum strain of NF-54. The calculated LogP values of these compounds suggest the importance of lipophilicity for the antimalarial activity. The EDTA esters are more active than the corresponding acids. The biophysical studies suggest that these compounds may inhibit the parasite growth by iron chelation mechanism.
Aminoquinolines↗
An overview of iron metabolism: molecular and cellular criteria for the selection of iron chelators.
Iron is a metal of capital importance in most living organisms. However, man differs from the rest of mammals by his incapacity to excrete significant amounts of iron. This means that both iron deficiency and iron overload are frequently encountered. We briefly review our current understanding of dietary iron absorption and then discuss iron transport and delivery to cells. The intracellular storage and utilisation of iron are then considered, with a particular emphasis on the transit iron pool. Cellular iron homeostasis appears principally to be regulated at the level of translation of key mRNA's involved in iron uptake, storage and utilisation, through iron regulatory proteins. The potential sites of iron chelation at the molecular level and cellular models which may be useful in the selection of potentially useful therapeutic iron chelators are briefly reviewed.
Animals↗
Chelation of iron within the erythrocytic Plasmodium falciparum parasite by iron chelators.
To examine the site of action of antimalarial iron chelators, iron ligands were added to control erythrocytes and to erythrocytes parasitized with Plasmodium falciparum, and the concentration of intracellular labile iron was monitored with the fluorescent probe, calcein. The fluorescence of calcein quenches upon binding iron and increases upon releasing iron. The chelators included desferrioxamine B, 2',2'-bipyridyl, and aminophenol II, a compound that is being newly reported as having anti-plasmodial properties. Calcein-loaded parasitized cells displayed fluorescence predominantly within the cytosol of both rings and trophozoites. The addition of chelators to both control and parasitized erythrocytes led to significant increases of fluorescence (P < 0.001). Fluorescence was observed to increase within the parasite itself after addition of iron chelators, indicating that these agents bound labile iron within the plasmodium. The relative increases of fluorescence after addition of chelators were greater in control than parasitized erythrocytes (P < 0.05) as were the estimated labile iron concentrations (P < or = 0.001). These results suggest that (i) the anti-malarial action of iron chelators might result from the ability to reach the infected cell's parasite compartment and bind iron within the parasite cytosol, and (ii) the labile iron pool of the host red cell may be either utilized or stored during plasmodial growth.
2,2'-Dipyridyl↗
Iron chelators and iron toxicity.
Iron chelation may offer new approaches to the treatment and prevention of alcoholic liver disease. With chronic excess, either iron or alcohol alone may individually injure the liver and other organs. In combination, each exaggerates the adverse effects of the other. In alcoholic liver disease, both iron and alcohol contribute to the production of hepatic fibrosis through their effects on damaged hepatocytes, hepatic macrophages, hepatic stellate cells, and the extracellular matrix. The pivotal role of iron in these processes suggests that chelating iron may offer a new approach to arresting or ameliorating liver injury. For the past four decades, deferoxamine B mesylate has been the only iron-chelating agent generally available for clinical use. Clinical experience with deferoxamine has demonstrated the safety and effectiveness of iron chelation for the prevention and treatment of iron overload. Determined efforts to develop alternative agents have at last resulted in the development of a variety of candidate iron chelators that are now in or near clinical trial, including (a) the hexadentate phenolic aminocarboxylate HBED [N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid], (b) the tridentate desferrithiocin derivative 4'-OH-dadmDFT [4'-hydroxy-(S)-desazadesmethyl-desferrithiocin; (S)-4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-thiazolecarboxylic acid], (c) the tridentate triazole ICL670A [CGP72 670A; 4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid], and (d) the bidentate hydroxypyridin-4-one deferiprone [L1, CP20; 1,2-dimethyl-3-hydroxypyridin-4-one]. These agents may provide new pharmacological means of averting or ameliorating liver damage in alcoholic liver disease by binding, inactivating, and eliminating the reactive forms of iron that contribute to oxidative injury of cellular components, are involved in signal transduction, or both.
Alcoholism↗
p53-independent apoptosis mediated by tachpyridine, an anti-cancer iron chelator.
Iron is involved in essential biochemical reactions ranging from respiration to DNA synthesis. Consequently, iron deprivation has been proposed as a strategy for inhibition of tumor cell growth. We recently described a novel iron chelator, tachypyridine [N,N',N"-tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane], and demonstrated that it not only inhibited growth of cultured tumor cells, but was actively cytotoxic. Here we explore the mechanisms underlying tachpyridine cytotoxicity. Using several criteria, including time-lapse video microscopy, DNA staining and TUNEL assays, tachpyridine was shown to specifically induce apoptotic cell death. Further, unlike numerous cytotoxic chemotherapeutic drugs which induce apoptosis by activating p53-dependent pathways, tachpyridine-mediated cell death did not require p53 activation. Although immunoblotting revealed rapid accumulation of p53 following treatment with tachpyridine, p21(WAF1) was not induced. Further, neither cytotoxicity nor apoptosis required p53. p53 null human lung cancer H1299 cells transfected with an ecdysone-inducible p53 exhibited equivalent sensitivity to tachpyridine in the presence and absence of p53, demonstrating the lack of requirement for p53 in an isogenic cell system. Further, time-lapse video microscopy and TUNEL assays demonstrated that both p53 null and p53 wild-type cells underwent apoptotic cell death in response to tachpyridine. In addition, in 55 human cancer cell lines the mean GI(50) of tachpyridine in cells with mutant p53 was virtually identical to the GI(50) in cells with wild-type p53. These results demonstrate that tachpyridine initiates an apoptotic mode of cell death that does not require functional p53. Since over 50% of human tumors contain a functionally defective p53 that reduces sensitivity to commonly used chemotherapeutic agents, such as etoposide and cisplatin, the ability of tachpyridine to induce apoptosis independently of p53 may offer an advantage in anti-tumor therapy.
Anticarcinogenic Agents↗
Bacteriostatic and fungostatic action of catecholamide iron chelators.
Iron starvation as a means of controlling the proliferation of microorganisms was evaluated in vitro with spermidine catecholamide iron chelators. The growth of Escherichia coli and Pseudomonas aeruginosa was sensitive only to (D,L)-parabactin, whereas the growth of Candida albicans and Staphylococcus aureus was sensitive to a variety of catecholamide chelators. The disappearance of catecholamide activity upon methylation of the catechol hydroxyls, as well as iron reversal experiments, strongly suggests that the mechanism by which these compounds suppress growth is dependent upon their ability to sequester iron.
Amides↗
Modified aca method for determination of iron chelated by deferoxamine and other chelators.
Iron in serum and urine specimens containing deferoxamine (a chelator used in treating acute iron intoxication) can be measured by the DuPont aca discrete-analyzer method for iron if 0.5 mL of a 100 mL/L solution of thioglycolic acid (mercaptoacetic acid) is added to the IRN-1 and IRN-2 test packs before their use. This reagent releases the unreactive chelated iron, allowing reliable colorimetry. Because about 50% of hemoglobin iron is measured by the modified method, hemolysed samples should not be used (or results should be corrected for hemoglobin iron). The modification allows emergency determination to total serum iron and assessment of urinary iron during chelation therapy, as well as measurement of plasma iron in samples treated with sodium citrate or oxalate plus fluoride (the unmodified aca iron method gives falsely low iron values in the presence of these chelators). About 60% of iron present as the dextran complex (Imferon) is measured by the modified aca method, as compared with <5% by the unmodified aca technique.
Anticoagulants↗
The effect of low molecular weight chelators on iron chelation and free radical generation as studied by ESR measurement.
The purpose of this work was to improve our current knowledge of the non-enzymatic mechanisms involved in brown rot fungal decay of wood, but also to improve our understanding of chelator-mediated reactions that may occur in other biological systems where low pH conditions may prevail. Several key steps (iron chelation and reduction) during early non-enzymatic wood decay processes have been studied by using electron spin resonance (ESR). It has been proposed that low molecular weight chelators as well as Fenton reagents are involved in brown rot decay, at least in early non-enzymatic stages. In this work, the binding between a catecholate model chelator and ferric iron was studied by ESR spectroscopy. The effects of the model chelator, Fenton reagents, as well as the reaction conditions on free radical generation were also studied using ESR spin-trapping techniques. The results indicate: (1) The relative quantity of the chelator-iron complex can be determined by measurement of the intensities of the characteristic g = 4.3 ESR signal. (2) The effects of the chelator:iron ratio, the pH, and other reaction parameters on the hydroxyl radical generation in a Fenton type system can be determined using ESR spin-trapping techniques. (3) Data support the hypothesis that superoxide radicals are involved in chelator-mediated Fenton processes.
Biodegradation, Environmental↗
The effect of 2,4-dihydroxypyridine-N-oxide, a new orally active iron chelator, on iron excretion in mice.
A comparative study of the iron chelating properties of 2,4-dihydroxypyridine-N-oxide with heteroaromatic chelators containing an alpha-ketohydroxy binding site has been performed in iron loaded mice labelled with 59Fe lactoferrin. All the chelators were administered at a dose of 300 mg/kg either intraperitoneally or intragastrically. The pyridine derivatives were the only chelators which caused increased 59Fe excretion following their intragastric administration to mice. 1,2-Dimethyl-3-hydroxypyrid-4-one was the most effective oral chelator of all, followed by 2,4-dihydroxypyridine-N-oxide which caused further increase in 59Fe excretion when it was administered twice a day at a 200 mg/kg dose.
Animals↗
Iron chelating agents for treating malaria.
BACKGROUND: Mortality from Plasmodium falciparum malaria remains high; death and sequelae occur in even in patients treated with antimalarial drugs. Researchers are exploring the effects of adding treatments to the main antimalarial regimens in an attempt to reduce mortality. Iron chelation is one potential chemotherapeutic adjuvant treatment. Before advocating adjunctive therapy, the effects of iron chelators in improving patient outcomes needs to be examined. OBJECTIVES: To assess the effects of iron-chelating agents combined with antimalarial drugs, or iron chelators alone, for treating Plasmodium falciparum malaria in adults and children, in relation to mortality, coma recovery time, parasite clearance, and adverse effects. SEARCH STRATEGY: Electronic searches of the Cochrane Library, MEDLINE, and EMBASE, using the standard Cochrane search strategy. Bibliographies of retrieved studies were scrutinized in order to identify further relevant trials. Organisations, experts and other individuals in malaria research were contacted for unpublished studies. SELECTION CRITERIA: All randomised controlled trials of adults or children with P.falciparum malaria. DATA COLLECTION AND ANALYSIS: Trials were identified and extracted by a single reviewer (HS) and checked by a second (MM). Inclusion criteria were applied, and data were extracted independently by both reviewers. Authors were contacted for missing and additional data. Meta-analysis used Relative Risk (RR) and 95% Confidence Intervals. MAIN RESULTS: No evidence of benefit or harm were shown in relation to mortality, but studies were small, and one trial was tending towards more deaths with the intervention when it was stopped. The risk of experiencing persistent seizures was significantly lower with desferrioxamine compared to placebo treatment (RR 0.80, 95% CI 0.67 to 0.95). Many adverse effects were more common in participants treated with desferrioxamine. REVIEWER'S CONCLUSIONS: Trends suggestive of both harm (death) and potential benefit (fewer seizures) are demonstrated in this review. It is not possible to comment on time to event outcomes that include coma recovery or parasitaemia as we are clarifying data with the trialists. Whether to conduct further trials will depend on a judgement about potential benefit.
Adult↗
Translation of ferritin light and heavy subunit mRNAs is regulated by intracellular chelatable iron levels in rat hepatoma cells.
Acute administration of iron to rats has been previously shown to induce liver ferritin synthesis by increasing the translation of inactive cytoplasmic ferritin mRNAs for both heavy (H) and light (L) subunits by mobilizing them onto polyribosomes. In this report rat hepatoma cells in culture are used to explore the relationship of this response to intracellular iron levels. After adding iron as ferric ammonium citrate to the medium, latent ferritin H- and L-mRNAs were extensively transferred to polyribosomes, accompanied by increased uptake of [35S]methionine into ferritin protein. Because total cellular levels of L- and H-mRNA were not significantly changed by exposure to iron, the increased ferritin mRNAs on polyribosomes most probably come from an inactive cytoplasmic pool, consistent with the inability of actinomycin-D and of cordycepin to inhibit iron-induced ferritin synthesis. When deferoxamine mesylate, an intracellular iron chelator, was added after the addition of iron to the medium, ferritin mRNA on the polyribosomes was reduced, while the free messenger pool increased, and ferritin synthesis diminished. In contrast, the extracellular iron chelator diethylenetriaminepentaacetic acid failed to inhibit the induction of ferritin protein synthesis. Addition of iron in the form of hemin also caused translocation of mRNA to polyribosomes, a response that could be similarly quenched by deferoxamine. Because hemin does not release chelatable iron extracellularly, we conclude that the level of chelatable iron within the cell has a regulatory role in ferritin synthesis through redistribution of the messenger RNAs between the free mRNA pool and the polyribosomes.
Animals↗
Effects of iron chelators and iron overload on Salmonella infection.
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Animals↗
Microbial iron chelates with iron donor properties in hemoglobin-synthesizing cells.
Iron incorporation into Friend virus infected leukemic murine spleen cells was studied using the two fungal iron trihydroxamates, fusigen and ferricrocin. Incorporation of 55Fe was measured by isolation of hemoglobin after dimethylsulfoxide-induced hemoglobin synthesis and compared with iron incorporation from 55Fe-labeled ferric citrate.
Animals↗
Evaluation of myocardial iron by magnetic resonance imaging during iron chelation therapy with deferrioxamine: indication of close relation between myocardial iron content and chelatable iron pool.
Evaluation of myocardial iron during iron chelation therapy is not feasible by repeated endomyocardial biopsies owing to the heterogeneity of iron distribution and the risk of complications. Recently, we described a noninvasive method based on magnetic resonance imaging. Here, the method was used for repeated estimation of the myocardial iron content during iron chelation with deferrioxamine in 14 adult nonthalassemic patients with transfusional iron overload. We investigated the repeatability of the method and the relationship between the myocardial iron estimates and iron status. The repeatability coefficient (2sD) was 2.8 micromol/g in the controls (day-to-day) and 4.0 micromol/g in the patients (within-day). Myocardial iron estimates were elevated in 10 of all 14 patients at first examination, but normalized in 6 patients after 6 to 18 months of treatment. If liver iron declined below 350 micromol/g all but one of the myocardial iron estimates were normal or nearly normal. At start (R2 = 0.69, P =.0014) and still after 6 months of iron chelation (R2 = 0.76, P =.001), the estimates were significantly and more closely related to the urinary iron excretion than to liver iron or serum ferritin levels. In conclusion, our preliminary data, which may only pertain to patients with acquired anemias, suggest the existence of a critical liver iron concentration, above which elevated myocardial iron is present, but its extent seems related to the size of the chelatable iron pool, as reflected by the urinary iron excretion. This further supports the concept of the labile iron pool as the compartment directly involved in transfusional iron toxicity.
Adult↗
Kinetic studies on the specificity of chelate-iron uptake in Aspergillus.
Three strains of the fungus Aspergillus, Aspergillus quadricinctus (E. Yuill), A. fumigatus (Fresenius), and A. melleus (Yukawa), each producing different iron-chelating compounds during iron-deficient cultivation, were used for 55Fe3+ uptake measurements. Iron from chelates of the ferrichrome-type family was taken up by young mycelia of all strains tested, irrespective of the ferrichrome-type compound these strains predominantly produce in low-iron cultures. Ferrichrysin-producing strains, however, seem to favor ferrichrysin iron uptake, whereas ferrichrome, ferricrocin, and even ferrirubin showed similar iron transport properties in all of these strains. Compared to iron uptake from ferrichrome-type compounds (Km approximately 4 uM) iron uptake from fusigen revealed completely different kinetic values (Km approximately 50 to 80 muM). Iron from exogenous chelates, e.g., from coprogen produced by Neurospora crassa for ferrioxamine B produced by Streptomyces pilosus, can obviously not be taken up by Aspergillus, confirming the pronounced specificity of chelate-iron transport in fungi.
Aspergillus↗
Chromatographic methods for the separation of biocompatible iron chelators from their synthetic precursors and iron chelates.
Chromatographic methods have been developed for the separation of the three novel biocompatible iron chelators pyridoxal isonicotinoyl hydrazone (PIH), salicylaldehyde isonicotinoyl hydrazone (SIH), and pyridoxal 2-chlorobenzoyl hydrazone (o-108) from their synthetic precursors and iron chelates. The chromatographic analyses were achieved using analytical columns packed with 5 microm Nucleosil 120-5 C18. For the evaluation of all chelators in the presence of the synthetic precursors, EDTA was added to the mobile phase at a concentration of 2 mM. The best separation of PIH and its synthetic precursors was achieved using a mixture of phosphate buffer (0.01 M NaH2PO4, 5 mM 1-heptanesulfonic acid sodium salt; pH 3.0) and methanol (55:45, v/v). For separation of SIH and its synthetic precursors, the mobile phase was composed of 0.01 M phosphate buffer (pH 6.0) and methanol (60:40, v/v). o-108 was analyzed employing a mixture of 0.01 M phosphate buffer (pH 7.0), methanol, and acetonitrile (60:20:20, v/v/v). These mobile phases were slightly modified to separate each chelator from its iron chelate. Furthermore, a RP-TLC method has also been developed for fast separation of all compounds. The chromatographic methods described herein could be applied in the evaluation of purity and stability of these drug candidates.
Aldehydes↗