Iron chelating agents for the treatment of iron overload

The importance of iron chelators in medicine has significantly increased in recent years. Iron is essential for life but it is also potentially more toxic than other trace elements. This is because we lack effective means to protect human cells against iron overload and because of the role of iron in the generation of free radicals. In order to protect patients from the consequences of iron toxicity, iron chelating agents have been introduced in clinical practice. Unfortunately, the ideal chelator for treating iron overload in humans has not been identified yet. In this paper we examine a few characteristics of iron chelators, with some emphasis on the effects of redox cycling, on absorption mechanisms and on some properties of the pFe. A brief summary is then made of the chelators recently proposed or in development for the treatment of iron overload.     

Chelating agents for human diseases related to aluminium overload

The aim of this review is to give a general view on the current status of the role of aluminium in human health and disease. The main aspects of aluminium metabolism in humans are covered, summarizing the state of knowledge on the absorption, distribution, retention and excretion of aluminium, giving particular emphasis to the main metabolic pathways of this metal ion in different organs. Then the pathological consequences of aluminium overload in man, its role in neurodegenerative diseases and the emerging implication of this metal ions in different pathologies are treated. Finally, the function of different chelators utilized in clinical practice in the therapy of aluminium depending diseases is discussed and the latest studies on aluminium chelators are presented. Some emphasis is given to the parallelism between iron and aluminium chelators, and in particular interesting correlations between structural parameters of these two trivalent metal ions are presented.     

Mechanism of binding of iron to potential therapeutic chelating agents

To aid in designing new therapeutic iron chelating agents, the mechanism of iron binding to prototypic heterocyclic carboxaldehyde thiosemicarbazones has been studied. Based on molecular orbital and spectroscopic studies, iron (II) is found to bind in a covalent manner, while iron(III) seems to interact ionically. However, with both iron(II) and iron(III), chelate formation is dependent on charge interaction between the metal and the coordinating atoms of the ligand.     

Use of some new chelating agents for the colorimetric determination of iron: Ethylenediamine-bis-sulphosalicylaldehyde

Ethylenediamine-bis-sulphosalicylaldehyde, which gives strong violet-red coloration with. ferric salts owing to the formation of a stable metal chelate complex, Fe(C₈H₉O₄NS)Cl.H₂O, has been utilized for the colorimetric determination of ferric iron, using a Hilger-Spekker photoelectric absorptiomcter. The maximum intensity of absorption occurs at pH 2.8–5.5 in the green region (510–520 mμ) of the visible spectrum.The colour complex has been found to obey Beer's law between 0.25 and 10 p.p.m. The influences of several foreign, ions on the reaction have been carefully studied. The metal chelate complex has been isolated and its properties studied.     

Comparison of two chelating agents immobilized on controlled-pore glass for the preconcentrationof aluminium from aqueous solutions

Aluminium at low μg cm^?3 levels can be preconcentrated on columns of 8-quinolinol or EDTA immobilized on controlled-pore glass. Distribution coefficients are ca. 45 and 370 cm² g^t-1, respectively, and recoveries of aluminium are >80% at pH >4.6 and pH >4.0, respectively. The eluted aliminium is determined by atomic absorption spectrometry in a nitrous oxide/acetylene flame.     

Evaluation of 2-methyl-3-hydroxy-4-pyridinecarboxylic acid as a possible chelating agent for iron and aluminium

In view of a possible application to Fe and Al chelation therapy, 2-methyl-3-hydroxy-4-pyridinecarboxylic acid (DT2) was synthesised, and its complex formation, electrochemical and cytotoxic properties were studied. The complexing properties of DT2 towards Fe(III) and Al(III) were investigated in aqueous 0.6 m (Na)Cl at 25 degrees C by means of potentiometric titrations, UV-vis spectrophotometry, and 1H NMR spectroscopy. DT2 is a triprotic acid (H3L+) having pKa1 = 0.47, pKa2 = 5.64 and pKa3 = 11.18. The metal-ligand complexes observed in solution and their corresponding stability constants (log beta values) are the following: FeLH (19.38), FeL (16.01), FeLH(-1) (12.28), FeL2H2 (37.29), FeL3H3 (53.41), FeL3H2 (47.99), FeL3H (41.21) and FeL3 (34.1); AlLH (17.43), AlL2H2 (33.74), AlL2H (27.6), AlL3H3 (48.72), AlL3H2 (42.67), AlL3H (35.8) and AlL3 (27.92). The complex formation between DT2 and Fe(II) was studied by UV-vis: the weak complex FeLH (log beta = 15.8) was detected. DT2 shows a lower complexation efficiency with Fe(III) and Al(III) than that of other available chelators, but higher than that of its non-methylated analogue 3-hydroxy-4-pyridinecarboxylic acid (DT0). The electrochemical behaviour of DT2 was investigated by means of cyclic voltammetry, indicating that the oxidation of the ligand proceeds through a two electron process with a CECE mechanism. Voltammetric curves suggest that the oxidation or the reduction of DT2 in vivo is unlikely. According to the thermodynamic data, also the Fe(III)-DT2 complexes do not undergo redox cycling at physiological pH. Amperometric titrations of solutions containing Fe(III) and DT2 at pH = 5 indicated the same Fe(III) : ligand stoichiometric ratio as calculated from potentiometric data. The toxicity of DT2 and of other simple hydroxypyridinecarboxylic acids was investigated in vitro and no cytotoxic activity was observed (IC50 > 0.1 mM) on cancer cell lines and also on primary human cells, following a three day exposure.     

Dinitrogen complexes of iron(II) with chelating agents as ligands

Two new dinitrogen compounds of formulae Na₂[Fe(EDTA)N₂].2H₂O and Na₂[Fe(CDTA)N₂].2H₂O have been synthesized from [Fe(H-EDTA)H₂O] and [Fe(H-CDTA)-H₂O], respectively, and NaN₃. Both complexes have been characterized by IR and electronic spectra. The thermal behaviour has been studied by TG and DTA techniques.     

Separation of titanium, iron and aluminium on a chelating resin with benzoylphenylhydroxylamine group and application to bauxite and clay

Summary A chelating polystyrene based resin containing N-benzoyl-N-phenylhydroxylamine has been sythesized by two methods and characterized. Conditions for quantitative separation of Ti(IV), Fe(III) and Al(III) on the resin have been studied. A method has been developed for the determination of these three metal ions in bauxite or clay samples after their separation on the resin with recoveries of 98.5–99.5% for different metal ions. The maximum sorption values are observed at pH 1, 2.5 and 2.5 for Ti(IV), Fe(III) and Al(III), respectively, which are recovered by successive elution with 1 mol/l H₂SO₄, 2 mol/l HCl and 4 mol/l H₂SO₄ in the above order.     

Supramolecular approaches to generate libraries of chelating bidentate ligands for homogeneous catalysis

The process of catalyst discovery and development relying on combinatorial methods has suffered so far from the difficult access to structurally diverse and large libraries of ligands, in particular the structurally more complex class of bidentate ligands. A completely new approach to streamline the difficult ligand synthesis process is to use structurally less complex monodentate ligands that self-assemble in the coordination sphere of a metal center through noncovalent attractive ligand-ligand interactions to generate bidentate, chelating ligands. When complementary attractive ligand-ligand interactions are employed, it is even possible to generate libraries of defined chelate-ligand catalysts by simply mixing two different monomeric ligands. This Minireview summarizes the first approaches and results in this new field of combinatorial homogeneous catalysis.     

Use of some new chelating agents for the colorimetric determination of iron: P-aminosalicylic acid (sodium salt)

The paper introduces P-aminosalicylic acid (sodium salt) as a. new, sensitive, stable and widely applicable reagent for the colorimetric determination of ferriciron. The reagent has several advantages over some of the known organic reagents for iron. It can be worked conveniently over a. long pu range: 1.5–3.05 or 3.4–5.05. The colour of the complex is also stable for a long period and is found to obey Beer's law over a wide range of concentration.     

New chelating agents for colorimetric determination of calcium

Two new calcium chromoionophores2 and3 are described and their potential application to colorimetric determination of calcium is assessed. Chromogenic compound2 bears two acetic acid chelating groups and a 4-(4-nitrophenyl)azophenol chromophore. Its complexation of Ca²⁺ at pH 9.0 is accompanied by a 109-nm bathochromic shift and increase in the absorptivity. Triaryl chromoionophore3 bears two phosphonic acid chelating groups and the same azophenol chromophore. Compound3 exhibits a 107-nm bathochromic shift of the absorption maximum, an increase in the absorptivity upon complexation with Ca²⁺, and good selectivity for Ca²⁺ over Mg²⁺ at pH 7.0. Both chromoionophores exhibit linear responses from 0 to 4×10^–3 M Ca²⁺.     

Synthesis of new semi-rigid chelating agents for samarium-153

This study describes a simple, efficient synthesis pathway from trans-1,2-diaminocyclohexane that provides access to a new class of semi-rigid polyamine, polycarboxylic, and polyphosphonic ligands. The key steps in synthesis were the functionalisation (with an appropriate branching group) of a bisphosphonate diaminocyclohexane derivative and the introduction of methanephosphonic functions by a rarely used method.     

Different multidimensional chromatographic approaches applied to the study of wine malolactic fermentation

Different multidimensional chromatographic techniques were used to study wine aroma pattern changes during malolactic fermentation (MLF). Ethyl lactate enantiomeric ratios were determined using on-line multidimensional gas chromatography. The values found agree with a spontaneous MLF. Off-line multidimensional HPLC/GC was used to deconvolute and enrich the sample and ease enantioselective chromatography. Chiral compound enantiomeric ratio changes during MLF were monitored. Evaluation of enantiomeric ratio changes during MLF has never been studied. (R,R), (S,S) and meso-butane-2,3-diol and pentane-2,4-diol (reported in wines for the first time) were submitted to untrained sensory panel tests. All stereoisomers revealed different sensory notes; pentane-2,4-diol showed an aromatic impact.     

A contribution to the use of chelating agents in anodic stripping voltammetry

The E(p)/(2), values of the ions Pb(2+), Bi(3+), Cu(2+), Cd(2+), Tl(+) were determined by means of cyclic voltammetry in solutions of acetate and Britton-Robinson buffers and in solutions containing EDTA and DCTA. DCTA was then utilized in the determination of small amounts of bismuth, down to 10(-7)M, in the presence of 10(4) times as much lead, and of traces of thallium down to 5 x 10(-9)M in the presence of 2 x 10(5) times as much cadmium by anodic stripping voltammetry. The precision was good. Further, the trace copper concentration in analytical grade DCTA was determined. A new flow-through vessel for stripping analysis with solution exchange is also described and the reproducibility of results without solution exchange, with manual solution exchange, and with the flow-through vessel is evaluated for a model determination of thallium in a DCTA solution.     

Hydrazone chelators for the treatment of iron overload disorders: iron coordination chemistry and biological activity

The potentially tridentate ligand 2-pyridinecarbaldehyde isonicotinoyl hydrazone (HPCIH) and its analogues are an emerging class of orally effective Fe chelators that show great promise for the treatment of Fe overload diseases. Herein, we present an extensive study of the Fe coordination chemistry of the HPCIH analogues including the first crystallographically characterised Fe(II) complex of these chelators. Unlike most other clinically effective Fe chelators, the HPCIH analogues bind Fe(II) and not Fe(III). In fact, these chelators form low-spin bis-ligand Fe(II) complexes, although NMR suggests that the complexes are close to the high-spin/low-spin crossover. All the Fe complexes show a high potential Fe(III/II) redox couple (> 500 mV vs. NHE) and cyclic voltammetry in aqueous or mixed aqueous/organic solvents is irreversible as a consequence of a rapid hydration reaction that occurs upon oxidation. A number of the HPCIH analogues show high activity at inducing Fe efflux from cells and also at preventing Fe uptake by cells from the serum Fe transport protein transferrin. As a class of ligands, these chelators are more effective at reducing Fe uptake from transferrin than inducing Fe mobilisation from cells. This may be related to their ability to intercept Fe(II) after its release from transferrin within the cell. Our studies indicate that their Fe chelation efficacy is due, at least in part, to the fact that these ligands and their Fe(II) complexes are neutral at physiological pH (7.4) and sufficiently lipophilic to permeate cell membranes.     

Mössbauer study of iron in the grain boundary of aluminium

Iron was diffused into aluminium along grain boundaries and studied by Mössbauer spectroscopy. The Mössbauer spectrum of the investigated sample contained one doublet with isomer shift =0.360/5/ mm s^–1 /relative to -iron/ and quadrupole splitting =0.84/l/ mm s^–1. These results suggest that the iron atoms in the grain boundaries of aluminium have environment very similar to that which is present in amorphous iron /III/ oxides.     

Coordination chemistry and biology of chelators for the treatment of iron overload disorders

Treatment of the medical condition generally referred to as iron overload through the delivery of chelators has recently received a major boost. In 2005 Novartis gained FDA approval for the drug deferasirox, which may be taken orally. Until this time most patients with Fe overload have had to endure long periods of subcutaneous infusions of the orally ineffective drug desferrioxamine (desferal) which has led to major problems with patient compliance. An effective Fe chelator must possess a number of properties for it to be able to complex Fe in vivo and be excreted intact. This Perspective will provide an overview of the current state of chelators for Fe overload; both those currently approved and those undergoing preclinical development.     

New chelating agents obtained by the addition of thiols to acetylene dicarboxylic acid

Four new chelating agents have been obtained by the addition of thiols to acetylenedicarboxylic acid. The thiols used were sodium 2-mercaptoethanesulfonate, mercaptosuccinic acid, N, N-dimethyl-2-mercaptoethylamine, and 3-mercaptopropionic acid. These chelating agents generally possess a very appreciable water solubility, as well as a multiplicity of donor sites. They all have LD50 values greater than 500 mg/kg when given ip to mice in pH 7 solution and three have LD50 values greater than 750 mg/kg; all as the simple compounds.     

Synthetic approaches to heterocyclic ligands for Gd-based MRI contrast agents

Magnetic Resonance Imaging (MRI) methods are currently used in the clinic for the non invasive detection and characterization of a wide variety of pathologies. Increases in the diagnostic efficiency of MRI have been helped by both the design of dedicated MR sequences revealing specific aspects of the pathology and by the development of more sensitive and selective Contrast Agents (CAs), capable of more precisely delineating the borderline regions. In the present review we focus on the synthetic strategies used to obtain MRI CAs containing heterocyclic rings.