Evaluation of new iron chelators and their therapeutic potential
Iron is a key metal in biology, and perturbation of its homeostasis, which increase iron loading, are implicated in many pathological conditions. We review ways in which potential iron chelators can be evaluated, using appropriate screening systems, and discuss their potential applications in the chelation of both iron and aluminium in the treatment of a number of human diseases.
Section snippets
Preamble
It is always both a pleasure and a privilege to contribute an article for a ‘Festchrift’ to celebrate the coming of a certain age of an admired, well-loved and respected colleague. When Bernhard Lippert asked me to contribute to this volume I was more than happy to agree. Helmut Sigel epitomises for me what is the quintessence of Bioinorganic Chemistry, namely the desire to find how the concepts and experimental approaches of inorganic chemistry can be applied to the extraordinary diversity and
Mobilisation of transferrin and NTBI iron
Transferrins are glycoproteins of molecular weight around 80 kD composed of a single polypeptide chain of 680 amino acid residues able to bind tightly, but reversibly, two Fe3+ ions with concomitant binding of two carbonate anions [1]. Serum transferrin has the specific role of transporting iron in vertebrates from sites of absorption and haem degradation to sites of utilisation, for red blood cell production (erythropoeisis) and for storage (in ferritin).
However, the transferrin iron pool
Mobilisation of ferritin and haemosiderin iron
Excess iron is stored within mammalian cells in cytoplasmic ferritin, and, particularly when there is significant iron loading, in lysosomal haemosiderin [1]. Both iron storage proteins sequester the metal in a nontoxic yet bioavailable form within the cell.
Haemosiderin was first identified histologically as iron rich granules in tissues, which gave an intense Prussian blue reaction with potassium ferrocyanide [25]; the intensity of Perl's staining is still used as an indication of the degree
Cellular and animal models of iron mobilisation
We have used several models of cellular iron overload—hepatocytes, macrophages and microglia, which have been loaded with either 55Fe-labelled ferritin or 55Fe-labelled iron dextran. The advantages of such in vitro model systems are several-fold. (i) We can ascertain whether the chelator penetrates within the cell and takes the iron out into the extracellular medium (it could, of course, be argued that the chelator interacts with a pool of ‘labile’ iron at, or close to, the plasma membrane of
Potential applications of iron chelation therapy and perspectives
Increased levels of brain iron are often associated with neurodegenerative diseases—for example Parkinson's disease [35], Alzheimer's disease [36], Huntington's disease [37] and human immunodeficiency virus (HIV) encephalopathy [38]. Very recently a mutation in the gene for the ferritin L chain has been found to cause basal ganglia disease [39] and brain iron accumulation accompanied by oxidative stress has been proposed as the mechanism for the pathophysiology associated with
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2021, Microbiological ResearchCitation Excerpt :Currently, several iron chelators such as Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) (Gojo et al., 2007), Desferrioxamine, and Deferasirox are tested in pre-clinical and clinical studies as anticancer agents (Yamasaki et al., 2011; Lui et al., 2013). Desferrioxamine (DFO) is a hexadentate siderophore isolated from Streptomyces pilosus that is used as an iron chelator in clinical treatment of iron overload in patients with beta thalassemia major (Aouad et al., 2002) and is the first iron chelator tested as an anti-cancer agent (Kontoghiorghes, 2006). Previous clinical studies and trials have shown that invasive tumors, including Neuroblastoma (NB) and leukemia, are susceptible to treatment with DFO iron chelator (Buss et al., 2003).
The interaction of phenolic acids with Fe(III) in the presence of citrate as studied by isothermal titration calorimetry
2014, Food ChemistryCitation Excerpt :Therefore, it is important to keep the balance between iron import and export to maintain the iron homeostasis. Some iron chelators such as Desferal® or ICL670A can be used in medicine to protect patients from the consequences of iron overload and iron toxicity in organs and tissues (Aouad et al., 2002; Faa & Crisponi, 1999; Liu & Hider, 2002; Wong & Richardson, 2003). Additionally, some polyphenols also have the potential to be used as chelators to modulate physiological reactions involving iron and other transition metals (Blache, Durand, Prost, & Loreau, 2002; Elhabiri, Carrer, Marmolle, & Traboulsi, 2006; Haslam, 1996).
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2012, Coordination Chemistry ReviewsEnzymatic synthesis of catechol and hydroxyl-carboxic acid functionalized chitosan microspheres for iron overload therapy
2011, European Journal of Pharmaceutics and BiopharmaceuticsCitation Excerpt :The first generations of drugs were based on siderophores, iron-chelating molecules produced by nearly all microorganisms [12]. Of the 500 characterized siderophores [13], only desferrioxamine introduced in 1962 and produced by Streptomyces pilosus is the current drug of choice [14]. Nevertheless, desferrioxamine is associated with several drawbacks including narrow therapeutic window and lacks bioavailability orally [15].
Trypanosoma cruzi: Desferrioxamine decreases mortality and parasitemia in infected mice through a trypanostatic effect
2011, Experimental ParasitologyCitation Excerpt :Six hours after treatment, parasite levels were similar to that found in untreated animals. This finding is probably due to the short half-life in plasma and the rapid metabolism of DFO (Aouad et al., 2002). Nevertheless, this limitation was overcome by combination therapy with BZ.
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