Elsevier

Inorganica Chimica Acta

Volume 339, 15 November 2002, Pages 470-480
Inorganica Chimica Acta

Evaluation of new iron chelators and their therapeutic potential

We dedicate this review to Helmut Sigel and, of course, to his wife Astrid, with our very best wishes and our profound thanks for all that they have done to advance the study of metals in a biological context.
https://doi.org/10.1016/S0020-1693(02)01040-XGet rights and content

Abstract

One of the most important challenges for biological inorganic chemistry is to understand metal ion homeostasis, particularly since we are becoming increasingly aware that its disequilibrium is at the basis of a large number of clinical disorders. It is, therefore, also an important objective of our research to seek solutions, which can alleviate the consequences of the perturbation of the homeostasis of key metal ions within cells, tissues and organisms. Iron is one of the key metals in biology, for which disorders of homeostasis are implicated in a vast panoply of pathological conditions. We review here the ways in which potential iron chelators can be evaluated, using appropriate in vivo or in vitro screening systems, and discuss their potential applications in the chelation of both iron and aluminium in the treatment of a number of human diseases.

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.

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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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