Natural siderophores desferrioxamine

The high efficiency and selectivity of the natural siderophores in binding iron(lll) inspired attempts to develop siderophore analogs with improved iron-scavenging properties amenable for chelation therapy. A most pertinent example is desferrioxamine B (DFO), where low patient compliance generates the need for developing oral means of administration for... 

Desferrioxamine (DFO-B), the natural siderophore initially isolated from Streptomyces pilosus, is the only iron chelator currently used for clinical treatment of iron-overload disease such as thalassemia, sickle cell anemia and hemochromatosis ° . ... 

Another factor that relates complex stability and siderophore architecture is the chelate effect. The chelate effect is represented by an increase in complex stability for a multidentate ligand when compared to complexes with homologous donor atoms of lower denticity. The effect can be observed when comparing the stability of complexes of mono-hydroxamate ligands to their tris-hydroxamate analogs, such as ferrichrome (6) or desferrioxamine B (4). However, the increase in stability alone is not sufficient to explain the preponderance of hexadentate siderophores over tetradentate or bidentate siderophores in nature, and the chelate effect is not observed to a great extent in some siderophore structures (10,22,50,51). 

Chelators of iron, which are now widely applied for the treatment of patients with thalassemia and other pathologies associated with iron overload, are the intravenous chelator desferal (desferrioxamine) and oral chelator deferiprone (LI) (Figure 19.23, see also Chapter 31). Desferrioxamine (DFO) belongs to a class of natural compounds called siderophores produced by microorganisms. The antioxidant activity of DFO has been studied and compared with that of synthetic hydroxypyrid-4-nones (LI) and classic antioxidants (vitamin E). It is known that chronic iron overload in humans is associated with hepatocellular damage. Therefore, Morel et al. [370] studied the antioxidant effects of DFO, another siderophore pyoverdin, and hydroxypyrid-4-ones on lipid peroxidation in primary hepatocyte culture. These authors found that the efficacy of chelators to inhibit iron-stimulated lipid peroxidation in hepatocytes decreased in the range of DFO > hydroxypyrid-4-ones > pyoverdin. It seems that other siderophores are also less effective inhibitors of lipid peroxidation than DFO [371],... 

Desferrioxamine E and its analogues are siderophores widely produced by Streptomyces and related bacteria.81 Their major role is ferric transportation cells secrete these cage compounds to their environment and then uptake their ferric-bound form (ferrioxamines) by the activity of a specific transporter to utilize ferric. Probably, the organisms had developed this complex retrieval system due to the insolubility and low availability of ferric in the natural environment. 

Siderophores,hexadentate tris-catecholate and tris-hydroxamate ligands, are produced by many microorganisms to facihtate iron uptake. Several synthetic models, such as trencam (35) and licams (36), for the tris-catecholate enterobactin (37) do not quite match its affinity for iron(ni) (Table 8). Similar tris-hydroxamate ligands model naturally occurring ferrichromes and desferrioxamines (e g. dfo, (38)). 

Research in the chelation of iron is sponsored by various Cooley s Anemia Fmmdations, the National Institute of Arthritis, Diabetes, and Digestive, and Kidney Diseases of the National Institutes of Health. Much of effort has been directly toward mimicking the naturally occurring siderophores such as desferrioxamine by inclusion of hydroxamic acids, catechols, and phenols into a variety of structures. This gives compoimds that have vary high stability constants for iron but are nontoxic and active in the human body. 

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