Natural siderophores

Siderophores are iron-complexing compounds of low molecular weight that are synthesized by bacteria and fungi, and serve to deliver iron to the microbes. Because of their exclusive affinity and specificity for Fe3+, natural siderophores and synthetic derivatives have been exploited in the treatment of human iron-overload diseases. The most successfully used example is Desferal , which is the methane sulfonate derivative of iron-free ferrioxamine B, a linear trihydroxamate (Figure 3.2). Ferrioxamine was isolated in 1958 from the culture supernatant of Streptomyces... 

IRON SEQUESTRATION BY SMALL MOLECULES THERMODYNAMIC AND KINETIC STUDIES OF NATURAL SIDEROPHORES AND SYNTHETIC MODEL COMPOUNDS... 

Pathogenic bacteria often make use of siderophores to obtain iron from their host organisms, and consequently the ironbinding capacity of the siderophore is closely related to the bacterial virulence. Enterobactin (1) is the natural siderophore... 

Kinetic and equilibrium data are available for complex formation between iron(III) and 4-Me0C6H4C(S)N(0 )H, a system studied in relation to the possibility that some natural siderophores may bind iron through a thiohydroxamate moiety. The Fe " " complex of this... 

The only clinically approved and therefore most studied natural siderophore is des-ferrioxamine B (DFO), and hence it serves as a reference compound in evaluating new biomimetic siderophores. The following discussion will include a short description of several natural hydroxamate siderophore families in separate tables, followed by the various attempts to prepare novel simplified structures that reproduce biological activity. These tables are not intended to cover the entire archive of known siderophores, but merely to allow the reader to observe structural variations, their chemical composition and location as well as conserved domains. 

The chemical nature of the linker, its size and buUciness will determine whether the drug remains attached to the siderophore or is released enzymatically into the cell. The synthesis of conjugates can proceed by derivatization of natural siderophores or by total synthesis. 

Siderophore drug conjugates can be utilized for both approaches. While the natural siderophores show generally low specificity, biomimetic analogs have been consistently improved to exhibit enhanced species specificity. 

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 ° . ... 

Iron Sequestration by Small Molecules Thermodynamic and Kinetic Studies of Natural Siderophores and Synthetic Model Compounds Alvin L. Crumbliss and James M. Harrington... 

Recently considerable effort has been devoted to the synthesis of natural siderophores, enantiomeric siderophores, and completely synthetic siderophore analogs. These compounds have been prepared as potential drugs in the treatment of iron overload, as potential antibiotics, and as probes for the stereospecific recognition and uptake of siderophore complexes by microbes. In addition, octadentate analogs have been prepared as actinide-specific sequestering agents 24). 

Table IV. Stability constants and redox potentials of ferric natural siderophore complexes ...

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