Synthetic 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... 

Much work has been performed in determining the stability constants of a variety of siderophores and synthetic siderophore... 

Another study of a synthetic siderophore analog of mixed cathechol and hydroxamate donor groups exhibited similar spectral shifts with pH as observed for tris-catecholate side-rophores, consistent with a salicylate-binding mode shift (102). While this synthetic siderophore mimic supports the growth of many species of bacteria, it also exhibits a low iron-binding affinity relative to other hexadentate siderophores, with a pFe value of 18.3 (see L(cat2hydroxamate) Table HE). 

Fig. 12. Non-catecholate donor group TREN family of synthetic siderophore mimics.

Table V shows redox potentials (Ey2) for ferric complexes of a series of natural and synthetic siderophores. The first coordination shell of the complex formed between iron and siderophore...

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],... 

Two examples of polycarbonyl and polyamino compounds are shown in Figure 5.7. Ethylenediaminetetraacetic add (EDTA) is a synthetic ligand. The other, a siderophore, is biologically derived. Other polycyclic structures that coordinate with iron are also common. 

These conjugated natural antibiotics prompted the search for novel synthetic siderophores that contain a variety of drugs . 

Kraemer, S.M. Hering, J.G. (1997) Influence of solution saturation state on the kinetics of ligand-controlled dissolution of oxide phases. Geochim. Cosmochim. Acta 61 2855-2866 Kraemer, S.M., Xu, J., Raymond, K.N. Spo-sito, G. (2002) Adsorption of Pb(II) and Eu(III) by oxide minerals in the presence of natural and synthetic hydroxamate sidero-phores. Environ. Sd. Technol. 36 1287-1291 Kraemer, S.M. Cheah, S.-F. Zapf, R. Xu, J. Raymond, KN. Sposito, G. (1999) Effect of hydroxamate siderophores on Fe release and Pb(II) adsorption by goefhite. Geochim. Cosmochim. Acta 63 3003—3008 Kratohvil, S. Matijevic, E. (1987) Preparation and properties of coated uniform colloidal partides. I. Aluminum (hydrous) oxide on hematite, diromia, and titania. Adv Ceram. Mater. 2 798-803... 

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

Microbes acquire iron by utilizing very specific, low molecular weight iron chelators called siderophores. The resistance of bacteria to previously effective antibiotics can be circumvented in part by covalent coupling of antibiotics to siderophores. Some synthetic siderophores have been found to possess significant antibacterial activity themselves. They have also been found to have considerable potential as nontoxic, organ selective MRI contrast agents (27). 

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