Ferrioxamines natural

Mikes and Turkova have given a classification of naturally occurring hydroxamic acids in terms of their biological function or activity. They have distinguished (a) growth factors, e.g., ferri-chromes, mycobactin, and ferrioxamines, ferrichrysins, ferrirubins, etc. (6) antibiotics, e.g, aspergillic acid, mycelianamide, albomycin, nocardamine and (c) microbial pigments such as pulcherrimin. 

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... 

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. 

Natural and biomimetic hydroxamic acid based siderophores TABLE 2. Natural ferrioxamines and their structural variations... 

The spacer length between the hydroxamate ligating groups in the natural ferrioxamines seems to present a case of optimal adjustment. Shortening the spacer reduced binding affinities by several orders of magnitude compared to the DFO °. When the spacer length and chemical composition are ideal, the backbone amides are optimally oriented for effective interaction with the receptor. 

In the ferrioxamine family, two approaches were followed one, based on modifying the amine at the end of the extended tail in the natural ferrioxamine B with an appropriate fluorophore the second, substituting biomimetic analogs 146-155 on either their amino or carboxy termini, to assess their chemical and biological differences. Both approaches were followed and two classes of compounds were prepared with various fluorescent tags. 

Iron-free ferrioxamine B ( Desferal", Ciba Pharmaceutical Company, Sum-mitt, New Jersey) reacts rapidly with ferrous ion, especially at neutral pH, forming the ferric chelate. This transition is blocked by mercaptoacetic acid, hydrosulfite and thiosulfate but not by weaker reducing agents such as ascorbic acid, hydroxylam-ine and sulfite (Nature 205, 281, 1965). 

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. 

A comparison of the stability constants of the naturally occurring siderophores uncovers a difference of f7 orders of magnitude between enterobactin (K most stable hydroxamate complex, ferrioxamine E. Using the more comparable pM values, enterobactin remains stiU eight orders of magnitude more effective than ferrioxamine E. Enterobactin has the highest affinity for Fe ion of any biological iron chelator tested so far. 

The first synthesis of a siderophore was the preparation of ferrioxamine B over 20 years ago in order to confirm the chemical structure of this natural product67). Synthesis of the other hydroxamate containing siderophores has as a central problem preparation of the constituent to-N-hydroxy amino acid in an optically pure form. The most important such subunit in hydroxamate siderophores is Ns-hydroxy ornithine. This is a chiral building block of the diketopiperazine-containing siderophores (rhodo-torulic acid 68), dimerum acid 69), coprogen 70) and coprogen B 69>), the cyclic hexa-peptides of the ferrichrome family27), the fusarinines 71 -73) and the antibiotic ferri-chrome derivatives albomycines Sl5 S2 and e 61-62). 

Studies on the chelation of iron(ii) with a number of individual monoamines and ATP have been performed. The nature of the interaction of phosphatidylserine (a membrane-bound phospholipid) with iron(ii) has also been studied. Amines and ATP chelate to iron(ii) in the pH range 6.8—7.2. Phosphatidylserine (PS) co-ordinates to iron(ii)-ATP to give the ternary chelate Fe(ATP)(PS) at pH 5—6.5. The Fe " ion in ferrioxamine E is co-ordinated in a cis configuration to three hydroxamate groups. The molecule is flat with a total thickness of 3.6 A. ... 

Naturally Occurring Ligands Table 7 The Known Ferrioxamines... 

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