Hydroxamates ferrioxamines

In accordance with Emery s retro-hydroxamate ferrichrome, mentioned above, two retro analogs of the linear ferrioxamine G and cyclic desferrioxamine E (129 and 130, respectively) were prepared. The iron-chelating properties were compared to DFO, showing that the linear retro-desferrioxamine G (131) binds iron faster and the cyclic retro desferrioxamine E (132) has improved affinity to iron, compared to the linear DFO. Based on these resnlts, many retro-hydroxamate ferrioxamines were prepared. In a later paper, Akiyama and coworkers reported the attachment of -cyclodextrin, a cyclic oligosaccharide, composed of seven a-D-glucopyranoside units, linked from position 1 to position 4, to linear retro-hydroxamate ferrioxamines (133 and 134), which formed 1 1 iron(III) complexes. Influenced by the chiral -cyclodextrin gronp, 133 and 134 formed A-selective coordination around the metal ion. In addition, Akiyama proposed that the... 

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. 

The ferrioxamines form a large group of ferric trihydroxamates composed of residues of acetic acid, succinic acid, l-amino-5-hydroxyl-aminopentane, and l-amino-4-hydroxylaminobutane. Of the.se, only ferrioxamines E (14) and D2 (15) are formally cyclic hydroxamic acids. 

The po.ssible role of a chelate reductase for iron uptake from microbial siderophores has been examined for several plant species (30,47). With certain microbial siderophores such as rhizoferrin and rhodotorulic acid, the reductase may easily cleave iron from the siderophore to allow subsequent uptake by the ferrous iron transporter. However, with the hydroxamate siderophore, ferrioxamine B, which is produced by actinomycetes and u.sed by diverse bacteria and fungi, it has been shown that the iron stress-regulated reductase is not capable... 

Ferrioxamines Hydroxamic acid 3 Species of Nocardia, Micromon-ospora, Streptomyces, and Actinomyces... 

Fig. 19. Plot of redox potentials (Ey2) as a function of pFe3+ values for a series of hexadentate, tetradentate, and bidentate hydroxamic acid siderophores and siderophore mimics. Data from Table V. Legend 1 — ferrioxamine E 2 — ferrioxamine B (4) 3 — H.aLjf4 (11) 4 — H >L 36 (12) 5 - coprogen 6 - ferricrocin 7 - ferrichrome (6) 8 - alcaligin 9 -rhodotorulic acid (3) 10 — NMAHA 11 — AHA 12 — Ly-AHA.

Fig. 29. Ternary complex formed between ferrioxamine B (4) and lauroyl hydroxamic acid.

As mentioned above, transport of siderophores across the cytoplasmic membrane is less specific than the translocation through the outer membrane. In E. coli three different outer membrane proteins (among them FepA the receptor for enterobactin produced by most E. coli strains) recognise siderophores of the catechol type (enterobactin and structurally related compounds), while only one ABC system is needed for the passage into the cytosol. Likewise, OM receptors FhuA, FhuE, and Iut are needed to transport a number of different ferric hydroxamates, whereas the FhuBCD proteins accept a variety of hydroxamate type ligands such as albomycin, ferrichrome, coprogen, aerobactin, shizokinen, rhodotorulic acid, and ferrioxamine B [165,171], For the vast majority of systems, the substrate specificity has not been elucidated, but it can be assumed that many siderophore ABC permeases might be able to transport several different but structurally related substrates. 

A multiple-path mechanism has been elaborated for dissociation of the mono- and binuclear tris(hydroxamato)-iron(III) complexes with dihydroxamate ligands in aqueous solution. " Iron removal by edta from mono-, bi-, and trinuclear complexes with model desferrioxamine-related siderophores containing one, two, or three tris-hydroxamate units generally follows first-order kinetics though biphasic kinetics were reported for iron removal from one of the binuclear complexes. The kinetic results were interpreted in terms of discrete intrastrand ferrioxamine-type structures for the di-iron and tri-iron complexes of (288). " Reactivities for dissociation, by dissociative activation mechanisms, of a selection of bidentate and hexadentate hydroxamates have been compared with those of oxinates and salicylates. ... 

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. 

A more complex set of 1,3,5-benzenetricarboxamids, composed of mono- di- and tritopic iron chelating groups, prepared by Tsubouchi and coworkers", showed that tripodal hydroxamates 47 and 48 were able to form tripodal interstrand complexes with one and two iron(III) ions. The tritopic hydroxamate 49 formed preferably ferrioxamine-like intrastrand structures, where each arm binds an iron(III) ion independently. No microbial activity was reported for 47-49. 

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. 

The five enantiomeric geometrical isomers of ferrioxamine B. The oxygen donor atoms of each hydroxamate group have been omitted for clarity. The A optical isomer is shown in each case. 

Ferrioxamines B and E are prime examples of the linear and cyclic species, respectively. Several members of the series have been prepared by total synthesis, thus establishing the sequence of the contained units (For example, four isomers could be constructed from the hydrolytic products of ferrioxamine B). The three hydroxamate functions must be spatially located so as to form a stable, intramolecular hexa-dentate ferric chelate. Acetylation of ferrioxamine B affords ferrioxa-mine Di ferrioxamine G corresponds to component B with succinic replacing acetic acid cyclization of G yields ferrioxamine E components Ai and D2 carry l-amino-4-hydroxyaminobutane in place of a residue of the next higher homologue. 

Schwarzenbach, G. and K. Schwarzenbach Hydroxamate complexes, I. The stability of the iron (III) complex of simple hydroxamic acids and ferrioxamine B. Helv. Chim. Acta 46, 1390 (1963). 

However, despite large differences in ligand molecular structure, all of the hydroxamate siderophores whose structures have been determined to date have been found to be cis complexes with a coordination geometry about the ferric ion which is substantially identical to the simple tris-(benzhydroxamato)-Fe(III) complex. Thus, while ferrioxamine E is racemic but with a cis geometry (13), x-ray structure analyses of ferrichrome A (14) and ferrichrysin (15) have shown both to be A-cis isomers. 

Both the cis and trans geometrical isomers of chromic ferrioxamine B isomerize to equilibrium solutions with half-lives of several days at room temperature. This is considerably slower than that found for the simple tris hydroxamate complexes such as Cr(men)3 and is caused by the steric constraints of the ferrioxamine B ligand and its hexadentate chelation. 

The second main class of Fem-specific sequestering agents (siderophores) responsible for the acquisition and assimilation of iron employ hydroxamate ligating groups (34).157158 186 Two important subclasses are the ferrioxamines and the ferrichromes (Figure 5). Examples are ferrioxamine B, a linear trihydroxamic acid and ferrichrome A, a cyclic hexapeptide carrying three hydroxamate-containing side chains. 

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. 

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