Bidentate siderophores

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). 

An examination of equilibrium expressions for different side-rophore denticities will illustrate nature s preference toward hexadentate siderophores. There is a concentration effect when comparing lower denticity siderophores to their higher denticity analogs. pH-independent equilibrium expressions for generic bidentate and hexadentate siderophores are shown below, where Hx represents a hexadentate siderophore and Bd a bidentate siderophore (charges are omitted for clarity). 

Thermodynamic Stability Constants for Iron(III)-Bidentate Siderophore and SlDEROPHORE MlMIC COMPLEXES, MEASURED AT 25 °C... 

Hydroxamate- or catecholate-containing siderophores are strongly absorbing species with characteristic spectra (see Table 1) which can be utilized for spectrophotometric determination of the complex formation constant. Iron(III) hydroxamates absorb in the visible region, producing a broad absorption band in the 420-440 nm region. Iron(III) catecholates exhibit pH-dependent absorption maxima. Unfortunately, the overall Fe + ion complex formation constants cannot be determined directly at neutral pH, because the extremely high stability of siderophore complexes precludes direct measurements of the equilibrium of interest, which would yield the desired formation constant for a tris-bidentate siderophore complex, /3no (equation (2)). ... 

Thus, the role of bidentate siderophores may be to solubilize iron and, by virtue of their kinetic lability, then donate the iron to the more kinetically inert hexadentate siderophores. for specific delivery to the secreting organism. 

Fig. 13. A series of bidentate terephthalamide-based siderophores with differently charged substituents.

One donor group that is only rarely observed in nature is hydroxypyridinone (Fig. 17). As mentioned previously, the sole example found in nature is cepabactin, a bidentate l-hydroxy-2-pyridinone siderophore (8 in Fig. 2) (46). The bidentate 1,... 

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.

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. ... 

Pyoverdins and Azotobactin are known examples of natural fluorescent siderophores that have been isolated from Pseudomonas aeruginosa and Azotobacter vinelandii, res-pectively ° ° . Pyoverdin Pa (171) ° and pyoverdin Pa Til (172) " are members of the pyoverdin family, which are peptide based hexadentate mixed siderophores that consist of a fluorescent chromophore dihydroxyquinoline, which provides a catecholate ligand for Fe(III) coordination in addition to two bidentate hydroxamate ligating groups. 

Azotobactin is a highly fluorescent hexadentate mixed siderophore containing a pyoverdin-like bidentate ligating chromophore, derived from 2,3-diamino-6,7-dihydroxyquinoline, a hydroxamate and a a-hydroxycarboxylic acid for Fe(in) coordination. ... 

Naturally occurring and synthetically accessible siderophores (iron carriers) contain predominantly bidentate pyrocatechinato- or hydroxamato ligands and are of special interest because of their high affinity towards trivalent metal ions, especially towards iron(III) ions [5, 118-127]. The methyl ( )-2-(l-alkyl/aryl-4,5-dihydro-l//-tetrazol-5-ylidene)-2-cyanoacetates 41a-c, first prepared by us [128], also appeared to be suitable as siderophores. 

The obvious method of choice is to model novel structures on natural hydroxamate and catechol siderophores which possess extremely high affinities for iron(III) [35], Hydroxamates possess many advantages for iron(III) chelation, as was outlined in the section on bidentate ligands. However, they tend to possess a low oral activity. Nevertheless, a number have been investigated, including rhodotorulic acid [36], synthetic hexadentate [37] and polymeric hydroxamates [38]. None has proved superior to DFO (Structure 2, Scheme IB). 

Figure 1 Representative siderophores of the hydroxamate and catecholate classes. The hydroxamates are synthesized from the amino acid ornithine that has been modified through hydroxylation and acetylation. Ferrichrome (a) is a prototypical example of the tri-hydroxamate class. Structurally, ferrichrome is a cyclic hexapeptide that consists of three modified ornithine residues (each of which has a hydroxamate side chain) and three glycines. Ferrichrome coordinates ferric iron through its three bidentate hydroxamate side chains. Triacetylfusarinine C (b) is also a cyclic tri-hydroxamate, but the three modified ornithine residues are joined by ester linkages rather than by peptide linkages. Ferrioxamine B (c) is a linear tri-hydroxamate consisting of three peptide-huked modified ornithine residues. Enterobactin (d) is a prototypical example of a catecholate siderophore. It consists of a tri-ester ring from which extend three side chains of chhydroxybenzoyl serine. Each of these siderophores binds ferric iron in a hexadentate manner, which results in full saturation of d orbitals and a very stable complex. Ferric forms are shown in (a) and (b). Desferri-forms are shown in (c) and (d)...

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