Hydroxamate iron chelators

Arceneau JEL, Davis WB, Downer DN, Haydon AH, Byers BR (1973) Fate of Labeled Hydroxamates during Iron Transport from Hydroxamate-Iron Chelates. J Bacteriol 115 919... 

Fig. 2. Bidentate and hexadentate hydroxamate iron chelating agents. Iron is most stable when bound by six oxygen atoms arranged octahedrally around the metal ion. A bidentate ligand occupies two of the above positions, requiring a total of three molecules to totally encompass the iron atoms. In contrast, all six coordination positions are occupied by a single hexadentate molecule.

More recently, the notion that the beneficial effects of iron-chelating agents are simply due to chelation of the metal ion has been challenged [64]. This is due to the demonstrated ability of the commonly used hydroxamate iron chelator desferrioxamine to act as a superoxide and hydroxyl-radical scavenger [65]. The relatively stable desferrioxamine nitroxide free radical (T1/2 10 min)... 

The first example of a helical complex with pre-determined chirality was the dinuclear complex [Fe2(rdt)3], where rdtFl2 is the fungal iron chelator rhodotorulic acid, (15), a dihydroxamate siderophore. Several more helical and chiral Fe " " and Fe complexes are documented in the diimine and in the hydroxamate and catechol sections. A doubly looped ( bow tie ) complex has been constructed with the aid of a tris-terimine ligand (Section 5.4.3.5.7). 

The high specificity of siderophore iron coordination has been extensively explored in iron-chelation therapy for various medical applications, including iron overload diseases, control of iron in specific brain tissues , arresting the growth and proliferation of malaria parasite within their host , as well as arresting the proliferation of cancer cells . Other directions for metal ligation involve enzyme inhibition, which have been demonstrated by the inhibition of urease by coordination of hydroxamate ligand to nickel ions and zinc coordination in matrix metalloprotease (MMP) inhibition by primary hydroxamates. ... 

The physical and coordination chemistry of hydroxamate-based iron chelators, their thermodynamic, kinetic, structural, spectroscopic and surface properties, have been extensively reviewed Therefore, only selective aspects that are relevant for the design of biomimetic siderophore analogs will be discussed. 

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. 

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... 

The second group of hydroxamate-based chelators consists of biomimetic ferrichrome analogs modified by introducing hydrophobic amino acids between the template and the hydroxamic acid binding sites 59, 60, 66, 68, 70, 199 and 200. Since they function to withhold iron from cells in contrast to their original function of iron delivery, they were named reversed siderophores (RSF) . ... 

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 mechanism of 5-LO inhibition by N-hydroxyureas and hydroxamates is clearly more complex than mere iron chelation. There is no doubt that these compounds bind strongly to iron in solution K = 10 /mol for BW-A4C) and that they are not powerful redox compounds, having relatively high electrode potentials Ecv2 V for BW-B70C, 8, and zileu-... 

The iron chelating ability of DFB is due to the hydroxamic acid, a functional group that possesses a natural affinity for iron(III). Also inherent in this structure is a powerful chelate effect due to the 9 atom spacing between hydroxamic acid groups, tdiich permits three neighboring hydroxamic acids to fit the octahedral coordination sphere of the iron(III) without severe steric strain. 

Again, these ferric complexes are very stable (/>K 28) as are the natural iron chelating compounds and they bind ferrous iron relatively weakly (50). In an acid medium (pH 2—6) the hydroxamic acid forms a deep purple 1 1 complex with ferric iron while in neutral or basic solution a brown-red 3 1 complex is formed in which the hydroxamates act as three bidentate ligands which occupy the six octahedral positions about the iron. The 1 1 purple complex has an absorption maximum at 5000—5200 A depending on the nature of the hydroxamic acid ligand. The 3 1 red-brown complex (it becomes yellow-orange on dilution) has an absorption maximum usually between 4250—4400 A with many of the same spectral features as the naturally occurring complexes of ferric iron. 

N, 6-N-di(2,3-dihydroxybenzoyl)-L-lysine (58) is a siderophore produced by Azotobacter vinelandii which has only two catechol groups. However, of the catecholate siderophores by far the best studied is enterobactin. A major difference between hydroxamate and catecholate siderophores occurs in their utilization as transport agents. For the former, the iron complex is taken up by the bacterial cell, the iron released, and the hydroxamate siderophore re-secreted for additional iron chelation. In contrast, enterobactin is destroyed by enzymatic hydrolysis within the cell and therefore the ligand is not recycled. This hydrolysis of the amide linkages of the iron(III) enterobactin lowers the redox potential of the chelate complex sufficiently to allow iron reduction — and thus uptake of iron into the cell metabolism (59, 60). 

Coelichelin, D-hfOrn-D-aHo-Ihr-L-hOrn-D-hfOrn, a tris-hydroxamate 4-peptide discovered by Streptomyces coelicolor genome mining. The ferric-iron-chelating peptide coelichelin contains, beside D-aHo-threo-nine, two unusual amino acid residues d-5-N-formyl-5-N-hydroxyornithine (D-hfOrn) and L-5-N-hydroxyornithine (L-hOrn) [S. Lautm et al.. Nature Chem. Biol. 2005, 1, 265]. 

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