Hydroxamates, iron removal from

Matsumoto et al. demonstrated that the removal of iron from diferric transferrin by the tris-hydroxamate siderophore mimic TAGE occurs in two discreet steps (90). The slower step corresponds to iron removal from the more stable C-lobe site on transferrin and the faster step to removal from the N-lobe. The rates of removal are similar to the rates of removal of iron from diferric transferrin by desferrioxamine B (4), signifying similar mechanisms of removal between the two systems (90). 

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. ... 

Fe(III) displacement of Al(III), Ga(III), or In(III) from their respective complexes with these tripodal ligands, have been determined. The M(III)-by-Fe(III) displacement processes are controlled by the ease of dissociation of Al(III), Ga(III), or In(III) Fe(III) may in turn be displaced from these complexes by edta (removal from the two non-equivalent sites gives rise to an appropriate kinetic pattern) (343). Kinetics and mechanism of a catalytic chloride ion effect on the dissociation of model siderophore-hydroxamate iron(III) complexes chloride and, to lesser extents, bromide and nitrate, catalyze ligand dissociation through transient coordination of the added anion to the iron (344). A catechol derivative of desferrioxamine has been found to remove iron from transferrin about 100 times faster than desferrioxamine itself it forms a significantly more stable product with Fe3+ (345). 

Froth flotation has proven to be an efficient method of removing titaniferous impurities (mainly iron-rich anatase) from kaolin clays. Fatty acid reagent, primarily tall oil, is used extensively in the reverse flotation of these impurities. This flotation collector typically requires divalent cations (usually Ca +) to activate the coloured impurities and enhance collector adsorption. This is not very selective since the tall oil can also absorb on the kaolinite particles. Alkyl hydroxamate collectors are relatively new in the kaolin industry but provide significant advantages. Hydroxamates do not require activators, substantially increase the removal of colored impurities and are very selective. 

As an alternative to polymers bearing pendant catechols, Winston and his colleagues have prepared hydroxamic acid polymers in which hydroxamate side-chains were linked by oligomethacroyl units216"218. From experiments on iron-overloaded mice four polymers were found to be as good as, or better, than DFOA in removing iron. Several of the polymers had quite low toxicity. A polymeric form of (25) of around 106 Daltons was particularly effective. 

In a departure from the biomimetic catecholamide-based siderophores, Raymond s group have turned to derivatives of l-hydroxy-2(I//)-pyridone a structure which can be regarded as a cyclic hydroxamic acid264. Unlike hydroxamate siderophores, l,5-bis[l,2-dihydro-l-hydroxy-2-oxo-pyridin-6-yl)carbonyl]-l,5-diazaheptane (33) rapidly removes iron from transferrin. 

Reddish-brown plates from water. C4iH5502oN9Fe-4H20. Gives tea-colored solutions with amM=3.74 at 4400 A. The iron is more tightly bound than in ferrichrome log Ks 32. Ferrichrome A is a tricarboxylic acid and on removal of iron with cyanide and Na2S2C>4, deferriferrichrome A is seen to acquire three new acid groups with pKa 9 (hydroxamates). 

The effects of hydroxyurea in the purified ribonucleotide reductase systems of E. coU, phage T4, calf thymus and mouse cells have been described above (p. 36, 42). Inhibition of substrate reduction in vitro (I50 = 2 - 3 10 ) is accompanied by loss of the tyrosyl radical, but not iron from E. coli subunit B2. Studies with substituted hydroxyl-amines and hydroxamates showed good correlation between their ability to undergo one-electron oxidation and enzyme inhibition, unless branched substituents prevented interaction with the protein (Table 8) Thus the mode of inhibition of E. coli ribonucleotide reductase is essentially solved Within steric restrictions of accessibility to the active site the compounds donate an electron to the enzyme s free radical, producing an inactive protein with still intact binuclear iron complex (Eq. VI). This process is irreversible in vitro until iron is removed, and then reintroduced with Fe(II)ascorbate in the presence of oxygen, whereupon radical and enzyme activity reappear. No other enzyme of E. coli has been found to be inactivated by hydroxyurea. 

The key factor is obviously the ability to remove ferric ion from transferrin. This is even more of a kinetic problem than a thermodynamic one. Thus, while the hydroxamates such as desferri-oxamlne B are thermodynamically capable of removing iron from transferrin, klnetlcally they are able to do so at a useful rate only in the presence of other ligands. 

The hydroxamic acid derivative known as Desferrioxamine B methane sulphonate (DFOA), a selective chelator for iron which has been widely used for the treatment of iron overload in man, is effective, either alone or in combination with NajCaDTPA, for the removal of plutonium from rats. However, the compound is ineffective for the removal of americium and the effectiveness for the removal of plutonium was limited to very short times after injection [see Taylor 1991 for references]. 

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