Iron chelation, modeling

The experimental results imply that the main reaction (eq. 1) is an equilibrium reaction and first order in nitrogen monoxide and iron chelate. The equilibrium constants at various temperatures were determined by modeling the experimental NO absorption profile using the penetration theory for mass transfer. Parameter estimation using well established numerical methods (Newton-Raphson) allowed detrxmination of the equilibrium constant (Fig. 1) as well as the ratio of the diffusion coefficients of Fe"(EDTA) andNO[3]. 

Polansky, J. and Weinreb, B. (1984). Anti-inflammatory agents steroids as anti-inflammatory agpnts. In Pharmacology of the Eye (ed. M.L. Sears) pp. 459-538. Springer Verl, Berlin. Rao, N., Romero, J., Fernandez, M. and Marak, G.E. (1986). Effect of iron chelation on severity of occular inflammation in an animal model. Arch. Ophthalmol. 104, 1369-1371. 

Chelators of transition metals like iron can remove free iron from the injury cascade. The iron chelator, desferri-oxamine, prevented the accumulation of lipid peroxides in 15 min cardiac arrest model in dogs followed by 2 h of resuscitation (Komara et al., 1986). 

Aconitase was first determined to be an Fe-S protein in 1972 by Kennedy, Rauner and Gawron (23). Chemical analyses of inactive enzyme gave values of 2 Fe and 3 S /protein of 66,000 daltons. The observed molar relaxivity of water protons by this preparation of aconitase was 473 M s l (25). This value was an order of magnitude lower than measured in the earlier preparation of Villafranca and Mildvan (21) and much closer to that of Fe-S proteins (26). One mole of Fe + per mole of protein was taken up by the enzyme upon activation in the presence of cysteine and ascorbate, or lost upon inactivation in the presence of the iron chelator ferrozine (27). Gawron s group also demonstrated a correlation between loss of one Fe and loss of enzyme activity, as well as the protection afforded by citrate against both losses. However, the presence of an Fe-S cluster in aconitase remained for the moment a curiosity, in particular because of the unusual Fe/S= stoichiometries. The essential Fe that is correlated with activity continued to be interpreted in terms of the "ferrous-wheel" model. 

Like practically aU living organisms, malaria parasites depend on iron for their growth and replication. This property makes them susceptible to iron deprivation, which can be induced by treatment with iron chelators as shown in in vitro cultures of P. falciparum in animal models of malaria ° and in human trials with... 

The observed selectivities for these reactions led to their proposed transition states. The rationalized model for iron chelation (72, Fig. 9.22) shows that iron... 

In 1993, Evans and co-workers examined phe-box 6, /-pr-box 45, and bu-box 3 ligands in the Diels-Alder reaction of cyclopentadiene 68 and 3-acryloyl-l,3-oxazolidin-2-one 69 using a weak Lewis acid such as copper(II) triflate." The results are summarized in Table 9.9. The reaction was carried out between —50 and —78 °C for 3-18 h and achieved selectivities of up to 98 2 (endo/exo) with an endo ee of >98% (using bu-box 3). Interestingly, the enantiomer produced in these reactions was the (25) configuration, compared to the (2K) isomer obtained with iron(III) and magnesium(II) as reported by Corey. This observed stereochemistry was explained by the chelation model of the copper(II) complex 74 (Fig. 9.23)... 

Although there is some experimental evidence which points to a binding of iron ions by specific cytosolic proteins (see Cytosolic Iron Donor, below), these proteins, with the exception of transferrin, are available only in minute quantities, and the nature and extent of iron-protein interactions are poorly understood. Therefore, a number of nonprotein iron chelates have been studied as possible model donor complexes (Table I). Because of the high stability constants of, for example, the Fe(II)/Fe(III)-8-hydroxyquinoline and Fe(III)-ADP complexes (20), these iron-chelate complexes are unfavorable as iron donors, and in fact no energy-dependent uptake of iron has been detected using these complexes (21, 23). 

The hydrophilic members of the 3-hydroxypyridin-4-one family, e.g. CP20 (Structure 4), also possess anti-inflammatory activities in the acute carrageenan-pleurisy model when presented at relatively high doses [66], Although iron chelators undoubtedly possess anti-inflammatory properties, high concentrations are necessary and selective direction of these molecules to the site of inflammation presents a major problem. 

Hence radical damage to DNA can be detected by the characterization and quantitative measurement of the products derived from the purine and pyrimidine bases. The method is demonstrated here by applying model systems of DNA treated with superoxide-generating systems or hydrogen peroxide in the presence of an iron chelate (Aruoma et al., 1989). Products of radical-mediated base damage in DNA are measured using GC-MS-SIM after acid hydrolysis of DNA and trimethy lsily lation. 

A. L. Crumbliss, Aqueous Solution Equilibrium and Kinetic Studies of Iron Siderophore and Model Siderophore Complexes, in Handbook of Microbial Iron Chelates , ed. G. Winkehnann, CRC Press, Boca Raton, FL, 1991, p. 177. 

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