Hydroxypyridinone ligands

Localised and temporary elevation of iron levels 7.1. Ischaemic tissue 

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) 

Iron and lipid peroxidation following cardiac arrest 

At present it is difficult to distinguish between the different oxygen-radical generating systems in relation to ischaemia/reperfusion-induced tissue injury. It is likely that the formation of oxygen radicals occurs as a result of metabolic processes and that redox-active metal catalysed reactions and the beneficial effects of iron chelators are due to both chelation of the metal and their radicalscavenging properties. 

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. 

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Zr L = a bidentate hydroxypyranonate or hydroxypyridinonate ligand and X is a halide or alkoxide leaving group (264,265). Replacement of chloride by thiocyanate, pyrazine, or water (in acetonitrile solution) in 3-hydroxy-4-pyranonate or 3-hydroxy-4-pyr-idinonate tin(IV) complexes in all cases follows a two-term rate law of the type... 

Trispyrazolylborates are models for tris-histidine active sites in zinc enzymes, e.g., the matrix metalloproteinases involved in breakdown of extracellular matrices. Inhibition of these metalloproteinases may prove valuable in the treatment of, inter alios, cancer and arthritis, so efforts are being made to find appropriate ligands to block the zinc active site. The search has recently moved on from hydroxamates to hydroxypyridinones - l-hydroxy-2-pyridinone is a cyclic analogue of hydroxamic acid. As reported in Section II.B.2 earlier, hydroxypyridinones form stable five-coordinate complexes on reaction with hydrotris(3,5-phenylmethylpyrazolyl)borate zinc hydroxide. Modeling studies suggest that hydroxypyridinonate ligands should be able to access the active site in the enzyme with ease (110). 

Durbin, P.W., Kullgren, B., Ehhe, S.N., Xu, J., Raymond, K.N. (2000). Chelating agents for uranium(VI) 2. Efficacy and toxicity of tetradentate catecholate and hydroxypyridinonate ligands in mice. Health Phys. 78 511-21. 

In Equation (21) the ligand acts in a deprotonated bidentate manner, where m can range from 0 to 4. While the hydroxypyridinonate ligands are themselves a class of compounds, their ability to extract Pu is directly related to their protonation constants. Octyl-1,2-HOPO has the lowest protonation constants among all hydroxypyridinonates thus making it the best agent for extraction from acid solutions, particularly at low acid concentrations. 

Catecholate. Pyrocatecholates of composition U02(l,2-C6H402) xH20(x= 1 or 3) and (pyH)-H[U02(1,2-C6H402)(0H)] H20, as well as the resorcinol compound, U02-(1,3-C6H402), have been reported. The uranyl complexes formed in aqueous solution with 4,5-dihydroxy-3,5-benze-nedisulfonate (Tiron) have been postulated to be trimeric, with the stoichiometry 3 3 U02 tiron based on EXAFS studies. " Mixed catecholate-hydroxypyridinonate ligands are described in the pyridonate section. 

Once the required ligands have been obtained, the formation of complexes is usually straightforward. Metal complexes can often be prepared by direct reaction in solution between the ligand and a metal salt, generally at pHs above seven so that the hydroxypyranone or hydroxypyridinone is in its anionic form. There can be difficulties with purification, as solubility characteristics of ligands and their respective complexes may be inconveniently similar, but recrystallization is usually effective. In cases of difficulty sublimation may successfully separate unreacted ligand from the complex. 

Osmium(VI) forms irons-0s02(malt)2 (98), while dioxouranium(VI) forms irons-U02(malt)2 (98) and many hydroxypyridinonate complexes, with bidentate and with tetradentate (177) ligands - trans-UO2L2 and UO2L, respectively. Several actinide elements form complexes with hexa- and octa-dentate hydrox5rpyridinonates (see Section IV.C.7 later). 

To put hydroxypyranonate and hydroxypyridinonate complexes in context, stability constants for kojate and l,2-dimethyl-3-hydroxy-4-pyridinonate complexes of Mg, Al, Fe, and Gd are compared with stability constants for complexes of these cations with a few other ligands in Table III. That these hydroxypyranonate and hydroxyp5rr-idinonate ligands form stable complexes is immediately apparent. In this section we shall present and discuss a generous, but far from... 

Table XVI shows a selection of stability constants and redox potentials for iron(II) and iron(III) complexes. This Table covers a wide range of the latter, showing how the relative stabilities of the iron(II) and iron(III) complexes are refiected in. B (Fe /Fe ) values. A more detailed illustration is provided by the complexes of a series of linear hexadentate hydroxypyridinonate and catecholate ligands, where again high stabilities for the respective iron(III) complexes are refiected in markedly negative redox potentials (213). The combination of the high stabilities of iron(III) complexes of hydrox5rpyridinones, as of hydroxamates, catecholates, and siderophores, and the low stabilities of their iron(II) analogues is also apparent in Fig. 8. Here redox potentials for hydroxypyranonate and hydroxypyridinonate complexes of iron are placed in the overall context of redox potentials for iron(III)/iron(II) couples. The -(Fe /Fe ) range for e.g., water, cyanide, edta, 2,2 -bipyridyl, and (substituted) 1,10-phenanthrolines is...

An opportunity to use the thermodynamic cycle shown in Fig. 7 was provided by the requirement to estimate stability constants for cerium(IV) complexes of a series of hydroxypyridinones. As stability constants for their cerium(III) analogues had been measured and F °(Ce /Ce ) values established, stability constants for one bidentate and two tetradentate 3-hydroxy-2-pyridinones could be obtained. Log P4 for the former was calculated to be 40.9, log P2 for the complexes of the tetradentate ligands 40.6 and 41.9. These very high values, expected for a 4+ cation, are paralleled by high pCe values between 37 and 38 for the tetradentate ligands (147). 

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