Phenolic iron chelator

Morel et al. (1993) have reported that three flavanoids (catechin, quercetin and diosmetin) are cytoprotective on iron-loaded hepatocyte cultures. Their cytoprotective activity (catechin > quercetin > diosmetin) correlated with their iron-chelating ability (Morel et al., 1993). These compounds should also be good phenolic antioxidants so iron chelation may only be part of the story. 

In the presence of Fe + it is possible to deprotonate polyphenols at physiological pFIs, to give phenolates which are good ligands for hard 3+ cations such as Fe " ". Speciation in iron(III) — polyphenolate systems has been discussed in relation to possible use of these ligands as iron chelating agents. 

F.sters and lactones of phenolic aminocarbox-ylic acids prodrugs for iron chelation, J. Med. Chem., 29, 1231, 1986. 

For example, a number of potentially useful iron-chelating drugs are derivatives of phenols, carboxylic acids, and amines. Carboxylic acids, being a metabolic end product, are stable to microsomal oxidation but are subject to conjugation. Phenols are similarly subject to conjugation and also to microsomal hydroxyla-tlon. Amines are subject to conjugation (if primary or secondary), and to oxidation and N-dealkylation. 

While chemical principles can be used to design chelators that form stable and specific Fe chelates, uncertainty about the nature and location of the chelatable iron pool and constraints on delivery of suitable chelators to the site of action have determined that iron chelator design is still dominated by empirical testing of structure-function relationships. This in itself adds a new challenge in that there is no perfect animal model for the human iron overload syndromes. Pitt (1981) has pointed out that rodents Fe-loaded with heat-damaged erythrocytes have been used most frequently to assess the ability of chelators to remove iron by the fecal (biliary) and urinary routes and lower parenchymal (liver) and RES (splenic) stores. He reviews LD50 and iron-removal data on many natural and synthetic hydroxa-mates, phenols, catechols, tropolones, salicylates, benzoates, azines, and carboxylates. No clear picture emerges and the search for the ideal iron chelator continues. 

Figure 6 shows the NMR spectra of the model complexes and 1,2-CTD after coordination of catechol and phenols [68-70]. In the case of model monodentate catecholate complexes, the methyl resonance appears at 100 ppm downfield if the 0(1) oxygen is coordinated to the iron and at -30 ppm upfield if the 0(2) oxygen is coordinated. The same shifts are observed for methyl-substituted phenols. For chelated catecholates, the methyl resonance appears at 50 ppm downfield. In the case of CTD, 4-methylcatecholate species exhibit a peak at 100 ppm downfield, indicating that 4-methylcatechol coordinates to the ferric center solely through the 0(1) oxygen, as 6 rather than 7 in Fig. 5. On the other hand, no methyl resonance has been observed with 3-methylcatechol. Considering that 3,6-dimethylcatechol exhibits only one peak near at -25 ppm, the coordination through 0(2) as 8 is suggested for 3-methylcatecholatoiron...

Mono- and polyl dric phenols and enols frequently form characteristically colored complexes with Fe + ions [4, 28, 29]. Here monohydric phenols usually produce reddish-violet colors, while pyrocatechol derivatives yield green chelates [4]. Detection of acetone using Legal s test is based on the formation of an iron complex [4]. The same applies to the thioglycolic acid reaction of the German Pharmacopoeia (DAB 9) [4, 30]. 

Figure 7 Mixld for iron (Fe) deficiency induced changes in root physiology and rhizo-sphere chemistry associated with Fc acquisition in strategy I plants. (Modified froin Ref. 1.) A. Stimulation of proton extru.sion by enhanced activity of the plasnialemma ATPase —> Felll solubilization in the rhizospherc. B. Enhanced exudation of reductanls and chela-tors (carhoxylates. phenolics) mediated by diffusion or anion channels Pe solubilization by Fein complexation and Felll reduction. C. Enhanced activity of plasma membrane (PM)-bound Felll reductase further stimulated by rhizosphere acidificalion (A). Reduction of FolII chelates, liberation of Fell. D. Uptake of Fell by a PM-bound Fell transporter.

V. Romheld, and H. Marschner, Mechanisms of iron uptake by peanut plants 1. Reduction, chelate splitting, and release of phenolics. Plant Physiol. 77 949 (1983). 

MnP is the most commonly widespread of the class II peroxidases [72, 73], It catalyzes a PLC -dependent oxidation of Mn2+ to Mn3+. The catalytic cycle is initiated by binding of H2O2 or an organic peroxide to the native ferric enzyme and formation of an iron-peroxide complex the Mn3+ ions finally produced after subsequent electron transfers are stabilized via chelation with organic acids like oxalate, malonate, malate, tartrate or lactate [74], The chelates of Mn3+ with carboxylic acids cause one-electron oxidation of various substrates thus, chelates and carboxylic acids can react with each other to form alkyl radicals, which after several reactions result in the production of other radicals. These final radicals are the source of autocataly tic ally produced peroxides and are used by MnP in the absence of H2O2. The versatile oxidative capacity of MnP is apparently due to the chelated Mn3+ ions, which act as diffusible redox-mediator and attacking, non-specifically, phenolic compounds such as biopolymers, milled wood, humic substances and several xenobiotics [72, 75, 76]. 

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