Iron overload chelating agents

Glycine, ethylene-N,N -bis-2-(0-hydroxyphenyl)-chelating agents iron overload, 6, 769 Glycine, glycyl-hydrolysis... 

Ponka et al. [372] showed that pyridoxal isonicotinoyl hydrazone (PIH, Figure 19.23) is an iron chelating agent. Numerous studies showed the possibility of using this chelator for the treatment of iron overload disease [373], In subsequent studies the antioxidant activity of PIN has been confirmed. For example, Hermes-Lima et al. [374,375] showed that PIN protected plasmid pUC-18 DNA and 2-deoxyribose against hydroxyl radical damage. 

Hydroxypyranones and hydroxypyridinones are promising candidates as chelating agents for the treatment of iron overload, since many are readily available, they form stable complexes with Fe, and some are permitted food additives. Hydroxypyridinones are to be preferred to hydroxypyranones as the former form the more stable complexes and are less readily metabolized. An extensive literature on synthetic iron chelators has been built up over the past 20 years -we can cite only a very small proportion here. In the 1980s it was established that hydroxypyridinones, usually in the form of... 

The use of chelating or complexing agents to treat metabolic dysfunction. The classical example is the use of D-penicillamine to treat Wilson s disease, which is caused by an inability of the body to metabolize copper in the normal way. Another example is the use of desferrioxamine for iron overload in Cooley s anemia, which is caused by a fault in hemoglobin synthesis. 

The biomimetic approach to the synthesis of new siderophores has not been restricted to studies in the USA Kontoghiorghes241 242,269) has synthesized hydroxypyridones (34, 35) and demonstrated their ability to mobilize iron(III) from ferritin. Intragastric administration of l,2-dimethyl-3-hydroxy-pyrid-4-one (34) proved to be as effective as intramuscular DFOA in mobilizing iron from the iron-overloaded rat. This effectiveness of an orally administered chelating agent is particularly noteworthy. 

Desferrioxamine (DFO) is a trihydroaminic acid obtained from isolates of Streptomyces pilosus. Since 1963 it has been clinically used as an iron-chelating agent in patients with iron overload [261], DFO effectively chelates trivalent ions such as iron and Al, producing respectively ferrioxamine and aluminox-amine [12, 30, 260-269]. DFO displays rather complicated physicochemical characteristics. Unchelated DFO is a straight chained lipophilic molecule that can penetrate plasma membranes and undergo metabolic breakdown. In contact with Al, it twines itself around the metal to form stable hydrophilic... 

Conventional treatments for hemochromatosis and for nutritional iron overload include reduction of dietary iron and periodic removal of blood (phlebotomy) until iron stores are reduced. In transfusion siderosis, it is necessary to eliminate iron via the urine by the intravenous infusion of highly specific chelating agents such as desferral (see Iron Transport Siderophores). This process is painful, laborious, and costly. The development of new orally effective iron chelators is expected. 

The treatment of thalassemia, as in other metal overload disorder, is chelation therapy. The chelating agent most widely nsed is deferoxamine administered subcutaneously. The search for an orally administered iron chelator has intensified in recent years, leading to cUnical trials of many potential new iron chelators snch as deferiprone(Ll). However, many issues regarding the nse of these drugs, such as dose-related toxicity and recommended age of initiation, remain unresolved. " ... 

Templeton D. M. (1995) Theraputic use of chelating agents in iron overload. In Toxicology of Metals—Biochemical Aspects, Handbook of Experimental Pharmacology (eds. R. A. Goyer and M. G. Cherian). Springer, Berlin, vol. 115, pp. 305-332. 

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