Iron-chelating agents

Iron-chelating agents 4.5 Use of microbial enzymes in sterility... 

Bowern, N., Ramshaw, LA., Clark, LA. and Doherty, P.C. (1984). Inhibition of autoimmune neuropathological process by treatment with an iron-chelating agent. J. Exp. Med. 160, 1532-1543. 

Dexrazoxane -iron chelating agent (cardioprotectant) -leukopenia and thrombocytopenia -nausea and vomiting -elevated liver function tests -hypotension... 

This was significant in the preparation of l,2-dimethyl-3-hydroxy-4-pyridone, employed clinically as an iron chelating agent. The aminoreductone is obtained by reaction of methylamine with maltol. Traces of metal within the system readily form highly colored complexes with reactant or product and these are difficult to remove. With the CMR, the preparation was achieved in 65 % yield without the need for decolorizing charcoal and the product was crystallized by collecting the effluent in acetone (Scheme 2.10) [22]. 

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. 

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. 

It is a iron chelating agent, available for intramuscular, subcutaneous and intravenous administration. 

The main dose-limiting toxicity of all anthracyclines is myelosuppression, with neutropenia more commonly observed than thrombocytopenia. In some cases, mucositis is dose-limiting. Two forms of cardiotoxicity are observed. The acute form occurs within the first 2-3 days and presents as arrhythmias or conduction abnormalities, other electrocardiographic changes, pericarditis, and myocarditis. This form is usually transient and is asymptomatic in most cases. The chronic form results in a dose-dependent, dilated cardiomyopathy associated with heart failure. The chronic cardiac toxicity appears to result from increased production of free radicals within the myocardium. This effect is rarely seen at total doxorubicin dosages below 500-550 mg/m2. Use of lower weekly doses or continuous infusions of doxorubicin appear to reduce the incidence of cardiac toxicity. In addition, treatment with the iron-chelating agent dexrazoxane (ICRF-187) is currently approved to prevent or reduce anthracycline-induced cardiotoxicity in women with metastatic breast cancer who have received a total cumulative dose of doxorubicin of 300 mg/m2. All anthracyclines can produce "radiation recall reaction," with erythema and desquamation of the skin observed at sites of prior radiation therapy. 

The incubation of spinach ferredoxin (Fry and San Pietro (46)) or bacterial ferredoxin (Lovenberg, Buchanan, and Rabinowitz (65)) with the iron chelating agent, o-phenanthroline, results in removal of the iron from the protein and in the formation of a ferrous triphenanthrolate complex. Under these conditions, all of the iron appears to be in the ferrous state, but this does not constitute proof that iron of the native protein is also in the ferrous state. Reduction of bound ferric iron could occur... 

The other therapeutic strategy is based on selective inhibition of iron-containing enzymes [260]. The inhibition of ferrochelatase by iron chelating agent l,2-diethyl-3-hydroxy-4-pyridione increases the level of its substrate protoporphyrin IX, which acts as an endogenous photosensitizer formed during PDT from 5-aminolevulinic acid [5,261]. 

Curnov A,McIlroy BW, Postle-Hacon MJ, Porter JB,MacRobert AJ,Bown SG. Enhancement of 5-aminolaevulinic acid induced photodynamic therapy using hydroxypyridi-none iron chelating agents. Br J Cancer 1998 78 1278. 

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... 

The reactivity of clostridial ferredoxin with iron chelating agents and... 

Fig. 2. Bidentate and hexadentate hydroxamate iron chelating agents. Iron is most stable when bound by six oxygen atoms arranged octahedrally around the metal ion. A bidentate ligand occupies two of the above positions, requiring a total of three molecules to totally encompass the iron atoms. In contrast, all six coordination positions are occupied by a single hexadentate molecule.

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)... 

Most bacteria have the ability to produce and secrete molecules—called siderophores—to fulfill their iron requirements. Siderophores are special iron-chelating agents that facilitate iron solubilization and uptake. They are water-soluble, low-molecular weight molecules that bind ferric ions strongly. The ability of bacteria to utilize siderophores is associated with the presence of transport systems that can recognize and mediate uptake of the ferric-siderophore complexes into the cell. These iron-acquisition systems are regulated in response to iron availability, and their action thus increases under iron limitation conditions. 

A safe, effective, inexpensive, orally-absorbed iron chelating agent would improve compliance and the quality of life of affected patients. Deferiprone, which is the best of many agents examined, is less effective than desferrioxamine, carries a risk of agranulocytosis and may itself cause tissue fibrosis. It remains under clinical trial but may be too toxic for general use. 

This is also true of the daily consumption of black tea (1 cup with 5 g tea in the morning and at lunchtime). Tea is deemed to be an iron-chelating agent (iron tan-nate), which significantly reduces the resorption of iron, particularly in a low-iron diet - with or without ascorbic acid or milk added. (424, 444) We have always made sure that these adjuvant measures are strictly adhered to. 

Adhikari D, Roy TB, Biswas A, Chakraborty ML, Bhattacharya B, Maitra TK, Basu AK, Chandra S. Efficacy and safety of oral iron chelating agent deferiprone in beta-thalassemia and hemoglobin E-beta thalassemia. Indian Pediatr 1995 32(8) 855-61. 

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