Iron chelators applications

In a recent patent application, mice treated with a related iron chelator, deferasirox (DFS), showed reduced body weight while on a high fat diet compared to untreated controls. Additionally, DFS was claimed to improve whole body metabolism and energy expenditure as measured by increased 02 consumption and C02 production as well as a reduction in white adipose and visceral fat, despite little difference between food intake in the control and treated animal groups [25]. 

The most successful up-to-date treatment of thalassemic patients is chelating therapy, which is based on patient s lifetime application of iron chelators. Removal of excess iron is supposed to be effective route for suppressing free radical-mediated damage. There is a great number of studies showing successful treatment of thalassemic patients with intravenous chelator desferal (desferrioxamine) and oral chelator deferiprone (LI). Biochemical studies show the efficacy of both chelators in removal of excess iron. For example, the incubation of thalassemic erythrocytes with 0.5 mmol 1 1 LI during 6h resulted in 96% removal of membrane-free iron [392], It was demonstrated that LI is able to remove pathologic deposits of... 

Vergne AF, Walz AJ, Miller MJ (2000) Iron Chelators from Mycobacteria (1954-1999) and Potential Therapeutic Applications. Nat Prod Rep 17 99... 

The high specificity of siderophore iron coordination has been extensively explored in iron-chelation therapy for various medical applications, including iron overload diseases, control of iron in specific brain tissues , arresting the growth and proliferation of malaria parasite within their host , as well as arresting the proliferation of cancer cells . Other directions for metal ligation involve enzyme inhibition, which have been demonstrated by the inhibition of urease by coordination of hydroxamate ligand to nickel ions and zinc coordination in matrix metalloprotease (MMP) inhibition by primary hydroxamates. ... 

Liu ZD, Hider RC. 2002. Design of iron chelators with therapeutic application. Coord Chem Rev 232 151-171. 

Tannic acid has been reported to inhibit the formation of hydroxyl radical by chelation of Fe2+ [16], Because tannic acid is a plant-derived material, it and other natural polyphenols may be important for subsurface applications of Fenton chemistry. A study of 50 different iron chelators assessed the affect of each chelator on the Fenton process initiated with Fe3+ and hydrogen peroxide [17]. Among the nine classes of chelators tested, results indicated that the chelators ranged from inactive to highly active in terms of hydroxyl radical formation. 

Since the development of chelate chemistry has taken place almost wholly within the last three decades, the number of applications that have been found for this class of compounds is quite remarkable. Mail may not, however, take credit for the two most important uses of chelate compounds the use of the magnesium chelate, chlorophyll, as a catalyst for the incorporation of the hydrogen of water into plant systems and the use of the iron chelate, heme, as an oxygen carrier in human respiration. The ring system in both heme and chlorophyll is essentially that shown for copper porphyrin in Figure 22-4, but there are organic substituents on... 

A wide range of iron chelators have been shown to inhibit ribonucleotide reductase [144-146] and this is likely to be the explanation of the cytotoxic properties of such molecules. Some iron chelators may also function as free radical scavengers. For instance, hydroxyurea appears to inhibit the enzyme by this latter mode of action [144], Such inhibitory agents block the cell division cycle in the S-phase because replication of cellular DNA is arrested. This also suggests possible therapeutic applications. 

Iron chelators of the hydroxypyridin-4-one class may well find application in treatment of tumour cell types which are relatively sensitive to cell synchronisation, an aspect which is under current investigation [86]. 

It was stated earlier that the vast majority of pharmaceutical solvates are hydrates. There are a few studies, however, in which other solvates of drugs have been studied. Ghosh et al. (27) examined a range of dialkylhydroxypyridones (iron chelators with possible application for the treatment of anemias) and compared their structures to their corresponding formic acid solvates. TGA was able to monitor the loss of formic acid, providing complementary information for spectroscopic studies that in turn were able to provide a molecular-level explanation for the desolvation profiles. 

We have also initiated MUssbauer spectroscopic studies of photochemical reactions of inorganic and organometallic compounds (iron chelate complexes, iron carbonyl and organotin compounds) isolated in low temperature matrices. Such systems provide a complimentary approach to solid-phase photochemistry since the reaction mechanisms may be simplified by isolating the reactant molecules in inert matrices (light transmission through the reactant is also facilitated by diluting tlie colored reactant with a transparent medium). Furthermore, we have a hope for the possible outcome of such studies — their application to syntheses of novel species which may be unstable at ordinary temperatures, unless trapped in inert matrices. 

The cellular levels of iron and ferrochelatase are important determinants of PpIX yield under exogenous ALA stimulation. The use of iron chelators is based on the relative inefficiency of ferrochelatase compared to other enzymes, which causes PpIX build-up when heme precursors are produced at an increased rate. In some cancer cell lines lower levels of ferrochelatase have been found than in normal cells and this may contribute to tumor selectivity in certain cancers [197]. In an attempt to further reduce or totally abrogate heme formation, exogenous chelating agents were used to remove iron. It was shown in vitro that iron chelation caused both increased PpIX formation and improved PDT efficacy and in vivo applications in animals and humans have confirmed the concept [191,198,199]. In lymphocytes that express the transferrin receptor (CD71), which is interpreted as an indication of low intracellular iron levels, higher PpIX concentrations were reached under ALA stimulation [200]. In addition, an analysis of iron availability at the molecular level... 

Lee, B.H., G.J. Gerfen, and M.J. Miller Constituents of Microbial Iron Chelators. Alternate Syntheses of 6-N-Hydroxy-a-ornithine Derivatives and Applications to the Synthesis of Rhodotorulic Acid. J. Organ. Chem. (USA) 49, 2418 (1984). 

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