Desferrioxamine DFO

DFO, desferrioxamine Dfx, desulfoferrodoxin DHA, docosahexaenoic acid DHE, dihydroethidium DHLA, dihydrolipoic acid DHR, dihydrorhodamine 123... 

Fig. 8. (upper panel) The oxidation of haem proteins, (lower panel) The cycling of haem proteins through the action of oxidation and reductants. Abbreviations DFO, desferrioxamine MH, /v -methyl-/V-hcxanoyl hydroxamate NAC,. V-acetyl cysteine GSH, glutathione MPG, mercaptopropionyl... 

Figure 4.1 PMl curves calculated for metal ion-chelating agents bj using computer simulation. PMI is as defined in the text. Ligand symbols Tren — tri-ethylenetetramine EDTA = ethylenediaminetetraacetic acid DTP A = diethylenetriaminepentaacetic acid CDTA = cyclohexylenedijiitrotetra-acetic acid Pen = n-penicillamine OxPen = D-penicillamine-S-S-D-penicillamine, i.e. dimer of Pen BAL = 2,3-dimercaptopropanol DFO = desferrioxamine...

Chelators of iron, which are now widely applied for the treatment of patients with thalassemia and other pathologies associated with iron overload, are the intravenous chelator desferal (desferrioxamine) and oral chelator deferiprone (LI) (Figure 19.23, see also Chapter 31). Desferrioxamine (DFO) belongs to a class of natural compounds called siderophores produced by microorganisms. The antioxidant activity of DFO has been studied and compared with that of synthetic hydroxypyrid-4-nones (LI) and classic antioxidants (vitamin E). It is known that chronic iron overload in humans is associated with hepatocellular damage. Therefore, Morel et al. [370] studied the antioxidant effects of DFO, another siderophore pyoverdin, and hydroxypyrid-4-ones on lipid peroxidation in primary hepatocyte culture. These authors found that the efficacy of chelators to inhibit iron-stimulated lipid peroxidation in hepatocytes decreased in the range of DFO > hydroxypyrid-4-ones > pyoverdin. It seems that other siderophores are also less effective inhibitors of lipid peroxidation than DFO [371],... 

Figure 2.3 (a) The metal chelator desferrioxamine (DFO) and (b) its complex with iron. 

The choice of iron chelators on the basis of both molecular and cellular criteria was discussed in 2003 (374). One 2005 review is concerned with the design of orally active iron chelators (375), another considers the prospects for effective clinical use of several hydro-x5rpyridinones, dealing with novel species such as the 1-allyl compound as well as with the established deferiprone (LI) and desferrioxamine (Desferal, DFO) (376). A review dated 2006 deals with relevance of iron mobilization from both transferrin and other iron-containing proteins by LI to the treatment of various anemias and other iron-overload conditions (377). Two 2007 reviews concentrate on LI, as the only hydroxypyridinone in general clinical use. One author concludes that, on balance, LI is to be preferred to DFO. This conclusion is on the grounds that, despite the not infrequent occurrence of minor side effects, the incidence of serious side effects... 

In accordance with Emery s retro-hydroxamate ferrichrome, mentioned above, two retro analogs of the linear ferrioxamine G and cyclic desferrioxamine E (129 and 130, respectively) were prepared. The iron-chelating properties were compared to DFO, showing that the linear retro-desferrioxamine G (131) binds iron faster and the cyclic retro desferrioxamine E (132) has improved affinity to iron, compared to the linear DFO. Based on these resnlts, many retro-hydroxamate ferrioxamines were prepared. In a later paper, Akiyama and coworkers reported the attachment of -cyclodextrin, a cyclic oligosaccharide, composed of seven a-D-glucopyranoside units, linked from position 1 to position 4, to linear retro-hydroxamate ferrioxamines (133 and 134), which formed 1 1 iron(III) complexes. Influenced by the chiral -cyclodextrin gronp, 133 and 134 formed A-selective coordination around the metal ion. In addition, Akiyama proposed that the... 

Unlike desferrioxamine analogs designed for specific therapeutic purposes described above, chiral DFO analogs that form conformationally unique complexes with iron(lll) were designed to serve as chemical probes of microbial iron(lll) uptake processes. As mentioned above, ferrioxamine B can form a total of five isomers when binding trivalent metal ions, each as a racemic mixture. Muller and Raymond studied three separate, kinetically inert chromium complexes of desferrioxamine B (N-cis,cis, C-cis,cis and trans isomers), which showed the same inhibition of Fe-ferrioxamine B uptake by Streptomyces pilosus. This result may indicate either that (i) ferrioxamine B receptor in this microorganism does not discriminate between geometrical isomers, or that (ii) ferrioxamine B complexes are conformationally poorly defined and are not optimal to serve as probes. 

The high efficiency and selectivity of the natural siderophores in binding iron(lll) inspired attempts to develop siderophore analogs with improved iron-scavenging properties amenable for chelation therapy. A most pertinent example is desferrioxamine B (DFO), where low patient compliance generates the need for developing oral means of administration for... 

Desferrioxamine (DFO-B), the natural siderophore initially isolated from Streptomyces pilosus, is the only iron chelator currently used for clinical treatment of iron-overload disease such as thalassemia, sickle cell anemia and hemochromatosis ° . ... 

There is a considerable difference in the antimalarial action of desferrioxamine B (DFO) and the hydrophobic chelators based on ferrichrome analogs. While the former is limited to mature forms in the life cycle of P. falciparum (trophozoites and schizonts), the latter effects to a greater extent early developing stages (ring). Therefore, studies explored... 

Clinically, the administration of desferrioxamine (DFO)76 has been reported to increase urinary A1 excretion in humans and to slow the progression of AD symptoms in a small number of patients.77 Very recently, a major step in the diagnosis of AD was reported in the preparation of antibodies that specifically recognize PHFs in human brain tissue.78 This may lead to a diagnostic test, which is a very pressing need because other conditions that cause dementia, such as depression and drug toxicity, are reversible. Also therapy for AD may be more effective if it is diagnosed early. Presently AD can only be confirmed on autopsy. 

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... 

Siderophores,hexadentate tris-catecholate and tris-hydroxamate ligands, are produced by many microorganisms to facihtate iron uptake. Several synthetic models, such as trencam (35) and licams (36), for the tris-catecholate enterobactin (37) do not quite match its affinity for iron(ni) (Table 8). Similar tris-hydroxamate ligands model naturally occurring ferrichromes and desferrioxamines (e g. dfo, (38)). 

Cianciulli P, Sorrentino F, Maffei L, Amadori S. Continuous low-dose subcutaneous desferrioxamine (DFO) to prevent allergic manifestations in patients with iron overload. Ann Hematol 1996 73(6) 279-81. 

---