Iron chelators design

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. 

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... 

The physical and coordination chemistry of hydroxamate-based iron chelators, their thermodynamic, kinetic, structural, spectroscopic and surface properties, have been extensively reviewed Therefore, only selective aspects that are relevant for the design of biomimetic siderophore analogs will be discussed. 

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

As important as calcium is probably iron [122]. Iron is the metal center of many essential proteins and enzymes, such as hemoglobin, an oxygen carrier, or peroxidase, that oxidizes hydrogen peroxide, or even the large family of cytochromes, which act as electron transfer proteins in many important biochemical processes [85]. New families of MRI contrast agents have been designed such that their relaxivity is iron concentration dependent [128-130]. The two latest are based on Gd(III) chelates (Fig. 20) but differ by the mechanism responsible for their iron sensitivity and will be described further. 

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