Synthetic iron chelators

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 uptake of iron from transferrin by reticulocytes is a time-, temperature-, and energy-dependent process in which integrity of both protein and cells is required (64, 65). Synthetic iron chelates, once thought to be effective iron donors (66), appear to depend on membrane-bound transferrin as an intermediate agent cells depleted of the protein by preincubation and washing no longer accept iron from such complexes (67). When such cells are reincubated with transferrin, their capacity to accept iron initially bound to synthetic chelators is largely restored. 

By substituting two phenyl groups for acetic acids In EDTA, Dr. Arthur Martell of Texas A M University has synthesized one of the strongest synthetic Iron chelators ever made BHBEDA (N,N -Bls((2-hydroxybenzyl))ethylenedlamlne-N,N -dlacetlc acid) (11). 

Fig.2. Some synthetic iron chelators. Structures are numbered for reference in the text. Ill, deferiprone IV, MECAM V, DTPA VII, 2,3-DHB X, EHPG XI, cholylhydroxamic acid XII, HBED XIII, PIH...

Gower, J.D., Ambrose, I.J., Manek, S., Bright, P.S., Dobbin, P.S., Hider, R.C., Goddard, J.G., Thomiley, M.S. and Green, C.J. (1993). The effect of a synthetic hexadentate iron chelator (CP130) and desferrioxamine on rabbit kidneys exposed to cold and warm ischaemia. Agents Actions 40, 96-105. 

M. Treeby, H. Mar.schner, and V. Roniheld, Mobilization of iron and other micronu-trient cations from a calcareous soil by plant-borne, microbial, and synthetic metal chelators. Plant Soil 114 211 (1989). 

Microbes acquire iron by utilizing very specific, low molecular weight iron chelators called siderophores. The resistance of bacteria to previously effective antibiotics can be circumvented in part by covalent coupling of antibiotics to siderophores. Some synthetic siderophores have been found to possess significant antibacterial activity themselves. They have also been found to have considerable potential as nontoxic, organ selective MRI contrast agents (27). 

The peptide bond that is cleaved is the bond between Leu-189 and Asp-190. There are two peptide bonds in close proximity to the iron chelate on Cys-212. The other peptide bond is between He-144 and Gly-145. The Cys-212 sulfur is 5.1 A from the carbonyl carbon of Gly-145, and 5.3 A from the carbonyl carbon of Leu-189. However, the main difference is that the peptide bond of Leu-189-Asp-190 is oriented parallel to Cys-212, while the peptide bond of lie-144-Gly-145 is oriented away for Cys-212. As was seen with cobalt(lll) hydrolysis of peptide bonds, the proximity and orientation of the carbonyl carbon is important for hydrolysis. This approach has been extended to the cleavage of multisubunit proteins. Palladium(n) and platinum(ll) complexes as synthetic peptidases have been reviewed elsewhere. ... 

---