Iron chelators for the treatment of iron overload disease: relationship between structure, redox activity, and toxicity.
The success of the iron (Fe) chelator desferrioxamine (DFO) in the treatment of beta-thalassemia is limited by its lack of bioavailability. The design and characterization of synthetic alternatives to DFO has attracted much scientific interest and has led to the discovery of orally active chelators that can remove pathological Fe deposits. However, chelators that access intracellular Fe pools can be toxic by either inhibiting Fe-containing enzymes or promoting Fe-mediated free radical damage. Interestingly, toxicity does not necessarily correlate with Fe-binding affinity or with chelation efficacy, suggesting that other factors may promote the cytopathic effects of chelators. In this review, we discuss the interactions of chelators and their Fe complexes with biomolecules that can lead to toxicity and tissue damage.
Chaston
Timothy B
TB
Children's Cancer Institute Australia for Medical Research, The Iron Metabolism and Chelation Program, Randwick, Sydney, New South Wales, Australia.
Richardson
Des R
DR
D003676:Deferoxamine / Q000494:pharmacology; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000627:therapeutic use*; D000090463:Iron Deficiencies; D019190:Iron Overload / Q000145:classification / Q000188:drug therapy*
D007502:Iron Chelating Agents; D007501:Iron; D003676:Deferoxamine