Synthetic and Natural Products as Iron Chelators

An evaluation of existing and proposed Fe chelators, both synthetic and natural products, for the treatment of Fe-overload disease must address a number of issues. There are fundamental parameters that determine the efficacy of a drug: absorption, distribution, metabolism, clearance and toxicity. However, the administration of chelators for Fe overload aims to generate Fe complexes in vivo that are able to be excreted. Hence, the chemical and pharmacological properties of the complexes formed are as equally important as the chelators themselves. The redox properties of the Fe complexes formed are particularly relevant to their toxicity. If both Fe-II and Fe-III oxidation states of the complexes are biologically accessible, then there is potential for the catalytic production of deleterious free radicals by Fenton-type chemistry. In addition, since the burden of Fe overload disease falls predominantly on some of the poorest economies, the cost of a drug must be considered, as well as the mode of delivery. There are also possible issues with the use of naturally occurring ligands, which may form Fe complexes capable of being utilised by opportunistic bacteria. This review will concentrate on recent developments in our chemical understanding of existing chelators approved or proposed for use and will also consider some of the candidates from natural sources that have been recently proposed.