Development of potential iron chelators for the treatment of Friedreich's ataxia: ligands that mobilize mitochondrial iron.
Friedreich's ataxia (FA) is a crippling neurodegenerative disease that is due to iron (Fe) overload within the mitochondrion. One therapeutic intervention may be the development of a chelator that could remove mitochondrial Fe. We have implemented the only well characterized model of mammalian mitochondrial Fe overload to examine the Fe chelation efficacy of novel chelators of the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH) class. In this model we utilize reticulocytes treated with the haem synthesis inhibitor succinylacetone which results in mitochondrial Fe-loading. Our experiments demonstrate that in contrast to desferrioxamine, several of the PCIH analogues show very high activity at mobilizing (59)Fe from (59)Fe-loaded reticulocytes. Further studies on these ligands in animals are clearly warranted considering their potential to treat FA.
Richardson
D R
DR
Iron Metabolism and Chelation Group, Heart Research Institute, Camperdown, Sydney, NSW, Australia. d.richardson@hri.org.au
Mouralian
C
C
Ponka
P
P
Becker
E
E
D000818:Animals; D015195:Drug Design; D005621:Friedreich Ataxia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D007501:Iron / Q000378:metabolism / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D007504:Iron Radioisotopes; D007538:Isoniazid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D010659:Phenylhydrazines; D011730:Pyridoxal / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D012156:Reticulocytes / Q000187:drug effects / Q000378:metabolism
D007502:Iron Chelating Agents; D007504:Iron Radioisotopes; D008024:Ligands; D010659:Phenylhydrazines; C030299:phenylhydrazine; D011730:Pyridoxal; C021079:pyridoxal isonicotinoyl hydrazone; D007501:Iron; D007538:Isoniazid