Substituent effects on desferrithiocin and desferrithiocin analogue iron-clearing and toxicity profiles.
Desferrithiocin (DFT, 1) is a very efficient iron chelator when given orally. However, it is severely nephrotoxic. Structure-activity studies with 1 demonstrated that removal of the aromatic nitrogen to provide desazadesferrithiocin (DADFT, 2) and introduction of either a hydroxyl group or a polyether fragment onto the aromatic ring resulted in orally active iron chelators that were much less toxic than 1. The purpose of the current study was to determine if a comparable reduction in renal toxicity could be achieved by performing the same structural manipulations on 1 itself. Accordingly, three DFT analogues were synthesized. The iron-clearing efficiency and ferrokinetics were evaluated in rats and primates; toxicity assessments were carried out in rodents. The resulting DFT ligands demonstrated a reduction in toxicity that was equivalent to that of the DADFT analogues and presented with excellent iron-clearing properties.
Department of Medicinal Chemistry, University of Florida, Box 100485 JHMHC, Gainesville, Florida 32610-0485, USA. rayb@ufl.edu
Raymond J
RJ
Bergeron
Jan
J
Wiegand
Neelam
N
Bharti
James S
JS
McManis
D000284:Administration, Oral; D000818:Animals; D002428:Cebus; D056831:Coordination Complexes / Q000737:chemistry / Q000378:metabolism; D004095:Dihydropyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D004987:Ethers / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D005290:Ferric Compounds / Q000737:chemistry / Q000378:metabolism; D006900:Hydroxylation; D007502:Iron Chelating Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D019190:Iron Overload / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008024:Ligands; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity
D056831:Coordination Complexes; D004095:Dihydropyridines; D004987:Ethers; D005290:Ferric Compounds; D007502:Iron Chelating Agents; D008024:Ligands; D013844:Thiazoles; C050223:desferrithiocin