Impact of the 3,6,9-trioxadecyloxy group on desazadesferrithiocin analogue iron clearance and organ distribution.
The impact of introducing a 3,6,9-trioxadecyloxyl group at various positions of the desazadesferrithiocin (DADFT) aromatic ring on iron clearance and organ distribution is described. Three DADFT polyethers are evaluated: (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT-PE, 3], (S)-4,5-dihydro-2-[2-hydroxy-5-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-5'-(HO)-DADFT-PE, 6], and (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-3'-(HO)-DADFT-PE, 9]. The iron-clearing efficiency (ICE) in rodents and primates is shown to be very sensitive to which positional isomer is evaluated, as is the organ distribution in rodents. The polyethers had uniformly higher ICEs than their corresponding parent ligands in rodents, consistent with in vivo ligand-serum albumin binding studies. Ligand 9 is the most active polyether analogue in rodents and is also very effective in primates, suggesting a higher index of success in humans. In addition, this analogue is also shown to clear more iron in the urine of the primates than many of the other chelators. If this trend were also observed in patients, it would facilitate iron-balance studies in a clinical setting.
Bergeron
Raymond J
RJ
Department of Medicinal Chemistry and McKnight Brain Institute, University of Florida, Gainesville, Florida 32610-0485, USA. rayb@ufl.edu
Wiegand
Jan
J
Bharti
Neelam
N
Singh
Shailendra
S
Rocca
James R
JR
D000818:Animals; D002428:Cebus; D004095:Dihydropyridines / Q000737:chemistry / Q000493:pharmacokinetics*; D007501:Iron / Q000493:pharmacokinetics*; D007502:Iron Chelating Agents / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013844:Thiazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D004095:Dihydropyridines; D007502:Iron Chelating Agents; D013844:Thiazoles; C477594:desazadesferrithiocin; D007501:Iron