Document Detail

Impact of the 3,6,9-trioxadecyloxy group on desazadesferrithiocin analogue iron clearance and organ distribution.
MedLine Citation:
PMID:  17564424     Owner:  NLM     Status:  MEDLINE    
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.
Raymond J Bergeron; Jan Wiegand; Neelam Bharti; Shailendra Singh; James R Rocca
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2007-06-12
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  50     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2007 Jul 
Date Detail:
Created Date:  2007-07-05     Completed Date:  2007-09-20     Revised Date:  2012-02-08    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3302-13     Citation Subset:  IM    
Department of Medicinal Chemistry and McKnight Brain Institute, University of Florida, Gainesville, Florida 32610-0485, USA.
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MeSH Terms
Dihydropyridines / chemistry,  pharmacokinetics*
Iron / pharmacokinetics*
Iron Chelating Agents / pharmacology
Magnetic Resonance Spectroscopy
Mass Spectrometry
Rats, Sprague-Dawley
Species Specificity
Thiazoles / chemistry,  pharmacokinetics*
Tissue Distribution
Grant Support
Reg. No./Substance:
0/Dihydropyridines; 0/Iron Chelating Agents; 0/Thiazoles; 0/desazadesferrithiocin; 7439-89-6/Iron

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