Document Detail


The design, synthesis, and evaluation of organ-specific iron chelators.
MedLine Citation:
PMID:  17125256     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A series of iron chelators, three (S)-4,5-dihydro-2-(2-hydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid (DADFT) and three (S)-4,5-dihydro-2-(2-hydroxyphenyl)-4-thiazolecarboxylic acid (DADMDFT) analogues are synthesized and assessed for their lipophilicity (log Papp), iron-clearing efficiency (ICE) in rodents and iron-loaded primates (Cebus apella), toxicity in rodents, and organ distribution in rodents. The results lead to a number of generalizations useful in chelator design strategies. In rodents, while log Papp is a good predictor of a chelator's ICE, chelator liver concentration is a better tool. In primates, log Papp is a good predictor of ICE, but only when comparing structurally very similar chelators. There is a profound difference in toxicity between the DADMDFT and DADFT series: DADMDFTs are less toxic. Within the DADFT family of ligands, the more lipophilic ligands are generally more toxic. Lipophilicity can have a profound effect on ligand organ distribution, and ligands can thus be targeted to organs compromised in iron overload disease, for example, the heart.
Authors:
Raymond J Bergeron; Jan Wiegand; James S McManis; Neelam Bharti
Related Documents :
2322316 - Generation of volatile hydrocarbons from amino acids and proteins by an iron/ascorbate/...
2564876 - Testing of methyleneiminodiacetic-catechol and other aromatic chelating agents for deco...
9477426 - Effect of callosobruchus chinensis (bruchid) infestation on antinutritional factors in ...
8267656 - Possible role of an iron-oxygen complex in 4(s)-4-hydroxyochratoxin a formation by rat ...
19904926 - Boron-catalyzed direct aldol reactions of pyruvic acids.
17374376 - A sensitive liquid chromatographic method for the analysis of isovaleric and valeric ac...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  49     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2006 Nov 
Date Detail:
Created Date:  2006-11-27     Completed Date:  2007-02-15     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7032-43     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Bile / metabolism
Carboxylic Acids / chemical synthesis*,  chemistry,  pharmacology
Cebus
Dihydropyridines / chemical synthesis,  chemistry,  pharmacology
Iron Chelating Agents / chemical synthesis*,  chemistry,  pharmacology
Iron-Dextran Complex / blood,  pharmacokinetics,  urine
Kidney / metabolism
Liver / metabolism
Male
Myocardium / metabolism
Organ Specificity
Pancreas / metabolism
Rats
Rats, Sprague-Dawley
Stereoisomerism
Structure-Activity Relationship
Thiazoles / chemical synthesis*,  chemistry,  pharmacology
Tissue Distribution
Grant Support
ID/Acronym/Agency:
R37 DK049108/DK/NIDDK NIH HHS; R37 DK049108-11/DK/NIDDK NIH HHS; R37 DK049108-11S1/DK/NIDDK NIH HHS; R37-DK49108/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Carboxylic Acids; 0/Dihydropyridines; 0/Iron Chelating Agents; 0/Thiazoles; 0/desazadesferrithiocin; 9004-66-4/Iron-Dextran Complex
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Carbonic anhydrase inhibitors: clash with Ala65 as a means for designing inhibitors with low affinit...
Next Document:  Analysis of the structure-activity relationship of four herpesviral UL97 subfamily protein kinases r...