| The design, synthesis, and evaluation of organ-specific iron chelators. | |
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MedLine Citation:
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PMID: 17125256 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Raymond J Bergeron; Jan Wiegand; James S McManis; Neelam Bharti |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 49 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 2006 Nov |
Date Detail:
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Created Date: 2006-11-27 Completed Date: 2007-02-15 Revised Date: 2012-02-08 |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
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Languages: eng Pagination: 7032-43 Citation Subset: IM |
Affiliation:
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Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610-0485, USA. rayb@ufl.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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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:
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R37 DK049108-11/DK/NIDDK NIH HHS; R37 DK049108-11S1/DK/NIDDK NIH HHS; R37-DK49108/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Carboxylic Acids; 0/Dihydropyridines; 0/Iron Chelating Agents; 0/Thiazoles; 0/desazadesferrithiocin; 9004-66-4/Iron-Dextran Complex |
| Comments/Corrections | |
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