Abstract |
Desferrioxamine B (DFOB) conjugates with adamantane-1-carboxylic acid, 3-hydroxyadamantane-1-carboxylic acid, 3,5-dimethyladamantane-1-carboxylic acid, adamantane-1-acetic acid, 4-methylphenoxyacetic acid, 3-hydroxy-2-methyl-4-oxo-1-pyridineacetic acid (N- acetic acid derivative of deferiprone), or 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl] benzoic acid ( deferasirox) were prepared and the integrity of Fe(III) binding of the compounds was established from electrospray ionization mass spectrometry and RP-HPLC measurements. The extent of intracellular (59)Fe mobilized by the DFOB-3,5-dimethyladamantane-1-carboxylic acid adduct was 3-fold greater than DFOB alone, and the IC(50) value of this adduct was 6- or 15-fold greater than DFOB in two different cell types. The relationship between logP and (59)Fe mobilization for the DFOB conjugates showed that maximal mobilization of intracellular (59)Fe occurred at a logP value approximately 2.3. This parameter, rather than the affinity for Fe(III), appears to influence the extent of intracellular (59)Fe mobilization. The low toxicity-high Fe mobilization efficacy of selected adamantane-based DFOB conjugates underscores the potential of these compounds to treat iron overload disease in patients with transfusional-dependent disorders such as beta-thalassemia.
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Authors | Joe Liu, Daniel Obando, Liam G Schipanski, Ludwig K Groebler, Paul K Witting, Danuta S Kalinowski, Des R Richardson, Rachel Codd |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 53
Issue 3
Pg. 1370-82
(Feb 11 2010)
ISSN: 1520-4804 [Electronic] United States |
PMID | 20041672
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Carboxylic Acids
- Chelating Agents
- Ferric Compounds
- Iron Chelating Agents
- Transferrin
- Iron
- Deferoxamine
- Adamantane
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Topics |
- Adamantane
(chemistry, metabolism)
- Administration, Oral
- Animals
- Binding Sites
- Carboxylic Acids
(chemistry)
- Cell Proliferation
(drug effects)
- Cells, Cultured
- Chelating Agents
(chemistry, metabolism)
- Chromatography, High Pressure Liquid
- Crystallography, X-Ray
- Deferoxamine
(chemistry, metabolism)
- Dogs
- Ferric Compounds
(chemistry, pharmacology)
- Humans
- Inhibitory Concentration 50
- Iron
(metabolism)
- Iron Chelating Agents
(chemical synthesis, chemistry, pharmacology)
- Iron Overload
(drug therapy)
- Kidney
(cytology, drug effects)
- Models, Molecular
- Molecular Structure
- Neuroectodermal Tumors, Primitive, Peripheral
(drug therapy)
- Spectrometry, Mass, Electrospray Ionization
- Structure-Activity Relationship
- Transferrin
(metabolism)
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