Conjugates of desferrioxamine B (DFOB) with derivatives of adamantane or with orally available chelators as potential agents for treating iron overload.

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.

• 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)

Chemical References

• Carboxylic Acids
• Chelating Agents
• Ferric Compounds
• Iron Chelating Agents
• Transferrin
• Iron
• Deferoxamine
• Adamantane

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)