di-2-pyridylketone-4-4-dimethyl-3-thiosemicarbazone has been researched along with Iron-Overload* in 2 studies
2 other study(ies) available for di-2-pyridylketone-4-4-dimethyl-3-thiosemicarbazone and Iron-Overload
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Conjugates of desferrioxamine B (DFOB) with derivatives of adamantane or with orally available chelators as potential agents for treating iron overload.
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. Topics: Adamantane; Administration, Oral; Animals; Binding Sites; Carboxylic Acids; Cell Proliferation; Cells, Cultured; Chelating Agents; Chromatography, High Pressure Liquid; Crystallography, X-Ray; Deferoxamine; Dogs; Ferric Compounds; Humans; Inhibitory Concentration 50; Iron; Iron Chelating Agents; Iron Overload; Kidney; Models, Molecular; Molecular Structure; Neuroectodermal Tumors, Primitive, Peripheral; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship; Transferrin | 2010 |
Structure-activity relationships of novel iron chelators for the treatment of iron overload disease: the methyl pyrazinylketone isonicotinoyl hydrazone series.
The design of novel Fe chelators with high Fe mobilization efficacy and low toxicity remains an important priority for the treatment of Fe overload disease. We have designed and synthesized the novel methyl pyrazinylketone isonicotinoyl hydrazone (HMPIH) analogs based on previously investigated aroylhydrazone chelators. The HMPIH series demonstrated high Fe mobilization efficacy from cells and showed limited to moderate antiproliferative activity. Importantly, this novel series demonstrated irreversible electrochemistry, which was attributed to the electron-withdrawing effects of the noncoordinating pyrazine N-atom. The latter functionality played a major role in forming redox-inactive complexes that prevent reactive oxygen species generation. In fact, the Fe complexes of the HMPIH series prevented the oxidation of ascorbate and hydroxylation of benzoate. We determined that the incorporation of electron-withdrawing groups is an important feature in the design of N, N, O-aroylhydrazones as candidate drugs for the treatment of Fe overload disease. Topics: Antineoplastic Agents; Ascorbic Acid; Benzoates; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Humans; Hydrazones; Hydroxylation; Iron; Iron Chelating Agents; Iron Overload; Iron Radioisotopes; Isonicotinic Acids; Ketones; Ligands; Oxidation-Reduction; Pyrazines; Structure-Activity Relationship | 2008 |