1. Novel Tetralone-Derived Retinoic Acid Metabolism Blocking Agents: Synthesis and in Vitro Evaluation with Liver Microsomal and MCF-7 CYP26A1 Cell Assays
- Author
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Mohamed Gomaa, Carole Elford, Liling Ooi, Michael P. Coogan, Laetitia Jarno, Richard Andrew McClelland, Robert Ian Nicholson, Andrea Brancale, Claire Simons, Bronwen Alice James Evans, and Sook Wah Yee
- Subjects
Models, Molecular ,medicine.drug_class ,Retinoic acid ,Tretinoin ,In Vitro Techniques ,Models, Biological ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cytochrome P-450 Enzyme System ,Cell Line, Tumor ,Drug Discovery ,Tetralone ,medicine ,Cytochrome P-450 Enzyme Inhibitors ,Humans ,Liarozole ,Retinoid ,Tetralones ,chemistry.chemical_classification ,Unspecific monooxygenase ,Binding Sites ,biology ,Chemistry ,Cytochrome P450 ,Stereoisomerism ,Retinoic Acid 4-Hydroxylase ,Enzyme ,Biochemistry ,Microsomes, Liver ,biology.protein ,Molecular Medicine ,medicine.drug - Abstract
The potent inhibitory activity of novel 2-benzyltetralone and 2-benzylidenetetralone derivatives vs liver microsomal retinoic acid metabolizing enzymes and a MCF-7 CYP26A1 cell assay is described. In the liver microsomal assay, the 2-biphenylmethyl-6-hydroxytetralone derivatives 16a and 16b were found to be potent inhibitors (IC50 = 0.5 and 0.8 microM) compared with the broad spectrum P450 inhibitor ketoconazole and the retinoid mimetic R115866 (IC50 = 18.0 and 9.0 microM, respectively). In the MCF-7 CYP26A1 cell assay, the 2-(4-hydroxybenzyl)-6-methoxytetralone 5 and unsaturated benzylidene precursor 6 were found to be the most potent (IC50 = 7 and 5 microM, respectively), which was comparable with liarozole (7 microM) but considerably less active than R115866 (IC50 = 5 nM). With a CYP26A1 homology model, the tetralones were shown to be positioned in a hydrophobic tunnel with additional interactions, e.g., transition metal coordination and hydrogen-bonding interactions with GLY300, observed for the potent 4-hydroxyphenyl substituted inhibitors.
- Published
- 2005
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