Novel Tetralone-Derived Retinoic Acid Metabolism Blocking Agents:  Synthesis and in Vitro Evaluation with Liver Microsomal and MCF-7 CYP26A1 Cell Assays

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 <BO>16a</BO> and <BO>16b</BO> were found to be potent inhibitors (IC<INF>50</INF> = 0.5 and 0.8 μM) compared with the broad spectrum P450 inhibitor ketoconazole and the retinoid mimetic R115866 (IC<INF>50</INF> = 18.0 and 9.0 μM, respectively). In the MCF-7 CYP26A1 cell assay, the 2-(4-hydroxybenzyl)-6-methoxytetralone <BO>5</BO> and unsaturated benzylidene precursor <BO>6</BO> were found to be the most potent (IC<INF>50</INF> = 7 and 5 μM, respectively), which was comparable with liarozole (7 μM) but considerably less active than R115866 (IC<INF>50</INF> = 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.