Novel tetralone-derived retinoic acid metabolism blocking agents: synthesis and in vitro evaluation with liver microsomal and MCF-7 CYP26A1 cell assays

Yee, Sook Wah, Jarno, Laetitia, Gomaa, Mohamed Sayed, Elford, Carole, Ooi, Liling, Coogan, Michael Peter, McClelland, Richard Andrew, Nicholson, Robert Ian, Evans, Bronwen Alice James, Brancale, Andrea and Simons, Claire 2005. Novel tetralone-derived retinoic acid metabolism blocking agents: synthesis and in vitro evaluation with liver microsomal and MCF-7 CYP26A1 cell assays. Journal of Medicinal Chemistry 48 (23) , pp. 7123-7131. 10.1021/jm0501681

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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 μM) compared with the broad spectrum P450 inhibitor ketoconazole and the retinoid mimetic R115866 (IC50 = 18.0 and 9.0 μM, 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 μM, respectively), which was comparable with liarozole (7 μM) 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Pharmacy Chemistry
Subjects:	R Medicine > RS Pharmacy and materia medica
Publisher:	American Chemical Society
ISSN:	0022-2623
Last Modified:	01 May 2018 18:33
URI:	http://orca.cf.ac.uk/id/eprint/948

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