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  ORCID: https://orcid.org/0000-0002-3082-1008, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419 and Simons, Claire ORCID: https://orcid.org/0000-0002-9487-1100
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
|
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: | Schools > Medicine Schools > Pharmacy Schools > Chemistry |
| Subjects: | R Medicine > RS Pharmacy and materia medica |
| Publisher: | American Chemical Society |
| ISSN: | 0022-2623 |
| Last Modified: | 05 Jan 2024 06:01 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/948 |
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