title: Novel tetralone-derived retinoic acid metabolism blocking agents: synthesis and in vitro evaluation with liver microsomal and MCF-7 CYP26A1 cell assays.
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.
authors.affiliation: Medicinal Chemistry, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK.
authors.forename: Sook Wah
authors.initials: SW
authors.lastname: Yee
authors.forename: Laetitia
authors.initials: L
authors.lastname: Jarno
authors.forename: Mohamed Sayed
authors.initials: MS
authors.lastname: Gomaa
authors.forename: Carole
authors.initials: C
authors.lastname: Elford
authors.forename: Li-Ling
authors.initials: LL
authors.lastname: Ooi
authors.forename: Michael P
authors.initials: MP
authors.lastname: Coogan
authors.forename: Richard
authors.initials: R
authors.lastname: McClelland
authors.forename: Robert Ian
authors.initials: RI
authors.lastname: Nicholson
authors.forename: Bronwen A J
authors.initials: BA
authors.lastname: Evans
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.forename: Claire
authors.initials: C
authors.lastname: Simons
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D000072516:Retinoic Acid 4-Hydroxylase; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D044024:Tetralones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014212:Tretinoin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D044024:Tetralones; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase