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 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.
Yee
Sook Wah
SW
Medicinal Chemistry, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK.
Jarno
Laetitia
L
Gomaa
Mohamed Sayed
MS
Elford
Carole
C
Ooi
Li-Ling
LL
Coogan
Michael P
MP
McClelland
Richard
R
Nicholson
Robert Ian
RI
Evans
Bronwen A J
BA
Brancale
Andrea
A
Simons
Claire
C
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
D065607:Cytochrome P-450 Enzyme Inhibitors; D044024:Tetralones; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase