Some 1,2-diphenylethane derivatives as inhibitors of retinoic acid--metabolising enzymes.
In a search for novel inhibitors of RA-metabolising enzyme inhibitors as potential anti-cancer agents some 1,2-ethandiones, 2-hydroxyethanones and 1-ethylenedioxyethanones based on aryl-substituted 1,2-diphenylethane have been examined. Several of the compounds were weak inhibitors of the non-specific rat liver microsomal P450 enzymes and moderate inhibitors of the RA-induced enzymes in cultured human genital fibroblasts, where the RA-specific enzyme CYP26 is probably expressed. The 2-hydroxyethanone (13) with a 1-(4-dimethylaminophenyl) substituent was overall the most potent compound for rat liver microsomal enzyme (IC50 = 52.1 microM; ketoconazole, 2.8 microM) and the RA-induced enzyme (100 microM, 65.9% inhibition; ketoconazole, 20 microM, 75.0%). Modification of the dimethylamino group in (13) with more hydrophobic dialkylamino functions or separate modification of the 2-(2,4-dichlorophenyl) function did not improve potency.
Greer
V P
VP
Welsh School of Pharmacy, Cardiff University, Cathays Park, Cardiff, CF10 3XF, UK.
Mason
P
P
Kirby
A J
AJ
Smith
H J
HJ
Nicholls
P J
PJ
Simons
C
C
D000818:Animals; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004980:Ethane / Q000737:chemistry*; D005347:Fibroblasts; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D013267:Stilbenes / Q000737:chemistry*; D014212:Tretinoin / Q000378:metabolism*; D000081014:Dihydrostilbenoids
D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D004791:Enzyme Inhibitors; D004980:Ethane; D013267:Stilbenes; D014212:Tretinoin; C038546:1,2-dihydrostilbene; D000081014:Dihydrostilbenoids