title: Synthesis and CYP24A1 inhibitory activity of (E)-2-(2-substituted benzylidene)- and 2-(2-substituted benzyl)-6-methoxy-tetralones.
abstract: A series of (E)-2-(2-substituted benzylidene)- and 2-(2-substituted benzyl)-6-methoxy-tetralones were prepared, using an efficient synthetic scheme, and evaluated for their inhibitory activity against cytochrome P450C24A1 (CYP24A1) hydroxylase. In general the reduced benzyl tetralones were more active than the parent benzylidene tetralones. The 2-ethyl and 2-trifluoromethyl benzyl tetralone derivatives (4c and 4b) showed optimal activity in this series with IC(50) values of 1.92 microM and 2.08 microM, respectively compared with the standard ketoconazole IC(50) 0.52 microM. The 2-bromobenzyl tetralone (4d) showed a preference for CYP27A1 (IC(50) 59 nM) over CYP24A1 (IC50 16.3 microM) and may be a useful lead in CYP27A1 inhibition studies. The 2-ethylphenyl benzyl derivative (9c), which showed weak activity against the wild type CYP24A1 (IC(50) 25.57 microM), exhibited enhanced inhibitory activity towards L148F and M416T mutants, this difference in activity for the L148F mutant has been explained using molecular modelling.
authors.affiliation: Medicinal Chemistry, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Aboraia
authors.forename: Bart
authors.initials: B
authors.lastname: Makowski
authors.forename: Alba
authors.initials: A
authors.lastname: Bahja
authors.forename: David
authors.initials: D
authors.lastname: Prosser
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.forename: Glenville
authors.initials: G
authors.lastname: Jones
authors.forename: Claire
authors.initials: C
authors.lastname: Simons
mesh_terms: D000818:Animals; D001597:Benzylidene Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D053493:Cholestanetriol 26-Monooxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009154:Mutation; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D044024:Tetralones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D001597:Benzylidene Compounds; D004791:Enzyme Inhibitors; D044024:Tetralones; D013250:Steroid Hydroxylases; D053493:Cholestanetriol 26-Monooxygenase; D065668:Vitamin D3 24-Hydroxylase