Synthesis and CYP24A1 inhibitory activity of (E)-2-(2-substituted benzylidene)- and 2-(2-substituted benzyl)-6-methoxy-tetralones

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• 作者：Ahmed S. Aboraia ; Bart Makowski ; Alba Bahja ; David Prosser ; Andrea Brancale ; Glenville Jones ; Claire Simons
• 关键词：Benzylidene tetralones ; Benzyl tetralones ; CYP24A1 ; CYP27A1 ; Enzyme inhibition ; Molecular modelling
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：October 2010
• 年：2010
• 卷：45
• 期：10
• 页码：4427-4434
• 全文大小：572 K

文摘

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 IC₅₀ values of 1.92 μM and 2.08 μM, respectively compared with the standard ketoconazole IC₅₀ 0.52 μM. The 2-bromobenzyl tetralone (4d) showed a preference for CYP27A1 (IC₅₀ 59 nM) over CYP24A1 (IC50 16.3 μM) 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 (IC₅₀ 25.57 μM), exhibited enhanced inhibitory activity towards L148F and M416T mutants, this difference in activity for the L148F mutant has been explained using molecular modelling.