Synthesis, biochemical evaluation of a range of potent 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17[alpha]-Hydroxylase/17,20-Lyase (P450[sub]17[alpha])

Shahid, Imran, Patel, Chirag H., Dhanani, Sachin, Owen, Caroline P. and Ahmed, Sabbir (2008) Synthesis, biochemical evaluation of a range of potent 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17[alpha]-Hydroxylase/17,20-Lyase (P450[sub]17[alpha]). The Journal of Steroid Biochemistry and Molecular Biology, 110(1-2), pp. 18-29. ISSN (print) 0960-0760

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Abstract

We report the synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a number of azole-based compounds as inhibitors of the two components of the cytochrome P-450 enzyme 17alpha-hydroxylase/17,20-lyase (P450(17alpha)), i.e. 17alpha-hydroxylase (17alpha-OHase) and 17,20-lyase (lyase). The results suggest that the compounds synthesised are potent inhibitors, with 7-phenyl heptyl imidazole (11) (IC(50)=320 nM against 17alpha-OHase and IC(50)=100 nM against lyase); 1-[7-(4-fluorophenyl) heptyl] imidazole (14) (IC(50)=170 nM against 17alpha-OHase and IC(50)=57 nM against lyase); 1-[5-(4-bromophenyl) pentyl] imidazole (19) (IC(50)=500 nM against 17alpha-OHase and IC(50)=58 nM against lyase) being the most potent inhibitors within the current study, in comparison to ketoconazole (KTZ) (IC(50)=3.76 microM against 17alpha-OHase and IC(50)=1.66 microM against lyase). Furthermore, consideration of the inhibitory activity against the two components shows that all of the compounds tested are less potent towards the 17alpha-OHase in comparison to the lyase component, a desirable property in the development of novel inhibitors of P450(17alpha). From the modelling of these compounds onto the novel substrate heme complex (SHC) for the overall enzyme complex, the length of the compound, along with its ability to undergo interaction with the active site corresponding to the C(3) area of the steroidal backbone, are suggested to play a key role in determining the overall inhibitory activity.

Item Type: Article
Uncontrolled Keywords: 17 alpha-hydroxylase/17,20-lyase (p450(17 alpha)), synthesis, imidazole-based inhibitors, biochemical evaluation, molecular modeling perspective, aromatase, rationalization, p-450(17-alpha), mechanism, cleavage
Research Area: Chemistry
Faculty, School or Research Centre: Faculty of Health and Social Care Sciences (until 2013)
Faculty of Science (until 2011)
Faculty of Science (until 2011) > School of Pharmacy and Chemistry
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Depositing User: Automatic Import Agent
Date Deposited: 08 Feb 2010 16:16
Last Modified: 20 Jan 2012 14:00
URI: http://eprints.kingston.ac.uk/id/eprint/7008

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