title: Synthesis and biochemical evaluation of a range of potent benzyl imidazole-based compounds as potential inhibitors of the enzyme complex 17alpha-hydroxylase/17,20-lyase (P450(17alpha)).
abstract: The cytochrome P-450 enzyme, 17alpha-hydroxylase/17,20-lyase (P450(17alpha)), is a potential target in hormone-dependent cancers. Here, we report the synthesis and biochemical evaluation of a range of benzyl imidazole-based compounds which have been targeted against the two components of this enzyme, that is, 17alpha-hydroxylase (17alpha-OHase) and 17,20-lyase (lyase). The results from the biochemical testing suggest that the compounds synthesised are good inhibitors, with N-4-iodobenzyl imidazole (5) (IC50=10.06 microM against 17alpha-OHase and IC50=1.58 microM against lyase) showing equipotent activity against lyase compared to the standard compound, ketoconazole (KTZ) (IC50=3.76+/-0.01 microM against 17alpha-OHase and IC50=1.66+/-0.15 microM against lyase). Furthermore, the compounds tested are less potent towards the 17alpha-OHase component, a desirable property in the development of novel inhibitors of P450(17alpha).
authors.affiliation: Department of Pharmacy, School of Pharmacy and Chemistry, Kingston University, Penrhyn Road, Kingston upon Thames, Surrey KT1 2EE, UK.
authors.forename: Caroline P
authors.initials: CP
authors.lastname: Owen
authors.forename: Sachin
authors.initials: S
authors.lastname: Dhanani
authors.forename: Chirag H
authors.initials: CH
authors.lastname: Patel
authors.forename: Imran
authors.initials: I
authors.lastname: Shahid
authors.forename: Sabbir
authors.initials: S
authors.lastname: Ahmed
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D013254:Steroid 17-alpha-Hydroxylase