Synthesis and biochemical evaluation of a range of potent benzyl imidazole-based compounds as potential inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha])

Owen, Caroline P, Dhanani, Sachin, Patel, Chirag H, Shahid, Imran and Ahmed, Sabbir (2006) Synthesis and biochemical evaluation of a range of potent benzyl imidazole-based compounds as potential inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha]). Bioorganic & Medicinal Chemistry Letters, 16(15), pp. 4011-4015. ISSN (print) 0960-894X

Official URL: http://dx.doi.org/10.1016/j.bmcl.2006.05.070

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).

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