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Abstract: We report the synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of (4-substituted phenyl)sulfonate derivatives of 4-hydroxybenzyl imidazole against the two components of 17α-hydroxylase/17,20-lyase (P45017α), namely, 17α-hydroxylase (17α-OHase) and 17,20-lyase (lyase). The results show the compounds to be highly potent inhibitors with limited selectivity towards the lyase component [e.g., toluene-4-sulfonic acid 4-imidazol-1-ylmethyl-phenyl ester (4) possessed an IC50 value of 40nM against 17α-OHase and 30nM against lyase]. [ABSTRACT FROM AUTHOR]

Abstract: The cytochrome P-450 enzyme, 17α-hydroxylase/17,20-lyase (P45017α), 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, 17α-hydroxylase (17α-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 =10.06μM against 17α-OHase and IC50 =1.58μM against lyase) showing equipotent activity against lyase compared to the standard compound, ketoconazole (KTZ) (IC50 =3.76±0.01μM against 17α-OHase and IC50 =1.66±0.15μM against lyase). Furthermore, the compounds tested are less potent towards the 17α-OHase component, a desirable property in the development of novel inhibitors of P45017α. [Copyright &y& Elsevier]

Abstract: We report the preliminary results of the synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a number of phenyl alkyl imidazole-based compounds as inhibitors of the two components of 17α-hydroxylase/17,20-lyase (P45017α), that is, 17α-hydroxylase (17α-OHase) and 17,20-lyase (lyase). The results show that N-3-(4-bromophenyl) propyl imidazole (12) (IC50 =2.95μM against 17α-OHase and IC50 =0.33μM against lyase) is the most potent compound within the current study, in comparison to ketoconazole (KTZ) (IC50 =3.76μM against 17α-OHase and IC50 =1.66μM against lyase). Modelling of these compounds suggests that the length of the alkyl chain enhances the interaction between the inhibitor and the area of the active site corresponding to the C(3) area of the steroid backbone, thereby increasing potency. [Copyright &y& Elsevier]

Abstract: We report the synthesis and biochemical evaluation of a range of 4-sulfonated derivatives of 4-hydroxybenzyl imidazole which has been targetted against the two components of 17α-hydroxylase/17,20-lyase (P-45017α), namely, 17α-hydroxylase (17α-OHase) and 17,20-lyase (lyase). The results from the biochemical testing suggest that the compounds synthesised are highly potent inhibitors possessing excellent selectivity towards the lyase component. [Copyright &y& Elsevier]