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  • br The cytochrome P enzyme hydroxylase lyase P

    2024-05-18


    The cytochrome P450 enzyme 17α-hydroxylase/17,20-lyase (P450) is involved in the production of the C containing androgen precursors from the C containing steroids such as the pregnanes and progestins (). Steroids such as androstenedione (AD) and dehydroepiandrosterone (DHEA) are therefore synthesised as a result of the action of P450 on progesterone and pregnenolone, respectively, involving an initial 17α-hydroxylation [via 17α-hydroxylase (17α-OHase)], followed by the cleavage of the C(17)–C(20) bond [via 17,20-lyase (lyase)]—both hydroxylation and C–C cleavage steps require NADPH and oxygen., P450 is a potential biological target in the treatment of hormone-dependent diseases such as prostate cancer which has been shown to be androgen-dependent in its early stages. A number of compounds has therefore been investigated, including the antimycotic ketoconazole (KTZ) and abiraterone acetate (). The latter 3CAI is currently in clinical trials, however, KTZ, a known azole-based P450 inhibitor (albeit an unselective inhibitor of steroid biosynthesis and which has been shown to inhibit other steroidogenic enzymes whilst possessing weak activity towards P450), has been used previously in the treatment of prostate cancer, however, was withdrawn for this use due to serious adverse effects. In more recent studies, however, KTZ has been evaluated against hormone-refractory prostate cancer in lower doses. Previously, we have outlined the synthesis and biochemical evaluation of halogenated derivatives of benzyl azole-based compounds which have been shown to be good inhibitors of P450 in comparison to the standard KTZ;, , , , recently we reported a range of (4-substituted phenyl)sulfonate derivatives of 4-hydroxybenzyl imidazole () which were found to possess good inhibitory activity against P450. Indeed, compounds based on the biphenyl backbone have also been developed and have also shown good level of potentcy., , Here, we report: the synthesis of a range of (4-alkyl-substituted phenyl)sulfonate derivatives of and their biochemical evaluation (in comparison to KTZ) against both components of P450 in an attempt to discover potent and highly specific inhibitors of P450. In an effort to compare the results of our previous studies, we also undertook the evaluation of the compounds previously reported by us as inhibitors of P450, in particular, benzyl imidazole () and 4-iodobenzyl imidazole () (the latter compound was shown to possess the highest inhibitory activity within the halogen derivatives of benzyl imidazole) as well as three previously reported sulfonate derivatives, namely, compounds , and (). In the synthesis of the (4-alkylsubstituted phenyl)sulfonate derivatives of (compounds –), the reactions outlined in were undertaken—we have reported previously the synthesis of other derivatives of compound where we have successfully utilised the reactions outlined in , as such, no specific methodology has been discussed within the current report. The biochemical evaluation of the synthesised compounds against both 17α-OHase and lyase components was undertaken using the method of Owen et al. and involved the use of thin layer chromatography (TLC) in the separation and identification of the radiolabelled substrate from the incubation mixture. shows the IC values obtained for the compounds considered within the current study against both 17α-OHase and lyase. P450 is also indirectly involved in the biosynthesis of the glucocorticoids and mineralocorticoids, in particular, the latter is produced directly from the 17α-hydroxylated derivatives of the progestins, as such, inhibitors of P450 should preferentially inhibit the C–C bond cleavage reaction in comparison to the hydroxylation step. This is therefore expected to have minimal effect on the hydroxylase reaction and therefore glucocorticoid biosynthesis. Initial consideration of the IC values show that compounds to are more potent than KTZ (which was found to possess an IC value of 2660nM and 206nM against the 17α-OHase and lyase components, respectively). Furthermore, with the exception of compound , all the compounds appear to possess greater potency against the lyase component in comparison to the 17α-OHase component; this was also observed with our own standard (compound ) which was found to possess an IC value of 730nM and 164nM against the 17α-OHase and lyase components, respectively. It should be noted that the previously reported values for these compounds appear to be inconsistent with the current study, however, this would be expected as different rat testicular tissues was utilised in the previous study when compared to the current study, as such, consistent data would not be expected.