Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of phenyl alkyl imidazole-based compounds as potent inhibitors of the enzyme complex 17α-hydroxylase/17,20-lyase (P45017α)

The cytochrome P450 enzyme, 17α-hydroxylase/17,20-lyase (P45017α), is a potential target in hormone-dependent cancers. 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 P45017α, i.e., 17α-hydroxylase (17α-OHase) and 17,20-lyase (lyase). The results suggest that the imidazole-based compounds are highly potent inhibitors of both components, with N-7-phenyl heptyl imidazole (21) (IC50 = 0.32 μM against 17α-OHase and IC50 = 0.10 μM against lyase) and N-8-phenyl octyl imidazole (23) (IC50 = 0.25 μM against 17α-OHase and IC50 = 0.21 μM against lyase) being the two most potent compounds within the current study, in comparison to ketoconazole (KTZ) (IC50 = 3.76 μM against 17α-OHase and IC50 = 1.66 μM against lyase). Furthermore, consideration of the inhibitory activity against the two components show that the compounds tested are less potent towards the 17α-OHase component, a desirable property in the development of novel inhibitors of P45017α. Structure–activity relationship determination of the range of compounds synthesised suggests that log P (log of the partition coefficient) is a key physicochemical factor in determining the overall inhibitory activity. In an effort to determine the viability of these compounds becoming potential drug candidates as well as to show specificity of these compounds, we undertook the biochemical evaluation of the synthesised compounds against two isozymes of 17β-hydroxysteroid dehydrogenase [namely type 1 (17β-HSD1) and type 3 (17β-HSD3)] and 3β-hydroxysteroid dehydrogenase (3β-HSD). Consideration of the inhibitory activity possessed by the compounds considered within the current study against 3β-HSD, 17β-HSD1 and 17β-HSD3 shows that there is no clear structure–activity relationship and that the compounds appear to possess similar inhibitory activity against both 3β-HSD and 17β-HSD3 whilst against 17β-HSD1, the compounds appear to possess poor inhibitory activity at [I] = 100 μM. Indeed, two of the most potent inhibitors of P45017α, (compounds 21 and 23), were found to possess relatively good levels of inhibition against the three enzymes—compound 21 was found to possess ∼32%, ∼21% and ∼37% inhibition whilst compound 23 was found to possess ∼38%, ∼30% and ∼28% inhibition against 3β-HSD, 17β-HSD1 and 17β-HSD3 respectively. We therefore concluded that the azole-based compounds synthesised within the current study are not suitable for further consideration as potential drug candidates due to their lack of specificity.