The synthesis of imidazole derivatives for the inhibition of steroid-mediated prostrate tumour growth

Jandu, Baljeet Kaur (2013) The synthesis of imidazole derivatives for the inhibition of steroid-mediated prostrate tumour growth. (PhD thesis), Kingston University, .


The majority of prostate cancer cases are shown to be androgen-dependant for growth as the blocking of androgen production has shown to reduce the size of prostate metastasis. The biosynthesis of the androgens is catalysed by the cytochrome P450 enzyme 17a-hydroxylase/17,20-lyase (P45017a) by converting the C21 steroids (pregnenolone and progesterone) to the androgens (dehydroepiandrosterone and androstenedione, respectively). Inhibition of P45017a would therefore bring about a decrease in the level of androgen production and furthermore prevent an increase in the stimulation of androgen-dependent prostate cancer cells. The current study was concerned with designing and synthesising compounds which were able to donate a lone pair of electrons to the Fe atom of the haem group with in the active site of the enzyme P45017a. As well as this, we were also interested in being able to mimic the C(3) of the natural substrate by varying the R group. In doing so, we were able to observe the impact of the interactions which take place within the active site. The compounds synthesised are based on the benzyl imidazole and the imidazolphenyl ethanonebackbone, where a small number of the synthesised products are phenyl alkyl imidazole based compounds, in order to consider physiochemical factors like hydrophobicity. Overall, the results of the study showed that the benzyl imidazole-based compounds were comparable to that of the standard ketoconazole (KTZ) in their inhibitory activity against 17,20-lyase and 17a-OHase (KTZ; %inhibition = 75% against 17,20-lyase: %inhibition = 64% against 17a-OHase). The nitro substituted derivatives (270-272) were shown to have improved inhibitory activity when compared to KTZ against 17a-OHase. With respect to the imidazol-phenyl ethananes, all with the exception of the 3-bromo substituted derivative ~88) were shown to possess either equipotent inhibitory activity to that of KTZ (%inhibition = 80% against 17a-OHase: %inhibiton = 82% against 17,20-lyase) or substantially lower activity. Compound 288 was found to possess greater inhibitory activity against the 17a-OHase component (288 %inhibition = 84%). Deliberation of structure-activity relationships determined no obvious correlation between the substitution pattern of the benzyl ring and the inhibitory activity against 17,20-lyase in the benzyl imidazole-based compounds. However, in the activity against 17a-OHase, a general trend towards the para substitution of the benzyl ring was shown to have an impact on the inhibition of the enzyme. In the imidazol-phenyl ethananes, consideration of the inhibitory activity of the halogen derivatives shows that there is an increase in potency with decreasing electronegativity of substituent group. In the inhibitory activity against 17a-OHase, some compounds show a correlation between decreasing electron-withdrawing ability and an increase in percentage inhibition. This would therefore appear to suggest that an ·interaction exists between the substituent and complementary group(s) at the active site of the enzyme - this interaction appears to be weaker within derivatives which possess substituents of high electronegativity. The substitution of the phenyl ring was too shown to influence the inhibitory activity of the compounds, which was rationalised by use of the SHC approach. This was proposed as results clearly indicate that the meta-substituted compounds were found to possess greater inhibitory activity in comparison to the para-substituted compounds.

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