Bhatti, Kishore (2007) Synthesis of benzyl imidazoles as potential inhibitors of the enzyme 17[alpha]-hydroxylase/17,20-lyase in the treatment of hormone-dependent prostate cancer. (MSc(R) thesis), Kingston University, .

Abstract

Both prostate cancer and benign prostate hyperplasia have been shown to be androgen-dependent. The biosynthesis of the androgens is catalysed by a number of enzymes, however, the cytochrome P-f1-50 enzyme 170,-hydroxylase/17,20-lyase, is an important enzyme in the conversion of pregnanes and proqestlns to the corresponding androgens (for example, the conversion of progesterone to androstenedione). The inhibition of this enzyme has been previously shown to lead to the overall reduction in the level of androgens and is a current target in the treatment of hormone-dependent prostate cancer. Within the current study, the attempted synthesis of a series of azole-based compounds as potential inhibitors is described. In particular, the synthesis of imidazole-, triazole- and tetrazole-based compounds were attempted - the rationale for these compounds to act as potential inhibitors is based upon the ability of the compounds to donate a lone pair of electrons to the iron atom within the haem group at the active site of 17a-hydroxylase/17,20-lyase enzyme complex. In general, the results of the study show that the imidazole-based compounds was readily synthesised (involving the reaction between the imidazole moiety and the substituted derivative of benzyl bromide in the presence of anhydrous potassium carbonate) in good yield (ranging from 35% to 98%) and without any major problems. The triazole and tetrazole-based compounds however, proved troublesome and due to the lack of time, were abandoned. The biochemical evaluation of a small range of the synthesised compounds showed that the compounds are, in general, weak inhibitors of the 17a-hydroxylase and the 17,20-lyase components in comparison to the standard used, namely ketoconazole (KTZ) which was found to possess an IC50 value of 3. 76~M and 1.66~M against 17a-hydroxylase and lyase components respectively. The most potent inhibitor evaluated was N-4-iodobenzyl imidazole (97) (IC50=10.06~M against 17 a-hydroxylase and IC50=1.58~M against lyase) as such, it was found to be equipotent against lyase compared to KTZ. Furthermore, the compounds were all found to be weaker inhibitors of the 17a-hydroxylase component, a feature which is considered to be a desirable property in the development of novel inhibitors of 17 a-hydroxylase/17,20-lyase.

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