Synthesis of potential enzyme inhibitors in the treatment of hormone-dependent prostate cancer

Abdulkadir, Huria (2006) Synthesis of potential enzyme inhibitors in the treatment of hormone-dependent prostate cancer. (PhD thesis), Kingston University,


A high proportion of prostate cancer has been shown to be hormone-dependent, in particular, dependent on testosterone (T) and dihydrotestosterone (OHT). The biosynthesis of the androgens is catalysed by the cytochrome P-450 enzyme 17a.-hydroxylase/17,20-lyase (P45017a) which is responsible for the conversion of pregnanes (for example progesterone) to . the androgens (for example androstenedione). However, the biosynthesis of OHT, the more potent androgen is catalysed by 5a-reductase (5aR). The inhibition of these two enzymes would therefore lead to the overall reduction in the level of T and OHT. Thereby leading to a decrease in the stimulation of androgen-dependent cancer cells. Within the current study, the synthesis of a series of potential inhibitors is described. The compounds synthesised against P45017ó were based upon the ability of the compounds to donate a lone pair of electrons to the iron atom within the haem group of the active site of P45017a. As such, compounds based on the Evan's chiral auxiliary were synthesised containing a phenylamine moiety. In the synthesis of the compounds, the initial R and S forms of the chiral auxiliary were initially alkylated (using sodium hydride and alkyl bromlde), followed by the nitration (with dilute fuming nitric acid) of the phenyl ring which was subsequently reduced (using palladium on charcoal and hydrogen gas) to give the phenylamine moiety. The reactions proceeded in moderate to good yield without many problems. The reactions were repeated with an alternative chiral auxiliary, namely, 4-methyl-5-phenyl-2- oxazolidinone, however, due to lack of time, only the initial alkylation step was undertaken and was found to proceed in good yield. The biochemical evaluation of the phenylamine based compounds using a literature based assay showed these compounds to be weak inhibitors of P45017a, with two compounds (of the range evaluated) showing close to 40% inhibition at 1mM. The compounds targeted against 5aR, were based upon the ability of the _inhibitors to mimic the substrate and thereby allow themselves to be reduced by NAOPH, as such, they were based upon pyrrolidine-2,5-dione structure with a C=O moiety to mimic the 11[sup]5 functionality in T. The N-substituted pyrrolidine-2,5-dione was therefore reacted with the appropriate ester in the presence of sodium hydride. In general, the reactions proceeded well, however, the products were obtained in poor yield (ranging from 30% to 12%). Attempts to use an activated carbonyl group (e.g. the use of acyl chloride derivative of the esters) did not result in increased yield. The compounds synthesised were not evaluated against 5aR due to the lack of an assay system.

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