Biochemical evaluation of potential enzyme inhibitors

Dhanani, Sachin Paryantray (2006) Biochemical evaluation of potential enzyme inhibitors. (PhD thesis), Kingston University,


A high proportion of prostate cancer and benign prostatic hyperplasia (BPH) have been shown to be dependent on androgen biosynthesis. The biosynthesis of androgens is undertaken by a number of important enzymes such as 17a-hydroxylase/17,20-lyase and 17[beta]-hydroxysteroid dehydrogenase. Through the inhibition of these enzymes it is possible to. reduce the amount of androgens present, which in turn reduces the stimulation of androgen-dependent prostatic diseases. Within the current study, we have undertaken the biochemical evaluation of a number of compounds of varying structural features and which were synthesised within our group as potential enzyme inhibitors in the tretament of androgen-dependent diseases. In general, the results from the current study show that the compounds evaluated against the enzyme complex 17a-hydroxylase/17,20-lyase possessed good inhibitory activity. In particular, the imidazole-based inhibitors were found to be more potent against 17,20-lyase in comparison to 17a-hydroxylase, and were more potent than the triazole-based compounds. The most potent compounds within the current study include: 1-(7-phenyl-heptyl)-1H-imidazole (171) (lC50=98.5±15.6nM, K¡=55.3±3AnM against 17,20-lyase and IC50=O.32±O.05I-lM, K¡=O.21±O.01¡.¡M against 17a-hydroxylase), 1-[7 -(4-fluoro-phenyl)-heptyl]-1 H-imidazole (179) (IC50=57.5±1.5nM, K¡=21.5±O.1nM against 17,20-lyase and IC50=173.62±7.00nM, K¡=77.5±2.5nM against 17 a-hydroxylase) and 1-[5-(4-bromo-phenyl)-pentyl]-1 H-imidazole (187) (IC50=58.1±5.2nM against 17,20-lyase and IC50=O.50±O.04I-lM against 17a-hydroxylase), these compounds were all potent inhibitors compared to the standard inhibitor ketoconazole (1) (lC50=1.66±O.15¡.JM, K¡=O.67±O.02¡.¡M against 17,20-lyase and IC50=3.76±O.01I-lM, K¡=1.24±O.01¡.¡M against 17a-hydroxylase). In an effort to discover lead compounds in the inhibition of the 17[beta]-hydroxysteroid dehydrogenase (17[beta]-HSD) family of enzymes, a range of commercially available compounds based on phenyl ketones were initially evaluated against type 1 (17[beta]-HSD1) and 3 (17[beta]-HSD3) of 17[beta]-HSD which are responsible for the reduction of estrone and androstenedione to estradiol and testosterone respectively. The majority of these compounds were found to possess weak inhibitory activity, however, some were found to possess good inhibitory activity. As such, a number of compounds were synthesised within our group as potential inhibitors of 17[beta]-HSD1 and 17[beta]-HSD3. The results show that the 4-hydroxyphenyl ketone-based compounds were found to be . highly potent against type 3 in comparison to type 1. For example, 1-(4-hydroxy-phenyl)-nonan-1-one (254) was found to possess (against type 3) inhibitory activity of 83.53±OA8% (at [1]=100¡.¡M) (IC5o of 2.86 ± O.03¡.¡M). Under similar conditions, 254 was found to possess 36.32±O.33% (at [1]=100¡.¡M) inhibitory activity against type1. A range of compounds were also synthesised based on the biphenyl ketones, however, these were found to be weaker inhibitors of type 3 in comparison to the 4- hydroxyphenyl ketones although they possessed greater inhibitory activity against type 1. In an effort to determine the selectivity of these compounds against the overall class of HSD enzymes, all inhibitors were evaluated for 3[beta]-hydroxysteroid dehydrogenase (3[beta]-HSD) inhibitory activity. We discovered that in general, all of the synthesised compounds possessed weak inhibitory activity against this enzyme at inhibitor concentration of 100¡.¡M and 500¡.¡M, as such, these synthesised compounds could be considered to be good lead compounds for the inhibition of 17[beta]-HSD.

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