Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of 4-hydroxyphenyl ketones as potent and specific inhibitors of the type 3 of 17β-hydroxysteroid dehydrogenase (17β-HSD3)

We report the synthesis and biochemical evaluation of a number of 4-hydroxyphenyl ketones as potential inhibitors of the enzyme 17β-hydroxysteroid dehydrogenase (17β-HSD). In particular, we evaluated compounds against the catalysis of the conversion of androstenedione (AD) to testosterone (T) [17β-HSD type 3 (17β-HSD3)], furthermore, in an effort to determine the specificity of our compounds, we evaluated the ability of the compounds to inhibit the catalysis of the conversion of estrone (E1) to estradiol (E2) [17β-HSD type 1 (17β-HSD1)] as well as the conversion of dehydroepiandrosterone (DHEA) to AD [by 3β-hydroxysteroid dehydrogenase (3β-HSD)]. The results of our study suggest that the synthesised compounds are, in general, able to inhibit 17β-HSD3 whilst being weak inhibitors of 17β-HSD1. Against 3β-HSD, we discovered that all of the synthesised compounds were weak inhibitors (all were found to possess less than 50% inhibition at [I] = 500 μM). More specifically, we discovered that 1-(4-hydroxy-phenyl)-nonan-1-one (15) was the most potent against 17β-HSD3 (IC50 = 2.9 μM) whilst possessing poor inhibitory activity against 17β-HSD1 (∼36% inhibitory activity against this reaction at [I] = 100 μM) and less than 10% inhibition for the conversion of DHEA to AD. We have therefore provided good lead compounds in the design and synthesis of novel non-steroidal inhibitors of 17β-HSD3.