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 17beta-hydroxysteroid dehydrogenase (17beta-HSD3)

• Published in: The Journal of steroid biochemistry and molecular biology 2008-07, Vol.111 (1-2), p.128
• Main Authors: Lota, Rupinder K, Olusanjo, Moniola S, Dhanani, Sachin, Owen, Caroline P, Ahmed, Sabbir
• Format: Article
• Language: English
• Subjects: 17-Hydroxysteroid Dehydrogenases - antagonists & inhibitors; Androstenedione - metabolism; Catalysis; Dehydroepiandrosterone - metabolism; Estradiol - metabolism; Estrone - antagonists & inhibitors; Inhibitory Concentration 50; Ketones - chemical synthesis; Ketones - chemistry; Ketones - pharmacology; Models, Chemical; Models, Molecular; Molecular Structure; Rationalization; Sensitivity and Specificity; Structure-Activity Relationship; Testosterone - metabolism
• ISSN: 0960-0760
• DOI: 10.1016/j.jsbmb.2008.05.008

We report the synthesis and biochemical evaluation of a number of 4-hydroxyphenyl ketones as potential inhibitors of the enzyme 17beta-hydroxysteroid dehydrogenase (17beta-HSD). In particular, we evaluated compounds against the catalysis of the conversion of androstenedione (AD) to testosterone (T) [17beta-HSD type 3 (17beta-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) [17beta-HSD type 1 (17beta-HSD1)] as well as the conversion of dehydroepiandrosterone (DHEA) to AD [by 3beta-hydroxysteroid dehydrogenase (3beta-HSD)]. The results of our study suggest that the synthesised compounds are, in general, able to inhibit 17beta-HSD3 whilst being weak inhibitors of 17beta-HSD1. Against 3beta-HSD, we discovered that all of the synthesised compounds were weak inhibitors (all were found to possess less than 50% inhibition at [I]=500 microM). More specifically, we discovered that 1-(4-hydroxy-phenyl)-nonan-1-one (15) was the most potent against 17beta-HSD3 (IC(50)=2.9 microM) whilst possessing poor inhibitory activity against 17beta-HSD1 ( approximately 36% inhibitory activity against this reaction at [I]=100 microM) 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 17beta-HSD3.