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 17[beta]-hydroxysteroid dehydrogenase (17[beta]-HSD3)

Lota, Rupinder K., Olusanjo, Moniola S., Dhanani, Sachin, Owen, Caroline P. and Ahmed, Sabbir (2008) 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 17[beta]-hydroxysteroid dehydrogenase (17[beta]-HSD3). The Journal of Steroid Biochemistry and Molecular Biology, 111(1-2), pp. 128-137. ISSN (print) 0960-0760

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Abstract

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.

Item Type: Article
Uncontrolled Keywords: synthesis, 17 beta-hydroxysteroid dehydrogenase, type 3, inhibitors, cancer, nonsteroidal inhibitors, prostate-cancer, phenol, 5-alpha-reductase, acylation, strategy, series
Research Area: Chemistry
Biological sciences
Faculty, School or Research Centre: Faculty of Science (until 2011) > School of Life Sciences
Faculty of Science (until 2011) > School of Pharmacy and Chemistry
Related URLs:
Depositing User: Automatic Import Agent
Date Deposited: 08 Feb 2010 14:38
Last Modified: 11 Nov 2011 15:59
URI: http://eprints.kingston.ac.uk/id/eprint/7001

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