Synthesis and biochemical evaluation of novel and potent inhibitors of the enzyme oestrone sulphatase (ES)

Ahmed, Sabbir, James, Karen, Owen, Caroline P. and Patel, Chirag K. (2002) Synthesis and biochemical evaluation of novel and potent inhibitors of the enzyme oestrone sulphatase (ES). The Journal of Steroid Biochemistry and Molecular Biology, 80(4-5), pp. 419-427. ISSN (print) 0960-0760

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In an effort to investigate the structural requirements for the inhibition of the enzyme oestrone sulphatase (ES), we have previously undertaken extensive structure-activity relationship studies. Using the data from molecular modelling and structure-activity relationship determination studies, we have designed a number of compounds based upon 4-sulphamated phenyl ketones. Here, we report the results of our study into a series of these compounds as potential inhibitors of ES. The results of the study show that these compounds are potent inhibitors the possessing greater inhibitory activity than 4-methylcoumarin-7-O-sulphamate derivative (COUMATE) (a potent non-steroidal inhibitor), but are weaker than oestrone-3-sulphamate (EMATE) and the recently reported 667- and 669-COUMATE, however, they provide good lead compounds in the search for potent inhibitors of ES. Furthermore, the compounds are observed to be irreversible inhibitors. From the consideration of the structure-activity relationship of these novel compounds, we have attempted to rationalise the significance of the log P factor in the inhibition of ES and suggest that a log P requirement of approximately 3.5 aids the inhibition through the rapid expulsion of the carbon backbone from the active site. We also propose that the same factor is responsible for the hydrolysis of oestrone sulphate reaction, appearing to be an irreversible process.

Item Type: Article
Uncontrolled Keywords: oestrone, sulphatase, inhibitors, novel, synthesis, biochemical evaluation, estrone sulfatase activity, site-directed inhibitor, steroid sulfatase, aromatase inhibitors
Research Area: Allied health professions and studies
Faculty, School or Research Centre: Faculty of Science (until 2011) > School of Pharmacy and Chemistry
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Depositing User: David Salliss
Date Deposited: 26 Jun 2007
Last Modified: 19 Nov 2010 14:57

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