Evidence for the mechanism of the irreversible inhibition of oestrone sulphatase (ES) by aminosulphonate based compounds.
In our search for the mechanism of the enzyme oestrone sulphatase (ES) we have synthesised and evaluated a number of compounds that were predicted to possess some inhibitory activity. Some of these compounds were indeed found to be inhibitors of ES, whilst other compounds were not. From a consideration of the structure-activity relationship (SAR) of the inhibitors and non-inhibitors of this enzyme, we discovered a factor which we now believe is the main inhibitory moiety within the aminosulphonated inhibitors. We therefore report the results of our study into a series of phenyl and alkyl sulphamated compounds as inhibitors of ES. The results of the study show that the substituted phenyl sulphamates are potent inhibitors, whereas the alkyl compounds are, in general, non-inhibitors. Using the results of our SAR study, we postulate the probable mechanism for the irreversible and reversible inhibition of ES, and rationalise the role of the different physicochemical factors in the inhibition of this crucial enzyme.
Ahmed
Sabbir
S
School of Chemical and Pharmaceutical Sciences, Kingston University, Penrhyn Road, Kingston upon Thames, Surrey KT1 2EE, UK. s.ahmed@kingston.ac.uk
Owen
Caroline P
CP
James
Karen
K
Patel
Chirag K
CK
Sampson
Luther
L
D000838:Anions; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D013329:Structure-Activity Relationship; D013425:Sulfanilic Acids / Q000737:chemistry* / Q000494:pharmacology*; D013429:Sulfatases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013451:Sulfonic Acids / Q000737:chemistry* / Q000494:pharmacology; D013997:Time Factors; D014867:Water / Q000378:metabolism
D000838:Anions; D013425:Sulfanilic Acids; D013451:Sulfonic Acids; D014867:Water; C005741:sulfamic acid; D013429:Sulfatases; C020121:estrone sulfatase