Derivation of a possible transition-state for the reaction catalysed by the enzyme Estrone Sulfatase (ES)

School of Applied Chemistry, Kingston University, Kingston upon Thames, Surrey, UK.
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.42). 07/1999; 9(12):1645-50. DOI: 10.1016/S0960-894X(99)00245-0
Source: PubMed


We have determined a possible transition-state for the reaction catalysed by the enzyme Estrone Sulfatase (ES) - as a representation of the active site. Using the derived structure, we have superimposed several steroidal and non-steroidal inhibitors in an attempt to rationalise the inhibitory activity of a number of potent inhibitors.

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    ABSTRACT: The steroid sulfatase or steryl sulfatase is a microsomal enzyme widely distributed in human tissues that catalyzes the hydrolysis of sulfated 3-hydroxy steroids to the corresponding free active 3-hydroxy steroids. Since androgens and estrogens may be synthesized inside the cancerous cells starting from aehydroepiandrosterone sulfate (DHEAS) and estrone sulfate (E1S) available in blood circulation, the use of therapeutic agents that inhibit steroid sulfatase activity may be a rewarding approach to the treatment of androgeno-sensitive and estrogeno-sensitive diseases. In the present study, we report the chemical synthesis and biological evaluation of a new family of steroid sulfatase inhibitors. The inhibitors were designed by adding an alkyl, a phenyl, a benzyl, or a benzyl substituted at position 17 alpha of estradiol (E-2), a C18-steroid, and enzymatic assays were performed using the steroid sulfatase of homogenized JEG-3 cells or transfected in HEK-293 cells. We observed that a hydrophobic substituent induces powerful inhibition of steroid sulfatase while a hydrophilic one was weak. Although a hydrophobic group at the 17 alpha -position increased the inhibitory activity, the steric factors contribute to the opposite effect. As exemplified by 17 alpha -decyl-E-2 and 17 alpha -dodecyl-E-2, a long flexible side chain prevents adequate fitting into the enzyme catalytic site, thus decreasing capacity to inhibit the steroid sulfatase activity. In the alkyl series, the best compromise between hydrophobicity and steric hindrance was obtained with the octyl group (IC50 = 440 nM) but judicious branching of side chain could improve this further. Benzyl substituted derivatives of estradiol were better inhibitors than alkyl analogues. Among the series of 17 alpha-(benzyl substituted)-E-2 derivatives studied, the 3'-bromobenzyl, 4'-tert-butylbenzyl, 4'-butylbenzyl, and 4'-benzyloxybenzyl groups provided the most potent inhibition of steroid sulfatase transformation of E1S into E-1 (IC50 = 24, 28, 25, and 22 nM, respectively). As an example, the tert-butylbenzyl group increases the ability of the E-2 nucleus to inhibit the steroid sulfatase by 3000-fold, and it also inhibits similarly the steroid sulfatase transformations of both natural substrates, E1S and DHEAS. Interestingly, the newly reported family of steroid sulfatase inhibitors acts by a reversible mechanism of action that is different from the irreversible mechanism of the known inhibitor estrone sulfamate (EMATE).
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    ABSTRACT: The enzyme oestrone sulfatase (ES) is responsible for the conversion of the stored (sulfated) form of oestrogens to the active form, namely oestrone. In our continuing quest to synthesize potent inhibitors of oestrone sulfatase and to determine the structural requirements for such inhibition, we have synthesized and evaluated several derivatives of phenyl sulfamate. We report the results of the synthesis and biochemical evaluation of a series of 3- and 4-aminosulfonated derivatives of phenol in an effort to investigate the role of the acid dissociation constant (pK(a)), and therefore the stability of the phenoxide ion, on the inhibitory activity of compounds against this enzyme. The results showed that there was a strong correlation between the observed pK(a) and inhibitory activity within the aminosulfonated compounds considered. This suggested that in the inhibition of oestrone sulfatase by these compounds, pK(a) was an important physicochemical property, and as such, the stability of the O(-) ion was a crucial factor in the inhibition, and therefore the drug design process.
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