3262-23-5Relevant academic research and scientific papers
Potent inhibition of steroid sulfatase activity by 3-O-sulfamate 17α- benzyl(or 4'-tert-butylbenzyl)estra-1,3,5(10)-trienes: Combination of two substituents at positions C3 and C17α of estradiol
Ciobanu, Liviu C.,Boivin, Roch P.,Luu-The, Van,Labrie, Fernand,Poirier, Donald
, p. 2280 - 2286 (1999)
Steroid sulfates are precursors of hormones that stimulate androgen- and estrogen-dependent cancers. Thus, steroid sulfatase, the enzyme that catalyzes conversion of DHEAS and E1S to the corresponding unconjugated steroids DHEA and E1, appears to be one of the key enzymes regulating the level of active androgenic and estrogenic steroids. Since 17α-substituted benzylestradiols and 3-O-sulfamate estrone (EMATE) represent two families of steroid sulfatase inhibitors that probably act through different mechanisms, we synthesized compounds 3-O-sulfamate 17α-benzylestradiol (4) and 3-O- sulfamate 17α-(tert-butylbenzyl)estradiol (5) that contain two kinds of substituents on the same molecule. In our enzymatic assay using a homogenate of human embryonal (293) cells transfected with steroid sulfatase, compounds 4 and 5 were found to be more potent inhibitors than already known steroid sulfatase inhibitors that have only a C17α-substituent or only a C3- sulfamate group (EMATE). The IC50 values of 4 and 5 were, respectively, 0.39 and 0.15 nM for the transformation of E1S to E1 and 4.1 and 1.4 nM for the transformation of DHEAS to DHEA. Compound 5 inhibited the steroid sulfatase activity in intact transfected (293) cell culture assays by inactivating the enzyme activity. Compound 5 also inactivates the steroid sulfatase activity at lower concentration than EMATE in microsomes of transfected (293) cells. In this assay, an excess of natural substrate E1S protects enzyme against inactivation by 5 or EMATE. Furthermore, the unsulfamoylated analogue of 5, compound 3, did not inactivate the steroid sulfatase.
17α-alkyl- or 17α-substituted benzyl-17β-estradiols: A new family of estrone-sulfatase inhibitors
Poirier, Donald,Boivin, Roch P.
, p. 1891 - 1896 (1998)
A series of 17α-derivatives of 17β-estradiol was synthesized and tested for their ability to inhibit the estrone-sulfatase activity transforming estrone sulfate to estrone. A strong inhibitory activity was obtained when an alkyl side chain or a substituted benzyl was introduced at position 17α of estradiol. The 17α-(3'-bromobenzyl)-estradiol (26) and 17α-(4'-t-butylbenzyl)-estradiol (30) were the most potent estrone- sulfatase inhibitors obtained in our study with IC50 values of 24 and 28 nM, respectively. They also represent a new family of estrone-sulfatase inhibitors. These compounds are about 300-fold more effective in interacting with the enzyme than the substrate estrone sulfate itself.
Structure-activity relationships of 17α-derivatives of estradiol as inhibitors of steroid sulfatase
Boivin,Luu-The,Lachance,Labrie,Poirier
, p. 4465 - 4478 (2007/10/03)
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 dehydroepiandrosterone 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 17α of estradiol (E2), 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 17α-position increased the inhibitory activity, the steric factors contribute to the opposite effect. As exemplified by 17α-decyl-E2 and 17α-dodecyl-E2, 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 17α-(benzyl substituted)-E2 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 E1 (IC50 = 24, 28, 25, and 22 nM, respectively). As an example, the tert-butylbenzyl group increases the ability of the E2 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).
