title: Inhibition of estrone sulfate-induced uterine growth by potent nonestrogenic steroidal inhibitors of steroid sulfatase.
abstract: The present study describes the biological in vitro and in vivo evaluation of 2-methoxy derivatives of estrogenic inhibitors of steroid sulfatase, namely 3-sulfamoyloxy-17alpha-p-tert-butylbenzyl(or benzyl)-1,3,5 (10)-estratrien-17beta-ols. The addition of the 2-methoxy group conserves the potent inhibitory effect on steroid sulfatase activity (IC(50)s of 0.024 and 0.040 nM) while removing the estrogenic action. Using an ovariectomized mouse model, we show that the first generation of steroid sulfatase inhibitors tested, 3-sulfamoyloxy-17alpha-p-tert-butylbenzyl(or benzyl)estra-1,3,5 (10)-trien-17beta-ols and estrone-3-O-sulfamate, are estrogenic compounds stimulating estrogen-sensitive uterine growth. Interestingly, the 2-methoxy-3-sulfamoyloxy-17alpha-benzylestra-1,3,5 (10)-trien-17beta-ol (7) has no estrogenic activity but efficiently blocks (s.c. and p.o.) uterine growth induced by estrone sulfate, which is converted into estrone and then estradiol by steroid sulfatase and type 1 17beta-hydroxysteroid dehydrogenase, respectively. This report clearly shows that a steroid sulfatase inhibitor can efficiently block estrogen action from the inactive precursor estrone sulfate, in vitro and in vivo.
authors.affiliation: Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center, Centre Hospitalier Universitaire de Québec-Pavillon CHUL, 2705 Laurier Boulevard, Québec, Canada G1V 4G2.
authors.forename: Liviu C
authors.initials: LC
authors.lastname: Ciobanu
authors.forename: Van
authors.initials: V
authors.lastname: Luu-The
authors.forename: Céline
authors.initials: C
authors.lastname: Martel
authors.forename: Fernand
authors.initials: F
authors.lastname: Labrie
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
mesh_terms: D000818:Animals; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D004970:Estrone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors*; D014599:Uterus / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development
chemical_list: D004965:Estrogen Antagonists; C037233:2-methylestradiol; D004970:Estrone; D004958:Estradiol; D043266:Steryl-Sulfatase; C017296:estrone sulfate