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Inhibition of Estrone Sulfate-induced Uterine Growth by Potent Nonestrogenic Steroidal Inhibitors of Steroid Sulfatase¹

Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center, Centre Hospitalier Universitaire de Québec-Pavillon CHUL, and Université Laval, Québec, G1V 4G2, Canada

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-17-p-tert-butylbenzyl(or benzyl)-1,3,5 (10)-estratrien-17ß-ols. The addition of the 2-methoxy group conserves the potent inhibitory effect on steroid sulfatase activity (IC₅₀s 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-17-p-tert-butylbenzyl(or benzyl)estra-1,3,5 (10)-trien-17ß-ols and estrone-3-O-sulfamate, are estrogenic compounds stimulating estrogen-sensitive uterine growth. Interestingly, the 2-methoxy-3-sulfamoyloxy-17-benzylestra-1,3,5 (10)-trien-17ß-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 17ß-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.

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