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

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-17 -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-17 -ols and estrone-3-O-sulfamate, are estrogenic compounds stimulating estrogen-sensitive uterine growth. Interestingly, the 2methoxy-3-sulfamoyloxy-17 -benzylestra-1,3,5 (10)-trien-17 -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 17 -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.