17α-Alkyl- or 17α-substituted benzyl-17β-estradiols: A new family of estrone-sulfatase inhibitors

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.