Scavestrogen sulfamates: correlation between estrone sulfatase inhibiting and antioxidant effects

Abstract

In the present study estrone sulfatase (steryl-sulfatase; EC 3.1.6.2) and phenylsulfatase (arylsulfatase B; EC 3.1.6.1) inhibiting as well as antioxidant effects exerted by ring B,C unsaturated sulfamates of estrone (J 1025), 17 beta-estradiol (J 1054, J 1059, J 1067), and 17 alpha-estradiol (J 1051, J 1064, J 1065) were examined as compared with their parent compounds, J 994, J 995, and J 1050, using six different in vitro models: (i) estrone sulfatase activity in human placental microsomes, (ii) phenylsulfatase activity isolated from Helix pomatia, (iii) Fenton reaction driven lipid peroxidation in rat synaptosomes, (iv) Fe(II)-chelating activities, (v) formation of superoxide anion radicals, and (vi) total antioxidative activities. Ring B,C unsaturated estrogen (so-called scavestrogen) sulfamates were found to act as potent inhibitors of the following enzyme activities and generated radicals: estrone sulfatase, phenylsulfatase, lipid peroxyl, and superoxide anion. In addition, scavestrogen sulfamates were able to influence the iron redox chemistry and total antioxidative activities. These findings indicate that relatively minor modifications in the chemical structure of classical steroid sulfamates can preserve or enhance their estrone sulfatase inhibiting properties and, simultaneously, amplify their antioxidant capacity to a great extent. Taken together, our data suggest that scavestrogen sulfamates such as J 1025, J 1051, or J 1054 (17 beta-dihydroequilenin sulfamate) may serve as a very promising basis for the development of steroid-derived estrone sulfate-sulfatase inhibitors characterized by promising estrone sulfatase inhibiting activities in combination with a "good" antioxidant potency.