title: Inhibition of steroid sulfatase with 4-substituted estrone and estradiol derivatives.
abstract: Steroid sulfatase (STS) catalyzes the desulfation of biologically inactive sulfated steroids to yield biologically active desulfated steroids and is currently being examined as a target for therapeutic intervention for the treatment of breast cancer. We previously demonstrated that 4-formyl estrone is a time- and concentration-dependent inhibitor of STS. We have prepared a series of 4-formylated estrogens and examined them as irreversible STS inhibitors. Introducing a formyl, bromo or nitro group at the 2-position of 4-formylestrone resulted in loss of concentration and time-dependent inhibition and a considerable decrease in binding affinity. An estradiol derivative bearing a formyl group at the 4-position and a benzyl group at the 17β-position yielded a potent concentration and time-dependent STS inhibitor with a K(I) of 85 nM and a k(inact) of 0.021 min(-1) (k(inact)/K(I) of 2.3 × 10(5)M(-1)min(-1)). Studies with estrone or estradiol substituted at the 4-position with groups other than a formyl group revealed that good reversible inhibitors can be obtained by introducing small electron withdrawing groups at this position. An estradiol derivative with fluorine at the 4-position and a benzyl group at the 17β-position yielded a potent, reversible inhibitor of STS with an IC(50) of 40 nM. The introduction of relatively small electron withdrawing groups at the 4-position of estrogens and their derivatives may prove to be a general approach to enhancing the potency of estrogen-derived STS inhibitors.
authors.affiliation: Department of Chemistry, University of Waterloo, 200 University Ave. West, Waterloo, Ontario, Canada N2L 3G1.
authors.forename: Chau-Minh
authors.initials: CM
authors.lastname: Phan
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Byoung-moo
authors.initials: BM
authors.lastname: Kim
authors.forename: Yaser
authors.initials: Y
authors.lastname: Mostafa
authors.forename: Scott D
authors.initials: SD
authors.lastname: Taylor
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004970:Estrone / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D007700:Kinetics; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D004970:Estrone; D004958:Estradiol; D043266:Steryl-Sulfatase