title: A-ring substituted 17β-arylsulfonamides of 17β-aminoestra-1,3,5(10)-trien-3-ol as highly potent reversible inhibitors of steroid sulfatase.
abstract: Steroid sulfatase (STS) catalyzes the hydrolysis of the sulfate ester group in biologically inactive sulfated steroids to give biologically active steroids. Inhibitors of STS are considered to be potential therapeutics for treating hormone-dependent cancers such as ER(+) breast cancer. A series of 4-substituted 17β-arylsulfonamides of 17β-aminoestra-1,3,5(10)-trien-3-ol were prepared and examined as STS inhibitors. The presence of a NO2 or Br at the 2-position of the A-ring resulted in a decrease in potency compared to their A-ring-unsubstituted counterparts. However the presence of a nitro group or fluorine atom at the 4-position of the A-ring resulted in an increase in potency and one of these compounds exhibited a Ki(app) value of 1 nM. Modeling studies provided insight into how these compounds interact with active site residues. The anti-proliferative activity of the 3'-Br, 3'-CF3, 4-NO2-3'-Br and 4-NO2-3'-CF3 derivatives were examined using the NCI 60-cell-line panel and found to have mean graph midpoint values of 1.9-3.4 μM.
authors.affiliation: Department of Chemistry, University of Waterloo, 200 University Ave. West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Yaser A
authors.initials: YA
authors.lastname: Mostafa
authors.affiliation: Department of Chemistry, University of Waterloo, 200 University Ave. West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Braden
authors.initials: B
authors.lastname: Kralt
authors.affiliation: School of Pharmacy, Health Sciences Campus, 200 University Ave. West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Praveen P N
authors.initials: PP
authors.lastname: Rao
authors.affiliation: Department of Chemistry, University of Waterloo, 200 University Ave. West, Waterloo, Ontario N2L 3G1, Canada. Electronic address: s5taylor@uwaterloo.ca.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Taylor
mesh_terms: D001192:Arylsulfatases / Q000737:chemistry* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D012739:Gonadal Steroid Hormones / Q000009:adverse effects*; D006801:Humans; D015394:Molecular Structure; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D012739:Gonadal Steroid Hormones; D013449:Sulfonamides; D001192:Arylsulfatases; D043266:Steryl-Sulfatase
keywords: Enzyme inhibitors; Hormone therapy; Steroid sulfatase