title: Novel D-ring modified steroid derivatives as potent, non-estrogenic, steroid sulfatase inhibitors with in vivo activity.
abstract: In pursuit of novel steroid sulfatase (STS) inhibitors devoid of estrogenicity, several D-ring modified steroid derivatives were synthesised. In vitro evaluation of the compounds identified two highly potent inhibitors, 4a and 4b, which were 18 times more active than estrone-3-O-sulfamate (EMATE), both having IC(50) values of ca. 1nM. These 16,17-seco-estra-1,3,5(10)-triene-16,17-imide derivatives were synthesised from estrone, via the intermediate 1, which was easily alkylated, deprotected and sulfamoylated affording the final compounds in high yields. In order to assess their biological profile, the selected inhibitors were tested for their in vivo inhibitory potency and estrogenicity in ovariectomised rats. After an oral dose of 10mg/kg per day for 5 days, 4a and 4b were found to inhibit rat liver steroid sulfatase by 99%. They were also devoid of estrogenic activity in the uterine weight gain assay, indicating that these two leads have therapeutic potential for the treatment of hormone-dependent breast cancer.
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, UK.
authors.forename: Delphine S
authors.initials: DS
authors.lastname: Fischer
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Chander
authors.forename: L W Lawrence
authors.initials: LW
authors.lastname: Woo
authors.forename: Janine C
authors.initials: JC
authors.lastname: Fenton
authors.forename: Atul
authors.initials: A
authors.lastname: Purohit
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Reed
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D000818:Animals; D001192:Arylsulfatases / Q000037:antagonists & inhibitors*; D001943:Breast Neoplasms / Q000188:drug therapy; D002855:Chromatography, Thin Layer; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004967:Estrogens / Q000378:metabolism; D004970:Estrone / Q000031:analogs & derivatives* / Q000032:analysis / Q000494:pharmacology; D005260:Female; D020128:Inhibitory Concentration 50; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008956:Models, Chemical; D010053:Ovary / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D043266:Steryl-Sulfatase; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D004967:Estrogens; C088768:estrone-3-O-sulfamate; D004970:Estrone; D001192:Arylsulfatases; D043266:Steryl-Sulfatase