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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.

Type

Journal article

Journal

J Steroid Biochem Mol Biol

Publication Date

02/2003

Volume

84

Pages

343 - 349

Keywords

Animals, Arylsulfatases, Breast Neoplasms, Chromatography, Thin Layer, Enzyme Inhibitors, Estrogens, Estrone, Female, Inhibitory Concentration 50, Liver, Models, Chemical, Ovary, Rats, Rats, Wistar, Steryl-Sulfatase, Time Factors