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Stilbene‐Based Inhibitors of Estrone Sulfatase with a Dual Mode of Action in Human Breast Cancer Cells
Author(s) -
Walter Georg,
Liebl Renate,
von Angerer Erwin
Publication year - 2004
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.200400904
Subject(s) - estrone , estrone sulfate , sulfatase , chemistry , steroid sulfatase , estrogen , enzyme , breast cancer , mcf 7 , pharmacology , biochemistry , cancer , medicine , endocrinology , hormone , human breast , biology , steroid
Estrone sulfate (E1S) is an endogenous prodrug that delivers estrone and, subsequently, estradiol to target cells, after hydrolysis by the enzyme estrone sulfatase, which is active in various tissues including hormone‐dependent breast cancer. Blockade of this enzyme should reduce the estrogen level in breast cancer cells and prevent hormonal growth stimulation. In this study, a number of sulfamoyloxy‐substituted stilbenes with side chains that guarantee antiestrogenic activity were synthesized and evaluated as inhibitors of estrone sulfatase. They inhibited this enzyme in human MDA‐MB 231 breast cancer cells, with IC 50 values in the submicromolar range. The effects of both the free hydroxy derivatives and the sulfamates on gene activation were determined in transfected MCF‐7/2a breast cancer cells stimulated either with estradiol or with estrone sulfate. The analysis of data revealed a dual mode of action of the majority of compounds. They blocked gene expression by inhibition of estrone sulfatase and by antiestrogenic action. This pharmacological profile was also observed in assays on antiproliferative activity. The most potent derivative 8g inhibited the growth of wild‐type human MCF‐7 cells with an IC 50 value of 13 nM.