Estrone sulfate (E1S) is an endogenous
prodrug that delivers
estrone and, subsequently,
estradiol to the target cells following the hydrolysis by the
enzyme estrone sulfatase which is active in various tissues including
hormone dependent
breast cancer cells. Blockade of this
enzyme should reduce the
estrogen level in
breast cancer cells and prevent hormonal growth stimulation. Sulfamates of a variety of phenolic compounds have been shown to be inhibitors of
estrone sulfatase. Our rational is based on findings that these inhibitors can undergo hydrolysis and the pharmacological effects of the free hydroxy compounds contribute to the bioactivity of the sulfamates. A desirable action of the metabolites would be an
estrogen antagonism to block stimulatory effects of residual amounts of
estrogens. Thus, we synthesized a number of sulfamoyloxy-substituted 2-phenylindoles with side chains at the
indole nitrogen that guarantee antiestrogenic activity. All of the new sulfamates were studied for their inhibitory effects on the
enzyme estrone sulfatase from human
breast cancer cells and their (anti)hormonal activities in stably transfected human MCF-7/2a mammary
carcinoma cells. The hormonal profile of the sulfamates was partly reflected by the properties of the corresponding hydroxy precursors. Some of the sulfamoylated
antiestrogens strongly inhibited
estrone sulfatase activity with IC(50) values in the submicromolar range. They were devoid of agonist activity and suppressed
estrone sulfate-stimulated gene expression mainly by blocking the
enzyme. Examples are the disulfamates of the
indoles ZK 119, 010 and ZK 164, 015. Their IC(50)s for
sulfatase inhibition were 0.3 and 0.2 microM, respectively, and 50 and 80 nM, respectively, for the inhibition of E1S-stimulated
luciferase expression in transfected MCF-7 cells. With some of the new sulfamates an additional direct antiestrogenic effect was noticed which might be due to a partial hydrolysis during incubation and would improve the growth inhibitory effect on
estrogen-sensitive
breast cancer cells.