title: Sulfamoyloxy-substituted 2-phenylindoles: antiestrogen-based inhibitors of the steroid sulfatase in human breast cancer cells.
abstract: 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.
authors.affiliation: Institut für Pharmazie, Universität Regensburg, D-93040 Regensburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Golob
authors.forename: Renate
authors.initials: R
authors.lastname: Liebl
authors.forename: Erwin
authors.initials: E
authors.lastname: von Angerer
mesh_terms: D001192:Arylsulfatases / Q000037:antagonists & inhibitors*; D001943:Breast Neoplasms / Q000473:pathology*; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D011869:Radioligand Assay; D043266:Steryl-Sulfatase; D013329:Structure-Activity Relationship; D013429:Sulfatases / Q000037:antagonists & inhibitors; D013451:Sulfonic Acids; D014407:Tumor Cells, Cultured
chemical_list: D020847:Estrogen Receptor Modulators; D007211:Indoles; D009363:Neoplasm Proteins; D013451:Sulfonic Acids; C005741:sulfamic acid; D013429:Sulfatases; C020121:estrone sulfatase; D001192:Arylsulfatases; D043266:Steryl-Sulfatase