Sulfamoyloxy-substituted 2-phenylindoles: antiestrogen-based inhibitors of the steroid sulfatase in human breast cancer cells

Golob, Thomas, Liebl, Renate und Angerer, Erwin von (2002) Sulfamoyloxy-substituted 2-phenylindoles: antiestrogen-based inhibitors of the steroid sulfatase in human breast cancer cells. Bioorganic & Medicinal Chemistry 10 (12), S. 3941-3953.

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Zusammenfassung

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.

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Dokumentenart:

Artikel

Datum:

2002

Institutionen:

Chemie und Pharmazie > Institut für Pharmazie > Lehrstuhl Pharmazeutische / Medizinische Chemie II (Prof. Buschauer)

Projekte:

DFG Projekt An 139/6

Identifikationsnummer:

Wert	Typ
12413846	PubMed-ID

Klassifikation:

Notation	Art
Arylsulfatases/antagonists & inhibitors	MESH
Breast Neoplasms/pathology	MESH
Estrogen Receptor Modulators/chemical synthesis	MESH
Female	MESH
Humans	MESH
Indoles/chemical synthesis	MESH
Inhibitory Concentration 50	MESH
Neoplasm Proteins/antagonists & inhibitors	MESH
Radioligand Assay	MESH
Steryl-Sulfatase	MESH
Structure-Activity Relationship	MESH
Sulfatases/antagonists & inhibitors	MESH
Sulfonic Acids	MESH
Tumor Cells, Cultured	MESH

Dewey-Dezimal-Klassifikation:

500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
500 Naturwissenschaften und Mathematik > 540 Chemie
600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin

Status:

Veröffentlicht

Begutachtet:

Ja, diese Version wurde begutachtet

An der Universität Regensburg entstanden:

Eingebracht am:

11 Dez 2008 16:57

Zuletzt geändert:

24 Mai 2018 09:58

Dokumenten-ID:

4778

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