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1-Carbamoylalkyl-2-phenylindoles: relationship between side chain structure and estrogen antagonism.
- Source :
-
The Journal of steroid biochemistry and molecular biology [J Steroid Biochem Mol Biol] 1994 May; Vol. 49 (1), pp. 51-62. - Publication Year :
- 1994
-
Abstract
- The 2-phenylindole system has proved to be a versatile structure for the design of potent antiestrogens, especially when functional groups have been introduced into the alkyl side chain in position 1. In analogy to steroidal structures such as ICI 164,384 a number of 2-phenylindoles with carbamoylalkyl and aminoalkyl side chains were synthesized. They bind to the calf uterine estrogen receptor with relative binding affinities between 2.1 and 21 (estradiol = 100). The antiestrogenic effect of these compounds was demonstrated by the inhibition of transcriptional activity which was measured in a new luciferase assay with the EREwtc luc as reporter plasmid. The derivative with a methyl-n-propyldodecanamide side chain (4h) antagonized the effect of estradiol (10(-9) M) completely at concentrations of 10(-7) M and higher. As a sensitive model for quantification of estrogenic and antiestrogenic effects in vitro we used HeLa-cells cotransfected both with the reporter plasmid and estrogen receptor expression vectors HEG0 and HE0. In cells transfected with these vectors transcriptional activity was strongly dependent on side chain structure. With mutated receptors we were able to show that this activity was mainly due to TAF-1 whereas TAF-2 remained silent. When we studied the effect of some of the new compounds in vivo using the mouse uterine weight assay, we observed a correlation between transcriptional activity in transfected HeLa cells and estrogenic effects in mice. Two of the 1-carbamoylalkyl-2-phenylindoles (4f, 4h) proved to be "pure" antiestrogens both in vitro and in vivo. In estrogen-sensitive MCF-7 breast cancer cells, they strongly inhibit cellular growth. Some of the IC50-values were close to 10(-8) M.
- Subjects :
- Animals
Breast Neoplasms metabolism
Cell Division drug effects
Estradiol analogs & derivatives
Estradiol metabolism
Estradiol pharmacology
Estrogen Antagonists metabolism
Female
HeLa Cells
Humans
Indoles metabolism
Mice
Organ Size drug effects
Polyunsaturated Alkamides
Radioligand Assay
Receptors, Estrogen genetics
Receptors, Estrogen metabolism
Sequence Deletion
Structure-Activity Relationship
Tamoxifen pharmacology
Transcriptional Activation
Tumor Cells, Cultured
Uterus drug effects
Estrogen Antagonists chemistry
Estrogen Antagonists pharmacology
Indoles chemistry
Indoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0960-0760
- Volume :
- 49
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of steroid biochemistry and molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 8003439
- Full Text :
- https://doi.org/10.1016/0960-0760(94)90300-x