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Effects of 7-O substitutions on estrogenic and anti-estrogenic activities of daidzein analogues in MCF-7 breast cancer cells.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2010 Aug 26; Vol. 53 (16), pp. 6153-63. - Publication Year :
- 2010
-
Abstract
- Daidzein (1) is a natural estrogenic isoflavone. We report here that 1 can be transformed into anti-estrogenic ligands by simple alkyl substitutions of the 7-hydroxyl hydrogen. To test the effect of such structural modifications on the hormonal activities of the resulting compounds, a series of daidzein analogues have been designed and synthesized. When MCF-7 cells were treated with the analogues, those resulting from hydrogen substitution by isopropyl (3d), isobutyl (3f), cyclopentyl (3g), and pyrano- (2) inhibited cell proliferation, estrogen-induced transcriptional activity, and estrogen receptor (ER) regulated progesterone receptor (PgR) gene expression. However, methyl (3a) and ethyl (3b) substitutions of the hydroxyl proton only led to moderate reduction of the estrogenic activities. These results demonstrated the structural requirements for the transformation of daidzein from an ER agonist to an antagonist. The most effective analogue, 2, was found to reduce in vivo estrogen stimulated MCF-7 cell tumorigenesis using a xenograft mouse model.
- Subjects :
- Animals
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Breast Neoplasms
Cell Line, Tumor
Estradiol pharmacology
Estrogen Antagonists chemistry
Estrogen Antagonists pharmacology
Estrogen Receptor alpha agonists
Estrogen Receptor alpha antagonists & inhibitors
Estrogens chemistry
Estrogens pharmacology
Female
Humans
Hydrophobic and Hydrophilic Interactions
Isoflavones chemistry
Isoflavones pharmacology
Mice
Mice, Nude
Models, Molecular
Receptors, Progesterone biosynthesis
Response Elements
Structure-Activity Relationship
Transcription, Genetic
Xenograft Model Antitumor Assays
Antineoplastic Agents chemical synthesis
Estrogen Antagonists chemical synthesis
Estrogens chemical synthesis
Isoflavones chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 53
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 20669983
- Full Text :
- https://doi.org/10.1021/jm100610w