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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Breast Neoplasms
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Cell Line, Tumor
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Estradiol / pharmacology
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Estrogen Antagonists / chemical synthesis*
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Estrogen Antagonists / chemistry
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Estrogen Antagonists / pharmacology
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Estrogen Receptor alpha / agonists
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Estrogen Receptor alpha / antagonists & inhibitors
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Estrogens / chemical synthesis*
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Estrogens / chemistry
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Estrogens / pharmacology
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Female
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Humans
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Hydrophobic and Hydrophilic Interactions
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Isoflavones / chemical synthesis*
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Isoflavones / chemistry
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Isoflavones / pharmacology
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Mice
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Mice, Nude
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Models, Molecular
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Receptors, Progesterone / biosynthesis
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Response Elements
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Structure-Activity Relationship
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Transcription, Genetic
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Xenograft Model Antitumor Assays
Substances
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3-(4-hydroxyphenyl)-8,8-dimethyl-8H-pyrano(2,3-f)chromen-4-one
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Antineoplastic Agents
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Estrogen Antagonists
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Estrogen Receptor alpha
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Estrogens
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Isoflavones
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Receptors, Progesterone
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Estradiol
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daidzein