【摘 要】
：
PURPOSE: To determine the structural requirements for the transformation from estrogenic to anti-estrogenic compounds in a series of daidzein derivatives.DESIGN METHODS: A series of daidzein analogues
【机 构】
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RCMI Cancer Research Program, Xavier University of Louisiana USA
【出 处】
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BIT`s 2nd Annual World Congress of Endobolism-2012(2012第二届内分
论文部分内容阅读
PURPOSE: To determine the structural requirements for the transformation from estrogenic to anti-estrogenic compounds in a series of daidzein derivatives.DESIGN METHODS: A series of daidzein analogues were designed and synthesized.MCF-7 breast cancer cells were treated with the synthetic analogues to evaluate effect of daidzein and daidzein analogues on estrogen responsive element (ERE) transcriptional activity,ERα binding affinity, MCF-7 breast cancer cells colonial survival, PgR gene expression.In vivo studies of the anti-estrogenic effects of the most potent analogue on MCF-7 cell tumorigenesis were conducted using a xenografi mouse model.RESULTS: Daidzein analogues resulting from hydrogen substitution by isopropyl, isobutyl, cyclopentyl, and pyranogroup, were found to inhibit cell proliferation, estrogen-induced transcriptional activity, and ER regulated progesterone receptor gene expression.However, methyl and ethyl substitutions of the hydroxyl proton only led to moderate reduction of the estrogenic activities.Molecular modeling study of representative daidzein analogues using the crystal structure of ERα revealed that daidzein and the methyl substituted analogue fitted well in the ligand binding pocket of ERα in its estrogen bound configuration.The pyrano-substituted analogue was found to dock better in ERα in its antiestrogenbound configuration.CONCLUSION: These results demonstrated the structural requirements for the transformation of daidzein from an ER agonist to an antagonist.The most effective compound, 2 was found to reduce in vivo estrogen stimulated MCF7 cell tumorigenesis using a xenograft mouse model, and may serve as a novel antiestrogen for breast cancer treatment based on the structural motif of a natural isoflavone.
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