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United States Department of Agriculture

Agricultural Research Service

Research Project: PHYTOESTROGENIC EFFECTS OF ELICITOR INDUCED ISOFLAVONOIDS IN LEGUMES

Location: Food and Feed Safety Research

Title: Effects of 7-O substitutions on estrogenic and anti-estrogenic activities of daidzein analogues in MCF-7 breast cancer cells

Authors
item Jiang, Quan -
item Payton-Stewart, Florastina -
item Elliott, Steven -
item Driver, Jennifer -
item Rhodes, Lyndsay -
item Zhang, Qiang -
item Zheng, Shilong -
item Bhatnagar, Deepak
item Boue, Stephen
item Collins-Burow, Bridgette -
item Sridhar, Jayalakshmi -
item Stevens, Cheryl -
item Mclachlan, John -
item Wiese, Thomas -
item Burow, Matthew -
item Wang, Guangdi -

Submitted to: Journal of Medicinal Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 22, 2010
Publication Date: November 10, 2010
Citation: Jiang, Q., Payton-Stewart, F., Elliott, S., Driver, J., Rhodes, L.V., Zhang, Q., Zheng, S., Bhatnagar, D., Boue, S.M., Collins-Burow, B.M., Sridhar, J., Stevens, C., Mclachlan, J.A., Wiese, T.E., Burow, M.E., Wang, G. 2010. Effects of 7-O substitutions on estrogenic and anti-estrogenic activities of daidzein analogues in MCF-7 breast cancer cells. Journal of Medicinal Chemistry. 53(16):6153-6163.

Interpretive Summary: Daidzein is a natural compound found in soybean that mimics the female hormone estrogen. We report here that daidzein can be transformed into an antiestrogenic compound by simple structural changes. 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 breast cancer cells were treated with the analogues, several inhibited cell proliferation, estrogen-induced transcriptional activity, and estrogen receptor (ER) regulated progesterone receptor (PgR) gene expression. However, some 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. One of the analogues was found to reduce in vivo estrogen stimulated breast cancer formation using an animal model.

Technical Abstract: Daidzein (1) is a natural estrogenic isoflavone. We report here that 1 can be transformed into an antiestrogenic ligand 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.

Last Modified: 8/22/2014