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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: Biomimetic synthesis and antiproliferative properties of racemic natural(-) and unnnatural(+) glyceollin I

Authors
item Khupse, Rahul -
item Sarver, Jeffrey -
item Trendel, Jill -
item Ellis, Nicole -
item Reese, Michael -
item Wiese, Thomas -
item Boue, Stephen
item Burow, Matthew -
item Cleveland, Thomas
item Bhatnagar, Deepak
item Erhardt, Paul -

Submitted to: Journal of Medicinal Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: April 7, 2011
Publication Date: July 1, 2011
Citation: Khupse, R.S., Sarver, J.G., Trendel, J.A., Ellis, N.R., Reese, M.D., Wiese, T.E., Boue, S.M., Burow, M.E., Cleveland, T.E., Bhatnagar, D., Erhardt, P.W. 2011. Biomimetic synthesis and antiproliferative properties of racemic, natural(-), and unnnatural(+) glyceollin I. Journal of Medicinal Chemistry. 54(10):3506-3523.

Interpretive Summary: A 14-step synthetic route to glyceollin I with a 1.5% overall yield has been developed. In addition to being useful for the creation of analogs, this route provides practical access to analytical standards that may be used for quality control purposes when glyceollin I is obtained naturally from stressed soybean. Different glyceollin I structures (natural, unnatural, and racemic) were tested for anticancer activity. Within the breast and ovarian cell culture panel, all three of the glyceollin I forms exhibited substantial growth inhibitory effects on several breast cancer cell lines. At similar concentrations within the prostate cancer cell culture panel, natural and racemic glyceollin I have a greater inhibitory effect on prostate cancer cell lines. Although not pronounced, there appear to be subtle differences between the glyceollin I structures.

Technical Abstract: A 14-step biomimetic synthetic route to glyceollin I in ca. 1.5% overall yield has been developed. In addition to being useful for the elaboration of analogs that can contribute to SAR, this route provides practical access to analytical standards that may be used for quality control purposes when glyceollin I is obtained naturally from stressed soy bean. For the latter, the use of asymmetric NMR shift reagents and chiral HPLC have been shown to be convenient methods for preliminary and final assessments of enantiomeric excess. Both enantiomers, as well as the glyceollin I racemate, were studied in antiproliferation studies using hormone-related human cancer cell lines. Within the breast and ovarian cell culture panel, all three of the glyceollin I forms exhibit substantial growth inhibitory (GI) effects on estrogen receptor negative (ER-) and ER+ cell lines at concentrations in the low to mid µM range. At similar concentrations within the prostate cancer cell culture panel, natural and racemic glyceollin I have a greater GI effect on androgen receptor positive (AR+) LNCaP cells than the AR- PC3 and DU145 cell lines. Although not pronounced, there appear to be subtle differences between the glyceollin I enantiomers in their overall GI profiles. Perhaps more importantly, however, the composite of these studies suggest that the overall antiproliferative properties exhibited by the glyceollin I stereoisomers may be derived from a more complicated mechanistic picture than can be explained by relying upon just the classical types of interactions with ERs.

Last Modified: 7/25/2014