SPIROISOXAZOLINES, BREAST CANCER, AND ESTROGEN RECEPTORS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Naturally occurring compounds such as flavanoids and isoflavones, which are found in green tea, soybeans, and fish, have been shown to be beneficial in breast cancer treatment through binding to estrogen receptors. Naturally occurring substances have been utilized as templates for the synthesis of structurally similar analogues that can be used for breast cancer treatment. Recently, the natural product 11-deoxyfistularin-3 was found to be cytotoxic towards MCF-7 breast cancer cells (LD50 = 17 mg/L). We performed some theoretical ligand binding studies of 11-Deoxyfistularin-3, and some potential synthetic analogues to determine if these compounds could theoretically bind to the alpha estrogen receptor (ER- ¿). Since the crystal structure of ER- ¿ with the antagonist raloxifene is know, we used a combination of docking studies of our compounds in the binding site of ER-¿, and a comparison of raloxifenes structure in the binding site to the analogues structures. Some of the potential synthetic analogues theoretically could fit into the binding site of ER- ¿, and the hydrophilic portions of these molecules were oriented in the right direction. The molecular comparison of many of the potential synthetic analogues also had some overlapping features to raloxifene. We have developed a synthetic methodology towards the synthesis of spiroisoxazoline compounds, and since our initial publication in November, we have reduced the number of steps required to synthesize the spiroisoxazoline compounds. Another publication in February resulted from our studies to improve the synthetic methodology. We also submitted a few of the isoxazoline precursors for in vitro estrogen binding studies. The estrogen receptor assays were performed by Dr. John Katzenellenbogen at the University of Illinois, Urbana-Champaign.