SPIROISOXAZOLINES, BREAST CANCER, AND ESTROGEN RECEPTORS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在绿色茶、大豆和鱼中发现的天然化合物，如类黄酮和异黄酮，已被证明通过与雌激素受体结合，对乳腺癌治疗有益。 天然存在的物质已被用作合成可用于乳腺癌治疗的结构相似的类似物的模板。 最近，发现天然产物11-deoxyfistularin-3对MCF-7乳腺癌细胞具有细胞毒性（LD 50 = 17 mg/L）。 我们对11-Deoxyfistularin-3和一些潜在的合成类似物进行了一些理论配体结合研究，以确定这些化合物理论上是否可以与α雌激素受体（ER-β）结合。 由于ER-<$与拮抗剂雷洛昔芬的晶体结构是已知的，我们结合使用了我们的化合物在ER-<$结合位点的对接研究，并比较雷洛昔芬类似物结合位点的结构 结构. 一些潜在的合成类似物理论上可以适合ER-β的结合位点，并且这些分子的亲水部分在正确的方向上取向。 许多潜在的合成类似物的分子比较也与雷洛昔芬有一些重叠的特征。 我们已经开发了一种合成螺异恶唑啉化合物的合成方法，自从我们在11月首次发表以来，我们已经减少了合成螺异恶唑啉化合物所需的步骤数量。 2月份的另一篇出版物是我们改进合成方法的研究成果。 我们还提交了一些异恶唑啉前体的体外雌激素结合研究。 雌激素受体测定由伊利诺伊大学厄巴纳-香槟分校的John Katzenellenbogen博士进行。

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.