SPIROISOXAZOLINES, BREAST CANCER, AND ESTROGEN RECEPTORS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 螺异恶唑类药物与乳腺癌和雌激素受体 在绿茶、大豆和鱼中发现的天然化合物，如类黄酮类和异黄酮类，已被证明通过与雌激素受体结合而在乳腺癌治疗中有益。天然产生的物质已被用作合成结构相似的类似物的模板，这些类似物可用于乳腺癌治疗。最近发现天然产物11-脱氧瘘管素-3对乳腺癌MCF-7细胞具有细胞毒作用(LD_(50)=17 mg/L)。我们进行了一些11-脱氧瘘管素-3的理论配基结合研究，以及一些潜在的合成类似物，以确定这些化合物在理论上是否可以与雌激素受体(ER-α)结合。由于ER-α与拮抗剂雷洛昔芬的晶体结构已知，我们使用了化合物在ER-α结合部位的对接研究，并将雷洛昔芬的结合部位的结构与类似物的结构进行了比较。一些潜在的合成类似物理论上可以适合ER-α的结合位置，并且这些分子的亲水部分定向在正确的方向。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。我们还提交了几个异恶唑啉前体用于体外雌激素结合研究。雌激素受体测试是由伊利诺伊大学香槟分校的John Katzenellenbogen博士进行的。

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. Spiroisoxazolines, Breast Cancer, and Estrogen Receptors 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-alpha). Since the crystal structure of ER-alpha with the antagonist raloxifene is know, we used a combination of docking studies of our compounds in the binding site of ER-alpha, and a comparison of raloxifene's structure in the binding site to the analogues' structures. Some of the potential synthetic analogues theoretically could fit into the binding site of ER-alpha, 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. 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.