SPECIFIC PROBES FOR THE ER HORMONE BINDING DOMAIN

该提案的广泛、长期目标是通过增强对17 α-取代雌激素和ER-激素结合结构域之间的关键相互作用之一的理解，开发用于治疗乳腺癌的新的和更有效的治疗剂。 该项目的具体目标是：1）。合成了四个系列的高亲和性雌二醇，2）. 分子构象的测定; 受体亲和力和活性的测定; 4）. 观察到的生物反应与计算的配体-受体结构，特别是AF-2（螺旋12）区域的相关性，5）。 迭代配体设计和假设的细化。 该项目的健康相关性在于，它将有助于开发更好的女性乳腺癌治疗药物，并扩大对雌激素反应步骤的理解。 研究设计从基本假设开始，该假设提出适当的17 α取代的雌激素与受体的关键螺旋12相互作用。 合成化学产生新的化合物（探针），进行构象分析和生物测定。 这些结果进行评估，导致改进的配体和/或细化的假设。 这些步骤将利用：1）。 立体化学控制的和通用的合成方法，2）。 通过使用高场NMR相关性和分子建模确定配体构象，3）。 确定生物学特性的竞争性受体结合和功能测定，和4）。 定量-结构活性关系和分子对接以关联观察到的和预测的结果。 这些结论将有助于设计更好的第二代配体和发展一个更好的假说的相互作用的受体效应复合物。

The broad, long-term objective of this proposal is the development of new and more effective therapeutic agents for the treatment of breast cancer by enhancing the understanding of one of the key interactions between 17alpha-substituted estrogens and the ER-Hormone Binding Domain. The specific aims for this project are: 1). the synthesis of four selected series of high affinity estradiols, 2). the determination of their molecular conformation, 3). the determination of receptor affinity and activity, 4). correlation of observed biological responses with the calculated ligand-receptor structure, especially the AF-2 (helix 12) region, 5). iterative ligand design and refinement of the hypothesis. The health relatedness of this project is that it will contribute to the development of better therapeutic agents for breast cancer in women and expand the understanding of the steps in the estrogenic response. The research design begins with the underlying hypothesis which proposes that appropriately 17alpha-substituted estrogens interact with the critical helix 12 of the receptor. The synthetic chemistry yields new compounds (probes) which undergo both conformational analyses and biological assays. These results are evaluated, leading to improved ligands and/or a refined hypothesis. These steps will utilize: 1). stereochemically controlled and versatile synthetic methods, 2). determination of ligand conformations by using high field NMR correlations and molecular modeling, 3). competitive receptor binding and functional assays to determine biological properties, and 4). quantitative-structure activity relationships and molecular docking to correlate the observed and predicted results. The conclusions will aid in the design of better second generation ligands and the development of a better hypothesis for the interactions of the hormone-receptor-effector complex.