SPECIFIC PROBES FOR THE ER HORMONE BINDING DOMAIN

这项建议的广泛和长期目标是通过加强对17α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了解，开发用于治疗乳腺癌的新的、更有效的治疗药物。本项目的具体目标是：1)。四个精选系列高亲和力雌二醇的合成，2)。它们的分子构象测定，3)。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-受体结构的相关性，特别是AF-2(螺旋12)区域，5)。迭代配基的设计和假设的细化。该项目与健康相关的是，它将有助于开发更好的女性乳腺癌治疗剂，并扩大对雌激素反应步骤的理解。研究设计始于潜在的假设，该假设提出，适当的17α取代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)，它们既要经过构象分析，又要经过生物分析。对这些结果进行评估，导致改进的配体和/或改进的假设。这些步骤将利用：1)。立体化学控制和多种合成方法，2)。3)利用高场核磁共振关联和分子模拟确定配体构象。竞争受体结合和功能分析以确定生物学特性，以及4)。定量结构活性关系和分子对接将观察到的结果和预测的结果相关联。这些结论将有助于设计更好的第二代配体，并为激素-受体-效应器复合体的相互作用开发更好的假说。

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.