Development and Application of Novel 3-Dimensional Hydrophobic Structures for Drug Design, Which Are Focused on Molecular Recognition between Ligand and Receptor

碳硼烷（二碳-近十二硼烷）是一类具有球形、优异的热稳定性和疏水性的含碳多面体硼簇化合物。在这项研究中，我们利用它们的分子形状和疏水表面来设计和合成核受体配体。研究了碳硼烷衍生物的疏水和氢键相互作用，以及碳硼烷衍生物的合成方法，用于分析和制备各种含碳硼烷化合物。结果总结如下：1。合成了在三维疏水核心结构上具有两个酚基残基的候选雌激素受体配体（碳硼烷、双环[2,2,2]辛烷、金刚烷）并进行了生物学评价。在含碳硼烷的化合物中，根据两个酚基的方向和距离，观察到激动剂/拮抗剂平衡的动态变化。以睾酮和芳香族抗雌激素药物为基础，设计了以碳硼烷为疏水药效团的候选雄激素受体配体，并进行了合成和生物学评价。发现了新型强效非甾体雄激素拮抗剂BA321、BA341。H-NMR研究了2-（2-羟基苯基）-o-碳硼烷和2-（2-羟基苯基）-对碳硼烷分子内氢键的形成。通过x射线、红外光谱和DFT计算证实了分子内氢键的存在。发展了几种碳硼烷衍生物的合成方法，如碳硼烷笼上的区域选择性碘化反应、碳上的易羟基化反应、碳硼烷笼。

Carboranes (dicarba-closo-dodecaboranes) are a class of carbon-containing polyhedral boron-cluster compounds having globular shape, remarkable thermal stability and hydrophobic character. In this study, we applied their molecular shape and hydrophobic surface of the molecules to design and synthesis of nuclear receptor ligands. Hydrophobic and hydrogen bonding interaction of carborane derivatives, and synthetic methods of carborane derivatives for analysis and preparation of various carborane-containing compounds were also investigated. The results were summarized as follows.1. Candidate estrogen receptor ligands with two phenolic residues on a 3-dimensional hydrophobic core structure (carborane, bicyclo[2, 2, 2]octane, adamantane) were synthesized and biologically evaluated. Amog the carborane-containing compounds, a dynamic change of agonist/antagonist balance was observed depending on the direction and the distance of the two phenolic groups.2. Candidate androgen receptor ligands bearing carborane as a hydrophobic pharmacophore were designed based on testosterone and aromatic anti-estrogen agents, and synthesized, biologically evaluated. Novel potent non-steroidal androgen antagonists BA321, BA341 were found.3. Intramolecular hydrogen bonding on 2-(2-hydroxyphenyl)-o-carborane and 2-(2-hydroxyphenyl)-p-carborane were observed on H-NMR study. The intranolecular hydrogen bonding was confirmed by X-ray, IR and DFT calculation.4. A few synthetic method of carborane derivatives, such as regioselective iodination reaction on the carborane cage, facile hydroxylation of a carbon on, the carborane cage were developed.