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(二碳杂环十二烷)是一类含碳的多面体含硼簇合物，具有球状结构、显著的热稳定性和疏水性。在本研究中，我们利用它们的分子形状和分子的疏水表面来设计和合成核受体配体。还研究了碳硼烷衍生物的疏水作用和氢键作用，以及用于分析和制备各种含碳硼烷化合物的碳硼烷衍生物的合成方法。主要研究结果如下：1.研究结果。合成了具有两个酚类残基的三维疏水核心结构的候选雌激素受体配体(卡波烷、双环[2，2，2]辛烷、金刚烷)，并对其进行了生物学评价。在含碳硼烷的化合物中，激动剂/拮抗剂的平衡随两个酚基的方向和距离的变化而发生动态变化。基于睾酮和芳香族抗雌激素药物设计了以碳硼烷为疏水药效团的候选雄激素受体配体，并对其进行了合成和生物学评价。发现了新型有效的非甾体雄激素拮抗剂BA321、BA341。对2-(2-羟基苯基)-邻碳硼烷和2-(2-羟基苯基)-对碳硼烷的氢键进行了H-核磁共振研究。X-射线衍射、红外光谱和密度泛函理论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，如碳硼笼上的区域选择性碘化反应、碳原子的简易羟基化反应、碳硼笼上的碳氢化法等。

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.