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

药物设计中新型三维疏水结构的开发和应用，重点关注配体和受体之间的分子识别

基本信息

批准号：
16390032
负责人：
ENDO Yasuyuki
金额：
$ 9.66万
依托单位：
Tohoku Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2007
项目状态：
已结题

项目摘要

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.

碳硼烷（dicarba-closo-dodecaboranes）是一类含碳多面体硼簇化合物，具有球形、显着的热稳定性和疏水性。在这项研究中，我们应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和氢键相互作用，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。研究结果如下： 1．合成了在 3 维疏水核心结构上具有两个酚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）并进行了生物学评估。在含碳硼烷化合物中，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。 2．基于睾酮和芳香族抗雌激素药物，设计并合成了带有碳硼烷作为疏水药效基团的候选雄激素受体配体，并进行了生物学评价。发现新型强效非甾体雄激素拮抗剂BA321、BA341。 3．通过 H-NMR 研究观察到 2-(2-羟基苯基)-邻-碳硼烷和 2-(2-羟基苯基)-对-碳硼烷上的分子内氢键。通过X射线、IR和DFT计算证实了分子内氢键的存在。 4．发展了碳硼烷笼上的区域选择性碘化反应、碳硼烷笼上碳的简易羟基化反应等几种碳硼烷衍生物的合成方法。