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.

Carboranes（Dicarba-Closo-DodeCaboranes）是一类具有球形形状，显着的热稳定性和疏水性特征的含碳多面体硼簇化合物。在这项研究中，我们将它们的分子形状和分子的疏水表面应用于核受体配体的设计和合成。还研究了Carborane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Carborane化合物的Carborane衍生物的合成方法。结果总结如下1。合成并对生物学评估了三维疏水性核心结构（Carborane，Bicyclo [2，2，2]辛烷）的候选雌激素受体配体（Carborane，Bicyclo [2，2，2]辛烷值）。 AMOG含卡硼烷化合物，根据两个酚类基团的方向和距离观察到激动剂/拮抗剂平衡的动态变化。2。基于睾丸激素和芳香族抗雌激素剂，设计了带有Carborane的候选雄激素受体配体作为疏水药实践，并合成了生物学评估。发现了新型有效的非甾体雄激素拮抗剂BA321，BA341。3。在H-NMR研究中，观察到在2-（2-羟基苯基）-O-碳纤维和2-（2-羟基苯基）-P-碳酸盐的2-（2-羟基苯基）-P-碳纤维上的分子内氢键。分子内氢键通过X射线，IR和DFT计算证实。4。开发了几种碳脂蛋白衍生物的合成方法，例如在卡堡笼上的区域选择性碘化反应，碳上的便捷羟基化，开发了卡堡笼。