GENERAL METHODS FOR SYNTHESIS OF BIOACTIVE MATERIALS

生物活性材料合成的通用方法

• 批准号: 3278736
• 负责人: LARRY E. OVERMAN
• 金额: $ 28.07万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-08-01 至 1994-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3278736
• 关键词: 6,7 benzomorphan; DNA directed DNA polymerase; alkaloids; analgesics; antibiotics; antiviral agents; aphidicolin; azo compounds; chemical structure function; cyclic compound; cyclization; diterpenes; drug adverse effect; drug design /synthesis /production; drug screening /evaluation; heterocyclic compounds; morphinans; silanes; stereochemistry

The overall objective of the research proposed in this application is to develop new chemical methods for the stereocontrolled synthesis of complex polycyclic molecules. The evolution of new efficient chemical synthesis methods will allow future promising pharmaceutical leads to be developed rapidly with potential therapeutic implications. During the proposed project period we will attempt to develop metal- catalyzed cyclizations of polyenes into a broadly applicable strategy for organic synthesis. This endeavor is founded on exciting new palladium- catalyzed cyclizations of dienyl aryl halides which were developed during the current GM-06-07 project years. We believe that metal-catalyzed polyene cyclinzations can evolve into a major synthesis method for preparing heterocycles and carbocycles and will compliment (not duplicate) existing methods based on cationic or radical intermediates. Our proposed studies are unusually broad in scope and encompass mechanistic, exploratory, and total synthesis endeavors. The total synthesis targets are structurally diverse and include the recently isolated scopadulcic acids A and B, which display cytotoxic and antiviral activity, and aphidicolin, a specific reversible inhibitor of type alpha eucaryotic DNA polymerases. A new approach for the synthesis of important analgesics of the morphinan and benzomorphan families will also be developed. This synthesis should be useful for preparing unusual analgesic analogs with electron-deficient aromatic rings. Other total synthesis targets include 6a-epipretazettine, the oxepene marine natural product isolaurepinnacin, and the unusual alkaloid nauclefiline. Where appropriate, analogs will be prepared to define structure activity relationships. Intermediates and target molecules prepared will be broadly screened for biological activity at NCI and Dow.

本应用程序提出的研究的总体目标是 开发新的化学方法来立体控制的合成 复杂的多环分子。新高效化学的演变 合成方法将使未来有希望的药物铅成为 迅速发展具有潜在的治疗意义。 在拟议的项目期间，我们将尝试开发金属 - 催化多烯的催化环化为广泛适用的策略 有机合成。这项努力建立在令人兴奋的新钯基于 在期间开发的二烯基芳基卤化物的催化环化 当前的GM-06-07项目年。我们相信金属催化 多烯旋风可以演变为主要的合成方法 准备杂环和碳循环，并会称赞（不是 重复）基于阳离子或自由基中间体的现有方法。 我们提出的研究在范围和涵盖范围异常广泛 机械，探索性和总合成努力。 总合成目标在结构上是多样的，包括 最近分离的s硫酸A和B，它们显示细胞毒性和 抗病毒活性和蚜虫蛋白，一种特定的可逆抑制剂 型α桉树DNA聚合酶。合成的新方法 Morphinan和Benzomorphan家族的重要镇痛学将 也可以开发。该综合对于准备不寻常应该有用 具有电子缺陷芳香环的镇痛类似物。其他总数 合成目标包括6a- epretrazettine，氧杂货海洋天然 产物分离的pin蛋白和异常的生物碱Nauclefiline。在哪里 适当的类似物将准备定义结构活动 关系。 制备的中间体和目标分子将被广泛筛选 NCI和DOW的生物活性。