Synthesis of Bioactive Natural Products

生物活性天然产物的合成

• 批准号: 6889534
• 负责人: Erik J. Sorensen
• 金额: $ 28.9万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6889534
• 关键词: androstane compound; antiAIDS agent; antibiotics; benzopyrans; biological products; chemical synthesis; kinase inhibitor; virus protein; virus replication

DESCRIPTION (provided by applicant): The long-term objectives of this research program are (1) to achieve efficient total syntheses of natural products, which could benefit human health, through the development of powerful chemical methods and strategies, and (2) to investigate the modes of action of bioactive natural products. This grant application addresses the chemical problems posed by five biologically active natural products and its Specific Aims are: (1) to develop novel synthetic routes to the natural products harziphilone and fleephilone and characterize how these compounds inhibit binding between the HIV-1 Rev protein and the Rev Responsive Element (RRE) of viral mRNA, a required event in the replication of HIV-1 ; and (2) to achieve concise syntheses of TAEMC-161 and the steroidal antibiotics viridiol and viridin. The function of the protein HIV-1 Rev is essential for the replication of HIV and, therefore, an excellent target for therapeutic intervention. Harziphilone and fleephilone are natural products that block the critical HIV-1 Rev/RRE RNA interaction. The important bioactivities and unique structural features of these compounds make them compelling objectives for organic synthesis. A tandem process comprising three structural transformations is proposed to convert an acyclic bis-ynone to harziphilone, while an aza-ring annulation featuring the intramolecular addition of a carbon nucleophile to pyridinium or iminium ions is the cornerstone of the proposed approach to the unusual structure of fleephilone. The furanosteroid viridin and its structural relatives are cell permeable, selective inhibitors of PI 3-kinase, an enzyme essential for many biological processes, and have potential as therapeutic agents for the treatment of neoplasms in humans. As such, these compounds and other natural products that act by analogous mechanisms are prime targets for organic synthesis. This grant application describes how an efficient reaction sequence featuring metal-catalyzed cyclotrimerization, carbonyl addition, and sequential electrocyclic reactions can be integrated into a general plan for syntheses of viridiol and viridin and also illustrates a structural and potential chemical relationship between these compounds and the recently described natural product TAEMC-161.

描述（由申请人提供）：该研究项目的长期目标是（1）通过开发强大的化学方法和策略，实现天然产物的高效全合成，从而有益于人类健康；（2）研究具有生物活性的天然产物的作用模式。该拨款申请解决了五种生物活性天然产物带来的化学问题，其具体目标是：(1) 开发天然产物 harziphilone 和 flephilone 的新合成路线，并表征这些化合物如何抑制 HIV-1 Rev 蛋白与病毒 mRNA Rev 反应元件 (RRE) 之间的结合，这是 HIV-1 复制中必需的事件； (2)实现TAEMC-161和甾体抗生素viridiol和viridin的简洁合成。 HIV-1 Rev 蛋白的功能对于 HIV 的复制至关重要，因此是治疗干预的绝佳靶点。 Harziphilone 和 flephilone 是阻断关键的 HIV-1 Rev/RRE RNA 相互作用的天然产物。这些化合物的重要生物活性和独特的结构特征使其成为有机合成的引人注目的目标。提出了一种包含三个结构转变的串联过程，将无环双炔酮转化为哈齐菲酮，而以碳亲核试剂分子内加成到吡啶鎓或亚胺鎓离子为特征的氮杂环成环是所提出的弗菲酮不寻常结构方法的基石。呋喃类固醇viridin及其结构相关物是PI 3-激酶的细胞渗透性、选择性抑制剂，PI 3-激酶是许多生物过程所必需的酶，并且具有作为治疗人类肿瘤的治疗剂的潜力。因此，这些化合物和其他通过类似机制起作用的天然产物是有机合成的主要目标。该资助申请描述了如何将以金属催化环三聚、羰基加成和连续电环反应为特征的有效反应序列整合到合成viridiol和viridin的总体计划中，并说明了这些化合物与最近描述的天然产物TAEMC-161之间的结构和潜在化学关系。