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）：本研究计划的长期目标是（1）通过开发强大的化学方法和策略，实现对人类健康有益的天然产物的有效全合成，以及（2）研究具有生物活性的天然产物的作用方式。该授权申请解决了五种具有生物活性的天然产物所带来的化学问题，其具体目标是：（1）开发天然产物哈兹菲隆和弗利特伍德的新型合成路线，并表征这些化合物如何抑制HIV-1 Rev蛋白与病毒mRNA的Rev反应元件（RRE）之间的结合，这是HIV-1复制所需的事件;（2）实现了TAEMC-161和甾体抗生素viridiol、viridin的简明合成。HIV-1 Rev蛋白的功能对于HIV的复制至关重要，因此是治疗干预的一个很好的靶点。Harziphilone和fleephilone是阻断关键HIV-1 Rev/RRE RNA相互作用的天然产物。这些化合物重要的生物活性和独特的结构特征使它们成为有机合成的重要目标。一个串联的过程，包括三个结构的转换，提出了一个无环的bis-ynone哈茨菲隆，而氮杂环成环的特点是分子内添加的碳亲核试剂吡啶或亚胺离子的基石所提出的方法的不寻常的结构fleephilone。呋喃类固醇绿啶及其结构相关物是PI 3-激酶的细胞可渗透的选择性抑制剂，PI 3-激酶是许多生物过程所必需的酶，并且具有作为治疗剂用于治疗人类肿瘤的潜力。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。该授权申请描述了如何将具有金属催化的环三聚、羰基加成和顺序电环化反应的有效反应序列整合到用于合成viridiol和viridin的总体计划中，并且还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。