Synthesis of Bioactive Natural Products

描述（由申请人提供）：该拟议计划的目标是开发想法和反应序列，将简单的市售化合物高效转化为结构复杂的生物活性天然产物，并研究这些物质在生物学背景下的特性。本申请中描述的化学研究的基本主题是设计和执行快速形成两种天然产物的拓扑和立体化学复杂结构的级联反应：（1）有前途的血管生成抑制剂Cortistatin A，以及（2）有效的和选择性的抗癌化合物Maoecrystal V。这些天然产物具有真正的潜力作为化疗剂治疗人类疾病和分子结构，激发概念的发展，为有机合成领域的利益。新的合成建议植根于这样一种想法，即合理的基本羰基依赖性反应序列将使这些具有挑战性的目标分子的快速合成成为可能。该计划中开发的合成途径将被用来深入了解这些迷人的天然产物的生物分子目标选择性。外行语言：用于治疗人类疾病的小分子药物和用于细胞生物学中基于发现的研究活动的分子探针是通过化学合成的方法和概念生产的。该计划的重要性来自于它将开发的强大的想法和方法，用于实现两种结构复杂的生物活性天然产物的短而有效的合成，以及发现用于攻击人类疾病的新生物分子靶点。公共卫生相关性：快速形成具有生物活性的天然产物的复杂分子结构的强有力的策略和反应序列的概念和发展是化学合成领域的前沿活动之一。该项目正在开发创新的羰基级联环化反应，用于合成几种具有改善人类健康特性的天然产物。

DESCRIPTION (provided by applicant): The objectives of this proposed program are to develop ideas and reaction sequences to transform simple, commercially available compounds into structurally complex, biologically active natural products with high efficiency and to investigate the properties of these substances in biological contexts. The underlying theme of the chemical studies described in this application is the design and execution of cascades of reactions that rapidly form the topologically and stereochemically complex structures of two natural products: (1) the promising angiogenesis inhibitor Cortistatin A, and (2) the potent and selective anticancer compound Maoecrystal V. These natural products have genuine potential as chemotherapeutic agents for the treatment of human diseases and molecular architectures that inspire the development of concepts for the benefit of the field of organic synthesis. The new synthesis proposals are rooted in the idea that judicious sequences of fundamental, carbonyl-dependent reactions will enable rapid syntheses of these challenging target molecules. The synthesis pathways developed in this program will be leveraged to gain insights into the biomolecular target selectivities of these fascinating natural products. Lay language: Small molecule drugs for the treatment of human diseases and molecular probes for discovery-based research activities in cell biology are produced by the methods and concepts of chemical synthesis. The significance of this program comes from the powerful ideas and methods that it will develop for achieving short, efficient syntheses of two structurally complex, biologically active natural products and the discoveries of new biomolecular targets for attacking diseases in humans. PUBLIC HEALTH RELEVANCE: The conception and development of powerful strategies and reaction sequences to rapidly form the complex molecular structures of biologically active natural products is one of the frontier activities in the field of chemical synthesis. This program is developing innovative carbonyl-based cascades of cyclizations for use in syntheses of several natural products with properties that could improve human health.