Chemical Synthesis of Bioactive Diterpenoids

生物活性二萜类化合物的化学合成

• 批准号: 10405930
• 负责人: Christopher D Vanderwal
• 金额: $ 42.86万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10405930
• 关键词: Address; Anti-Bacterial Agents; Antibiotics; Antimalarials; Architecture; Area; Artemisinins; Bicycling; Biological; Biology; Chemicals; Chemistry; Clinical; Cobalt; Complex; Cyclization; Development; Diterpenes; Equilibrium; Goals; Hydrazones; Investigation; Laboratories; Lead; Life; Malignant Neoplasms; Methodology; Modernization; Natural Products; Nature; Neurologic; Organic Chemistry; Paclitaxel; Polyenes; Process; Production; Research; Savings; Structure-Activity Relationship; Synthesis Chemistry; Terpenes; Time; Work; analog; bioactive natural products; chemical synthesis; design; empowered; innovation; novel; pre-clinical; programs; small molecule

Project Summary Polycyclic terpenoid natural products are endowed with a broad range of medicinally relevant biological activities. Taxol and artemisinin are two premier examples of life-saving terpenoids; the former is used clinically to treat several different cancers, while the latter is a critical antimalarial agent used worldwide. Chemical synthesis approaches to natural products provide opportunities to make compounds that might be scarcely available from nature, to generate analogues that are only available by total synthesis, and to make probe molecules for increased understanding of the underlying biology. A balance of innovative strategy and new chemical methodology promises efficient syntheses that can serve to answer important biological questions that often can only be probed with small molecules. As part of our laboratory’s long-term goal to enhance efficiency in the synthesis of complex natural products to facilitate important studies in biology, the objective of the proposed research program is to develop concise and creative synthesis designs and empowering methodological advances to permit access to many bioactive diterpenoid natural products. The rationale for this work is that synthetic chemistry is critical to the development of natural product “hit molecules” into legitimate preclinical lead compounds by analogue production, by identification of structure-activity relationships, by the synthesis of chemical probe molecules for mechanism of action studies, and more. An efficient total synthesis of targeted natural products provides a platform from which to address each of these key areas of research. The proposed research is significant because chemical synthesis will provide access to a broad range of biologically important secondary metabolites and analogues with which to interrogate key processes; at the same time, the underlying synthesis designs and methodologies will lead to vertical advancement of the field of organic chemistry. These contributions are innovative by virtue of the chemistry-driven, multi-faceted investigations into the biological activity of diterpenoids with immunosuppressive, antiviral, antibiotic, and neurological activity; the development of new stereocontrolled polyene cyclization strategies to access polycyclic diterpenoid natural products; and the elaboration of new radical bicyclization strategies to make complex architectures relevant to bioactive natural products.

项目摘要 多环萜类天然产物具有广泛的药用价值。 活动。紫杉醇和青蒿素是两个主要的救命萜类化合物；前者用于临床 用于治疗几种不同的癌症，而后者是全世界使用的一种关键的抗疟疾药物。化学制品 天然产物的合成方法提供了制造化合物的机会，这些化合物可能几乎 从大自然中获得，以产生只有通过全合成才能获得的类似物，并进行探测 分子，以增加对潜在生物学的理解。创新战略与创新战略的平衡 化学方法论承诺进行有效的合成，以回答重要的生物学问题 这通常只能用小分子来探测。 作为我们实验室提高复杂天然产物合成效率的长期目标的一部分 为了促进重要的生物学研究，拟议的研究计划的目标是开发 简明和创造性的综合设计和授权的方法进步，允许访问许多 生物活性二萜类天然产物。这项工作的基本原理是，合成化学对 天然产物“HIT分子”通过类似物开发成合法的临床前先导化合物 通过鉴定结构-活性关系，通过合成化学探针分子进行生产 行动机制研究，等等。目标天然产物的高效全合成提供了一种 解决这些关键研究领域的每一个问题的平台。 这项拟议的研究意义重大，因为化学合成将提供广泛的 生物上重要的次生代谢物和类似物，用来询问关键过程； 同时，基本的综合设计和方法学将导致垂直领域的进步 有机化学。这些贡献是创新的，得益于化学驱动的、多方面的 二萜类化合物具有免疫抑制、抗病毒、抗菌和抗肿瘤活性的研究 神经活动；新的立体控制的多烯环化策略的开发 多环二萜类天然产物；以及阐述新的激进自行车策略，以使 与生物活性天然产品相关的复杂建筑。