Cyclization Cascades to Access Bioactive Diterpenoids

环化级联以获得生物活性二萜类化合物

• 批准号: 10217197
• 负责人: Christopher D Vanderwal
• 金额: $ 39.71万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217197
• 关键词: Actinic keratosis; Address; Alkenes; Anti-Infective Agents; Antimalarials; Antineoplastic Agents; Antioxidants; Antiviral Agents; Architecture; Area; Artemisinins; Bicycling; Binding; Biochemical; Biological; Biological Assay; Biology; Breathing; Cells; Chemicals; Chemistry; Chlorine; Cholesterol; Clinical; Complex; Cyclization; Cytotoxin; Development; Diterpenes; Docking; Epoxy Compounds; Equilibrium; Evolution; Family; Goals; Guanine; HIV; HIV-1; Health; Human; Hydrazones; Investigation; Kidney Diseases; Laboratories; Lead; Life; Malignant Neoplasms; Methodology; Methods; Modernization; Molecular; Natural Products; Nature; Organic Chemistry; Paclitaxel; Pharmaceutical Preparations; Polyenes; Problem Solving; Process; Production; Property; Protein Biosynthesis; Protein Synthesis Inhibition; RNA Binding; Reaction; Recording of previous events; Renal carcinoma; Research; Ribosomal Interaction; Ribosomes; Savings; Structure; Structure-Activity Relationship; Synthesis Chemistry; Terpenes; Time; Translations; Work; analog; anti-cancer; base; bioactive natural products; cell killing; chemical synthesis; compactin; cytotoxic; design; empowered; inhibitor/antagonist; innovation; novel; osteoclastogenesis; pre-clinical; reactivation from latency; small molecule; structural biology; success; tool; Actinic keratosis; Address; Alkenes; Anti-Infective Agents; Antimalarials; Antineoplastic Agents; Antioxidants; Antiviral Agents; Architecture; Area; Artemisinins; Bicycling; Binding; Biochemical; Biological; Biological Assay; Biology; Breathing; Cells; Chemicals; Chemistry; Chlorine; Cholesterol; Clinical; Complex; Cyclization; Cytotoxin; Development; Diterpenes; Docking; Epoxy Compounds; Equilibrium; Evolution; Family; Goals; Guanine; HIV; HIV-1; Health; Human; Hydrazones; Investigation; Kidney Diseases; Laboratories; Lead; Life; Malignant Neoplasms; Methodology; Methods; Modernization; Molecular; Natural Products; Nature; Organic Chemistry; Paclitaxel; Pharmaceutical Preparations; Polyenes; Problem Solving; Process; Production; Property; Protein Biosynthesis; Protein Synthesis Inhibition; RNA Binding; Reaction; Recording of previous events; Renal carcinoma; Research; Ribosomal Interaction; Ribosomes; Savings; Structure; Structure-Activity Relationship; Synthesis Chemistry; Terpenes; Time; Translations; Work; analog; anti-cancer; base; bioactive natural products; cell killing; chemical synthesis; compactin; cytotoxic; design; empowered; inhibitor/antagonist; innovation; novel; osteoclastogenesis; pre-clinical; reactivation from latency; small molecule; structural biology; success; tool

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 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 of small molecules that can provide answers to important biological questions that are not easily solved by other means. 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 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. Our specific aims include (1) the synthesis of the lissoclimide family of cytotoxic translation inhibitors, to aid in refining our understanding of the molecular basis of protein synthesis inhibition using biological and biochemical assays, as well as the tools of structural biology; (2) the application of methodology developed for the lissoclimides to develop efficient syntheses of a range of other complex, polycyclic diterpenoids; and (3) the development of new radical bicyclization strategies for the synthesis of two architecturally complex anti-infective natural products. 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 mechanism of ribosome inhibition by the lissoclimides, the development of new stereocontrolled polyene cyclization strategies to access particularly challenging diterpenoid natural products, and the elaboration of new radical bicyclization strategies to make complex polycyclic architectures relevant to bioactive natural products.

项目摘要 多循环萜类天然产品具有广泛的药物相关生物学 活动。紫杉醇和青蒿素是挽救生命的萜类化合物的两个主要例子。前者在临床上使用 治疗几种癌症，而后者是全球使用的关键抗疟药。化学合成 天然产品的方法提供了制造可能几乎无法使用的化合物的机会 从自然来产生只能通过总合成可用的类似物，并制作探针分子 对潜在生物学的了解增加。创新策略和新化学的平衡 方法论有望有效的小分子合成，可以为重要生物学提供答案 不容易通过其他方式解决的问题。 作为我们实验室长期目标的一部分，以提高复杂自然综合效率 促进生物学重要研究的产品，拟议的研究的目的是开发简洁 以及创造性的综合设计和赋予方法论的能力，允许获得许多生物活性 数字型天然产品。这项工作的理由是合成化学对于发展至关重要 天然产物的“命中分子”被模拟生产成合法的临床前铅化合物， 通过合成化学探针分子来鉴定结构活性关系 行动研究等等。有效的目标天然产品的总体合成提供了一个平台 要解决这些关键研究领域。我们的具体目的包括（1）合成 细胞毒性翻译抑制剂的lissoclimide家族，有助于完善我们对分子基础的理解 使用生物学和生化测定法以及结构生物学工具的蛋白质合成抑制作用； （2）为Lissoclives开发的方法的应用，以开发一系列的有效合成 其他复杂的多环芳烃； （3）开发新的激进式式式骑行策略 两种结构复杂的抗感染天然产物的合成。 拟议的研究很重要，因为化学合成将提供广泛的途径 生物学上重要的二级代谢产物和类似物，以询问关键过程；在 同时，基础合成设计和方法将导致田地的垂直进步 有机化学。这些贡献是由化学驱动的，多方面的 研究核糖体抑制核糖体的机制，新的发展 立体控制的多烯环化策略，以访问特别具有挑战性的数字天然产品， 并阐述了新的激进式式式式骑行策略，以使复杂的多环体系结构与 生物活性天然产品。