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Cyclization Cascades to Access Bioactive Diterpenoids

环化级联以获得生物活性二萜类化合物

基本信息

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
项目类别：
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

项目摘要

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.

项目概要多环萜类天然产物具有广泛的药用相关生物活性活动。紫杉醇和青蒿素是拯救生命的萜类化合物的两个主要例子；前者用于临床治疗多种癌症，而后者是全世界使用的重要抗疟药物。化学合成天然产物的方法提供了制造可能难以获得的化合物的机会从自然界中提取，产生只能通过全合成获得的类似物，并制造探针分子增加对基础生物学的了解。创新战略与新化学品的平衡该方法有望有效合成小分子，为重要的生物学问题提供答案通过其他方式无法轻易解决的问题。作为我们实验室提高复杂天然物质合成效率的长期目标的一部分产品以促进生物学的重要研究，拟议研究的目标是开发简明的产品和创造性的合成设计并赋予方法论进步以允许获得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于发展至关重要通过类似物生产将天然产物“命中分子”转化为合法的临床前先导化合物通过合成化学探针分子来识别结构-活性关系，以了解其作用机制行动研究等等。目标天然产物的高效全合成提供了一个平台来解决这些关键研究领域中的每一个。我们的具体目标包括（1）综合细胞毒性翻译抑制剂的利索克酰亚胺家族，有助于完善我们对分子基础的理解使用生物和生化测定以及结构生物学工具抑制蛋白质合成； (2) 应用为利索克酰亚胺开发的方法来开发一系列的有效合成其他复杂的多环二萜类化合物； (3) 制定新的激进自行车化策略两种结构复杂的抗感染天然产物的合成。拟议的研究意义重大，因为化学合成将提供广泛的途径生物学上重要的次生代谢物和类似物，用于询问关键过程；在同时，底层的合成设计和方法将导致该领域的垂直进步有机化学。这些贡献凭借化学驱动的多方面的创新而具有创新性研究lissoclimides的核糖体抑制机制，开发新的立体控制多烯环化策略以获得特别具有挑战性的二萜类天然产物，以及新的激进双环化策略的阐述，以使复杂的多环结构与具有生物活性的天然产物。