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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.

项目摘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;前者用于临床用于治疗几种癌症，而后者是全世界使用的一种重要的抗疟剂。化学合成利用天然产物的方法提供了制造可能很难获得的化合物的机会从自然界，产生类似物，只有通过全合成，并使探针分子，增加了对潜在生物学的理解。创新战略和新化学品的平衡该方法有望有效地合成小分子，可以为重要的生物学问题提供答案。用其他方法不容易解决的问题。作为我们实验室的长期目标的一部分，以提高效率，在合成复杂的自然产品，以促进生物学的重要研究，建议的研究目标是制定简明和创造性的合成设计和授权方法的进步，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，合成化学是至关重要的发展通过类似物生产，将天然产物“命中分子”转化为合法的临床前先导化合物，结构活性关系的鉴定，通过合成化学探针分子的机制，行动研究等等。目标天然产物的有效全合成提供了一个平台，来解决这些关键的研究领域。我们的具体目标包括：（1）合成利索克林家族的细胞毒性翻译抑制剂，以帮助完善我们的分子基础的理解蛋白质合成抑制使用生物和生物化学测定，以及结构生物学的工具; (2)应用为利索克利酰胺开发的方法学来开发一系列其他复杂的，多环二萜类化合物;和（3）新的自由基双环化策略的发展，合成两种结构复杂的抗感染天然产物。拟议的研究是重要的，因为化学合成将提供一个广泛的生物学上重要的次生代谢产物和类似物，可用于询问关键过程;在与此同时，潜在的合成设计和方法学将导致该领域的垂直发展，有机化学。这些贡献是创新的凭借化学驱动的，多方面的研究核糖体抑制机制的利索环胺，开发新的立体控制的多烯环化策略以获得特别具有挑战性的二萜类天然产物，以及制定新的自由基双环化策略，使复杂的多环结构与生物活性天然产物。