权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Synthesis of a Complex Brasilicardin Analogue Utilizing a Cobalt-Catalyzed MHAT-Induced Radical Bicyclization Reaction.

DOI：
10.1021/acs.orglett.3c01019
发表时间：
2023-05-19
期刊：
Organic letters
影响因子：
5.2
作者：
Niman SW;Buono R;Fruman DA;Vanderwal CD
通讯作者：
Vanderwal CD

Stereocontrolled Synthesis and Structural Revision of Plebeianiol A.

DOI：
10.1021/acs.orglett.1c03791
发表时间：
2021-12-17
期刊：
Organic letters
影响因子：
5.2
作者：
Johnson LK;Niman SW;Vrubliauskas D;Vanderwal CD
通讯作者：
Vanderwal CD

The Recurring Roles of Chlorine in Synthetic and Biological Studies of the Lissoclimides.

DOI：
10.1021/acs.accounts.0c00866
发表时间：
2021-03-02
期刊：
Accounts of chemical research
影响因子：
18.3
作者：
Pak BS;Supantanapong N;Vanderwal CD
通讯作者：
Vanderwal CD

Enantioselective Syntheses of Wickerols A and B.

DOI：
10.1021/jacs.3c00448
发表时间：
2023-03-22
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
Chung, Jonathan;Capani, Joseph S.;Goehl, Matthias;Roosen, Philipp C.;Vanderwal, Christopher D.
通讯作者：
Vanderwal, Christopher D.

Stereocontrolled Radical Bicyclizations of Oxygenated Precursors Enable Short Syntheses of Oxidized Abietane Diterpenoids.