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

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:
  • 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:
  • 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:
  • 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:
  • 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.
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Christopher D Vanderwal其他文献

Christopher D Vanderwal的其他文献

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{{ truncateString('Christopher D Vanderwal', 18)}}的其他基金

Chemical Synthesis of Bioactive Diterpenoids
生物活性二萜类化合物的化学合成
  • 批准号:
    10405930
  • 财政年份:
    2022
  • 资助金额:
    $ 39.71万
  • 项目类别:
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:
    9753289
  • 财政年份:
    2018
  • 资助金额:
    $ 39.71万
  • 项目类别:
Structural Elucidation, Synthesis and Study of the Chlorosulfolipids
氯磺脂的结构解析、合成与研究
  • 批准号:
    7788733
  • 财政年份:
    2010
  • 资助金额:
    $ 39.71万
  • 项目类别:
Structural Elucidation, Synthesis and Study of the Chlorosulfolipids
氯磺脂的结构解析、合成与研究
  • 批准号:
    8011218
  • 财政年份:
    2010
  • 资助金额:
    $ 39.71万
  • 项目类别:
Structural Elucidation, Synthesis and Study of the Chlorosulfolipids
氯磺脂的结构解析、合成与研究
  • 批准号:
    8401523
  • 财政年份:
    2010
  • 资助金额:
    $ 39.71万
  • 项目类别:
Structural Elucidation, Synthesis and Study of the Chlorosulfolipids
氯磺脂的结构解析、合成与研究
  • 批准号:
    8600291
  • 财政年份:
    2010
  • 资助金额:
    $ 39.71万
  • 项目类别:
Structural Elucidation, Synthesis and Study of the Chlorosulfolipids
氯磺脂的结构解析、合成与研究
  • 批准号:
    8207970
  • 财政年份:
    2010
  • 资助金额:
    $ 39.71万
  • 项目类别:

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