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Total synthesis and target identification of marine cyclopiane diterpenes

Author

Listed:
  • Tian Li

    (Northwest A&F University)

  • Shan Jiang

    (Peking University)

  • Yuanhao Dai

    (Northwest A&F University)

  • Xia Wu

    (Peking University)

  • Huihui Guo

    (Northwest A&F University)

  • Liang Shi

    (Northwest A&F University)

  • Xueli Sang

    (Northwest A&F University)

  • Li Ren

    (Northwest A&F University)

  • Jie Wang

    (Peking University)

  • Lili Shi

    (Peking University Shenzhen Graduate School)

  • Wenming Zhou

    (Northwest A&F University)

  • Houhua Li

    (Peking University)

  • Hong-Dong Hao

    (Northwest A&F University
    Peking University Shenzhen Graduate School)

Abstract

Marine cyclopianes are a family of diterpenoid with novel carbon skeleton and diverse biological activities. Herein, we report our synthetic and chemical proteomics studies of cyclopiane diterpenes which culminate in the asymmetric total synthesis of conidiogenones C, K and 12β-hydroxy conidiogenone C, and identification of Immunity-related GTPase family M protein 1 (IRGM1) as a cellular target. Our asymmetric synthesis commences from Wieland-Miescher ketone and features a sequential intramolecular Pauson-Khand reaction and gold-catalyzed Nazarov cyclization to rapidly construct the 6-5-5-5 tetracyclic skeleton. The stereocontrolled cyclopentenone construction is further investigated on complex settings to demonstrate its synthetic utility. Furthermore, using an alkyne-tagged conidiogenone C-derived probe, IRGM1, a master regulator of type I interferon responses, is identified as a key cellular target of conidiogenone C responsible for its anti-inflammatory activity. Preliminary mechanism of action studies shows that conidiogenone C activates IRGM1-mediate dysfunctional mitochondria autophagy to maintain mitochondria quality control of inflammatory macrophages.

Suggested Citation

  • Tian Li & Shan Jiang & Yuanhao Dai & Xia Wu & Huihui Guo & Liang Shi & Xueli Sang & Li Ren & Jie Wang & Lili Shi & Wenming Zhou & Houhua Li & Hong-Dong Hao, 2024. "Total synthesis and target identification of marine cyclopiane diterpenes," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-55189-8
    DOI: 10.1038/s41467-024-55189-8
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    References listed on IDEAS

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    1. Roman Lagoutte & Christelle Serba & Daniel Abegg & Dominic G. Hoch & Alexander Adibekian & Nicolas Winssinger, 2016. "Divergent synthesis and identification of the cellular targets of deoxyelephantopins," Nature Communications, Nature, vol. 7(1), pages 1-11, November.
    2. Barbara Mikulak-Klucznik & Patrycja Gołębiowska & Alison A. Bayly & Oskar Popik & Tomasz Klucznik & Sara Szymkuć & Ewa P. Gajewska & Piotr Dittwald & Olga Staszewska-Krajewska & Wiktor Beker & Tomasz , 2020. "Computational planning of the synthesis of complex natural products," Nature, Nature, vol. 588(7836), pages 83-88, December.
    3. Pengfei Hu & Hyung Min Chi & Kenneth C. DeBacker & Xu Gong & Jonathan H. Keim & Ian Tingyung Hsu & Scott A. Snyder, 2019. "Quaternary-centre-guided synthesis of complex polycyclic terpenes," Nature, Nature, vol. 569(7758), pages 703-707, May.
    4. Brendan T. Parr & Christos Economou & Seth B. Herzon, 2015. "A concise synthesis of (+)-batzelladine B from simple pyrrole-based starting materials," Nature, Nature, vol. 525(7570), pages 507-510, September.
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