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A Bischler-Napieralski and homo-Mannich sequence enables diversified syntheses of sarpagine alkaloids and analogues

Author

Listed:
  • Hanyue Qiu

    (Chongqing University)

  • Xinghai Fei

    (Chongqing University)

  • Jiaojiao Yang

    (Chongqing University)

  • Zhen Qiao

    (Chongqing University)

  • Shan Yuan

    (Chongqing University)

  • Hu Zhang

    (Chongqing University)

  • Ling He

    (Chongqing University)

  • Min Zhang

    (Chongqing University)

Abstract

Sarpagine alkaloids offer signicant opportunities in drug discovery, yet the efficient total syntheses and diverse structural modifications of these natural products remain highly challenging due to the architectural complexity. Here we show a homo-Mannich reaction of cyclopropanol with imines generated via a Bischler-Napieralski reaction enables a protecting-group-free, redox economic, four-step access to the tetracyclic sarpagine core from L-tryptophan esters. Based on this advancement, diversified syntheses of sarpagine alkaloids and analogues are achieved in a short synthetic route. The systematic anticancer evaluation indicates that natural products vellosimine and Na-methyl vellosimine possess modest anticancer activity. Intensive structural optimization of these lead molecules and exploration of the structure−activity relationship lead to the identification of analogue 15ai with an allene unit showing a tenfold improvement in anticancer activities. Further mechanism studies indicate compound 15ai exertes antiproliferation effects by inducing ferroptosis, which is an appealing non-apoptotic cell death form that may provide new solutions in future cancer therapies.

Suggested Citation

  • Hanyue Qiu & Xinghai Fei & Jiaojiao Yang & Zhen Qiao & Shan Yuan & Hu Zhang & Ling He & Min Zhang, 2023. "A Bischler-Napieralski and homo-Mannich sequence enables diversified syntheses of sarpagine alkaloids and analogues," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41268-9
    DOI: 10.1038/s41467-023-41268-9
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