沙尔碱生物碱在药物发现领域具有重要机遇，然而由于其结构复杂性，这些天然产物的高效全合成和多样结构修饰仍然存在巨大挑战。本研究展示了环丙醇与双氮化合物通过Bischler-Napieralski反应生成的亚胺进行同型曼尼希反应，可以无保护基、氧化铁经济的、通过四步反应从L-色氨酸酯类化合物中快速地合成四环沙尔碱核心。基于此进展，在短合成路径下，实现了沙尔碱生物碱及类似物的多样化合成。系统的抗癌评估表明，天然产物威隆胺和N-甲基威隆胺具有适度的抗癌活性。通过对这些主要分子的结构优化和结构-活性关系的探索，鉴定了具有尼尔内酰烯单位的15ai类似物，其抗癌活性提高了十倍。进一步的机理研究表明，化合物15ai通过诱导铁死亡作用（一种非凋亡细胞死亡形式）发挥抗增殖作用，可能为未来的癌症治疗提供新的解决方案。 © 2023. Springer Nature Limited.

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.© 2023. Springer Nature Limited.