Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Innovative Drug Research Center, School of Pharmaceutical Sciences, Chongqing University, Chongqing, 401331, China.
Nat Commun. 2023 Sep 9;14(1):5560. doi: 10.1038/s41467-023-41268-9.
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 N-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.
薤白生物碱在药物发现中具有重要的应用前景，但由于其结构的复杂性，这些天然产物的高效全合成和多样的结构修饰仍然极具挑战性。在这里，我们展示了环丙醇与通过 Bischler-Napieralski 反应生成的亚胺的同分子 Mannich 反应，能够从 L-色氨酸酯中无需保护基和氧化还原经济的方式，以四步反应得到四环薤白碱核心。基于这一进展，通过短合成路线实现了薤白生物碱及其类似物的多样化合成。系统的抗癌评估表明，天然产物vellosimine 和 N-甲基 vellosimine 具有适度的抗癌活性。对这些先导分子进行了深入的结构优化和构效关系的探索，确定了具有丙二烯单元的类似物 15ai，其抗癌活性提高了十倍。进一步的机制研究表明，化合物 15ai 通过诱导铁死亡发挥抗增殖作用，铁死亡是一种有吸引力的非凋亡细胞死亡形式，可能为未来的癌症治疗提供新的解决方案。
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