A natural product scopoletin, which also contains an ortho-substituted phenolic structure in its skeleton, was found in some medicinal plants. In this study, to develop scopoletin-based autophagy activators, various aryl substitutes were introduced at the 3-positon or 4-position of scopoletin skeleton with the ortho-substituted phenolic structure retained. A total of twenty-three derivatives were synthesized, evaluated for their antiproliferation activity against four cancer cells (MCF-7, HeLa, PC3, and MGC803), and discussed for their structure-activity relationships (SARs). Among these derivatives, 5c was the most potent compound with an excellent improvement of antiproliferation activity against PC3 and MGC803 cells compared to the parental scopoletin. 5c displayed up to 17.9- and 5.7-fold improvement of antiproliferation activities against PC3 and MGC803 cells compared to 5-FU (IC₅₀ = 0.14 μM vs IC₅₀ = 2.50 μM, IC₅₀ = 1.02 μM vs IC₅₀ = 5.81 μM), respectively. Moreover, 5c showed excellent selectivity between cancer cells and one normal cell (GES-1). Further mechanism investigations confirmed that 5c inhibited PC3 and MGC803 cell proliferation via inducing autophagy. Interestingly, 5c also induced mitochondria-mediated apoptosis in PC3 cells but not in MGC803 cells. Moreover, 5c possessed the ability to suppress colony formation and migration of PC3 and MGC803 cells. In addition, 5c arrested the cell cycle at the G2/M phase of PC3 cells.

在一些药用植物中发现了一种天然产物东莨菪素，其骨架中也含有邻位取代的酚结构。在这项研究中，为了开发基于东莨菪碱的自噬激活剂，在东莨菪素骨架的 3 位或 4 位引入了各种芳基取代基，并保留了邻位取代的酚结构。共合成了 23 种衍生物，评估了它们对四种癌细胞（MCF-7、HeLa、PC3 和 MGC803）的抗增殖活性，并讨论了它们的构效关系 (SAR)。在这些衍生物中，5c是最有效的化合物，与亲代东莨菪碱相比，其对 PC3 和 MGC803 细胞的抗增殖活性有显着提高。与 5-FU 相比， 5c对 PC3 和 MGC803 细胞的抗增殖活性提高了 17.9 倍和 5.7 倍（IC ₅₀  = 0.14 μM对比IC ₅₀  = 2.50 μM，IC ₅₀  = 1.02 μM对比IC ₅₀  = 5.81 μM），分别。此外，5c在癌细胞和一种正常细胞 (GES-1) 之间显示出极好的选择性。进一步的机制研究证实，5c通过诱导自噬抑制 PC3 和 MGC803 细胞增殖。有趣的是，5c还在 PC3 细胞中诱导线粒体介导的细胞凋亡，但在 MGC803 细胞中没有。此外，5c具有抑制 PC3 和 MGC803 细胞集落形成和迁移的能力。此外，5c使 PC3 细胞的细胞周期停滞在 G2/M 期。