Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
Bioorg Chem. 2021 Mar;108:104646. doi: 10.1016/j.bioorg.2021.104646. Epub 2021 Jan 18.
The transcriptional repressor Snail trriggers epithelial-mesenchymal transition (EMT), the process allowing cancer cells with invasive and metastasis properties. In this study, we screened medicinal plants for the Snail inhibitory active components by high content screen (HCS) and found that the crude extract of Xylopia vielana leaves showed potential activity. Subsequently, bioassay-guided isolation of the extract of Xylopia vielana was performed to obtain twenty-four dimeric guaianes (1-24), including 16 new analogues (1-5, 8-11, 13-15, 17, 18, 21, and 22). Their structures were elucidated by the comprehensive application of multiple spectroscopic methods. Compounds 1, 11, 12, and 16 were initially identified as the active compounds. Wound healing assay, transwell migration assay and western blot experiments verified that compounds 1 and 12 inhibited the expression of Snail in a concentration-dependent manner, and compound 12 was verified as a potent tumor migration inhibitory agent. This work showed a practical strategy for the discovery of new Snail inhibitors from natural products and provided potential insights for dimeric guaianes as anticancer lead compounds specifically targeting Snail protein.
转录抑制因子 Snail 触发上皮-间充质转化（EMT），使具有侵袭和转移特性的癌细胞发生转化。在这项研究中，我们通过高内涵筛选（HCS）筛选了药用植物中抑制 Snail 的活性成分，发现三叶花椒叶的粗提物具有潜在的活性。随后，对三叶花椒叶提取物进行了基于生物活性导向的分离，得到了二十四种二萜倍半萜（1-24），包括 16 种新的类似物（1-5、8-11、13-15、17、18、21 和 22）。通过多种光谱方法的综合应用，阐明了它们的结构。化合物 1、11、12 和 16 最初被鉴定为活性化合物。划痕愈合实验、Transwell 迁移实验和 Western blot 实验验证了化合物 1 和 12 能够浓度依赖性地抑制 Snail 的表达，并且化合物 12 被证实是一种有效的肿瘤迁移抑制剂。这项工作展示了从天然产物中发现新型 Snail 抑制剂的实用策略，并为二萜倍半萜类化合物作为专门针对 Snail 蛋白的抗癌先导化合物提供了潜在的见解。
