Carnosic acid could disrupt the β-catenin/BCL9 protein-protein interaction and inhibit β-catenin dependent transcription, thereby reduce the incidence of colorectal cancer induced by abnormal activation of Wnt/β-catenin signalling pathway. However, its activity was weak (IC₅₀ for SW480: 28.2 ± 2.05 μM) and total synthesis was difficult. During the structural simplification of natural products, S0 was revealed to be the basic pharmacophore of carnosic acid. Subsequent structural optimization of S0 led to the discovery of S11 as a possible anticancer agent with prominent proliferation inhibition effect (IC₅₀ for SW480: 9.56 ± 0.91μM) and best selectivity index (SI=3.0) against Wnt hyperactive cancer cells. Futher mechanism investigation through TOP/FOP dual luciferase reporter assay, immunofluorescence, co-immunoprecipitation, microscale thermophoresis, downstream oncoprotein expression and cell apoptosis showed that compound S11 could significantly inhibit the proliferation of SW480 cells via obvioudsly decreasing the nucleus translocation of β-catenin and effectively disrupting β-catenin/BCL9 protein-protein interaction. Additionally, cell migration, molecule docking, in vitro stability and solubility assays were also conducted. Overall, S11 was worthy of in-depth study as a potential inhibitor for the Wnt/β-catenin pathway and its discovery also proved that the structural simplification of natural products was still one of the effective methods to find new lead compounds or candidate drugs.

鼠尾草酸可破坏β-catenin/BCL9蛋白-蛋白相互作用，抑制β-catenin依赖性转录，从而降低Wnt/β-catenin信号通路异常激活所致结直肠癌的发生率。然而，它的活性很弱（SW480 的 IC ₅₀：28.2 ± 2.05 μM）并且很难进行全合成。在天然产物的结构简化过程中，发现S0是鼠尾草酸的基本药效团。S0的后续结构优化导致发现S11作为一种可能的抗癌剂，具有显着的增殖抑制作用（IC ₅₀对于 SW480：9.56 ± 0.91μM）和针对 Wnt 过度活跃癌细胞的最佳选择性指数（SI=3.0）。通过 TOP/FOP 双荧光素酶报告基因检测、免疫荧光、免疫共沉淀、微量热泳、下游癌蛋白表达和细胞凋亡等进一步机制研究表明，化合物S11可通过明显降低 β-catenin 的核转位和有效地破坏 β-catenin/BCL9 蛋白-蛋白相互作用。此外，还进行了细胞迁移、分子对接、体外稳定性和溶解度测定。总的来说，S11作为Wnt/β-catenin通路的潜在抑制剂值得深入研究，其发现也证明了天然产物的结构简化仍然是寻找新的先导化合物或候选药物的有效方法之一。