Natural compound valepotriate exhibits inhibitory activity against a number of cancers, but the effect of valepotriate against pancreatic cancer is unclear, and the structure–activity relationship of valepotriate has not been characterized. In this study, we performed a structure-based similarity search and found 16 hit compounds. Among the 16 hits, (1S,6S,7R)-6-(acetyloxy)-1-[(3-methylbutanoyl)oxy]-4a,5,6,7a-tetrahydro-1H-spiro[cyclopenta[c]pyran-7,2’-oxiran]-4-ylmethyl 3-methylbutanoate (denoted as Amcp) exhibited superior anticancer activity against human pancreatic cancer BxPC-3 and SW1990 cells. The anti-proliferation activity of Amcp was validated in human pancreatic cancer BxPC-3 and SW1990 cells in vitro. Amcp more effectively induced apoptosis in BxPC-3 and SW1990 cells than gemcitabine. At a concentration of 15 μM, Amcp significantly suppressed the PI3K/AKT pathway and disrupted the mitochondrial membrane equilibrium through modulation of Noxa and Mcl-1 balance in both cell lines. Meanwhile, knockdown of Noxa substantially attenuated Amcp-induced reduction of cell viability and anti-apoptotic protein Mcl-1 level in BxPC-3 cells. In addition, Amcp showed synergistic anticancer effects when combined with gemcitabine in BxPC-3 cells. To conclude, this work not only suggests that Amcp possesses a dual-inhibitory activity towards PI3K/AKT pathway and Mcl-1, but also enlightens further development of bioactive valepotriate derivatives.

天然化合物戊酸对多种癌症具有抑制活性，但戊酸对胰腺癌的作用尚不清楚，戊酸的构效关系尚未确定。在这项研究中，我们进行了基于结构的相似性搜索，发现了 16 个热门化合物。在 16 个命中中，(1S,6S,7R)-6-(乙酰氧基)-1-[(3-甲基丁酰基)氧基]-4a,5,6,7a-四氢-1H-螺[环戊[c]吡喃- 7,2'-oxiran]-4-ylmethyl 3-methylbutanoate（表示为 Amcp）对人胰腺癌 BxPC-3 和 SW1990 细胞表现出优异的抗癌活性。Amcp 的抗增殖活性在体外人胰腺癌 BxPC-3 和 SW1990 细胞中得到验证。Amcp 在 BxPC-3 和 SW1990 细胞中比吉西他滨更有效地诱导细胞凋亡。在 15 μM 的浓度下，Amcp 通过调节两种细胞系中的 Noxa 和 Mcl-1 平衡显着抑制 PI3K/AKT 通路并破坏线粒体膜平衡。同时，Noxa 的敲低显着减弱了 Amcp 诱导的 BxPC-3 细胞中细胞活力和抗凋亡蛋白 Mcl-1 水平的降低。此外，Amcp 与吉西他滨联合在 BxPC-3 细胞中显示出协同抗癌作用。综上所述，这项工作不仅表明 Amcp 对 PI3K/AKT 通路和 Mcl-1 具有双重抑制活性，而且为进一步开发具有生物活性的戊酸衍生物提供了启示。Noxa 的敲低显着减弱了 Amcp 诱导的 BxPC-3 细胞中细胞活力和抗凋亡蛋白 Mcl-1 水平的降低。此外，Amcp 与吉西他滨联合在 BxPC-3 细胞中显示出协同抗癌作用。综上所述，这项工作不仅表明 Amcp 对 PI3K/AKT 通路和 Mcl-1 具有双重抑制活性，而且为进一步开发具有生物活性的戊酸衍生物提供了启示。Noxa 的敲低显着减弱了 Amcp 诱导的 BxPC-3 细胞中细胞活力和抗凋亡蛋白 Mcl-1 水平的降低。此外，Amcp 与吉西他滨联合在 BxPC-3 细胞中显示出协同抗癌作用。综上所述，这项工作不仅表明 Amcp 对 PI3K/AKT 通路和 Mcl-1 具有双重抑制活性，而且为进一步开发具有生物活性的戊酸衍生物提供了启示。