Piperlongumine (1) 通过多种途径增加活性氧 (ROS) 水平并诱导癌细胞凋亡。一氧化氮 (NO) 供体已表现出有效的抗癌活性，外源性 NO 被肿瘤微环境中的 ROS 氧化，形成高活性的氮氧化物 (RNOS)。这会放大氧化应激级联反应，最终诱导癌细胞凋亡。为了利用这种协同作用，设计并合成了一系列释放 NO 的胡椒长明衍生物 (2-5)。这些化合物有望在癌细胞中释放NO，同时产生胡椒长明衍生物片段以增强抗癌效果。化合物6在结构上与化合物2-5相似但不释放NO，用作对照。在这些衍生物中，化合物 5 对 HCT-116 细胞表现出最有效的抗增殖活性，并在此细胞系中有效释放 NO。进一步研究表明，化合物 5 通过调节 β-catenin 表达来抑制结肠癌细胞增殖，β-catenin 是 Wnt/β-catenin 信号通路中的关键蛋白。这些发现凸显了化合物 5 作为针对 Wnt/β-catenin 通路的结肠癌治疗的有希望的候选者。

Piperlongumine (1) increases reactive oxygen species (ROS) levels and induces apoptosis in cancer cells through various pathways. Nitric oxide (NO) donors have demonstrated potent anticancer activities with exogenous NO being oxidized by ROS in the tumor microenvironment to form highly reactive N-oxides (RNOS). This amplifies oxidative stress cascade reactions, ultimately inducing cancer cell apoptosis. To exploit this synergy, a series of NO-releasing piperlongumine derivatives (2-5) were designed and synthesized. These compounds were expected to release NO in cancer cells, simultaneously generating piperlongumine derivative fragments to enhance the anticancer effects. Compound 6, structurally similar to compounds 2-5 but not releasing NO, served as a control. Among these derivatives, compound 5 exhibited the most potent antiproliferative activity against HCT-116 cells and efficiently released NO in this cell line. Further investigation revealed that compound 5 inhibited colon cancer cell proliferation by modulating β-catenin expression, which is a pivotal protein in the Wnt/β-catenin signaling pathway. These findings highlight compound 5 as a promising candidate for colon cancer treatment targeting the Wnt/β-catenin pathway.