Piperlongumine 1 increases reactive oxygen species (ROS) levels and preferably induces cancer cell apoptosis by triggering different pathways. However, the poor solubility of 1 limits its intensive investigation and clinical application. Ligustrazine possesses a water-soluble pyrazine skeleton and can inhibit proliferation and metastasis of cancer cells. We synthesized compound 3 by replacement of the trimethoxyphenyl of 1 with ligustrazine moiety and further introduced 2-Cl, -Br, and -I to 3 for synthesis of 4-6, respectively. Compound 4 possessed 14-fold greater aqueous solubility than 1 and increased ROS levels in colorectal cancer HCT-116 cells. Additionally, 4 preferably inhibited proliferation, migration, invasion, and heteroadhesion of HCT-116 cells. Treatment with 4 suppressed tumor growth and lung metastasis in vivo and prolonged the survival of tumor-bearing mice. Furthermore, 4 mitigated TGF-β1-induced epithelial-mesenchymal transition and Wnt/β-catenin activation by inhibiting the Akt and GSK-3β phosphorylation in HCT-116 cells. Collectively, 4 displayed significant antiproliferation and antimetastasis activities, superior to 1.

中文翻译：

---

新的基于川gust嗪的哌隆明类似物有效地抑制了体内和体外结直肠癌细胞的增殖和转移。

Piperlongumine 1可增加活性氧（ROS）的水平，并优选通过触发不同的途径诱导癌细胞凋亡。但是，1的较差的溶解度限制了其深入的研究和临床应用。川gust嗪具有水溶性吡嗪骨架，可以抑制癌细胞的增殖和转移。我们通过用川gust嗪部分取代1的三甲氧基苯基来合成化合物3，并进一步将2-Cl，-Br和-I引入3分别合成4-6。化合物4在结肠直肠癌HCT-116细胞中的水溶性比1高14倍，并且ROS水平升高。另外，优选4种抑制HCT-116细胞的增殖，迁移，侵袭和异粘附。用4处理可抑制体内肿瘤的生长和肺转移，并延长荷瘤小鼠的生存期。此外，4通过抑制HCT-116细胞中的Akt和GSK-3β磷酸化，减轻了TGF-β1诱导的上皮-间质转化和Wnt /β-catenin活化。总的来说，有4个显示出显着的抗增殖和抗转移活性，优于1。