State Key Laboratory of Natural Medicines , China Pharmaceutical University , Nanjing 210009 , P. R. China.
Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases , China Pharmaceutical University , Nanjing 210009 , P. R. China.
J Med Chem. 2018 Mar 8;61(5):1821-1832. doi: 10.1021/acs.jmedchem.7b01096. Epub 2018 Feb 15.
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.
胡椒碱 1 通过触发不同的途径增加活性氧 (ROS) 水平，优选诱导癌细胞凋亡。然而，1 的溶解度差限制了其深入研究和临床应用。川芎嗪具有水溶性吡嗪骨架，可抑制癌细胞的增殖和转移。我们通过用川芎嗪部分取代 1 的三甲氧基苯基合成了化合物 3，并进一步在 3 上引入 2-Cl、-Br 和 -I，分别合成了 4-6。化合物 4 的水溶解度比 1 大 14 倍，并且增加了结直肠癌细胞 HCT-116 中的 ROS 水平。此外，4 优选抑制 HCT-116 细胞的增殖、迁移、侵袭和异粘附。4 在体内抑制肿瘤生长和肺转移，并延长荷瘤小鼠的存活时间。此外，4 通过抑制 Akt 和 GSK-3β磷酸化减轻 TGF-β1 诱导的上皮-间充质转化和 Wnt/β-catenin 激活。总之，4 显示出显著的增殖抑制和抗转移活性，优于 1。
