2. Academic Validation
  3. Novel Ligustrazine-Based Analogs of Piperlongumine Potently Suppress Proliferation and Metastasis of Colorectal Cancer Cells in Vitro and in Vivo

Novel Ligustrazine-Based Analogs of Piperlongumine Potently Suppress Proliferation and Metastasis of Colorectal Cancer Cells in Vitro and in Vivo

  • J Med Chem. 2018 Mar 8;61(5):1821-1832. doi: 10.1021/acs.jmedchem.7b01096.
Yu Zou 1 2 3,  Di Zhao 1 4,  Chang Yan 1 2,  Yanpeng Ji 1 2,  Jin Liu 1 2,  Jinyi Xu 1,  Yisheng Lai 1 2,  Jide Tian 5,  Yihua Zhang 1 2,  Zhangjian Huang 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines , China Pharmaceutical University , Nanjing 210009 , P. R. China.
  • 2 Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases , China Pharmaceutical University , Nanjing 210009 , P. R. China.
  • 3 Department of Pharmacy, College of Medicine , Wuhan University of Science and Technology , Wuhan , Hubei Province 430065 , P. R. China.
  • 4 Clinical Pharmacokinetics Laboratory, Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy , China Pharmaceutical University , Nanjing 211198 , P. R. China.
  • 5 Department of Molecular and Medical Pharmacology , University of California , Los Angeles , California 90095 , United States.
PMID: 29424539 DOI: 10.1021/acs.jmedchem.7b01096
Abstract

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.

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