2. Academic Validation
  3. Efficacy of novel methylenecyclohexenone derivatives as TrxR inhibitors in suppressing the proliferation and metastasis of human cancer cells

Efficacy of novel methylenecyclohexenone derivatives as TrxR inhibitors in suppressing the proliferation and metastasis of human cancer cells

  • Bioorg Chem. 2020 Dec;105:104360. doi: 10.1016/j.bioorg.2020.104360.
Chi Meng 1,  Jianqiang Qian 1,  Zhongyuan Xu 2,  Ji Liu 2,  Wenpei Shan 2,  Peng Zhu 2,  Weizhong Zhu 2,  Jiefei Miao 3,  Chang-Chun Ling 4,  Yong Ling 5
Affiliations

Affiliations

  • 1 The Affiliated Hospital of Nantong University, Nantong University, Nantong 226001, People's Republic of China; School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, People's Republic of China.
  • 2 School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, People's Republic of China.
  • 3 The Affiliated Hospital of Nantong University, Nantong University, Nantong 226001, People's Republic of China.
  • 4 The Affiliated Hospital of Nantong University, Nantong University, Nantong 226001, People's Republic of China; School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, People's Republic of China. Electronic address: [email protected].
  • 5 The Affiliated Hospital of Nantong University, Nantong University, Nantong 226001, People's Republic of China; School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, People's Republic of China. Electronic address: [email protected].
PMID: 33074118 DOI: 10.1016/j.bioorg.2020.104360
Abstract

A series of mono- and di-methylenecyclohexenone derivatives, 3a-f and 4a-f, respectively, were designed and synthesized from piperlongumine (PL) and their in vitro and in vivo pharmacological properties were evaluated. A majority of the compounds exhibited a potent antiproliferative effect on five human Cancer cell lines, especially those causing breast Cancer. Compound 4f showed the highest antiproliferative potency among all of the compounds, almost a 10-fold higher inhibitory potency against thioredoxin reductase (TrxR) compared with PL in cells causing breast Cancer. In addition, 4f was found to increase the levels of Reactive Oxygen Species (ROS), thus leading to more potent antiproliferative effects. More importantly, the suppression assays of migration and invasion revealed that compound 4f could reverse the epithelial-mesenchymal transition induced by the transforming growth factor β1, and exhibit prominent anti-metastasis effects. Compound 4f also showed strong inhibition potency toward solid tumors of breast Cancer in vivo. Our findings show that compound 4f is a promising therapeutic candidate in the treatment of breast Cancer, which, however, needs further research to be proved.

Keywords

Antimetastasis; Antitumor activity; Methylenecyclohexenone; Piperlongumine; Reactive oxygen species (ROS).

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