2. Academic Validation
  3. Design and synthesis of benzylidenecyclohexenones as TrxR inhibitors displaying high anticancer activity and inducing ROS, apoptosis, and autophagy

Design and synthesis of benzylidenecyclohexenones as TrxR inhibitors displaying high anticancer activity and inducing ROS, apoptosis, and autophagy

  • Eur J Med Chem. 2020 Oct 15;204:112610. doi: 10.1016/j.ejmech.2020.112610.
Jianqiang Qian 1,  Zhongyuan Xu 1,  Chi Meng 1,  Ji Liu 1,  Pei-Ling Hsu 2,  Yangyang Li 1,  Weizhong Zhu 1,  Yumin Yang 3,  Susan L Morris-Natschke 2,  Kuo-Hsiung Lee 4,  Yanan Zhang 5,  Yong Ling 6
Affiliations

Affiliations

  • 1 School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, People's Republic of China.
  • 2 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, United States.
  • 3 School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, People's Republic of China; Key Laboratory of Neuroregeneration, Ministry of Education and Jiangsu Province, Co-innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, 226001, People's Republic of China.
  • 4 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, United States; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan. Electronic address: khlee@unc.edu.
  • 5 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: zhangyanan@gmail.com.
  • 6 School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, People's Republic of China; Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, United States. Electronic address: Lyyy111@sina.com.
PMID: 32736231 DOI: 10.1016/j.ejmech.2020.112610
Abstract

Oxidative therapy, a strategy that specifically increases Reactive Oxygen Species (ROS) levels in tumor cells by disrupting the redox homeostasis has gained increasing interest. The antitumor effects of the natural product piperlongumine (PL) appear to result from its ability to increase intracellular ROS levels via inhibition of antioxidative thioredoxin reductase (TrxR). Twenty-seven benzylidenecyclohexenone-based PL analogues (2a-v and 15a-e) were designed, synthesized and evaluated for their pharmacological properties. Most of the compounds exhibited potent antiproliferative activities against five human Cancer cell lines, especially against breast tumor cells. One of the most promising analogueues 2c showed 12-fold higher inhibitory activity against the thioredoxin reductase (TrxR) than PL and surpressed the expression of TrxR1 protein in breast Cancer cells and inhibited TrxR enzymatic activity. In addition, 2c increased ROS levels and resulted in marked Apoptosis by regulating apoptosis-related proteins expressed in the breast Cancer cells. Compound 2c also triggered the formation of autophagosomes and autolysosomes by promoting the expression of LC3-II and Beclin-1 and diminishing the expression of LC3-I and p62 proteins. Finally, 2c displayed low acute toxicity and good inhibitory potency to tumors in mice. Overall, 2c is a promising anti-breast Cancer candidate warranting further investigation.

Keywords

Antitumor activities; Benzylidenecyclohexenones; Piperlongumine; Reactive oxygen species (ROS); Thioredoxin reductase (TrxR).

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-146307
    TrxR抑制剂
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