Design, synthesis and biological evaluations of diverse Michael acceptor-based phenazine hybrid molecules as TrxR1 inhibitors

• Published in: Bioorganic chemistry Vol. 109; p. 104736
• Main Authors: Zhong, Yucheng, Liu, Jing, Cheng, Xiangyu, Zhang, Hao, Zhang, Chunhua, Xia, Zhuolu, Wu, Zhongxi, Zhang, Lu, Zheng, Yuting, Gao, Zhanyu, Jiang, Zhidong, Wang, Zhixiang, Huang, Dechun, Lu, Yuanyuan, Jiang, Feng
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.04.2021; Elsevier
• Subjects: Antiproliferative activity; Biochemistry & Molecular Biology; Chemistry; Chemistry, Organic; Life Sciences & Biomedicine; Michael receptor; Phenazines; Physical Sciences; Science & Technology; TrxR1 inhibitor; Antiproliferative activity; TrxR1 inhibitor; Michael receptor; Phenazines
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.104736

[Display omitted] •Novel hybrid molecules (1~27) containing phenazine skeleton and Michael acceptor scaffold were designed and synthesized.•Compound 26 was found to be a promising lead of the TrxR1 inhibitor with excellent antitumor activities against Bel-7402 cells.•Antitumor mechanism of action of compound 26 was proven to can activate apoptosis through the ROS-Trx-ASK1-p38 pathway. A series of novel phenazine derivatives (1~27) containing the Michael acceptor scaffolds were designed and synthesized in this study. Some compounds exhibited selective cytotoxicity against Bel-7402 cancer cell line in vitro, in which compound 26 were found to have the best antiproliferative activity. Meanwhile, compound 26 showed no obvious cell toxicity against human normal liver epithelial L02 cells, which means this compound possessed a better safety potential. In the following research, compound 26 was verified to inhibit TrxR1 enzyme activity, ultimately resulting in cellular molecular mechanism events of apoptosis including growth of intracellular ROS level, depletion of reduced Trx1, liberation of ASK1 and up-regulation of p38, respectively. Together, all these evidences implicated that compound 26 acted as the TrxR1 inhibitor against Bel-7402 cells, and could activate apoptosis through the ROS-Trx-ASK1-p38 pathway.