Synthesis of naphthazarin derivatives and identification of novel thioredoxin reductase inhibitor as potential anticancer agent

  • Eur J Med Chem. 2017 Nov 10:140:435-447. doi: 10.1016/j.ejmech.2017.09.027.
Junmin Zhang  1 ,  Yaping Liu  2 ,  Danfeng Shi  3 ,  Guodong Hu  2 ,  Baoxin Zhang  2 ,  Xinming Li  2 ,  Ruijuan Liu  4 ,  Xiao Han  2 ,  Xiaojun Yao  3 ,  Jianguo Fang  5
Affiliations
  • 1. State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, China; School of Pharmacy, Lanzhou University, Lanzhou, Gansu 730000, China; College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China.
  • 2. State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, China; College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China.
  • 3. College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China.
  • 4. State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, China; School of Pharmacy, Lanzhou University, Lanzhou, Gansu 730000, China.
  • 5. State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, China; College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China. Electronic address: [email protected].
PMID: 28987605 DOI: 10.1016/j.ejmech.2017.09.027
Abstract

Mammalian thioredoxin reductase (TrxR) Enzymes play a crucial role in regulating multiple redox-based signaling pathways and have attracted increasing attention as promising Anticancer drug targets. We report here the synthesis of a panel of naphthazarin derivatives and discovery of 2-methyl-5,8-dihydroxy-1,4-naphthoquinone (3, 2-methylnaphthazarin) as a potent cytotoxic agent with a submicromolar half maximal inhibitory concentration to the human promyelocytic leukemia HL-60 cells. Mechanism studies reveal that the compound selectively inhibits TrxR to induce oxidative stress-mediated Apoptosis of HL-60 cells. Knockdown of TrxR sensitizes the cells to 3 insults, while overexpression of the functional enzyme confers resistance to the compound treatment, underpinning the physiological significance of targeting TrxR by 3. Clarification of the interaction of compound 3 with TrxR unveils a mechanism underlying the cellular action of the compound, and sheds light in considering development of the compound as a potential Cancer chemotherapeutic agent.

Keywords
2-Methylnaphthazarin; Apoptosis; Naphthazarin derivatives; Oxidative stress; Reactive oxygen species; Thioredoxin reductase.