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

Bioorg Chem. 2021 Apr:109:104736. doi: 10.1016/j.bioorg.2021.104736. Epub 2021 Feb 19.

Abstract

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.

Keywords: Antiproliferative activity; Michael receptor; Phenazines; TrxR1 inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Structure
  • Phenazines / chemical synthesis
  • Phenazines / chemistry
  • Phenazines / pharmacology*
  • Structure-Activity Relationship
  • Thioredoxin Reductase 1 / antagonists & inhibitors*
  • Thioredoxin Reductase 1 / metabolism
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Phenazines
  • TXNRD1 protein, human
  • Thioredoxin Reductase 1