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Keywords:

  • anthraquinone;
  • apoptosis;
  • cell death;
  • mechanism;
  • necrosis;
  • polyamine;
  • synthesis

Investigation on designed polyaminoanthraquinones revealed that the anthraquinones bearing triamine motifs are generally more potent than their counterparts with diamine or tetramine motifs. Compared with the reference drug mitoxantrone (MTX), 9b and 9c exhibited better inhibitory activity on cancerous HepG2 cells and preferable cell selectivity in the further screen of normal QSG7701 cells, although they were not assimilated by cancer cells via the polyamine transporter. The presence of polyamine motifs elevated the interaction of compounds 9b and 9c with lysosomes and resulted in distinct mode of cell death. 9c and MTX could cause caspases-dependent HepG2 cell apoptotic death involving in mitochondrial membrane potential (MMP) loss, cytochrome c release, and caspase-3 activation. However, 9b, which contained only one less methylene group in the polyamine tail, produced cytotoxicity by necrosis. In conclusion, the modification of anthraquinones with polyamines may furnish potent anticancer drug candidates against hepatocellular carcinoma undergoing distinct cell death mechanisms.