Novel pyrrolidine-aminophenyl-1,4-naphthoquinones: structure-related mechanisms of leukemia cell death

Maher Hallak, Michael Danilenko, Thida Win, Shmuel Bittner, Yosef Granot, Ofer Shpilberg, Itai Levi, Ilana Nathan

Research output: Contribution to journalArticlepeer-review


Novel derivatives of aminophenyl-1,4-naphthoquinones, in which a pyrrolidine group was added to the naphthoquinone ring, were synthesized and investigated for the mechanisms of leukemic cell killing. The novel compounds, TW-85 and TW-96, differ in the functional (methyl or hydroxyl) group at the para-position of the aminophenyl moiety. TW-85 and TW-96 were found to induce concentration- and time-dependent apoptotic and/or necrotic cell death in human U937 promonocytic leukemia cells but only TW-96 could also kill K562 chronic myeloid leukemia cells and CCRF-CEM lymphoblastic leukemia cells. Normal peripheral blood mononuclear cells were noticeably less responsive to both compounds than leukemia cells. At low micromolar concentrations used, TW-85 killed U937 cells mainly by inducing apoptosis. TW-96 was a weaker apoptotic agent in U937 cells but proved to be cytotoxic and a stronger inducer of necrosis in all three leukemic cell lines tested. Both compounds induced mitochondrial permeability transition pore opening, cytochrome c release, and caspase activation in U937 cells. Cytotoxicity induced by TW-96, but not by TW-85, was associated with the elevation of the cytosolic levels of reactive oxygen species (ROS). The latter was attenuated by diphenyleneiodonium, indicating that NADPH oxidase was likely to be the source of ROS generation. Activation of p38 MAPK by the two agents appeared to prevent necrosis but differentially affected apoptotic cell death in U937 cells. These results further expand our understanding of the structure–activity relationship of aminophenyl-1,4-naphthoquinones as potential anti-leukemic agents with distinct modes of action.

Original languageEnglish
Pages (from-to)393-406
Number of pages14
JournalMolecular and Cellular Biochemistry
Issue number2
StatePublished - 1 Feb 2023


  • Apoptosis
  • Leukemia
  • Naphthoquinones
  • Necrosis
  • Reactive oxygen species

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology


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