Deoxynyboquinone (DNQ) is a potent
antineoplastic agent with an unknown mechanism of action. Here we describe a facile synthetic route to this
anthraquinone, and we use this material to determine the mechanism by which DNQ induces death in
cancer cells. DNQ was synthesized in seven linear steps through a route employing three
palladium-mediated coupling reactions. Experiments performed on
cancer cells grown in
hypoxia and normoxia strongly suggest that DNQ undergoes bioreduction to its semiquinone, which then is re-oxidized by molecular
oxygen, forming
superoxide that induces cell death. Furthermore, global transcript profiling of cells treated with DNQ shows elevation of transcripts related to oxidative stress, a result confirmed at the
protein level by Western blotting. In contrast to most other
antineoplastic agents that generate
reactive oxygen species (ROS), DNQ potently induces death of
cancer cells in culture, with IC(50) values between 16 and 210 nM. In addition, unlike the experimental therapeutic
elesclomol, DNQ is still able to induce
cancer cell death under hypoxic conditions. This mechanistic understanding of DNQ will allow for a more comprehensive evaluation of the potential of direct ROS generation as an anticancer strategy, and DNQ itself has potential as a novel
anticancer agent.