Designing salicylaldehyde isonicotinoyl hydrazones as Cu(II) ionophores with tunable chelation and release of copper for hitting redox Achilles heel of cancer cells.

Higher levels of copper, reduced glutathione (GSH) and reactive oxygen species (ROS) observed in cancer cells than in normal cells, favor the idea of developing copper ionophores as prooxidative anticancer agents (PAAs) to hit the altered redox homeostasis (redox Achilles heel) of cancer cells. In this work, we used salicylaldehyde isonicotinoyl hydrazone (SIH-1) as a basic scaffold to design Cu(II) ionophores with tunable chelation and release of Cu(II) by introducing electron-withdrawing nitro and electron-donating methoxyl groups in the para position to phenolic hydroxyl, or by blocking the phenolic hydroxyl site using methyl. These molecules were used to probe how chelation and release of copper influence their ionophoric role and ability to target redox Achilles heel of cancer cells. Among these molecules, SIH-1 was identified as the most potent Cu(II) ionophore to kill preferentially HepG2 cells over HUVEC cells, and also superior to clioquinol, a copper ionophore evaluated in clinical trials, in terms of its relatively higher cytotoxicity and better selectivity. Higher oxidative potential, despite of lower stability constant, of the Cu(II) complex formed by SIH-1 than by the other molecules, is responsible for its stronger ability in releasing copper by GSH, inducing redox imbalance and triggering mitochondria-mediated apoptosis of HepG2 cells. This work gives useful information on how to design copper ionophores as PAAs for selective killing of cancer cells.