Synthesis of TPEN variants to improve cancer cells selective killing capacity

N,N,N′-tris(2-pyridylmethyl)-N′-ethyl-1,2-ethanenediamine (TPEEN) is a novel transition metal chelators derived from TPEN that generates reactive oxygen species (ROS) resulting in cell death. [Display omitted] •The metal chelator TPEN is know to selectively kill cancer cells.•Generated three novel derivatives of TPEN to improve metal chelation selectivity.•One of the derivative TPEEN exhibits reduced affinity for transition metals.•TPEEN is effective at inducing cell death in breast cancer cells.•TPEEN kills cancer cells by chelating redox active metals (iron and copper). TPEN is an amino chelator of transition metals that is effective at the cellular and whole organism levels. Although TPEN of often used as a selective zinc chelators, it has affinity for copper and iron and has been shown to chelate both biologically. We have previously shown that TPEN selectively kills colon cancer cells based on its ability to chelate copper, which is highly enriched in colon cancer cells. The TPEN-copper complex is redox active thus allowing for increased ROS production in cancer cells and as such cellular toxicity. Here we generate TPEN derivatives with the goal of increasing its selectivity for copper while minimizing zinc chelation to reduce potential side effects. We show that one of these derivatives, TPEEN despite the fact that it exhibits reduced affinity for transition metals, is effective at inducing cell death in breast cancer cells, and exhibits less toxicity to normal breast cells. The toxicity effect of the both chelators coupled to the metal content of the different cell types reveals that they exhibit their toxicity through chelating redox active metals (iron and copper). As such TPEEN is an important novel chelators that can be exploited in anti-cancer therapies.