Concurrent Cu()-initiated Fenton-like reaction and glutathione depletion to escalate chemodynamic therapy

Chemodynamic therapy is an evolving therapeutic strategy but there are certain limitations associated with its treatment. Herein, we present de novo synthesis and mechanistic evaluation of HL1-HL8 ligands and their corresponding Cu II (L1) 2 -Cu II (L8) 2 . The most active Cu(L2) 2 (IC 50 = 5.3 μM, MCF-7) complex exclusively depletes glutathione while simultaneously promoting ROS production. Cu(L2) 2 also affects other macromolecules like the mitochondrial membrane and DNA while activating the unfolded protein response cascade. Cu( ii ) complexes of HDAC inhibitor analogues efficiently overcoming limitations of chemodynamic therapy.