ROS-mediated cell death induced by mixed ligand copper(II) complexes of l-proline and diimine: effect of co-ligand

A series of mixed-ligand Cu(II) complexes of the type: (i) [Cu(l-pro)(diimine)(H₂O)_n](ClO₄) (n = 0 or 1), where l-pro is l-proline and diimine is 2,2′-bipyridine (bpy; 1), (ii) 4,4′-dimethyl-2,2′-bipyridine (dmbpy; 2), (iii) 1,10-phenanthroline (phen; 3), (iv) 5,6-dimethyl-1,10-phenanthroline (5,6-dmp; 4), (v) 3,4,7,8-tetramethyl-1,10-phenanthroline (3,4,7,8-tmp; 5), (vi) dipyrido-[3,2-f:2′,3′-h]-quinoxaline (dpq; 6), and (vii) dipyrido[3,2-a:2′,3′-c]phenazine (dppz; 7) have been synthesized and characterized systematically. Complexes 2 and 3 have been structurally characterized. DNA- and protein-binding and cleavage studies revealed that 7 possesses stronger DNA- and protein-binding efficiency and also exhibits self-activating DNA-cleavage in the absence of an activating agent. The hydrophobic complexes 4 and 5 induced self-activated protein cleavage and yielded a single-cleaved fragment each. The cytotoxic property of all the seven complexes was examined by incubation with the human small cell lung carcinoma cell line A549. Complexes 4 and 6 exhibited almost similar cytotoxic properties [IC₅₀ = 1.4 µM (4) and 1.3 µM (6)], which was 9.3 and 10 times, respectively, more efficient than cisplatin (IC₅₀ = 13 µM). Complex 4 induced generation of the highest level of intracellular ROS which correlates with its efficient cytotoxic activity and provides scope for further investigation as a potential anticancer agent.