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

Abstract

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.

Keywords:

• Copper complexes
• DNA binding and cleavage
• protein cleavage
• gel electrophoresis
• cytotoxicity
• ROS

Acknowledgements

The technical assistance of Dr. Dhivya Rajkumar in conducting the in vitro study is gratefully acknowledged. We thank Dr. A. Chandrashekaran, Department of Mathematics, Central University of Tamil Nadu, Thiruvarur, India, for help in non-linear regression analysis.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

V.R. is recipient of Raman Fellowship (5-104/2016 IC) of University Grants Commission, New Delhi. We thank the Science and Engineering Research Board (SERB), DST, New Delhi, for funding the Start-Up Research Grant (Young Scientists) - Chemical Sciences (SB/FT/CS-187/2011).