Abstract
The new mixed-ligand copper(II) complexes [Cu(FAA)(diimine)(H2O)](ClO4)(2) (1-4) [FAA is folic acid-conjugated ethyl pyridyl amine; diimine is 1,10-phenanthroline (phen; 1), 5,6-dimethyl-1,10-phenanthroline (5,6-dmp; 2), 3,4,7,8-tetramethyl-1,10-phenanthroline (3,4,7,8-tmp; 3), and dipyrido-[3,2-f:2',3'-h]-quinoxaline (dpq; 4)] were synthesized and characterized adopting appropriate analytical and spectroscopic techniques. DNA and protein binding studies showed that the complex [Cu(FAA)(5,6-dmp)(H2O)](2+) (2) has higher DNA- and protein-binding abilities than the other complexes. In the presence of the activating agent ascorbic acid, the same complex 2 caused pronounced DNA cleavage. The mechanistic study revealed that the oxidative DNA cleavage induced by complex 2 was effected through the freely diffusible hydroxyl radical; the same complex induced the highest incidence of cytotoxicity in the triple-negative breast cancer cell MDA-MB-231 (IC50) = 0.54 mu M) compared to its congeners in the series, cisplatin, and the free ligand (FAA). AO/EthBr staining assay revealed induction of cell death by apoptosis. Interestingly, the complex 2 demonstrated greater selectivity toward cancer cells as revealed in only the negligible cytotoxicity to normal cells (lymphocytes), which emphasizes an important role to the cancer-targeting ligand folic acid conjugated to the Cu(II) complexes in dealing with triple-negative breast cancers.