DNA and protein binding, double-strand DNA cleavage and cytotoxicity of mixed ligand copper(II) complexes of the antibacterial drug nalidixic acid

Abstract The water soluble mixed ligand complexes [Cu(nal)(diimine)(H 2 O)](ClO 4 ) 1 – 4 , where H(nal) is nalidixic acid and diimine is 2,2′-bipyridine ( 1 ), 1,10-phenanthroline ( 2 ), 5,6-dimethyl-1,10-phenanthroline ( 3 ), and 3,4,7,8-tetramethyl-1,10-phenanthroline ( 4 ), have been isolated. The coordination geometry around Cu(II) in 1 and that in the Density Functional Theory optimized structures of 1 – 4 has been assessed as square pyramidal. The trend in DNA binding constants ( K b ) determined using absorption spectral titration ( K b : 1 , 0.79 ± 0.1  2 , 1.06 ± 0.1  3 , 1.79 ± 0.2  4 , 1.84 ± 0.2 × 10 5  M − 1 ) is in line with that ( K app ) determined by competitive ethidium bromide binding studies. The large red-shift (10 nm) observed for 2 suggests that the phen co-ligand is stacked with a frayed DNA base pair. In contrast, 3 and 4 are involved in intimate hydrophobic interaction with DNA through the methyl substituents on phen ring, which is supported by viscosity and protein binding studies. DNA docking studies imply that 4 is involved preferentially in DNA major groove binding while 1 – 3 in minor groove binding and that all the complexes, upon removing the axially coordinated water molecule, bind in the major groove. Interestingly, 3 and 4 display prominent double-strand DNA cleavage while 1 and 2 effect only single-strand DNA cleavage in the absence of an activator. The complexes 3 and 4 show cytotoxicity higher than 1 and 2 against human breast cancer cell lines (MCF-7). The complex 4 induces apoptotic mode of cell death in cancer cells.