Copper ( II ) complex of methionine conjugated bis-pyrazole based ligand promotes dual pathway for DNA cleavage

Three Cu(II) complexes of bis-pyrazole based ligands have been synthesized and structurally characterized by X-ray crystallography. One of the ligand (L2) contains a methionine ester conjugated to a bis-pyrazole carboxylate through an amide linkage. The binding constant for complexes 1-3 with CT DNA are of the order of 10(4) M(-1). The crystal structure suggests that the axial Cu-O bonds (ca. 2.31(4) Å) are relatively labile and hence during the redox cycle with ascorbic acid and oxygen one or both the axial Cu-O bonds might open to promote copper oxygen reaction and generate ROS. The chemical nuclease activity of complexes 1-3 in dark, show complete relaxation of supercoiled DNA at 100 μM concentration in presence of ascorbic acid (H2A). The mechanistic investigation suggests that the complexes 1 and 2 show involvement of peroxo species whereas 3 shows involvement of both singlet oxygen and peroxo species in DNA cleavage. The singlet oxygen formation in dark is otherwise unfavourable but the presence of methionine as pendant arm in L2 might activate the generation of singlet oxygen from the metal generated peroxo species. The results of DNA cleavage studies suggest that methionine based copper(II) complexes can promote dual pathway for DNA cleavage. Probing the cytotoxic activity of these complexes on MCF-7, human breast cancer cell line shows that 3 is the most effective one with an IC50 of 70(2) μM.


Contents:
Table S1 Literature reports on DNA cleavage activity of methionine based metal complexes in presence of light and in dark Table S2 Crystallographic data and structure refinement parameters for 1-3 Table S3 Bond Valence Sum calculation for 1-3 with two possible oxidation states.

Table S4
Lipophilicity metal complexes and the ligands in octanol/water system.

Fig. S8
Fig. S8 Effects of treatment of the complexes 1-3 with MCF-7 tumor cell line for 48 h with rising concentrations: (A) 1, (B) 2, (C) 3.The IC 50 obtained from the curves are calculated using GraphPad Prism.Data are means ± SD of three independent experiments.

Fig. S8
Fig. S8 Effects of treatment of the complexes 1-3 with MCF-7 tumor cell line for 48 h with rising concentrations: (A) 1, (B) 2, (C) 3. Top panel of graphs showing % survival against log of concentration of complexes and bottom panel showing % survival against concentration of complexes).The IC 50 obtained from the curves are calculated using GraphPad Prism.Data are means ± SD of three independent experiments.
Electronic Supplementary Material (ESI) for Dalton TransactionsThis journal is © The Royal Society of Chemistry 2013

Table S2
Crystallographic data and structure refinement parameters for 1-3.

Table S4
Lipophilicity of metal complexes and the ligands in octanol/water system.