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

Abstract

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.

Spectroscopic Definition of the CuZ° Intermediate in Turnover of Nitrous Oxide Reductase and Molecular Insight into the Catalytic Mechanism

“…In other systems, for example, the zeolite Cu-ZSM-5, N 2 O is reduced by a binuclear copper site with no bridging ligands to provide a superexchange pathway between the copper centers. 39 In the zeolite system, N 2 O must coordinate in a μ -1,1-O mode, so that one electron can transfer from one Cu at the TS and the second electron from the other, leading to an oxo bridged product that is active in the zeolite but would be inactive in the N 2 OR enzymatic system. To avoid this, the Cu 4 S cluster stabilizes the O at Cu IV using second sphere hydrogen bonding and thus has a very covalent μ 4 -bridging sulfide ligand, which provides sufficiently good superexchange that both electrons can be transferred to N 2 O via one copper center (Cu IV ).…”

Mechanistic insights into a novel chromone-appended Cu(ii) anticancer drug entity: in vitro binding profile with DNA/RNA substrates and cytotoxic activity against MCF-7 and HepG2 cancer cells

“…28 The effective magnetic moment of the Cu(II) complex was calculated at room temperature using the equation μ eff = 2.828 [χ m T] for the Cu(II) complex with one unpaired electron in an octahedral geometry. The electronic spectrum recorded in a DMSO solution revealed two well resolved absorption maxima at 252 and 305 nm corresponding to π-π* and n-π* intraligand transitions, respectively.…”

Effect of methionine and glucosamine conjugation on the anticancer activity of aromatic dinitrobenzamide mustards

“…The compounds were found to be stable in acidic and basic conditions. The results showed that even at pH ∼1 there was no dissociation for 12 h at 37 • C ( 1 H, 13 C NMR spectra and HRMS are in Figures S32-S34, respectively). The bis(2-chloroethyl)amine moiety was stable to aziridine formation (scheme S4) even at pH > 12 when tested for compound 1c.…”

“…11,12 We have recently shown that conjugation of methionine to Cu(II) complex of bis-pyrazolyl ligands imparts better toxicity and * For correspondence two different ROS species can be formed. 13 Earlier it has been shown the methionine bearing ligand has positive effect on phototoxicity. 14 However, we found that conjugation of methionine to a bis-pyrazolyl ligand and formation of its Zn(II) complex did not render a higher toxicity.…”