Nickel(ii), copper(ii) and zinc(ii) metallo-intercalators: structural details of the DNA-binding by a combined experimental and computational investigation

Abstract

We present a thorough characterization of the interaction of novel nickel(II) (1), copper(II) (2) and zinc(II) (3) Schiff base complexes with native calf thymus DNA (ct-DNA), in buffered aqueous solution at pH 7.5. UV-vis absorption, circular dichroism (CD) and viscometry titrations provided clear evidence of the intercalative mechanism of the three square-planar metal complexes, allowing us to determine the intrinsic DNA-binding constants (K(b)), equal to 1.3 × 10(7), 2.9 × 10(6), and 6.2 × 10(5) M(-1) for 1, 2 and 3, respectively. Preferential affinity, of one order of magnitude, toward AT compared to GC base pair sequences was detected by UV-vis absorption titrations of 1 with [poly(dG-dC)]2 and [poly(dA-dT)]2. Structural details of the intercalation site of the three metal complexes within [dodeca(dA-dT)]2 were obtained by molecular dynamics (MD) simulations followed by density functional theory/molecular mechanics (DFT/MM) calculations. The calculations revealed that three major intermolecular interactions contribute to the strong affinity between DNA and the three metal complexes: (1) the electrostatic attraction between the two positively charged triethylammoniummethyl groups of the metal complexes and the negatively charged phosphate groups of the DNA backbone; (2) the intercalation of the naphthalene moiety within the four nitrogen bases of the intercalation site; (3) the metal coordination by exocyclic donor atoms of the bases, specifically the carbonyl oxygen and amine nitrogen atoms. Remarkably, the Gibbs formation free energy calculated for the intercalation complexes of 1, 2 and 3 with [dodeca(dA-dT)]2 in the implicit water solution is in agreement with the experimental Gibbs free energy values obtained from the DNA-binding constants as ΔG° = -RT ln(K(b)). In particular, the DNA-binding affinity trend, 1 > 2 > 3, is reproduced. Finally, the first shell coordination distances calculated for the intercalation complex 3/[dodeca(dA-dT)]2 are in excellent agreement with the experimental distances extracted from the extended X-ray absorption fine structure (EXAFS) spectrum of the corresponding 3/ct-DNA solutions. The latter results provided the first evidence of metal ion coordination by native DNA in aqueous solution.

Synthesis of a DNA-targeting nickel (II) complex with testosterone thiosemicarbazone which exhibits selective cytotoxicity towards human prostate cancer cells (LNCaP)

“…However, the K b values of both compounds are comparable to reported value of typical classical intercalator ethidium bromide (EB-DNA) 1.4 Â 10 6 M À1 in 25 mM Tris-HCl/40 mM NaCl buffer (pH = 7.9) [62]. This reflects a strong binding interaction between CT-DNA with both L and 1, which probably confers to their anticancer properties [67].…”

Nuclear blebbing of biologically active organoselenium compound towards human cervical cancer cell (HeLa): In vitro DNA/HSA binding, cleavage and cell imaging studies

“…Interestingly, the halogen (F-F) distance in compound 1 was 2.713(3) Å, which was quite favorable for halogen interactions thereby helping the molecules to interact and stay closer. Density functional theory (DFT) is a popular computational method of medicinal chemists widely used today for screening of biologically relevant molecular systems in a time and cost effective manner [15,16]. The DFT studies were performed using Turbomole 6.0 program with B3LYP functional and three different basis sets {6-31G(d,P), LanL2MB, TZVP} for a close agreement of the optimized structure with the experimental crystal structure.…”

Cu(II), Ni(II) complexes derived from chiral Schiff-base ligands: Synthesis, characterization, cytotoxicity, protein and DNA–binding properties

“…Nowadays, Schiff-base metal complexes, in particular transition metal Schiff-base complexes have received increasing attention due to their special structures, antitumor activity and biological activity [10,11]. Copper (II) and nickel (II) complexes are regarded as the most of promising anti-carcinogen to replace the cisplatin, an idea supported by a considerable number of research articles describing the synthesis, DNA binding, and cytotoxic activities of numerous copper (II) complexes [12][13][14][15][16][17]. Certainly, a wide variety of polydentate organic ligands play a pivotal role to determine the properties of complexes [18].…”