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New gold pincer-type complexes: synthesis, characterization, DNA binding studies and cytotoxicity

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Abstract

With the aim of assessing whether Au(III) compounds with pincer type ligands might be utilized as potential antitumor agents, three new monofunctional Au(III) complexes of the general formula [Au(NN’N)Cl]Cl2, where NN’N = 2,6-bis(5-tert-butyl-1H-pyrazol-3-yl)pyridine (H2LtBu, 1), 2,6-bis(5-tert-butyl-1-methyl-1H-pyrazol-3-yl)pyridine (Me2LtBu, 2) or 2,6-bis((4S,7R)-1,7,8,8-tetramethyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)pyridine (Me2*L, 3) were synthesized. All complexes were characterized by elemental analysis, spectroscopic techniques (IR, UV-Vis, 1D and 2D NMR) and mass spectrometry (MALDI TOF MS). The chemical behavior of the complexes under physiological conditions was studied by UV-Vis spectroscopy, which showed that all compounds were remarkably stable and that the gold center remained in the 3+ oxidation state. The kinetics and the mechanism of the reaction of complexes 1–3 with guanine derivatives (i.e. guanosine (Guo) and guanosine-5′-monophosphate (5′-GMP)) and calf thymus DNA (CT DNA) were studied by stopped-flow spectroscopy. The three complexes displayed moderately different rate constants in their reactions with Guo, 5′-GMP and CT DNA, which can be explained by the steric hindrance and σ-donicity of the methyl substituent on the bis-pyrazolylpyridine fragment in complexes 2 and 3. The measured enthalpies and entropies of activation (ΔH > 0, ΔS < 0) supported an associative mechanism for the substitution process. The interaction of the newly synthesized complexes 1–3 with CT DNA was investigated by UV-Vis and fluorescence spectroscopy, and also by viscosity measurements, which all indicated that complexes 1–3 bound to CT DNA with moderate binding affinity (Kb = 1.6–5.7 × 103 M−1) and stabilized the duplex of CT DNA. Molecular docking indicated that complexes 1–3 interacted with DNA via intercalation. Complex 1 reduced the cell survival of all the investigated cell lines (A549, A375, and LS-174) with IC50 values being up to 20 μM. We have shown that 1 induced perturbations of the cell cycle and led to apoptosis in human melanoma A375 cells. Complex 1 also affected the level of reactive oxygen species (ROS) in the same cells. However, pre-treatment of A375 cells with NAC (ROS scavenger) reversed the effect of 1 on their survival.

Graphical abstract: New gold pincer-type complexes: synthesis, characterization, DNA binding studies and cytotoxicity

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Publication details

The article was received on 17 Jul 2018, accepted on 30 Aug 2018 and first published on 31 Aug 2018


Article type: Paper
DOI: 10.1039/C8DT02903B
Citation: Dalton Trans., 2018, Advance Article
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    New gold pincer-type complexes: synthesis, characterization, DNA binding studies and cytotoxicity

    S. Radisavljević, I. Bratsos, A. Scheurer, J. Korzekwa, R. Masnikosa, A. Tot, N. Gligorijević, S. Radulović and A. Rilak Simović, Dalton Trans., 2018, Advance Article , DOI: 10.1039/C8DT02903B

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