New gold pincer-type complexes: synthesis, characterization, DNA binding studies and cytotoxicity
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Gligorijević, Nevenka N.
Radulović, Siniša S.
Rilak Simović, Ana
Чланак у часопису (Објављена верзија)
© 2018 The Royal Society of Chemistry
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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(N-N'-N)Cl]Cl-2, where N-N'-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 (Me-2*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 sigma-donicity of the methyl substituent on the bis-pyrazolylpyridine fragment in complexes 2 and 3. The measured enthalpies and entropies of activation (Delta H-not equal > 0, Delta S-not equal < 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 (K-b = 1.6-5.7 x 10(3) 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 mu M. 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.
Извор:Dalton Transactions, 2018, 47, 38, 13696-13712
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ISSN: 1477-9226 (print); 1477-9234 (electronic)