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

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(N-N'-N)Cl]Cl2, 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 (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.

New gold pincer-type complexes induce caspase-dependent apoptosis in human cancer cells in vitro

“…The cytotoxicity of complex 1 and its ligand was partially tested on cell lines of colon carcinoma (LS-174), lung carcinoma (A549) and melanoma (A375) cell lines. The results of this study have shown that complex 1 exhibited stronger anti-tumor effect on all three types of tumor cells tested compared to cisplatin [15]. Since some compounds may show delayed toxicity, it is concluded that the analysis of cytotoxicity should be performed after an interval of at least 48 hours [20].…”

“…The synthesis and characterization of 2,6-bis(5-tert-butyl-1H-pyrazol-3-yl)pyridine (H2L tBu ), 2,6-bis(5-tert-butyl-1-methyl-1H-pyrazol-3-yl)pyridine (Me2L tBu ), and 2,6bis((4S,7R)-1,7,8,8-tetramethyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)pyridine (Me2*L) was discussed in detail in previously published article [15]. The newly synthesized complexes, namely [Au(H2LtBu)Cl]Cl2 (1), [Au(Me2LtBu)Cl]Cl2 (2) and [Au(Me2*L)Cl]Cl2…”

“…The newly synthesized complexes, namely [Au(H2LtBu)Cl]Cl2 (1), [Au(Me2LtBu)Cl]Cl2 (2) and [Au(Me2*L)Cl]Cl2 (3) were characterized by elemental analysis, spectroscopic techniques (IR, UV-Vis, 1D and 2D NMR) and mass spectrometry (MS) methods: MALDI TOF and ESI Q-TOF. These three gold(III) complexes had also been tested against three types of cancer cells (A549, A375, LS-174) in vitro [15].…”

Gold(III) Complexes: An Overview on Their Kinetics, Interactions With DNA/BSA, Cytotoxic Activity, and Computational Calculations

“…The same conclusion was derived for structurally similar complexes with terpyridine ligands (Liu et al, 1995;Messori et al, 2005;Shi et al, 2006). The other method, fluorescence spectroscopy, was employed in the aim to clarify the mode 1 | The DNA-binding constants (K b ) and Stern-Volmer constants (K sv ) from EB-DNA fluorescence for complexes 1-9 and bovine serum albumin (BSA) constants and parameters (K sv , k q , K, and n) derived for complexes 4-9 (Radisavljević et al, 2018(Radisavljević et al, , 2019.…”

“…The interactions between newly synthesized gold(III) complexes that contain structurally distinct nitrogen-donor ligands (Figure 1), such as 2,6-bis(5-tert-butyl-1H-pyrazol-3-yl)pyridine (complex 1), 2,6-bis(5-tert-butyl-1-methyl-1H-pyrazol-3yl)pyridine (complex 2), 2,6-bis((4S, 7R)−1,7,8,8-tetramethyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)pyridine (complex 3), 1,4-diaminobutane (complexes 4 and 7), 1,6diaminohexane (complexes 5 and 8), 1,8-diaminooctane (complexes 6 and 9), combination of 2,2 ′ -bipyridine and N-(3-((4-nitrophenyl) thio)phenyl)methanediimine (complex 10), and (Z)-1-(4-morpholinophenyl)-N-((4-(trifluoromethyl) pyrimidin-2-yl)methyl)methanimine (complex 11) (Radisavljević et al, 2018(Radisavljević et al, , 2019Sankarganesh et al, 2019;Tabrizi et al, 2020), and primary biomolecules were examined by different experimental methods. These complexes were selected having in mind that the presence of different nitrogen-donor inert ligands in the structure of some gold(III) complexes have great potential to stabilize metal ion and improve its binding affinity toward biomolecules under physiological conditions (Radisavljević et al, 2019).…”