New gold pincer-type complexes: synthesis,characterization, DNA binding studies andcytotoxicity
Creators
- 1. University of Kragujevac, Faculty of Science, R. Domanovića 12, P. O. Box 60,34000 Kragujevac, Serbia
- 2. I.N.N., Department of Physical Chemistry, NCSR"Demokritos", 15310 Ag.Paraskevi, Athens, Greece
- 3. Inorganic Chemistry, Department of Chemistry and Pharmacy, University of Erlangen-Nürnberg, Erlangen, Germany
- 4. Department of Physical Chemistry, Vinča Institute of Nuclear Sciences, University of Belgrade, Mike Petrovića Alasa 12-14, 11000 Belgrade, Serbia
- 5. University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistryand Environmental Protection, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia
- 6. Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
Description
With the aim of assessing whether Au(III) compounds with pincer type ligands might be utilized as poten-tial antitumor agents, three new monofunctional Au(III) complexes of the general formula [Au(N–N’–N)Cl]Cl2, whereN–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 byelemental 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 byUV-Vis spectroscopy, which showed that all compounds were remarkably stable and that the gold centerremained in the 3+ oxidation state. The kinetics and the mechanism of the reaction of complexes1–3with guanine derivatives (i.e.guanosine (Guo) and guanosine-5’-monophosphate (5’-GMP)) and calfthymus DNA (CT DNA) were studied by stopped-flow spectroscopy. The three complexes displayed mod-erately different rate constants in their reactions with Guo, 5’-GMP and CT DNA, which can be explainedby the steric hindrance andσ-donicity of the methyl substituent on the bis-pyrazolylpyridine fragment incomplexes2and3. The measured enthalpies and entropies of activation (ΔH≠>0,ΔS≠< 0) supported anassociative mechanism for the substitution process. The interaction of the newly synthesized complexes1–3with CT DNA was investigated by UV-Vis andfluorescence spectroscopy, and also by viscositymeasurements, which all indicated that complexes1–3bound to CT DNA with moderate binding affinity(Kb= 1.6–5.7 × 103M−1) and stabilized the duplex of CT DNA. Molecular docking indicated that complexes1–3interacted with DNAviaintercalation. Complex1reduced the cell survival of all the investigated celllines (A549, A375, and LS-174) with IC50values being up to 20 μM. We have shown that1induced pertur-bations of the cell cycle and led to apoptosis in human melanoma A375 cells. Complex1also affectedthe level of reactive oxygen species (ROS) in the same cells. However, pre-treatment of A375 cells withNAC (ROS scavenger) reversed the effect of1on their survival.
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Funding
- Pharmacodynamic and pharmacogenomic research of new drugs in the treatment of solid tumors 41026
- Ministry of Education, Science and Technological Development
- Mechanistic studies of the reactions of transition metal ion complexes with biologically relevant molecules 172011
- Ministry of Education, Science and Technological Development