Ni(II) complex with bishydrazone ligand: synthesis, characterization, DNA binding studies and pro-apoptotic and pro-differentiation induction in human cancerous cell lines
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AuthorsFilipović, Nenad R.
Todorović, Tamara R.
Blagojević, Vladimir A.
Muller, Christian D.
Begović, Nebojša N.
Minić, Dragica M.
Article (Published version)
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A new Ni(II) complex, [Ni(L)(H2O)] (1), with diethyl 3,3′-(2,2′-(1,1′-(pyridine-2,6-diyl)bis(ethan-1-yl-1-ylidene))bis(hydrazin-1-yl-2-ylidene))bis(3-oxopropanoate) ligand (H2L) was synthesized as a potential chemotherapeutic agent. Polidentate ligand was coordinated to Ni(II) NNN-tridentately, in dianionic form, while monodentate water coordination completed square-planar geometry around metal. Structure in the solution was determined by NMR spectroscopy and the same coordination mode was observed in the solid state using IR spectroscopy and further verified by DFT calculations and electrochemical studies. Thermal stability of 1 was determined in both air and nitrogen atmosphere. Anticancer activity of 1 was investigated on acute monocytic leukemia (THP-1) and pancreatic adenocarcinoma (AsPC-1) cell lines. On THP-1 cells 1 induced powerful apoptotic response (ED50 = 10 ± 3 μM), which was revealed to be only partially caspase-dependent, with activation of caspase-8 as the dominant cour...se. This suggested that experimentally validated covalent binding of 1 to DNA is not the only mechanism responsible for programmed cell death. This was supported with experiments on AsPC-1 cells. Although treatment of those cells with 1 resulted in poor apoptotic response, cell cycle changes showed concentration-dependent shifts indicating a dual mechanism of activity. This study also reviews the results of preliminary biological screening, which demonstrates that 1 displays a unique pattern of anticancer activity with at least two mechanisms involved.
Keywords:Ni(II) complexes / bishydrazone ligands / DNA binding / human cancerous cell lines
Source:RSC Advances, 2016, 6, 108726-108740
- Royal Society of Chemistry
- COST Action CM1106 StemChem – “Chemical Approaches to Targeting Drug Resistance in Cancer Stem Cells”
- Directed synthesis, structure and properties of multifunctional materials (RS-172057)
- Peer-reviewed manuscript available:http://dais.sanu.ac.rs/handle/123456789/860