Ni(II) complex with bishydrazone ligand: synthesis, characterization, DNA binding studies and pro–apoptotic and pro–differentiation induction in human cancerous cell lines
Authors
Filipović, Nenad R.
Bjelogrlić, Snežana
Todorović, Tamara R.

Blagojević, Vladimir A.

Muller, Christian D.

Marinković, Aleksandar

Vujčić, Miroslava
Janović, Barbara

Malešević, Aleksandar
Begović, Nebojša N.
Senćanski, Milan

Minić, Dragica M.

Article (Accepted 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.
The authors acknowledge networking support by the COST Action CM1106 StemChem – “Chemical Approaches to Targeting Drug Resistance in Cancer Stem Cells”. The work was funded by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grant 172055).
Keywords:
Ni(II) complexes / bishydrazone / DNA binding / anticancer activitySource:
RSC Advances, 2016, 110, 108726-108740Funding / projects:
- Directed synthesis, structure and properties of multifunctional materials (RS-172057)
- COST Action CM1106 StemChem – “Chemical Approaches to Targeting Drug Resistance in Cancer Stem Cells”
DOI: 10.1039/C6RA24604D
ISSN: 2046-2069
WoS: 000389342800068
Scopus: 2-s2.0-84997501324
Institution/Community
Институт техничких наука САНУ / Institute of Technical Sciences of SASATY - JOUR AU - Filipović, Nenad R. AU - Bjelogrlić, Snežana AU - Todorović, Tamara R. AU - Blagojević, Vladimir A. AU - Muller, Christian D. AU - Marinković, Aleksandar AU - Vujčić, Miroslava AU - Janović, Barbara AU - Malešević, Aleksandar AU - Begović, Nebojša N. AU - Senćanski, Milan AU - Minić, Dragica M. PY - 2016 UR - https://dais.sanu.ac.rs/123456789/860 AB - 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 course. 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. The authors acknowledge networking support by the COST Action CM1106 StemChem – “Chemical Approaches to Targeting Drug Resistance in Cancer Stem Cells”. The work was funded by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grant 172055). T2 - RSC Advances T1 - Ni(II) complex with bishydrazone ligand: synthesis, characterization, DNA binding studies and pro–apoptotic and pro–differentiation induction in human cancerous cell lines SP - 108726 EP - 108740 VL - 110 VL - 6 DO - 10.1039/C6RA24604D UR - https://hdl.handle.net/21.15107/rcub_dais_860 ER -
@article{ author = "Filipović, Nenad R. and Bjelogrlić, Snežana and Todorović, Tamara R. and Blagojević, Vladimir A. and Muller, Christian D. and Marinković, Aleksandar and Vujčić, Miroslava and Janović, Barbara and Malešević, Aleksandar and Begović, Nebojša N. and Senćanski, Milan and Minić, Dragica M.", year = "2016", abstract = "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 course. 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. The authors acknowledge networking support by the COST Action CM1106 StemChem – “Chemical Approaches to Targeting Drug Resistance in Cancer Stem Cells”. The work was funded by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grant 172055).", journal = "RSC Advances", title = "Ni(II) complex with bishydrazone ligand: synthesis, characterization, DNA binding studies and pro–apoptotic and pro–differentiation induction in human cancerous cell lines", pages = "108726-108740", volume = "110, 6", doi = "10.1039/C6RA24604D", url = "https://hdl.handle.net/21.15107/rcub_dais_860" }
Filipović, N. R., Bjelogrlić, S., Todorović, T. R., Blagojević, V. A., Muller, C. D., Marinković, A., Vujčić, M., Janović, B., Malešević, A., Begović, N. N., Senćanski, M.,& Minić, D. M.. (2016). Ni(II) complex with bishydrazone ligand: synthesis, characterization, DNA binding studies and pro–apoptotic and pro–differentiation induction in human cancerous cell lines. in RSC Advances, 110, 108726-108740. https://doi.org/10.1039/C6RA24604D https://hdl.handle.net/21.15107/rcub_dais_860
Filipović NR, Bjelogrlić S, Todorović TR, Blagojević VA, Muller CD, Marinković A, Vujčić M, Janović B, Malešević A, Begović NN, Senćanski M, Minić DM. Ni(II) complex with bishydrazone ligand: synthesis, characterization, DNA binding studies and pro–apoptotic and pro–differentiation induction in human cancerous cell lines. in RSC Advances. 2016;110:108726-108740. doi:10.1039/C6RA24604D https://hdl.handle.net/21.15107/rcub_dais_860 .
Filipović, Nenad R., Bjelogrlić, Snežana, Todorović, Tamara R., Blagojević, Vladimir A., Muller, Christian D., Marinković, Aleksandar, Vujčić, Miroslava, Janović, Barbara, Malešević, Aleksandar, Begović, Nebojša N., Senćanski, Milan, Minić, Dragica M., "Ni(II) complex with bishydrazone ligand: synthesis, characterization, DNA binding studies and pro–apoptotic and pro–differentiation induction in human cancerous cell lines" in RSC Advances, 110 (2016):108726-108740, https://doi.org/10.1039/C6RA24604D ., https://hdl.handle.net/21.15107/rcub_dais_860 .