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Antitumor activity of organoruthenium complexes with chelate aromatic ligands, derived from 1,10-phenantroline: Synthesis and biological activity

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Abstract
The monocationic chloro complexes containing chelating N boolean AND N ligands: [(eta(6)-p-cymene)Ru(L1-4)Cl](+) (1-4), where L1 = 4-methyl-1,10-phenantroline, L2 = dipyrido[3,2-a:2',3'-c]phenazine, L3 = 11-chloro-dipyrido[3,2-a:2',3'-c]phenazine, L4 = 11-nitro-dipyrido [3,2-a:2',3'-c] phenazine; p-cymene = 1-methyl-4-isopropylbenzene) have been prepared and characterized as the hexafluorophosphate salts. The biological activity of 1-4 has been investigated in selected 2D monolayer cell cultures (A549, PANC-1, MDA-MB-231, MRC-5). All investigated ruthenium complexes showed similar or even better cytotoxicity to cisplatin. However, there was no significant reduction in growth of PANC-1 cells in a 3D cell culture of multicellular tumor spheroids (MCTS) after treatment with 2-4, while the cisplatin treatment induced retardation in MCTS growth. Flow cytometry analysis of the cell cycle of PANC-1 cells shows that 3 caused changes of cell cycle phase distribution characterized by slight accumulation of cells in the G2-M phase. Absence of the Sub-G1 phase in the cell cycle of the treated cells indicated that there was no fragmentation of DNA for the analyzed rime intervals (48 and 72 h treatment). Fluorescent microscopy, after acridine orange/ethidium bromide staining, revealed that the investigated ruthenium complexes induced some characteristics of apoptotic morphology (shrinking and condensation of chromatin) with notably preserved integrity of the plasma membrane. Investigation of cellular uptake and DNA - fraction accumulation performed by inductively coupled plasma mass spectrometry in PANC-1 cells with equimolar concentrations (5 mu M) of 2-4 and cisplatin showed more efficient cellular uptake and DNA- fraction accumulation of complex 3 compared to complexes 2 and 4.

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MLA
Savic, Aleksandar, et al. “Antitumor Activity of Organoruthenium Complexes with Chelate Aromatic Ligands, Derived from 1,10-Phenantroline: Synthesis and Biological Activity.” JOURNAL OF INORGANIC BIOCHEMISTRY, vol. 202, 2020.
APA
Savic, A., Gligorijevic, N., Arandelovic, S., Dojcinovic, B., Kaczmarek, A., Radulovic, S., … Van Hecke, K. (2020). Antitumor activity of organoruthenium complexes with chelate aromatic ligands, derived from 1,10-phenantroline: Synthesis and biological activity. JOURNAL OF INORGANIC BIOCHEMISTRY, 202.
Chicago author-date
Savic, Aleksandar, Nevenka Gligorijevic, Sandra Arandelovic, Biljana Dojcinovic, Anna Kaczmarek, Sinisa Radulovic, Rik Van Deun, and Kristof Van Hecke. 2020. “Antitumor Activity of Organoruthenium Complexes with Chelate Aromatic Ligands, Derived from 1,10-Phenantroline: Synthesis and Biological Activity.” JOURNAL OF INORGANIC BIOCHEMISTRY 202.
Chicago author-date (all authors)
Savic, Aleksandar, Nevenka Gligorijevic, Sandra Arandelovic, Biljana Dojcinovic, Anna Kaczmarek, Sinisa Radulovic, Rik Van Deun, and Kristof Van Hecke. 2020. “Antitumor Activity of Organoruthenium Complexes with Chelate Aromatic Ligands, Derived from 1,10-Phenantroline: Synthesis and Biological Activity.” JOURNAL OF INORGANIC BIOCHEMISTRY 202.
Vancouver
1.
Savic A, Gligorijevic N, Arandelovic S, Dojcinovic B, Kaczmarek A, Radulovic S, et al. Antitumor activity of organoruthenium complexes with chelate aromatic ligands, derived from 1,10-phenantroline: Synthesis and biological activity. JOURNAL OF INORGANIC BIOCHEMISTRY. 2020;202.
IEEE
[1]
A. Savic et al., “Antitumor activity of organoruthenium complexes with chelate aromatic ligands, derived from 1,10-phenantroline: Synthesis and biological activity,” JOURNAL OF INORGANIC BIOCHEMISTRY, vol. 202, 2020.
@article{8645723,
  abstract     = {The monocationic chloro complexes containing chelating N boolean AND N ligands: [(eta(6)-p-cymene)Ru(L1-4)Cl](+) (1-4), where L1 = 4-methyl-1,10-phenantroline, L2 = dipyrido[3,2-a:2',3'-c]phenazine, L3 = 11-chloro-dipyrido[3,2-a:2',3'-c]phenazine, L4 = 11-nitro-dipyrido [3,2-a:2',3'-c] phenazine; p-cymene = 1-methyl-4-isopropylbenzene) have been prepared and characterized as the hexafluorophosphate salts. The biological activity of 1-4 has been investigated in selected 2D monolayer cell cultures (A549, PANC-1, MDA-MB-231, MRC-5). All investigated ruthenium complexes showed similar or even better cytotoxicity to cisplatin. However, there was no significant reduction in growth of PANC-1 cells in a 3D cell culture of multicellular tumor spheroids (MCTS) after treatment with 2-4, while the cisplatin treatment induced retardation in MCTS growth. Flow cytometry analysis of the cell cycle of PANC-1 cells shows that 3 caused changes of cell cycle phase distribution characterized by slight accumulation of cells in the G2-M phase. Absence of the Sub-G1 phase in the cell cycle of the treated cells indicated that there was no fragmentation of DNA for the analyzed rime intervals (48 and 72 h treatment). Fluorescent microscopy, after acridine orange/ethidium bromide staining, revealed that the investigated ruthenium complexes induced some characteristics of apoptotic morphology (shrinking and condensation of chromatin) with notably preserved integrity of the plasma membrane. Investigation of cellular uptake and DNA - fraction accumulation performed by inductively coupled plasma mass spectrometry in PANC-1 cells with equimolar concentrations (5 mu M) of 2-4 and cisplatin showed more efficient cellular uptake and DNA- fraction accumulation of complex 3 compared to complexes 2 and 4.},
  articleno    = {110869},
  author       = {Savic, Aleksandar and Gligorijevic, Nevenka and Arandelovic, Sandra and Dojcinovic, Biljana and Kaczmarek, Anna and Radulovic, Sinisa and Van Deun, Rik and Van Hecke, Kristof},
  issn         = {0162-0134},
  journal      = {JOURNAL OF INORGANIC BIOCHEMISTRY},
  title        = {Antitumor activity of organoruthenium complexes with chelate aromatic ligands, derived from 1,10-phenantroline: Synthesis and biological activity},
  url          = {http://dx.doi.org/10.1016/j.jinorgbio.2019.110869},
  volume       = {202},
  year         = {2020},
}

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