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

• Published in: Journal of inorganic biochemistry 2020-01, Vol.202, p.110869-110869, Article 110869
• Main Authors: Savić, Aleksandar, Gligorijević, Nevenka, Aranđelović, Sandra, Dojčinović, Biljana, Kaczmarek, Anna M., Radulović, Siniša, Van Deun, Rik, Van Hecke, Kristof
• Format: Article
• Language: English
• Subjects: 3D cell culture; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Apoptosis; Cell Proliferation; Cisplatin - pharmacology; Coordination Complexes - chemistry; Crystal structure; Cytotoxicity; Drug Screening Assays, Antitumor; Humans; Neoplasms - drug therapy; Neoplasms - pathology; Organometallic Compounds - chemistry; Organoruthenium complexes; Phenanthrolines - chemistry; Ruthenium - chemistry; Tumor Cells, Cultured
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2019.110869

The monocationic chloro complexes containing chelating N∩N ligands: [(η6-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 time 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 μM) of 2–4 and cisplatin showed more efficient cellular uptake and DNA - fraction accumulation of complex 3 compared to complexes 2 and 4. High antitumor activity of new organoruthenium complexes, with IC50 values ranging from 5 to 9 μM in cisplatin resistant cell lines. This study provides important information for further development and investigation of Ru(II)-arene complexes with dipyridophenazine type ligands, as anticancer agents. [Display omitted] •Synthesis, characterization and biological evaluation of organoruthenium complexes•Crystallographic analysis confirms a piano-stool geometry of complexes.•Investigation of antitumor activity on 2D and 3D cell cultures•High cytotoxicity of investigated compounds, even higher than cisplatin