Antitumor activity of organoruthenium complexes with chelate aromatic ligands, derived from 1,10-phenantroline: Synthesis and biological activity
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Kaczmarek, Anna M.
Van Deun, Rik
Van Hecke, Kristof
Article (Published version)
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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.
Keywords:3D cell culture / Crystal structure / Cytotoxicity / Organoruthenium complexes
Source:Journal of Inorganic Biochemistry, 2020, 202, 110869-
- Erasmus Mundus Basileus V project
- Hercules Foundation (project AUGE/11/029 “3D-SPACE: 3D Structural Platform Aiming for Chemical Excellence”)
- Special Research Fund (BOF) – UGent (project 01N03217)
- Rational design and synthesis of biologically active and coordination compounds and functional materials, relevant for (bio)nanotechnology (RS-172035)
- Pharmacodynamic and pharmacogenomic research of new drugs in the treatment of solid tumors (RS-41026)