Ruthenium(II)-Polypyridyl Compounds with π-Extended Nitrogen Donor Ligands Induce Apoptosis in Human Lung Adenocarcinoma (A549) Cells by Triggering Caspase-3/7 Pathway

作者：Bruno Peña, Sayan Saha, Rola Barhoumi, Robert C. Burghardt, Kim R. Dunbar · 发表于：Inorganic Chemistry · 年份：2018 · DOI：10.1021/acs.inorgchem.8b01988 · 被引用次数：25 · 研究领域：Metal complexes synthesis and properties、Ferrocene Chemistry and Applications、Synthesis and Characterization of Heterocyclic Compounds

Ru(II)-polypyridyl complexes exhibit antitumor properties that can be systematically tailored by means of adjusting the ligand environment. In this work, the effect of incorporating π-extended moieties into anionic N ∧ O – based chelating ligands on the cytotoxic properties of Ru compounds is explored. Four new Ru(II) complexes, [Ru(bpy) 2 (dphol)][PF 6 ] ( 1; bpy = 2,2′-bipyridine, dphol = dibenzo[ a, c ]phenazin-10-olate), [Ru(phen) 2 (dphol)][PF 6 ] ( 2; phen = 1,10-phenanthroline), [Ru(bpy) 2 (hbtz)][PF 6 ] ( 3; hbtz = 2-(benzo[ d ]thiazol-2-yl)phenolate), and [Ru(phen) 2 (hbtz)][PF 6 ] ( 4 ) were synthesized and thoroughly characterized. In vitro cytotoxicity was investigated in human lung adenocarcinoma (A549) cells, which revealed that 4 is the most cytotoxic compound (IC 50 = 0.8 μM) in the series including a control compound [Ru(bpy) 2 (quo)][PF 6 ] ( 5; quo = 8-hydroxyquinolinate) and is nearly 8-fold more cytotoxic than cisplatin. An investigation of the mechanism of cell death led to the finding that compounds 1 – 4 disrupt the mitochondrial transmembrane potential (ΔΨ m ) in a concentration-dependent fashion, which is an event associated with the intrinsic pathway of apoptosis. Moreover, compound 4 triggers the activity of caspase-3/7, which eventually induces the apoptotic cellular death of A549 cells. Thus, increasing the overall lipophilicity of the Ru compounds by introducing π-extended moieties in the anionic N ∧ O – ligand is a successful strategy for reali...