Ruthenium(II)-Polypyridyl Compounds with -Extended Nitrogen Donor Ligands Induce Apoptosis in Human Lung Adenocarcinoma (A549) Cells by Triggering Caspase-3/7 Pathway.
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abstract
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 -extended moieties into anionic NO- based chelating ligands on the cytotoxic properties of Ru compounds is explored. Four new Ru(II) complexes, [Ru(bpy)2(dphol)][PF6] (1; bpy = 2,2'-bipyridine, dphol = dibenzo[ a, c]phenazin-10-olate), [Ru(phen)2(dphol)][PF6] (2; phen = 1,10-phenanthroline), [Ru(bpy)2(hbtz)][PF6] (3; hbtz = 2-(benzo[ d]thiazol-2-yl)phenolate), and [Ru(phen)2(hbtz)][PF6] (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 (IC50 = 0.8 M) in the series including a control compound [Ru(bpy)2(quo)][PF6] (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 (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 -extended moieties in the anionic NO- ligand is a successful strategy for realizing a new family of pro-apoptotic compounds with a [RuIIN5O]+ coordination environment.
