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Ruthenium(II) trisdiimine complexes of the formula, [Ru(dip) n (L-L) 3-n ] 2+ , where n=0-3; dip=4,7-diphenyl-1,10-phenanthroline; L-L=2,2'-bipyridine (bpy) or 1,10-phenanthroline (phen) were prepared and tested for cytotoxicity in two cell lines (H358, MCF7). Cellular uptake and subcellular localization were determined by harvesting treated cells and determining the ruthenium concentration in whole or fractionated cells (cytosolic, nuclear, mitochondrial/ ER/Golgi, and cytoskeletal proteins) by Ru ICP-MS. The logP values for the chloride salts of these complexes were measured and the data were analyzed to determine the role of lipophilicity versus structure in the various biological assays. Cellular uptake increased with lipophilicity but shows the biggest jump when the complex contains two or more dip ligands. Significantly, preferential cytoskeletal localization is also correlated with increased cytotoxicity. All of the RPCs promote tubulin polymerization in vitro, but [Ru(dip) 2 phen] 2+ and [Ru(dip) 3 ] 2+ show the strongest activity. Analysis of the pellet formed by centrifugation of MTs formed in the presence of [Ru(dip) 2 phen] 2+ establish a binding stoichiometry of one RPC per tubulin heterodimer. Complexes of the general formula [Ru(dip) 2 (L-L)] 2+ possess the necessary characteristics to target the cytoskeleton in live cells and increase cytotoxicity, however the nature of the L-L ligand does influence the extent of the effect., (© 2023 Wiley-VCH GmbH.)

Four mononuclear [(L-L) 2 Ru(tatpp)] 2+ and two dinuclear [(L-L) 2 Ru(tatpp)Ru(L-L) 2 ] 4+ ruthenium(II) polypyridyl complexes (RPCs) containing the 9,11,20,22-tetraazatetrapyrido[3,2-a:2',3'-c:3'',2''-l:2''',3'''-n]pentacene (tatpp) ligand were synthesized, in which L-L is a chelating diamine ligand such as 2,2'-bipyridine (bpy), 1,10-phenanthroline (phen), 3,4,7,8-tetramethyl-1,10-phenanthroline (Me 4 phen) or 4,7-diphenyl-1,10-phenanthroline (Ph 2 phen). These Ru-tatpp analogues all undergo reduction reactions with modest reducing agents, such as glutathione (GSH), at pH 7. These, plus several structurally related but non-redox-active RPCs, were screened for DNA cleavage activity, cytotoxicity, acetylcholinesterase (AChE) inhibition, and acute mouse toxicity, and their activities were examined with respect to redox activity and lipophilicity. All of the redox-active RPCs show single-strand DNA cleavage in the presence of GSH, whereas none of the non-redox-active RPCs do. Low-micromolar cytotoxicity (IC 50 ) against malignant H358, CCL228, and MCF7 cultured cell lines was mainly restricted to the redox-active RPCs; however, they were substantially less toxic toward nonmalignant MCF10 cells. The IC 50 values for AChE inhibition in cell-free assays and the acute toxicity of RPCs in mice revealed that whereas most RPCs show potent inhibitory action against AChE (IC 50 values <15 μm), Ru-tatpp complexes as a class are surprisingly well tolerated in animals relative to other RPCs., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)