Ruthenium− and Osmium−Arene Complexes of 2-Substituted Indolo[3,2-<i>c</i>]quinolines: Synthesis, Structure, Spectroscopic Properties, and Antiproliferative Activity

Filak, Lukas K.; Mühlgassner, Gerhard; Bacher, Felix; Roller, Alexander; Galanski, Markus; Jakupec, Michael A.; Keppler, Bernhard K.; Arion, Vladimir B.

doi:10.1021/om101004z

Cited by 54 publications

(53 citation statements)

References 44 publications

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“…The 1D and 2D NMR spectra showed chemical shifts typical for this class of compounds, 23,27−29 in particular, the rather upfield-shifted resonances for carbon atom C 6a (for the atom numbering scheme used for the assignment of resonances see Supporting Information, Scheme S1) at approximately 106–107 ppm. Although a weak resonance for quaternary carbon atom C 6 could be seen in complexes [ 1a ]Cl and [ 1b ]Cl, this was not detected in the remaining four metal complexes.…”

Section: Resultsmentioning

confidence: 99%

Effect of the Piperazine Unit and Metal-Binding Site Position on the Solubility and Anti-Proliferative Activity of Ruthenium(II)- and Osmium(II)- Arene Complexes of Isomeric Indolo[3,2-c]quinoline—Piperazine Hybrids

et al. 2014

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In this study, the indoloquinoline backbone and piperazine were combined to prepare indoloquinoline–piperazine hybrids and their ruthenium- and osmium-arene complexes in an effort to generate novel antitumor agents with improved aqueous solubility. In addition, the position of the metal-binding unit was varied, and the effect of these structural alterations on the aqueous solubility and antiproliferative activity of their ruthenium- and osmium-arene complexes was studied. The indoloquinoline–piperazine hybrids L1–3 were prepared in situ and isolated as six ruthenium and osmium complexes [(η6-p-cymene)M(L1–3)Cl]Cl, where L1 = 6-(4-methylpiperazin-1-yl)-N-(pyridin-2-yl-methylene)-11H-indolo[3,2-c]quinolin-2-N-amine, M = Ru ([1a]Cl), Os ([1b]Cl), L2 = 6-(4-methylpiperazin-1-yl)-N-(pyridin-2-yl-methylene)-11H-indolo[3,2-c]quinolin-4-N-amine, M = Ru ([2a]Cl), Os ([2b]Cl), L3 = 6-(4-methylpiperazin-1-yl)-N-(pyridin-2-yl-methylene)-11H-indolo[3,2-c]quinolin-8-N-amine, M = Ru ([3a]Cl), Os ([3b]Cl). The compounds were characterized by elemental analysis, one- and two-dimensional NMR spectroscopy, ESI mass spectrometry, IR and UV–vis spectroscopy, and single-crystal X-ray diffraction. The antiproliferative activity of the isomeric ruthenium and osmium complexes [1a,b]Cl–[3a,b]Cl was examined in vitro and showed the importance of the position of the metal-binding site for their cytotoxicity. Those complexes containing the metal-binding site located at the position 4 of the indoloquinoline scaffold ([2a]Cl and [2b]Cl) demonstrated the most potent antiproliferative activity. The results provide important insight into the structure–activity relationships of ruthenium- and osmium-arene complexes with indoloquinoline–piperazine hybrid ligands. These studies can be further utilized for the design and development of more potent chemotherapeutic agents.

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Section: Resultsmentioning

confidence: 99%

Effect of the Piperazine Unit and Metal-Binding Site Position on the Solubility and Anti-Proliferative Activity of Ruthenium(II)- and Osmium(II)- Arene Complexes of Isomeric Indolo[3,2-c]quinoline—Piperazine Hybrids

et al. 2014

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“…10 However, significantly less is known about the corresponding osmium complexes with the [Os II (g 6 -arene)] entity. Half-sandwich osmium(II) compounds with (N,N) [11][12][13][14] (N,O) 15,16 or (O,O) 11,17 chelating ligands have been synthesized and tested against different cancer cell lines. In particular, acetylacetonato 11 or maltolato 17 containing complexes, [Os(g 6 -p-cym)(O,O)Cl], were found to be capable of fast ligand exchange in aqueous solution, resulting in the formation of an inactive hydroxo species at physiological pH.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and X-ray diffraction structures of novel half-sandwich Os(ii)-and Ru(ii)-hydroxamate complexes

et al. 2012

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Novel water soluble half-sandwich complexes of the general formulae [M(g 6 -p-cym)(ha)] 2 (CF 3 SO 3 ) 2 , [M(g 6 -p-cym)(ha)Cl] or [M(g 6 -p-cym)(ha)(py)]X (M = Os, Ru; ha = hydroxamate; py = pyridine; X = Cl 2 or CF 3 SO 3 2 ), incorporating metal-containing entities and hydroxamates both with potential anti-proliferative features, were prepared and characterized by elemental analysis, spectroscopy (NMR, IR) and ESI mass spectrometry. The X-ray crystal structure of (17) occurs, and the crystal and molecular structure has been determined by X-ray method. Complexes 1, 5-8, 10 and 14 were tested for their in vitro cytotoxicity, using human-derived ovarian cancer cell lines (A2780 and A2780 cisR), and showed no anti-proliferative effect in the concentration range (0-200 mM) studied.

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“…2,3 For example, Jaouen et al have designed ferricenium complexes which target hormone receptors in breast cancer cells, 4 certain Ru II arene complexes are active in vitro and in vivo, [5][6][7] , 8 and a few reports of anticancer active organometallic osmium complexes have recently appeared. [9][10][11][12][13][14][15] Osmium complexes are often considered to be relatively inert (a common characteristic of low-spin d 6 metal ions and especially 3 rd row transition metals). 16,17 Organometallic Os II and Ru II arene complexes can adopt very similar threedimensional structures.…”

Section: Introductionmentioning

confidence: 99%

Structure–activity relationships for organometallic osmium arene phenylazopyridine complexes with potent anticancer activity

Habtemariam

Basri

et al. 2011

Dalton Trans.

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We report the synthesis and characterisation of 32 half sandwich phenylazopyridine Os II arene complexes [Os(h 6 -arene)(phenylazopyridine)X] + in which X is chloride or iodide, the arene is p-cymene or biphenyl and the pyridine and phenyl rings contain a variety of substituents (F, Cl, Br, I, CF 3 , OH or NO 2 ). Ten X-ray crystal structures have been determined. Cytotoxicity towards A2780 human ovarian cancer cells ranges from high potency at nanomolar concentrations to inactivity. In general the introduction of an electron-withdrawing group (e.g. F, Cl, Br or I) at specific positions on the pyridine ring significantly increases cytotoxic activity and aqueous solubility. Changing the arene from p-cymene to biphenyl and the monodentate ligand X from chloride to iodide also increases the activity significantly. Activation by hydrolysis and DNA binding appears not to be the major mechanism of action since both the highly active complex [Os(h 6 -bip)(2-F-azpy)I]PF 6 (9) and the moderately active complex [Os(h 6 -bip)(3-Cl-azpy)I]PF 6 ( 23) are very stable and inert towards aquation. Studies of octanol-water partition coefficients (log P) and subcellular distributions of osmium in A2780 human ovarian cancer cells suggested that cell uptake and targeting to cellular organelles play important roles in determining activity. Although complex 9 induced the production of reactive oxygen species (ROS) in A2780 cells, the ROS level did not appear to play a role in the mechanism of anticancer activity. This class of organometallic osmium complexes has new and unusual features worthy of further exploration for the design of novel anticancer drugs.

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Ruthenium− and Osmium−Arene Complexes of 2-Substituted Indolo[3,2-c]quinolines: Synthesis, Structure, Spectroscopic Properties, and Antiproliferative Activity

Cited by 54 publications

References 44 publications

Effect of the Piperazine Unit and Metal-Binding Site Position on the Solubility and Anti-Proliferative Activity of Ruthenium(II)- and Osmium(II)- Arene Complexes of Isomeric Indolo[3,2-c]quinoline—Piperazine Hybrids

Effect of the Piperazine Unit and Metal-Binding Site Position on the Solubility and Anti-Proliferative Activity of Ruthenium(II)- and Osmium(II)- Arene Complexes of Isomeric Indolo[3,2-c]quinoline—Piperazine Hybrids

Synthesis and X-ray diffraction structures of novel half-sandwich Os(ii)-and Ru(ii)-hydroxamate complexes

Structure–activity relationships for organometallic osmium arene phenylazopyridine complexes with potent anticancer activity

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