Catalytic organometallic anticancer complexes Dougan, Sarah J; Habtemariam, Abraha; McHale, Sarah E ...
Proceedings of the National Academy of Sciences - PNAS,
08/2008, Letnik:
105, Številka:
33
Journal Article
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Organometallic complexes offer chemistry that is not accessible to purely organic molecules and, hence, potentially new mechanisms of drug action. We show here that the presence of both an iodido ...ligand and a σ-donor/π-acceptor phenylazopyridine ligand confers remarkable inertness toward ligand substitution on the half-sandwich "piano-stool" ruthenium arene complexes (η⁶-arene)Ru(azpy)I⁺ (where arene = p-cymene or biphenyl, and azpy = N,N-dimethylphenyl- or hydroxyphenyl-azopyridine) in aqueous solution. Surprisingly, despite this inertness, these complexes are highly cytotoxic to human ovarian A2780 and human lung A549 cancer cells. Fluorescence-trapping experiments in A549 cells suggest that the cytotoxicity arises from an increase in reactive oxygen species. Redox activity of these azopyridine RuII complexes was confirmed by electrochemical measurements. The first one-electron reduction step (half-wave potential -0.2 to -0.4 V) is assignable to reduction of the azo group of the ligand. In contrast, the unbound azopyridine ligands are not readily reduced. Intriguingly the ruthenium complex acted as a catalyst in reactions with the tripeptide glutathione (γ-L-Glu-L-Cys-Gly), a strong reducing agent present in cells at millimolar concentrations; millimolar amounts of glutathione were oxidized to glutathione disulfide in the presence of micromolar ruthenium concentrations. A redox cycle involving glutathione attack on the azo bond of coordinated azopyridine is proposed. Such ligand-based redox reactions provide new concepts for the design of catalytic drugs.
We have synthesized cis-Ru(bpy)2(NO2-κN)Ln-(n-1) and cis-Ru(bpy)2(NO2-κO)L n-(n-1) (bpy = 2,2′-bipyridine; k = indication of the coordinated center to Ruthenium; L = pyridine type ligand) by reacting ...cis-Ru(bpy)2(H2O)Ln-(n-2) with sodium nitrite or conducting basic cis-Ru(bpy)2NO(Ln-)(n-3) hydrolysis. Photolysis at the metal-ligand charge transfer band (MLCT) of the isomers yielded nitric oxide (NO) as determined by NO measurement. The NO photorelease rates obtained upon 447 nm laser irradiation of the ruthenium complexes showed that cis-Ru(bpy)2(NO2-κO)Ln-(n-1) released NO three times faster than cis-Ru(bpy)2(NO2-κN)Ln-(n-1). We investigated endothelium-dependent vasodilation induced by cis-Ru(bpy)2(4-pic)(NO2-κN)+ and cis-Ru(bpy)2(4-pic)(NO2-κO)+ (4-pic = 4-picoline) in isolated 3 mm aortic rings precontracted with L-phenylephrine. Maximum vasodilation was achieved under 447 nm laser irradiation of 0.5 μMol.L−1 ruthenium complexes for 100 s.
Vasodilation induced by nitric oxide photo-released from nitro ruthenium bipyridine isomers. Display omitted
•Nitro ruthenium-bipyridine complexes photorelease nitric oxide at 447 nm.•Vasodilation activity was achieved by Nitro ruthenium-bipyridine complexes.•Ru-ONO and Ru-NO2 producing different amount of nitric oxide by visible light stimulation.
Photodynamic therapy (PDT) is a noninvasive medical technique that has received increasing attention over the last years and been applied for the treatment of certain types of cancer. However, the ...currently clinically used PDT agents have several limitations, such as low water solubility, poor photostability, and limited selectivity towards cancer cells, aside from having very low two‐photon cross‐sections around 800 nm, which limits their potential use in TP‐PDT. To tackle these drawbacks, three highly positively charged ruthenium(II) polypyridyl complexes were synthesized. These complexes selectively localize in the lysosomes, an ideal localization for PDT purposes. One of these complexes showed an impressive phototoxicity index upon irradiation at 800 nm in 3D HeLa multicellular tumor spheroids and thus holds great promise for applications in two‐photon photodynamic therapy.
Very positive: The title complexes can be used for two‐photon photodynamic therapy (PDT). They selectively accumulate in lysosomes through endocytosis and exhibit high phototoxicity against 2D monolayer cancer cells and 3D multicellular tumor spheroids upon two‐photon laser irradiation.
Ruthenium (Ru) complexes are known for their promising anticancer activity presumably due to octahedral coordination geometry, slow ligand exchange rate, the range of different oxidation states and ...target specificity. This review article summarizes the physicochemical processes which are responsible for the selectivity of Ru complexes toward cancer cells over the normal cells. Emphasis has been given on the activation mechanism of Ru(III) complex administered as a prodrug and then the release of active species in an acidic environment of cancer cell through normal or photo induced hydrolysis or ligand oxidation. This article also elaborates how active Ru complex can be designed by their rate of hydrolysis, kinetics of ligand exchange, pKa of the aquated species. The article further articulates how Ru complexes inhibit tumor growth via multiple events such as transferrin/albumin binding, ROS generation, inhibition of glutathione-S-transferases and kinases and DNA intercalation. Based on the above understanding, examples of various Ru complexes with their in-vitro cell based cytotoxicity and mechanism of action have been described to make this review comprehensive for future Ru based anticancer drug development. In the end, comments have been made on some emerging concepts regarding lack of innertness of Ru(III) complexes vis-à-vis Ru(II) species.
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•Ruthenium coordination complexes as anti-proliferative agent.•Administration of Ru complex in cancer cell preferentially over normal cell.•Prodrug approach, ligand Oxidation, photo irradiation as mode of activation.•Mode of action of Ru complexes as anticancer agents.•Ruthenium anticancer drugs under clinical trial.
In an earlier study of π‐expansive ruthenium complexes for photodynamic and photochemo‐therapies, it was shown that a pair of structural isomers differing only in the connection point of a ...naphthalene residue exhibited vastly different biological activity. These isomers are further explored in this paper through the activity of their functionalized derivatives. In normoxia, the inactive 2‐NIP isomer (5) can be made as photocytotoxic as the active 1‐NIP isomer (1) by functionalizing with methyl or methoxy groups, while methoxy variants of the 1‐NIP isomer became inactive. In all cases, the singlet oxygen sensitization quantum yield was below 1%. Hypoxic photocytotoxicity was attenuated, with only three of the series showing any activity, notwithstanding the photodissociative ligands. The results here are consistent with the earlier findings in that seemingly minor structural modifications on the non‐strained ligand can dramatically modulate the normoxic and hypoxic activity of these strained compounds and that these changes appear to exert a greater influence on photocytotoxicity than singlet oxygen sensitization or rates of photosubstitution in cell‐free conditions would suggest.
Light activation of the photolabile complex leads to stark contrast in photobiological activity ‐ based on the R‐group's orientation and functionalization.
The reaction of the Ru(PPh3)3Cl2 with HL1−3−OH (−OH stands for the oxime hydroxyl group; HL1−OH=diacetylmonoxime‐S‐benzyldithiocarbazonate; ...HL2−OH=diacetylmonoxime‐S‐(4‐methyl)benzyldithiocarbazonate; and HL3−OH=diacetylmonoxime‐S‐(4‐chloro)benzyl‐dithiocarbazonate) gives three new ruthenium complexes RuII(L1−3−H)(PPh3)2Cl (1–3) (−H stands for imine hydrogen) coordinated with dithiocarbazate imine as the final products. All ruthenium(II) complexes (1–3) have been characterized by elemental (CHNS) analyses, IR, UV‐vis, NMR (1H, 13C, and 31P) spectroscopy, HR‐ESI‐MS spectrometry and also, the structure of 1–2 was further confirmed by single crystal X‐ray crystallography. The solution/aqueous stability, hydrophobicity, DNA interactions, and cell viability studies of 1–3 against HeLa, HT‐29, and NIH‐3T3 cell lines were performed. Cell viability results suggested 3 being the most cytotoxic of the series with IC50 6.9±0.2 μM against HeLa cells. Further, an apoptotic mechanism of cell death was confirmed by cell cycle analysis and Annexin V‐FITC/PI double staining techniques. In this regard, the live cell confocal microscopy results revealed that compounds primarily target the mitochondria against HeLa, and HT‐29 cell lines. Moreover, these ruthenium complexes elevate the ROS level by inducing mitochondria targeting apoptotic cell death.
Synthesis, characterization, ruthenium‐assisted oxime to imine transformation, solution/aqueous phase stability, hydrophobicity, DNA interaction, and cytotoxicity studies (cellular localization, and apoptosis) of three new ruthenium(II)‐dithiocarbazate complexes are documented. This report reveals the detailed study of Ru(II) complexes as effective anticancer agents by inducing a mitochondrial‐targeted apoptotic mode of cell death in human cancer cells.
Two novel ruthenium-nitrosyl complexes were prepared and investigated towards photoinduced NO release and metal–metal electronic communication.
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•Photo-release of chloride is major ...upon irradiation of RuLANO at 377 nm.•Strong stabilization of Rucentral dxy, dxz, and dyz in Ru3LBNO.•High MLCT Ru → NO+ energy accounts for Ru3LBNO photo-inactivity.•Electrochemistry supports no relevant electronic communication in Ru3LBNO.
Polymetallated-2,2′-bipyridine–ruthenium(II) complexes exhibit photosensitization properties and can enhance optically induced NO release, thus modeling multi-site catalysts. Two novel ruthenium-nitrosyl complexes RuCl2LA(NO)PF6 (herein called RuLANO, LA = 2,6-bis(aniline)methyl-pyridine) and RuCl2(NO)({Ru(bpy)2}2-μ-LB)(PF6)5 (herein called Ru3LBNO, LB = 2,6-bis(1,10-phenantroline-5-amine)methyl-pyridine) were prepared and structurally characterized (1H-, 13C-, DEPT-135 NMR, FTIR, UV–Vis, elemental analysis, ESI-HRMS, and single crystal x-ray diffraction). RuLANO showed a trans configuration of the chloride ligands, and photo-release of chloride is the major process upon irradiation of RuLANO at 377 nm, along with some NO dissociation to a small extent. In contrast, the trinuclear ruthenium complex Ru3LBNO was found to be photo-inactive with irradiation between 377 and 447 nm (region of absorption of the {Ru(bpy)2(phen)}2+ chromophore) in the same conditions of RuLANO. This result agrees with the strong stabilization of Rucentral dxy, dxz, and dyz orbitals as shown by calculations using density functional theory (DFT), as well as with the electrochemical response, which supports that there is no major electronic communication between the central and the peripherals ruthenium ions in the trinuclear complex.
The development of highly active and stable bifunctional noble‐metal‐based electrocatalysts for the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER) is a crucial goal for ...clean and renewable energy, which still remains challenging. Herein, we report an efficient and stable catalyst comprising a Co single atom incorporated in an RuO2 sphere for HER and OER, in which the Co single atom in the RuO2 sphere was confirmed by XAS, AC‐STEM, and DFT. This tailoring strategy uses a Co single atom to modify the electronic structures of the surrounding Ru atoms and thereby remarkably elevates the electrocatalytic activities. The catalyst requires ultralow overpotentials, 45 mV for HER and 200 mV for OER, to deliver a current density of 10 mA cm−2. The theoretical calculations reveal that the energy barriers for HER and OER are lowered after incorporation of a cobalt single atom.
A Co single atom is incorporated in a RuO2 sphere through a one‐pot hydrothermal process, as revealed by EXAFS, HRTEM, and AC‐STEM. The Co single atoms could tailor the local electronic structure of the bifunctional electrocatalyst for high‐performance HER and OER, which significantly reduces the energy barrier, and the catalyst shows the lowest overpotential of 45 mV for HER and 200 mV for OER at a current density of 10 mA cm−2.
Die weite Verbreitung von C‐Arylglykosiden in biologisch aktiven Naturstoffen und zugelassenen Arzneimitteln hat seit langem zur Entwicklung effizienter Strategien für ihre selektive Synthese ...motiviert. Kreuzkupplungen wurden häufig verwendet, waren aber größtenteils auf Palladiumkatalysatoren und vorfunktionalisierten Substraten angewiesen, während sich die Ruthenium‐katalysierte Herstellung von C‐Arylglykosiden bisher als schwer zugänglich erwiesen hat. Wir stellen hier eine vielseitige Ruthenium(II)‐katalysierte meta‐C−H‐Glykosylierung vor, um meta‐C‐Arylglykoside aus leicht verfügbaren Glykosylhalogenid‐Donoren zu gewinnen. Die Robustheit der Ruthenium‐Katalyse zeigte sich in milden Reaktionsbedingungen, hervorragender anomerer Selektivität und ausschließlicher meta‐Selektivität.
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