📚 BiometalDB

Polypyridine Ru(II) complexes have long been deemed to excellent antitumor agents that inhibit the proliferation of breast cancer cells. Nevertheless, their effects on the metastatic potency of breast cancer cells need further research. Herein, a class of polypyridine Ru(II) complexes coordinated with phenazine derivates (DPPZ) ([Ru(bpy)₂(DPPZ-R)](ClO₄)₂, Ru(bpy) ₂ DPPZ: R = -H, Ru(bpy) ₂ BrDPPZ: R = -Br, Ru(bpy) ₂ MDPPZ: R = -CH₃, Ru(bpy)2BnDPPZ: R = -acene, Ru(bpy) ₂ BEDPPZ: R = -C ≡ C(C₆H₅)) was synthesized by introducing different substituent groups to regulate the electron cloud density and planarity of the main ligands. Results indicated that this class of DPPZ-based Ru(II) complexes exhibited promising inhibitory effect against MDA-MB-231 triple-negative breast cancer cells, especially for Ru(bpy) ₂ BEDPPZ, which is comparable with that of cisplatin. In addition, Ru(bpy) ₂ BEDPPZ effectively inhibited the migration and invasion of MDA-MB-231 cells in vitro and suppressed focal adhesion and stress fiber formation. Moreover, it effectively blocked MDA-MB-231 cell metastasis in blood vessels and restrained angiogenesis formation in a zebrafish xenograft breast cancer model. Further studies showed that the mechanisms may involve DNA damage-mediated apoptosis probably due to Ru(bpy) ₂ BEDPPZ, which was enriched in the cell nucleus and induced DNA damage. All these results suggested that the DPPZ-based Ru(II) complexes can act as potent anti-metastasis agents. Show less

Three new compounds have been synthesized and completely characterized by analytical and spectroscopic techniques. The new bipyridine-perfluorinated ligand L1 and the new organometallic complex [Ru(η⁵-MeCp)(PPh₃)₂Cl] (Ru1) crystalize in the centrosymmetric triclinic space group P1¯. Analysis of the phenotypic effects induced by both organometallic complexes Ru1 and [Ru(η⁵-MeCp)(PPh₃)(L1)][CF₃SO₃] (Ru2), on human colorectal cancer cells (SW480 and RKO) survival, showed that Ru2 has a potent anti-proliferative activity, 4-6 times higher than cisplatin, and induce apoptosis in these cells. Data obtained in a noncancerous cell line derived from normal colon epithelial cells (NCM460) revealed an intrinsic selectivity of Ru2 for malignant cells at low concentrations, showing the high potential of this compound as a selective anticancer agent. Show less

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)][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 μM) 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 (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 realizing a new family of pro-apoptotic compounds with a [Ru^IIN₅O]⁺ coordination environment. Show less

Emergence of resistance in cancer cells and dose-limiting side effects severely limit the widespread use of platinum (Pt) anticancer drugs. Multi-action hybrid anticancer agents that are constructed by merging two or more pharmacophores offer the prospect of circumventing issues of Pt drugs. Herein, we report the design, synthesis, and in-depth biological evaluation of a ruthenium-ferrocene (Ru-Fc) bimetallic agent [(η⁶-p-cymene)Ru(1,1,1-trifluoro-4-oxo-4-ferrocenyl-but-2-en-2-olate)Cl] and its five analogues. Along with aquation/anation chemistry, we evaluated the in vitro antitumor potency, Pt cross-resistance profile, and in vivo antiangiogenic properties. A structure activity analysis was performed to understand the impact of Fc, CF₃, and p-cymene groups on the anticancer potency of the Ru-Fc hybrid. Finally, in addition to assessing cellular uptake and intracellular distribution, we demonstrated that the Ru-Fc hybrid binds to nucleophilic biomolecules and produces reactive oxygen species, which causes mitochondrial dysfunction and induces ER stress, leading to poly(ADP-ribose) polymerase-mediated necroptotic cell death. Show less

In the present study, the interaction between GC-rich sequence of bcl-2 gene P1 promoter (Pu39) and two ruthenium (II) polypyridyl complexes, [Ru(bpy)₂(tip)]²⁺ (1) and [Ru(phen)₂(tip)]²⁺ (2), was investigated by UV-Visible, fluorescence spectroscopy, circular dichroism, fluorescence resonance energy transfer melting assay and polymerase chain reaction stop assay. Those experimental results indicated that the two complexes can effectively stabilize the G-quadruplex of Pu39. It was found that the complex 2 exhibited greater cytotoxic activity than 1 against human Hela cells and can enter into Hela cells in a short period of time to effectively induce apoptosis of cells. Further experiments found that complexes 1 and 2 had as potent inhibitory effects on ECV-304 cell migration as suramin. Those noteworthy results provide new insights into the development of anticancer agents for targeting G-quadruplex DNA. Show less

A library of new bis-picolinamide ruthenium(III) dihalide complexes of the type [RuX₂ L₂ ] (X=Cl or I, L=picolinamide) have been synthesised and characterised. The complexes exhibit different picolinamide ligand binding modes, whereby one ligand is bound (N,N) and the other bound (N,O). Structural studies revealed a mixture of cis and trans isomers for the [RuCl₂ L₂ ] complexes but upon a halide exchange reaction to yield [RuI₂ L₂ ], only single trans isomers were detected. High cytotoxic activity against human cancer cell lines was observed, with the potencies of some complexes similar to or better than cisplatin. The conversion to [RuI₂ L₂ ] substantially increased the activity towards cancer cell lines by more than twelvefold. The [RuI₂ L₂ ] complexes displayed potent activity against the A2780cis (cisplatin-resistant human ovarian cancer) cell line, with a more than fourfold higher potency than cisplatin. Equitoxic activity was observed against normoxic and hypoxic cancer cells, which indicates the potential to eradicate both the hypoxic and aerobic fractions of solid tumours with similar efficiency. The activity of selected complexes against non-cancer ARPE-19 cells was also tested. The [RuI₂ L₂ ] complexes were found to be more potent than the [RuCl₂ L₂ ] analogues and also more selective towards cancer cells with a selectivity factor in excess of sevenfold. Show less

A series of ruthenium(II) polypyridyl complexes were synthesized and evaluated for their in vitro anticancer activities. The results showed that ruthenium polypyridyl complexes, especially [Ru(bpy)2 (p-tFPIP)](2+) (2 a; bpy=bipyridine, tFPIP=2-(2-trifluoromethane phenyl)imidazole[4,5-f][1,10]phenanthroline), exhibited novel anticancer activity against human cancer cell lines, but with less toxicity to a human normal cell line. The results of flow cytometry and caspase activities analysis indicated that the 2 a-induced growth inhibition against MG-63 osteosarcoma cells was mainly caused by mitochondria-mediated apoptosis. DNA fragmentation and nuclear condensation as detected by TUNEL-DAPI co-staining further confirmed 2 a-induced apoptotic cell death. Further, fluorescence imaging revealed that ruthenium(II) polypyridyl complexes could target mitochondria to induce mitochondrial fragmentation, accompanied by depletion of mitochondrial membrane potential. Taken together, these findings suggest a potential application of theses ruthenium(II) complexes in the treatment of cancers. Show less

Two ruthenium(II) complexes (Ru-complexes) were synthesized and characterized in this study. The selectivity and ability of the complexes to interact with bcl-2 DNA were investigated here. It turned out that [Ru(ip)3](ClO4)2·2H2O (complex 1, ip = 1H-iminazole [4,5-f][1,10] phenanthroline) could induce and stabilize the formations of G-quadruplexes more effectively than [Ru(pip)3](ClO4)2·2H2O (complex 2, pip = 2-phenylimidazo-[4,5-f][1,10]phenanthroline) did. Considering the important role of the Ru-complex ligand in inducing and stabilizing the formations of G-quadruplex in our previous studies, we speculate that the overlarge ligand of complex 2 may block its binding affinity for G-quadruplexes. Complex 1 also induced cell apoptosis in in vitro assays. In general, this study provided potentially important information for further development of the Ru-complexes as good inducers and stabilizers of bcl-2 G-quadruplex DNA for cancer treatment. Show less

The chemical structures of Ru (II) complexes are known to affect their cellular behavior and toxicity. In this study, three new luminescent Ru (II) complexes, [Ru(bpy)₂(HIPMP)](ClO₄)₂ (Ru1, bpy = 2,2'-bipyridine, HIPMP = 2-(1H-imidazo-[4,5-f] [1,10] phenanthrolin-2-yl)-4-methylphenol), [Ru(phen)₂(HIPMP)](ClO₄)₂ (Ru2, phen = 1,10-phenanthroline), [Ru(dmb)₂(HIPMP)](ClO₄)₂ (Ru3, dmb = 4,4'-dimethyl-2,2'-bipyridine), were synthesized, and their anticancer activities were examined. All three complexes displayed anticancer activities against various cancer cells, with Ru2 exhibiting the highest cytotoxic activities. Ru2 was shown to accumulate specifically in the endoplasmic reticulum (ER) and induce ER stress-mediated apoptosis. In addition, Ru2 could generate reactive oxygen species (ROS) and trigger mitochondrial membrane potential depolarization. These results demonstrated that Ru2 induced apoptosis in HeLa cells through ER stress and ROS production. Show less

The light-protected reaction of [(eta(6)-p-cymene)Ru(II)Cl(2)](2) with 1-(2-hydroxyethyl)piperazine in dry methanol, followed by addition of excess NH(4)PF(6), afforded the complex [(eta(6)-p-cymene)Ru(II)(NH(3))(2)Cl](PF(6)) () in 47% yield. Attempts to use the same protocol for the synthesis of [(eta(6)-p-cymene)Os(II)(NH(3))(2)Cl](PF(6)) led to the isolation of the binuclear triply methoxido-bridged arene-osmium compound [{(eta(6)-p-cymene)Os}(2)(mu-OCH(3))(3)](PF(6)) (). Both compounds were characterised by X-ray crystallography and (1)H NMR spectroscopy, and the ruthenium complex also by spectroscopic techniques (IR and UV-vis spectroscopies). The antiproliferative activity of complex in vitro was studied in A549 (non-small cell lung carcinoma), CH1 (ovarian carcinoma), and SW480 (colon carcinoma) cells and compared to that of [(eta(6)-p-cymene)Ru(II)(en)Cl](PF(6)) (). In contrast to the latter compound, is only modestly cytotoxic in all three cell lines (IC(50): 293-542 muM), probably due to the instability of the diammine ruthenium complex in aqueous solution. Show less

The rapid and modular synthesis of the aminophosphine core has been exploited as a tool for rapid development of antitumoral metallodrug candidates. Starting with a series of structurally diverse aminophosphines, all obtained in a single step from commercial amines, a family of Ru(ii)-cymene complexes have been generated and tested in vitro for anti-tumoral activity in a series of cell lines, including the platinum-resistant A2780R. Through this approach, Ru(ii)-aminophosphine complexes have been identified with the IC₅₀ value range as low as 10-0.8 μM. Several biological assays were carried out to gain insight into the mechanism of action. Cell death by apoptosis and pH-independent action has been demonstrated. In addition, a selective cytotoxicity profile for tumoral cells over non-tumoral cells has been identified. Importantly, for the key candidates no loss of activity was observed when applied to the Pt-resistant A2780R, which highlights the potential utility of the bis-phospinoamine scaffold as an easily-tunable auxiliary ligand core in both drug discovery and subsequently a logical design of new anticancer metal-containing drugs. The complexes are characterised by NMR spectroscopy, mass spectrometry and single-crystal X-ray diffraction. Show less

In this work, we aimed to understand the biological activity and the mechanism of action of three polymer-'ruthenium-cyclopentadienyl' conjugates (RuPMC) and a low molecular weight parental compound (Ru1) in cancer cells. Several biological assays were performed in ovarian (A2780) and breast (MCF7, MDA-MB-231) human cancer derived cell lines as well as in A2780cis, a cisplatin resistant cancer cell line. Our results show that all compounds have high activity towards cancer cells with low IC₅₀ values in the micromolar range. We observed that all Ru-PMC compounds are mainly found inside the cells, in contrast with the parental low molecular weight compound Ru1 that was mainly found at the membrane. All compounds induced mitochondrial alterations. PMC3 and Ru1 caused F-actin cytoskeleton morphology changes and reduced the clonogenic ability of the cells. The conjugate PMC3 induced apoptosis at low concentrations comparing to cisplatin and could overcame the platinum resistance of A2780cis cancer cells. A proteomic analysis showed that these compounds induce alterations in several cellular proteins which are related to the phenotypic disorders induced by them. Our results suggest that PMC3 is foreseen as a lead candidate to future studies and acting through a different mechanism of action than cisplatin. Here we established the potential of these Ru compounds as new metallodrugs for cancer chemotherapy. Show less

The first examples of Ru^II and Rh^III piano-stool complex histone deacetylase (HDAC) inhibitors are presented. The novel complexes have antiproliferative activity against H460 non-small-cell lung carcinoma cells that is comparable to the clinically used HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). Strong evidence for HDAC inhibition as a primary mechanism of action is provided. The complexes reported here represent an important step towards the design of highly active and selective HDAC inhibitors. Show less

Four related ruthenium(III) complexes, with the formula mer-[RuCl(3)(dmso)(N-N)] (dmso=dimethyl sulfoxide; N-N=2,2'-bipyridine (1), 1,10-phenantroline (2), dipyrido[3,2-f:2',3'-h]quinoxaline (3) and dipyrido[3,2-a:2',3'-c]phenazine (4)), have been reported. Complexes 3 and 4 are newly synthesized and characterized by X-ray diffraction. The hydrolysis process of 1-4 has been studied by UV-vis measurement, and it has been found that the extension of the N-N ligands can increase the stability of the complexes. The binding of these complexes with DNA has been investigated by plasmid cleavage assay, competitive binding with ethidium bromide (EB), DNA melting experiments and viscosity measurements. The DNA binding affinity is increased with the extension of the planar area of the N-N ligands, and complex 4 shows an intercalative mode of interaction with DNA. The in vitro anticancer activities of these compounds are moderate on the five human cancer cell lines screened. Show less

The six mononuclear Schiff's base Ru(III) complexes viz., [Ru(BZP)(LA)₂].2NO₃ (MRA), [Ru(BZP)(LB)₂].2NO₃ (MRB), [Ru(BZP))(LC)₂].2NO₃ (MRC), [Ru(BZP))(LD)₂].2NO₃ (MRD), [Ru(BZP)(LE)₂].2NO₃ (MRE) and [Ru(BZP)(LF)₂].2NO₃ (MRF), were synthesized using of (BZP=2,6-bis(2-benzimidazolyl)pyridine and p-sub-benzylthiosemicarbazones (BTS) [(Sub=4-NO₂ (LA), 4-N(CH₃)₂ (LB), 4-Cl (LC), 4-OCH₃ (LD), 4-OCH₂Ph (LE), and 4-OH (LF)] as an ancillary ligands. The thiosemicarbazones ligands (LA-LF) were obtained by the condensation of p-substituted benzaldehyde and thiosemicarbazide. These complexes were characterized by elemental analysis, IR, ESR, ESI-MS, electronic absorption spectroscopy. The geometry was optimized by theoretical calculation using DFT and structure reveals that MRA-MRF adopt octahedral geometry. Further, the complexes were examined for anti-cancer against Leukemia cancer cell line K562 and shown significant responses to these cells. Moreover, DNA binding studies were conducted with all complexes MRA-MRF and the binding constant (K_b) were found i.e., 1.10×10⁴, 1.54×10⁴, 2.87×10⁴, 1.67×10⁴, 1.98×10⁴ and 1.59×10⁴, respectively. It was found that DNA binds in intercalation mode which is also validated by the docking studies. Show less

TLDR: These complexes can inhibit A549 cell migration, suggesting their potential to reduce cancer metastasis and Mechanistic studies suggested a redox-driven pathway involving the catalytic oxidation of NADH to NAD+, the elevation of ROS levels and depolarization of the mitochondrial membrane. Show less

We report the synthesis and characterization of four neutral organometallic tethered complexes, [Ru(η⁶-Ph(CH₂)₃-ethylenediamine-N-R)Cl], where R = methanesulfonyl (Ms, 1), toluenesulfonyl (Ts, 2), 4-trifluoromethylbenzenesulfonyl (Tf, 3), and 4-nitrobenzenesulfonyl (Nb, 4), including their X-ray crystal structures. These complexes exhibit moderate antiproliferative activity toward human ovarian, lung, hepatocellular, and breast cancer cell lines. Complex 2 in particular exhibits a low cross-resistance with cisplatin. The complexes show potent catalytic activity in the transfer hydrogenation of NAD⁺ to NADH with formate as hydride donor in aqueous solution (310 K, pH 7). Substituents on the chelated ligand decreased the turnover frequency in the order Nb > Tf > Ts > Ms. An enhancement of antiproliferative activity (up to 22%) was observed on coadministration with nontoxic concentrations of sodium formate (0.5-2 mM). Complex 2 binds to nucleobase guanine (9-EtG), but DNA appears not to be the target, as little binding to calf thymus DNA or bacterial plasmid DNA was observed. In addition, complex 2 reacts rapidly with glutathione (GSH), which might hamper transfer hydrogenation reactions in cells. Complex 2 induced a dose-dependent G₁ cell cycle arrest after 24 h exposure in A2780 human ovarian cancer cells while promoting an increase in reactive oxygen species (ROS), which is likely to contribute to its antiproliferative activity. Show less

Current anticancer drug discovery efforts focus on the identification of first-in-class compounds with a mode-of-action distinct from conventional DNA-targeting agents for chemotherapy. An emerging trend is the identification of endoplasmic reticulum (ER) targeting compounds that induce ER stress in cancer cells, leading to cell death. However, a limited pool of such compounds has been identified to date, and there are limited studies done on such compounds to allow for the rational design of ER stress-inducing agents. In our present study, we present a series of highly cytotoxic, ER stress-inducing Ru(II)-arene Schiff-Base (RAS) complexes, bearing iminoquinoline chelate ligands. We demonstrate that by structural modification to the iminoquinoline ligand, we could tune its π-acidity and influence reactive oxygen species (ROS) induction, switching between a ROS-mediated ER stress pathway activation and one that is not mediated by ROS induction. Our current study adds to the available ER stress inducers and shows how structural tuning could be used as a means to modulate the mode-of-action of such compounds. Show less

Our study demonstrates that four novel kinetically inert C,N-cyclometalated Ru^II complexes of the type [Ru(C^N)(N^N)₂ ][PF₆ ] containing a handle for functionalization on the C^N ligand are very potent cytotoxic agents against several different human cancer cell lines and are up to 400-fold more potent than clinically used cisplatin. In addition, the investigated ruthenium complexes are less cytotoxic in noncancerous cells, and exhibit higher selectivity for cancer cells than conventional platinum anticancer drugs. The high potency of the investigated ruthenium compounds can be attributed to several factors, including enhanced internalization and their capability to change mitochondrial transmembrane potential in cells. The new ruthenium complexes also interfere with protein synthesis with a markedly higher potency than conventional inhibitors of DNA translation. Notably, the latter mechanism has not been hitherto described for other cytotoxic Ru compounds and cisplatin. Show less