This paper describes the synthesis of new 6-aminoflavone (6AFl (3)) and 6-aminochromone (6AC (4)) complexes with Cu(ii) and Ru(ii) ions ([Cu(6AC)2Cl2] (3a), [Cu(6AFl)2Show more
This paper describes the synthesis of new 6-aminoflavone (6AFl (3)) and 6-aminochromone (6AC (4)) complexes with Cu(ii) and Ru(ii) ions ([Cu(6AC)2Cl2] (3a), [Cu(6AFl)2Cl2] (4a), [Ru(p-cymene)(6AC)Cl2] (4b)) and comparison of their properties with the previously described 7-aminoflavone (7AFl (1)) and 7-amino-2-methylchromone (7A2MC (2)) analogues. The cytotoxic effect of all these complexes against two human leukaemia cell lines (HL-60 and NALM-6), melanoma WM-115 cells and COLO205 cells, is determined. The cytotoxicity of copper(ii) complexes, especially [Cu(6AFl)2Cl2] (3a) was higher than ruthenium(ii) complexes with the same ligands. Their cytotoxic potency was also stronger in comparison to the referential agents like cisplatin. The pro-oxidative properties were determined for the most active complexes and their ability to generate ROS (reactive oxygen species)/RNS (reactive nitrogen species) in cancer cells was confirmed. The type of ligand and the chemical structure of the tested complexes had an influence on the level of ROS/RNS generated in cancer cells. The redox properties of the copper complex compounds were evaluated by cyclic voltammetry, and compared with the data for Ru(ii) complexes. The reduction and oxidation processes of Ru(iii)/Ru(ii) and Cu(ii)/Cu(i) were described as quasi-reversible. Show less
Ru(ii) polypyridine complexes which can undergo photo-induced ligand dissociation and subsequent DNA covalent binding may potentially serve as photoactivated chemotherapeutic (PACT) agents. In this pa Show more
Ru(ii) polypyridine complexes which can undergo photo-induced ligand dissociation and subsequent DNA covalent binding may potentially serve as photoactivated chemotherapeutic (PACT) agents. In this paper, three fluorinated dppz ligand coordinated Ru(ii) complexes (2-4) containing four monodentate pyridine ligands were studied. All complexes released one pyridine and covalently bound to DNA upon 470 nm irradiation. Compared with the parent complex [Ru(dppz)(py)4]2+ (1), 2-4 displayed enhanced phototoxicity but diminished dark cytotoxicity, more favorable for PACT application. Complex 3 is the most efficient one with IC50 values of about 8 μM toward HeLa and SKOV-3 cell lines, and also has a much higher IC50 value toward normal L-02 cells. Our results indicate that fluorination on the retaining ligand may be an efficient way to improve the drug activity of Ru(ii) PACT agents. Show less
Thioredoxin reductase (TrxR), a major component of the thioredoxin system, makes a critical role in regulating cellular redox signaling and is found to be overexpressed in many human cancer cells. Trx Show more
Thioredoxin reductase (TrxR), a major component of the thioredoxin system, makes a critical role in regulating cellular redox signaling and is found to be overexpressed in many human cancer cells. TrxR has become an attractive target for anticancer agents. In this work, three Ru(II) complexes with salicylate as ligand, [Ru(phen)2(SA)] (phen = 1,10-phenanthroline, SA = salicylate, 1), [Ru(dmb)2(SA)] (dmb = 4,4'-dimethyl-2,2'-bipyridine, 2) and [Ru(bpy)2(SA)] (bpy = 2,2'-bipyridine, 3), were synthesized and characterized. The anticancer effect exerted by them was evaluated. Complex 1 was found to exhibit obvious anticancer activity, in comparison with cisplatin, against cancer cell lines, while displaying low toxicity to the normal cell line BEAS-2B. The mechanism of complex 1 cancer cell growth suppress was investigated in A549 cells. Complex 1 exerted its anticancer through inducing apoptosis and triggering cell cycle arrest at the G0/G1 phase. Complex 1 can selectively inhibit TrxR activity and thus promote the generation and accumulation of reactive oxygen species (ROS), which subsequently trigger mitochondrial dysfunction and DNA damage, activate oxidative stress-sensitive mitogen activated protein kinase (MAPK), and suppress the protein kinase B (PKB or AKT) signal pathway, resulting in apoptosis in A549 cells. Show less
The use of ruthenium complexes as chemotherapeutic agents has been recently explored as one of the alternatives to conventional treatments. In the present study, two Ru(ii) polypyridyl complexes were Show more
The use of ruthenium complexes as chemotherapeutic agents has been recently explored as one of the alternatives to conventional treatments. In the present study, two Ru(ii) polypyridyl complexes were synthesized and characterized: a strained [Ru(bipy)2(BC)]Cl2 (complex 1) where [bipy = 2,2'-bipyridine and BC = bathocuproine] along with the unstrained control [Ru(bipy)2(phen)]Cl2 (complex 2) where [phen = 1,10-phenanthroline]. The photophysical and photochemical analyses proved that unlike the photostable complex 2, complex 1 ejected both bipy and BC ligands at a ratio of 3 : 1 respectively. Results showed that the activity of complex 1 was significantly enhanced upon photoactivation. The response was however particularly significant in B16-F10 melanoma cells where phototoxicity index (PI = IC50 dark/IC50 light) was >900. When compared to cisplatin, the photoproducts were more potent against all tested cell lines, implying that the complex acquired significant chemotherapeutic potential upon irradiation. Cellular uptake of complex 1 and the free BC ligand were found to be significantly facilitated as evidenced by 400-600 fold increase in concentration of the compounds inside the cells relative to the extracellular culture medium. Complex 2 exhibited 35 times lower cellular concentration relative to complex 1. Flow cytometry and plasmid DNA gel electrophoresis measurements showed that complex 1 interacts with DNA inducing apoptosis in the dark and either late-apoptosis or necrosis upon irradiation. These findings corroborate the importance of lipophilic ligands such as BC to enhance uptake and subsequently improve the photochemotherapy potential of Ru(ii) polypyridyl complexes. Show less
In this paper, four new ruthenium complexes, [Ru(N-S)(dppm)2]PF6 (1), [Ru(N-S)(dppe)2]PF6 (2), [Ru(N-S)2(dppp)] (3) and [Ru(N-S)2(PPh3)2] (4) [dppm = 1,1-bis(diphenylphosphino)methane, dppe = 1,2-bis( Show more
In this paper, four new ruthenium complexes, [Ru(N-S)(dppm)2]PF6 (1), [Ru(N-S)(dppe)2]PF6 (2), [Ru(N-S)2(dppp)] (3) and [Ru(N-S)2(PPh3)2] (4) [dppm = 1,1-bis(diphenylphosphino)methane, dppe = 1,2-bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenylphosphino)propane, PPh3 = triphenylphosphine and N-S = 2-mercaptopyrimidine anion] were synthesized and characterized using spectroscopy techniques, molar conductance, elemental analysis, electrochemical techniques and X-ray diffraction. The DNA binding studies were investigated using voltammetry and spectroscopy techniques. The results show that all complexes exhibit a weak interaction with DNA. HSA interaction with the complexes was studied using fluorescence emission spectroscopy, where the results indicate a spontaneous interaction between the species by a static quenching mechanism. The cytotoxicity of the complexes was evaluated against A549, MDA-MB-231 and HaCat cells by MTT assay. Complexes (1) and (2), which are very active against triple negative MDA-MB-231, were subjected to further biological tests with this cell line. The cytotoxic activity triggered by the complexes was confirmed by clonogenic assay. Cell cycle analyses demonstrated marked anti-proliferative effects, especially at the G0/G1 and S phases. The morphological detection of apoptosis and necrosis - HO/PI and Annexin V-FITC/PI assay, elucidated that the type of cell death triggered by these complexes was probably by apoptosis. The in vivo toxicological assessment performed on zebrafish embryos revealed that complexes (1) and (2) did not present embryotoxic or toxic effects during embryonic and larval development showing that they are promising new prototypes of safer and more effective drugs for triple negative breast cancer treatment. Show less
Near-IR-emitting and/or efficiently photodynamic water-soluble Ru(II) complexes that hold great application potentials as photodynamic therapy and/or photodetection agents for cancers have been poorly Show more
Near-IR-emitting and/or efficiently photodynamic water-soluble Ru(II) complexes that hold great application potentials as photodynamic therapy and/or photodetection agents for cancers have been poorly explored. In this paper, the solvatochromism, calf thymus DNA binding, and singlet oxygen generation properties of a known ruthenium(II) complex of visible-emitting [Ru(bpy)2(dtdpq)](ClO4)2 (Ru1) and a new homoleptic complex of near-IR-emitting [Ru(dtdpq)3](ClO4)2 (Ru2) (bpy = 2,2'-bipyridine, dtdpq = 2,3-bis(thiophen-2-yl)pyrazino[2,3-f][1,10]phenanothroline) in water are reported. Moreover, DNA photocleavage, singlet oxygen generation in HeLa cells, cellular uptake/localization, and in vitro photodynamic therapy for cancer cells of water-soluble Ru1 are described in detail. The results show that Ru1 acted as potent photodynamic cancer therapy and mitochondrial imaging agents. Ru2 exhibited very strong solvatochromism from a visible emission maximum at 588 nm in CH2Cl2 to the near-IR region at 700 nm in water and singlet oxygen generation yield in water (23%) and DNA binding properties (intercalative DNA binding constant on the order of 106 M-1) comparable to those of Ru1, which should make Ru2 attractive for the aforementioned applications of Ru1 if the water solubility of Ru2 can be improved enough for the studies above. Show less
Ru(ii) polypyridyl complexes which can undergo photo-induced ligand dissociation and DNA covalent binding are considered as potential photoactivated chemotherapeutic (PACT) agents. Herein four pyridin Show more
Ru(ii) polypyridyl complexes which can undergo photo-induced ligand dissociation and DNA covalent binding are considered as potential photoactivated chemotherapeutic (PACT) agents. Herein four pyridine-2-sulfonate (py-SO3-) ligand based Ru(ii) complexes [Ru(N-N)2(py-SO3)]+ (1-4) were synthesized and studied. All the complexes can undergo fast py-SO3- ligand dissociation and DNA covalent binding upon visible light irradiation. However, only complex 4 exhibited high photo-induced anticancer activities towards a series of cancer cells, with half maximal inhibitory concentration (IC50) values in 100-300 nM regions and phototoxicity index (PI) values of about 100. In particular, complex 4 can also kill cisplatin resistant SKOV-3 and A549 cancer cells with IC50 values in 200-400 nM regions and PI values of about 50, which should be the first report of Ru(ii) based PACT agents that are also effective towards cisplatin resistant cancer cells. Complex 4 exhibited much higher cell uptake and nuclear accumulation levels, which may be the main reasons for its high anticancer activities. The in vivo anticancer experiments indicated that complex 4 can inhibit tumor growth significantly with fewer side effects. Our results may provide guidelines for developing novel photoactivatable Ru(ii) anticancer agents. Show less
This paper reports the synthesis, structure characterization, and anticancer properties of 13 organometallic Ru(ii)-arene complexes: [Ru(η6-p-cymene)Cl-(L1)] (1), [Ru(η6-p-cymene)Cl-(L2)] (2), [Ru(η6- Show more
This paper reports the synthesis, structure characterization, and anticancer properties of 13 organometallic Ru(ii)-arene complexes: [Ru(η6-p-cymene)Cl-(L1)] (1), [Ru(η6-p-cymene)Cl-(L2)] (2), [Ru(η6-p-cymene)Cl-(L3)] (3), [Ru(η6-p-cymene)Cl-(L4)] (4), [Ru(η6-p-cymene)Cl-(L5)] (5), [Ru(η6-p-cymene)I-(L1)] (6), [Ru(η6-p-cymene)I-(L2)] (7), [Ru(η6-p-cymene)I-(L3)] (8), [Ru(η6-p-cymene)I-(L4)] (9), [Ru(η6-p-cymene)I-(L5)] (10), [Ru(η6-p-cymene)I-(L6)] (11), [Ru(η6-p-cymene)I-(L7)] (12), and [Ru(η6-p-cymene)Cl-(L8)] (13) respectively containing deprotonated 5,7-dichloro-2-methyl-8-quinolinol (H-L1), 5,7-dibromo-2-methyl-8-quinolinol (H-L2), 5-chloro-7-iodo-8-hydroxy-quinoline (H-L3), 5,7-dibromo-8-quinolinol (H-L4), 5,7-diiodo-8-hydroxyquinoline (H-L5), 8-hydroxy-2-methylquinoline (H-L6), 2,8-quinolinediol (H-L7), or 6,7-dichloro-5,8-quinolinedione (H-L8). MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay showed that 13 organometallic Ru(ii)-arene complexes 1-13 are more selective for HeLa cells than normal HL-7702 cells. In addition, 1, 2, 5, and 6, which contain the active ligands H-L1 and H-L2, showed remarkable cell cytotoxicity, giving the respective IC50 values of 2.00 ± 0.20 nM, 0.89 ± 0.62 μM, 25.00 ± 0.30 nM, and 2.18 ± 0.35 μM on HeLa cancer cells. These values indicated higher activity than 6,7-dichloro-5,8-quinolinedione and other 8-hydroxyquinoline derivative Ru(ii)-arene complexes. Interestingly, all these Ru(ii)-arene complexes 1-13 were significantly less toxic to human hepatic (HL-7702) cells. Moreover, 1- and 2-induced HeLa cell apoptosis was mediated by the inhibition of telomerase activity and dysfunction of mitochondria, and resulted in DNA damage and increased anti-migration activity on HeLa cells. The organometallic Ru(ii)-arene complex 1 exhibited evident priority to the antitumor activity compared to 2, which should be highly associated with the key roles of the 5,7-dichloro substituted groups in the L1 ligand of organometallic Ru(ii)-arene complexes 1. Remarkably, 1 showed higher inhibitory activity against the xenograft tumor growth of human cervical cells (HeLa) in vivo (tumor growth inhibition rate (TGIR) = 58.5%) than cisplatin. This study was the first to show that the 5,7-dihalogenated-2-methyl-8-quinolinol organometallic Ru(ii)-arene complexes 1 and 2 are novel Ru(ii) anticancer drug candidates. Show less
Due to acquired resistance or limitations of the currently approved drugs against cancer, there is an urgent need for the development of new classes of compounds. Among others, there is an increasing Show more
Due to acquired resistance or limitations of the currently approved drugs against cancer, there is an urgent need for the development of new classes of compounds. Among others, there is an increasing attention towards the use of Ru(II) polypyridyl complexes. Most studies in the literature were made on complexes based on the coordination of N-donating bidentate ligands to the ruthenium core whereas studies on 2,2':6', 2″-terpyridine (terpy) coordinating ligands are relatively scare. However, several studies have shown that [Ru(terpy)2]2+ derivatives are able bind to DNA through various binding modes making these compounds potentially suitable as chemotherapeutic agents. Additionally, light irradiation of these compounds was shown to enable DNA cleavage, highlighting their potential use as photosensitizers (PSs) for photodynamic therapy (PDT). In this work, we present the systematic investigation of the potential of 7 complexes of the type [Ru(terpy)(terpy-X)]2+ (X = H (1), Cl (2), Br (3), OMe (4), COOH (5), COOMe (6), NMe2 (7)) as potential chemotherapeutic agents and PDT PSs. Importantly, six of the seven complexes were found to be stable in human plasma as well as photostable in acetonitrile upon continuous light irradiation (480 nm). The determination of the distribution coefficient logP values for the 7 complexes revealed their good water solubility. Complex 7 was found to be cytotoxic in the micromolar range in the dark as well as to have some phototoxicity upon light exposure at 480 nm in non-cancerous retinal pigment epithelium (RPE-1) and cancerous human cervical carcinoma (HeLa) cells. SYNOPSIS: The systematic investigation of the potential of 7 complexes of the type [Ru(terpy)(terpy-X)]2+ (terpy: 2,2':6', 2″-terpyridine; X = H (1), Cl (2), Br (3), OMe (4), COOH (5), COOMe (6), NMe2 (7)) as potential chemotherapeutic agents and photosensitizers for photodynamic therapy is presented. Show less
Three novel Ru(II) complexes, namely, (RuCl2[La][DMSO]2)·H2O (Ru1), (RuCl2[Lb][DMSO]2) (Ru2), and (RuCl2 Show more
Three novel Ru(II) complexes, namely, (RuCl2[La][DMSO]2)·H2O (Ru1), (RuCl2[Lb][DMSO]2) (Ru2), and (RuCl2[Lc][DMSO]2) (Ru3), which respectively contain 3-(2'-benzimidazolyl)coumarin (La), 3-(2'-benzimidazolyl)-7-fluoro-coumarin (Lb), and 3-(2'-benzimidazolyl)-7-methoxyl-coumarin (Lc), were first designed and characterized. Ru2 showed potent antitumor activity against NCI-H460 cells (IC50 = 0.30 ± 0.02 μM) and high selectivity between NCI-H460 cancer cells and normal HL-7702 cells. Ru2 induced NCI-H460 apoptosis via telomerase inhibition, which involved DNA damage, cell-cycle distribution, and S phase-protein down-regulation. However, Ru1 did not demonstrate such effects in NCI-H460 cells, which is undoubtedly associated with the key regulatory role of the 7-fluoro substituted group in the Lb ligand of Ru2. Ru2 exhibited considerably higher anticancer efficacy (inhibition rate [IR] = 61.3%) compared with cisplatin (IR= 25.5%) in a NCI-H460 xenograft mouse model. Thus, this coumarin Ru(II) compound is a promising Ru2-targeting telomerase anticancer agent. Show less
The triple-negative breast cancer subtype (TNBC) is highly aggressive and metastatic and corresponds to 15-20% of diagnosed cases. TNBC treatment is hampered, because these cells usually do not respon Show more
The triple-negative breast cancer subtype (TNBC) is highly aggressive and metastatic and corresponds to 15-20% of diagnosed cases. TNBC treatment is hampered, because these cells usually do not respond to hormonal therapy, and they develop resistance to chemotherapeutic drugs. On the other hand, the severe side effects of cisplatin represent an obstacle for its clinical use. Ruthenium (Ru)-based complexes have emerged as promising antitumor and antimetastatic substitutes for cisplatin. In this study, we demonstrated the effects of a Ru/biphosphine complex, containing gallic acid (GA) as a ligand, [Ru(GA)(dppe)2]PF6, hereafter called Ru(GA), on a TNBC cell line, and compared them to the effects in a nontumor breast cell line. Ru(GA) complex presented selective cytotoxicity against TNBC over nontumor cells, inhibited its migration and invasion, and induced apoptosis. These effects were associated with the increased amount of transferrin receptors (TfR) on tumor cells, compared to nontumor ones. Silencing of TfR decreased Ru(GA) effects on TNBC cells, demonstrating that these receptors were at least partially responsible for Ru(GA) delivery into tumor cells. The Ru(GA) compound must be further studied in different in vivo assays in order to investigate its antitumor properties and its toxicity in complex biological systems. Show less
Herein, ruthenium complexes containing heterocyclic thioamidates [Ru(mmi)(bipy)(dppb)]PF6 (1), [Ru(tzdt)(bipy)(dppb)]PF6 (2), [Ru(dmp)(bipy)(dppb)]PF6 (< Show more
Herein, ruthenium complexes containing heterocyclic thioamidates [Ru(mmi)(bipy)(dppb)]PF6 (1), [Ru(tzdt)(bipy)(dppb)]PF6 (2), [Ru(dmp)(bipy)(dppb)]PF6 (3) and [Ru(mpca)(bipy)(dppb)]PF6 (4) were investigated for their cellular and molecular effects in cancer cell lines. Complexes 1 and 2 were the most potent of the four compounds against a panel of different cancer cell lines in monolayer cultures and showed potent cytotoxicity in a 3D model of multicellular spheroids that formed from human hepatocellular carcinoma HepG2 cells. In addition, both complexes were able to bind to DNA in a calf thymus DNA model. Compared to the controls, a reduction in cell proliferation, phosphatidylserine externalization, internucleosomal DNA fragmentation, and the loss of the mitochondrial transmembrane potential were observed in HepG2 cells that were treated with these complexes. Additionally, coincubation with a pan-caspase inhibitor (Z-VAD(OMe)-FMK) reduced the levels of apoptosis that were induced by these compounds compared to those in the negative controls, indicating that cell death through apoptosis occurred via a caspase-dependent pathway. Moreover, these complexes also induced the phosphorylation of ERK1/2, and coincubation with an MEK inhibitor (U0126), which is known to inhibit the activation of ERK1/2, but not JNK/SAPK and p38 MAPK inhibitors, reduced the complexes-induced apoptosis compared to that in the negative controls, indicating that the induction of apoptotic cell death occurred through ERK1/2 signaling in HepG2 cells. On the other hand, no increase in oxidative stress was observed in HepG2 cells treated with the complexes, and the complexes-induced apoptosis was not reduced with coincubation with the antioxidant N-acetylcysteine or a p53 inhibitor compared to that in the negative controls, indicating that apoptosis occurred via oxidative stress- and p53-independent pathways. Finally, these complexes also reduced the growth of HepG2 cells that were engrafted in C.B-17 SCID mice compared to that in the negative controls. These results indicated that these complexes are novel anticancer drug candidates for liver cancer treatment. Show less
The steady rise in the cancer burden and grim statistics set a vital need for new therapeutic solutions. Given their high efficiency, metallodrugs are quite appealing in cancer chemotherapy. This work Show more
The steady rise in the cancer burden and grim statistics set a vital need for new therapeutic solutions. Given their high efficiency, metallodrugs are quite appealing in cancer chemotherapy. This work examined the anticancer activity of an anti-trypanosomal ruthenium-based compound bearing the 5-nitrofuryl pharmacophore, [RuII(dmso)2(5-nitro-2-furaldehyde semicarbazone)] (abbreviated as RuNTF; dmso is the dimethyl sulfoxide ligand). The cytotoxicity of RuNTF was evaluated in vitro against ovarian adenocarcinoma, hormone-dependent breast adenocarcinoma, prostate carcinoma (grade IV) and V79 lung fibroblasts human cells. The activity of RuNTF was similar to the benchmark metallodrug cisplatin for the breast line and inactive against the prostate line and lung fibroblasts. Given the known role of serum protein binding in drug bioavailability and the distribution via blood plasma, this study assessed the interaction of RuNTF with human serum albumin (HSA) by circular dichroism (CD) and fluorescence spectroscopy. The fluorescence emission quenching from the HSA-Trp214 residue and the lifetime data upon RuNTF binding evidenced the formation of a 1:1 {RuNTF-albumin} adduct with log Ksv = (4.58 ± 0.01) and log KB = (4.55 ± 0.01). This is supported by CD data with an induced CD broad band observed at ~450 nm even after short incubation times. Importantly, the binding to either HSA or human apo-transferrin is beneficial to the cytotoxicity of the complex towards human cancer cells by enhancing the cytotoxic activity of RuNTF. Show less
Human acute promyelocytic leukemia (APL) is the most malignant form of acute leukemia. The fusion of PML and RARα genes is responsible for over 98% of cases of APL. In this work, we found that a Ru(ii Show more
Human acute promyelocytic leukemia (APL) is the most malignant form of acute leukemia. The fusion of PML and RARα genes is responsible for over 98% of cases of APL. In this work, we found that a Ru(ii) arene complex, [(η6-p-bip)Ru(en)Cl][PF6] (Ru-1), can selectively react with PML, leading to zinc-release and protein unfolding. Consequently, the degradation of the fusion protein PML-RARα occurs, which causes the differentiation of APL cells. In addition, Ru-1 can also bind to DNA and trigger apoptosis of APL cells. Therefore, Ru-1 acts as a dual functional agent that inhibits the growth of APL cells and induces cell differentiation. In contrast, the other non-selective Ru(ii) compound, though also highly reactive to PML, does not exhibit anti-APL activity. The selectivity of Ru-1 to PML suggests a new strategy for the development of anti-APL drugs using ruthenium agents. Show less