📚 BiometalDB

The main purpose of this study was to synthesize a new set of naphthoquinone-based ruthenium(II) arene complexes and to develop an understanding of their mode of action. This study systematically reviews the steps of synthesis, aiming to provide a simplified approach using microwave irradiation. The chemical structures and the physicochemical properties of this novel group of compounds were examined by ¹H-NMR and ¹³C-NMR spectroscopy, X-ray diffractometry, HPLC-MS and supporting DFT calculations. Several aspects of the biological activity were investigated in vitro, including short- and long-term cytotoxicity tests, cellular accumulation studies, detection of reactive oxygen species generation, apoptosis induction and NAD(P)H:quinone oxidoreductase 1 (NQO1) activity as well as cell cycle analysis in A549, CH1/PA-1, and SW480 cancer cells. Furthermore, the DNA interaction ability was studied in a cell-free assay. A positive correlation was found between cytotoxicity, lipophilicity and cellular accumulation of the tested complexes, and the results offer some important insights into the effects of the arene. The most obvious finding to emerge from this study is that the usually very chemosensitive CH1/PA-1 teratocarcinoma cells showed resistance to these phthiocol-based organometallics in comparison to the usually less chemosensitive SW480 colon carcinoma cells, which pilot experiments suggest as being related to NQO1 activity. Show less

Both ruthenium-containing complexes and 8-quinolinoline compounds have emerged as a potential novel agent for malignant tumor therapy. Here, three triphenylphosphine ruthenium complexes, [Ru(ZW1)(PPh₃)₂Cl₂] (PPh₃ = triphenylphosphine) (RuZ1), [Ru(ZW2)(PPh₃)₂Cl₂] (RuZ2) and [Ru(ZW2)₂(PPh₃)Cl₂]·CH₂Cl₂ (RuZ3) bearing 5,7-dichloro-8-quinolinol (H-ZW1) and 5,7-dichloro-8-hydroxyquinaldine (H-ZW2), have been synthesized, characterized and tested for their anticancer potential. We showed that triphenylphosphine ruthenium complexes RuZ1-RuZ3 impaired the cell viability of ovarian adenocarcinoma cisplatin-resistant SK-OV-3/DDP (SKO3CR) and SK-OV-3 (SKO3) cancer cells with greater selectivity and specificity than cisplatin. In addition, RuZ1-RuZ3 show higher excellent cytotoxicity than cisplatin towards SKO3CR cells, with IC₅₀ values of 9.66 ± 1.08, 4.05 ± 0.67 and 7.18 ± 0.40 μM, respectively, in which the SKO3CR cells was the most sensitive to RuZ1-RuZ3. Depending on the substituent type, the antiproliferative ability of RuZ1-RuZ3 followed the trend: -CH₃ > -H. However, RuZ1-RuZ3 have no obvious toxicity to normal cell HL-7702. Besides, RuZ1 and RuZ2 could induce mitophagy related-apoptosis pathways through suppression of mitochondrial membrane potential (ΔΨm), accumulation of [Ca²⁺] and reactive oxygen species (ROS), and regulation of LC3 II/LC3 I, Beclin-1, P62, FUNDC1, PINK1, Parkin, cleaved-caspase-3, caspase-9 and cytochrome c signaling pathway, and hindering the preparation of mitochondrial respiration complexes I and IV and ATP levels. Mechanistic study revealed that RuZ1 and RuZ2 induce apoptosis in SKO3CR cells via mitophagy related-apoptosis pathways induction and energy (ATP) generation disturbance. Taken together, the studied triphenylphosphine ruthenium complexes RuZ1-RuZ3 are promising chemotherapeutic agents with high effectiveness and low toxicity. Show less

A series of [RuCl₂(p-cymene)(NHC)] complexes were obtained by reacting [RuCl₂(p-cymene)]2 with in situ generated Ag-N-heterocyclic carbene (NHC) complexes. The structure of the obtained complexes was determined by the appropriate spectroscopy and elemental analysis. In addition, we evaluated the biological activities of these compounds as antienzymatic, antioxidant, antibacterial, anticancer, and antiparasitic agents. The results revealed that complexes 3b and 3d were the most potent inhibitors against AchE with IC₅₀ values of 2.52 and 5.06 μM mL^-1. Additionally, 3d proved very good antimicrobial activity against all examined microorganisms with IZ (inhibition zone) over 25 mm and MIC (minimum inhibitory concentration) < 4 µM. Additionally, the ligand 2a and its corresponding ruthenium (II) complex 3a had good cytotoxic activity against both cancer cells HCT-116 and HepG-2, with IC₅₀ values of (7.76 and 11.76) and (4.12 and 9.21) μM mL^-1, respectively. Evaluation of the antiparasitic activity of these complexes against Leishmania major promastigotes and Toxoplasma gondii showed that ruthenium complexes were more potent than the free ligand, with an IC₅₀ values less than 1.5 μM mL^-1. However, 3d was found the best one with SI (selectivity index) values greater than 5 so it seems to be the best candidate for antileishmanial drug discovery program, and much future research are recommended for mode of action and in vivo evaluation. In general, Ru-NHC complexes are the most effective against L. major promastigotes. Show less

This paper reports on the synthesis and characterization of two new polypyridyl-hydrazone Schiff bases, (E)-N'-(6-oxo-1,10-phenanthrolin-5(6H)-ylidene)thiophene-2-carbohydrazide (L¹) and (E)-N'-(6-oxo-1,10-phenanthrolin-5(6H)-ylidene)furan-2-carbohydrazide (L²), and their two Ru(II) complexes of the general formula [RuCl(DMSO)(phen)(Lⁿ)](PF6). Considering that hydrazides are a structural part of severa l drugs and metal complexes containing phenanthroline derivatives are known to interact with DNA and to exhibit antitumor activity, more potent anticancer agents can be obtained by covalently linking the thiophene acid hydrazide or the furoic acid hydrazide to a 1,10-phenanthroline moiety. These ligands and the Ru(II) complexes were characterized by elemental analyses, electronic, vibrational, ¹H NMR, and ESI-MS spectroscopies. Ru is bound to two different N-heterocyclic ligands. One chloride and one S-bonded DMSO in cis-configuration to each other complete the octahedral coordination sphere around the metal ion. The ligands are very effective in inhibiting cellular growth in a chronic myelogenous leukemia cell line, K562. Both complexes are able to interact with DNA and present moderate cytotoxic activity, but 5 min of UV-light exposure increases cytotoxicity by three times. Show less

The complexes cis-[Ru(quin)(dppm)₂]PF₆ and cis-[Ru(kynu)(dppm)₂]PF₆ (quin = quinaldate; kynu = kynurenate; dppm = bis(diphenylphosphino)methane) were prepared and characterized by elemental analysis, electronic, FTIR, ¹H, and ³¹P{¹H} NMR spectroscopies. Characterization data were consistent with a cis arrangement for the dppm ligands and a bidentate coordination through carboxylate oxygens of the quin and kynu anions. These complexes were not able to intercalate CT-DNA as shown by circular dichroism spectroscopy. On the other hand, bovine serum albumin (BSA) binding constants and thermodynamic parameters suggest spontaneous interactions with this protein by hydrogen bonds and van der Waals forces. Cytotoxicity assays were carried out on a panel of human cancer cell lines including HepG2, MCF-7, and MO59J and one normal cell line GM07492A. In general, the new ruthenium(II) complexes displayed a moderate to high cytotoxicity in all the assayed cell lines with IC₅₀ ranging from 10.1 to 36 µM and were more cytotoxic than the precursor cis-[RuCl₂(dppm)₂]. The cis-[Ru(quin)(dppm)₂]PF₆ were two to three times more active than the reference metallodrug cisplatin in the MCF-7 and MO59J cell lines. Show less

This report presents the first known p-cymene ruthenium quinaldamide complexes which are stabilised by a hydrogen-bridging atom, [{(p-cym)Ru(II)X(N,N)}{H(+)}{(N,N)XRu(II)(p-cym)}][PF6] (N,N = functionalised quinaldamide and X = Cl or Br). These complexes are formed by a reaction of [p-cymRu(μ-X)2]2 with a functionalised quinaldamide ligand. When filtered over NH4PF6, and under aerobic conditions the equilibrium of NH4PF6 ⇔ NH3 + HPF6 enables incorporation of HPF6 and the stabilisation of two monomeric ruthenium complexes by a bridging H(+), which are counter-balanced by a PF6 counterion. X-ray crystallographic analysis is presented for six new structures with OO distances of 2.420(4)-2.448(15) Å, which is significant for strong hydrogen bonds. Chemosensitivity studies against HCT116, A2780 and cisplatin-resistant A2780cis human cancer cells showed the ruthenium complexes with a bromide ancillary ligand to be more potent than those with a chloride ligand. The 4'-fluoro compounds show a reduction in potency for both chloride and bromide complexes against all cell lines, but an increase in selectivity towards cancer cells compared to non-cancer ARPE-19 cells, with a selectivity index >1. Mechanistic studies showed a clear correlation between IC50 values and induction of cell death by apoptosis. Show less

Two new complexes of Ru(II) with mixed ligands were prepared: [Ru(bpy)₂smp](PF₆) (1) and [Ru(phen)₂smp](PF₆) (2), in which smp = sulfamethoxypyridazine; bpy = 2,2'-bipyridine; phen = 1,10-phenanthroline. The complexes have been characterized by elemental and conductivity analyses; infrared, NMR, and electrospray ionization mass spectroscopies; and X-ray diffraction of single crystal. Structural analyses reveal a distorted octahedral geometry around Ru(II) that is bound to two bpy (in 1) or two phen (in 2) via their two heterocyclic nitrogens and to two nitrogen atoms from sulfamethoxypyridazine-one of the methoxypyridazine ring and the sulfonamidic nitrogen, which is deprotonated. Both complexes inhibit the growth of chronic myelogenous leukemia cells. The interaction of the complexes with bovine serum albumin and DNA is described. DNA footprinting using an oligonucleotide as substrate showed the complexes' preference for thymine base rich sites. It is worth notifying that the complexes interact with the Src homology SH3 domain of the Abl tyrosine kinase protein. Abl protein is involved in signal transduction and implicated in the development of chronic myelogenous leukemia. Nuclear magnetic resonance (NMR) studies of the interaction of complex 2 with the Abl-SH3 domain showed that the most affected residues were T79, G97, W99, and Y115. Show less

The organoruthenium complex [(eta(6)-hmb)Ru(en)(Cl)][PF6] (hmb is hexamethylbenzene, en is ethylenediamine) undergoes facile aquation and then reacts with KSCN in unbuffered solution to give the S-coordinated thiocyanato product [(eta(6)-hmb)Ru(en)(S-SCN)]+ which slowly converts to the thermodynamically favored N-bound complex [(eta(6)-hmb)Ru(en)(N-NCS)]+ (1+). Complex 1 was synthesized and characterized by X-ray crystallography and mass spectrometry. Despite its lack of hydrolysis over 24 h, complex 1 exhibits moderate cytotoxicity (IC(50) 24 microM) towards the human ovarian cancer cell line A2780, comparable with that of the chlorido analogue which is thought to be activated (towards potential target DNA) via a rapid aquation (Wang et. al. in Proc Natl Acad Sci USA 102:18269-18274, 2005). Detailed kinetic studies suggest that complex 1 binds to guanosine 5'-monophosphate (GMP) through direct N7 substitution of the N-bound SCN ligand. In the presence of a high concentration of chloride (104 mM), however, complex 1 may bind partly to GMP via Cl substitution. Show less

The number of cancer cases continues to increase worldwide, and unfortunately the main systemic treatments available have numerous of side effects. Ruthenium complexes have shown to be promising chemotherapeutic agents, since they present low toxicity and are more selective for tumor tissues. We report the synthesis, characterization and biological properties of two new ruthenium (II) complexes containing Lapachol and Lawsone as ligands: (1) [Ru(Law)(dppb)(phen)]PF₆ and (2) [Ru(Lap)(dppb)(phen)]PF₆, where Law = Lawsone, Lap = Lapachol, dppb = 1,4-bis(diphenylphosphine)butane and phen = 1,10-phenanthroline. The ability of the complexes (1) and (2) to interact with CT-DNA (Calf Thymus) was investigated, and the results indicate that the complexes have shown a weak interaction with this macromolecule. Complexes (1) and (2) showed a moderate interaction with BSA, via a spontaneous process with the involvement of van der Waals and hydrogen bond interactions. Both complexes were tested against human lung cancer cell lines, chronic human myeloid leukemia, murine melanoma and human cervical and non-tumoral murine fibroblast adenocarcinoma, human lung fibroblasts and monkey kidney epithelia. The potential for cytotoxicity was tested out using the MTT assay and the neutral red test, to calculate inhibitory concentrations (IC50) and selectivity indices (IS). Both complexes showed a higher selectivity index of 1.17 and 10.91, respectively, for the HeLa tumor line. Studies of toxicological evaluation, using the micronucleus test and the comet assay against non-tumor cells, as well as an assessment of the potential for acute toxicity and neurotoxicity in zebrafish (Danio rerio). In the in vitro micronucleus test, complex (1) showed the least genotoxic potential, and in the in vitro comet assay both compounds had revealed a genotoxic potential at 0.5 and 1.0 mg L^-1, with no difference between 24 h and 48 h exposure times. In the acute toxicity tests on zebrafish embryos, complex (1) showed sublethal effects such as decreased blood circulation and heartbeat rate, which were less pronounced than with complex (2). In contrast to complex 2, which caused lethality even before 48h, complex (1) did not cause the death of the embryos at concentrations up to (2.0 mg L^-1). Complex (2) also lead to a delay in the embryo. Cell based in vitro methods thus proved able to provide specific toxicological data, allowing a significant reduction in ∖animal experimentation. Given that in vitro tests cannot completely replace animal tests, the use of less advanced developmental stages such as zebrafish embryos, which - at least in the European Union - are not regarded protected, could be shown to be an excellent alternative for testing with, e.g., mammals. Show less

In this study, two isomeric ruthenium(II) complexes [Ru(bpy)(2)(p-mopip)](2+) (1) and [Ru(bpy)(2)(o-mopip)](2+) (2) (bpy = 2, 2-bipyridine; L: p-mopip = 2-(4-methoxylphenyl) imidazo [4,5-f][1,10]phenanthroline, o-mopip = 2-(2-methoxylphenyl) imidazo[4,5-f][1,10] phenan-throline) contained -OCH(3) at different positions on the phenyl ring and their enantiomers Λ-1, -2 and Δ-1, -2 displayed different properties. The cell viability of these ruthenium(II) complexes was evaluated by MTT, and complex Λ-1 has shown significant higher anticancer potency than Δ-1 against all the cell lines screened. Fluorescence microscopy and flow cytometric analyses demonstrated that complex Λ-1 was able to induce apoptosis. The interactions of complexes Λ-1, 1, and Δ-1 with bovine serum albumin (BSA) were investigated by fluorescence and circular dichroism (CD) measurements. The fluorescence quenching mechanism of BSA by complexes Λ-1, 1, and Δ-1 was determined to be a static process, and the apparent binding constant K(a) values is as follows: Λ-1 >1 > Δ-1. The number of binding sites n for all these complexes was 1. The result of CD showed that the secondary structure of BSA molecules was changed in the presence of the ruthenium(II) complex. Show less

The photophysical and biological properties of two new phenanthroline-based ligand ruthenium complexes were investigated in detail. Their DNA interaction modes were determined to be the intercalation mode using spectra titration and viscosity measurements. Under irradiation, obvious photo-reduced DNA cleavages were observed in the two complexes via singlet oxygen generation. Furthermore, complex 2 showed higher DNA affinity, photocleavage activity, and singlet oxygen quantum yields than complex 1. The two complexes showed no toxicity towards tumor cells (HeLa, A549, and A375) in the dark. However, obvious photocytotoxicities were observed in the two complexes. Complex 2 exhibited large PIs (phototherapeutic indices) (ca. 400) towards HeLa cells. The study suggests that these complexes may act as DNA intercalators, DNA photocleavers, and photocytotoxic agents. Show less

Synthesis, structure and properties of two new flavanone complexes of Ru(ii) are described. The new complexes form during the reaction of ruthenium(iii) chloride with 3-aminoflavone (3-af) dissolved in an aliphatic alcohol. The formed products depend on the alcohol used and were found to be: cis-dichloridobis(3-imino-2-methoxyflavanone)ruthenium(ii)·3H(2)O (1) from a methanolic solution and cis-dichloridobis(3-imino-2-ethoxyflavanone)ruthenium(ii)·2H(2)O (2) from an ethanolic solution, in which the original ligand 3-af had been converted by dehydrogenative alcoholysis to an entirely new ligand. This paper presents the X-ray structure and detailed (1)H-NMR analysis of both new compounds, as well as the study of their antiproliferative activity. The coordination of Ru(ii) is octahedral with [RuCl(2)N(2)O(2)] chromophores, having trans chlorides and common Ru-L distances. Both 1 and 2 are highly cytotoxic towards the cisplatin resistant EJ and L1210 cell lines, and both complexes are as active as cisplatin in the sensitive cell lines. They display the ability to overcome cisplatin resistance in the drug resistant sub-lines EJcisR and L1210R. The present evidence suggests that the mechanism of biological activity may be different for these ruthenium compounds compared to cisplatin. Show less

In this work, a series of novel C-N cyclometalated 2H-indazole Ru(II) and Ir(III) complexes were synthesized, wherein chelating ligands with substituents like H, and isopropyl group in the R₄ position of the phenyl ring of the 2H-indazole chelating ligand are present. The cytotoxicity of Ru(II) and Ir(III) complexes has been evaluated against different human cancer cell lines (HeLa, MCF-7, and A549) in a concentration-dependent manner. The new iridium complex with isopropyl substituent in the phenyl ring of the 2H-indazole moiety showed good cytotoxic activity against MCF-7 cells with an IC₅₀ value 3.5 μM. The complex also exhibited cytotoxicity comparable to that of cisplatin. The ability of this compound inducing apoptosis was tested by nuclear condensation, cell membrane blebbing and caspase 3/7 activation. Further, this iridium complex is capable of inhibiting cancer cell migration when tested in MCF-7 cell line. Subsequently, we have studied the DNA binding and protein binding ability of the newly synthesized iridium complex. Show less

Ruthenium(II) complexes with 6-methyl-2-thiouracil cis-[Ru(6m2tu)₂(PPh₃)₂] (1) and [Ru(6m2tu)₂(dppb)] (2) (where PPh_3 =triphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane; and 6m2tu = 6-methyl-2-thiouracil) are potent cytotoxic agents and able to bind DNA. The aim of this study was to evaluate in vitro cellular underlying mechanism and in vivo effectiveness of these ruthenium(II) complexes in human acute promyelocytic leukemia HL-60 cells. Both complexes displayed potent and selective cytotoxicity in myeloid leukemia cell lines, and were detected into HL-60 cells. Reduction of the cell proliferation and augmented phosphatidylserine externalization, caspase-3, -8 and -9 activation and loss of mitochondrial transmembrane potential were observed in HL-60 cells treated with both complexes. Cotreatment with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, reduced Ru(II) complexes-induced apoptosis. In addition, both metal complexes induced phosphorylation of histone H2AX (S139), JNK2 (T183/Y185) and p38α (T180/Y182), and cotreatment with JNK/SAPK and p38 MAPK inhibitors reduced complexes-induced apoptosis, indicating DNA double-strand break and activation of caspase-mediated apoptosis through JNK/p38 pathways. Complex 1 also reduced HL-60 cell growth in xenograft model. Overall, the outcome indicated the ruthenium(II) complexes with 6-methyl-2-thiouracil as a novel promising antileukemic drug candidates. Show less

Targeted delivery of clinically approved anticancer drug to tumor sites is an effective way to achieve enhanced drug efficacy as well as reduced side effects and toxicity. Here bicalutamide is caged by the Ru(II) center through the nitrile group, and three photoactive Ru(II) complexes were designed and synthesized. Docking study showed that the ruthenium(II) fragments can effectively block the binding of complexes 1-3 with AR (androgen receptor) owing to the large steric structures, thus bicalutamide in complexes 1-3 could not interact with AR-LBD (ligand binding domain). Once irradiation with blue light (465nm), complexes 1-3 can release bicalutamide and anticancer Ru(II) fragments, which possesses dual-action of AR binding and DNA interaction simultaneously. In vitro cytotoxicity study on these complexes further confirmed that complexes 1-3 exhibited considerable cytotoxicity upon irradiation with blue light. Significantly, complex 3 could be activated at 660nm, which greatly increases the scope of complex 3 to treat deeper within tissue. Theoretical calculations showed that the lowest singlet excitation energy of complex 3 is lower than those of complexes 1-2, which explains the experimental results well. Moreover, the ³MC (metal centered) states of these complexes are more stable than their ³MLCT (metal to ligand charge transfer) states, indicating that the photoactive processes of these complexes are likely to result in ligand dissociation. Show less

To develop next-generation metal drugs with high efficiency and low toxicity for targeting inhibition of gastric tumor growth and metastasis, we not only optimized a series of ruthenium (Ru, III) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes to obtain a Ru(III) complex (4b) with remarkable cytotoxicity in vitro but also constructed a 4b-decitabine (DCT)/liposome (Lip) delivery system (4b-DCT-Lip). The in vivo results showed that 4b-DCT-Lip not only had a stronger capacity to inhibit gastric tumor growth and metastasis than 4b-DCT but also addressed the co-delivery problems of 4b-DCT and improved their targeting ability. Furthermore, we confirmed the mechanism of 4b-DCT/4b-DCT-Lip inhibiting the growth and metastasis of a gastric tumor. DCT-upregulated gasdermin E (GSDME) was cleaved by 4b-activated caspase-3 to afford GSDME-N terminal and then was aggregated to form nonselective pores on the cell membrane of a gastric tumor, thereby inducing pyroptosis and a pyroptosis-induced immune response. Show less

A series of benzothiazole-substituted trisbipyridine ruthenium(II) analogues {[Ru(bpy)(2)(4,5'-bbtb)](2+), [Ru(bpy)(2)(5,5'-bbtb)](2+) and [Ru(bpy)(2)(5-mbtb)](2+) [bpy is 2,2'-bipyridine, bbtb is bis(benzothiazol-2-yl)-2,2'-bipyridine, 5-mbtb is 5-(benzothiazol-2-yl),5'-methyl-2,2'-bipyridine]} have been prepared and compared with the complex [Ru(bpy)(2)(4,4'-bbtb)](2+) reported previously. From the UV-vis spectral studies, substitution at the 5-position of the bpy causes the ligand-centred transitions to occur at considerably lower energy than for those with the functionality at the 4-position, while at the same time causing the emission to be effectively quenched. However, substitution at the 4-position causes the metal-to-ligand charge transfer to occur at lower energies. Fluorescent intercalator displacement studies indicate that the doubly substituted complexes displace ethidium bromide from a range of oligonucleotides, with the greater preference shown for bulge and hairpin sequences by the Lambda enantiomer. Since the complexes only show small variation in the UV-vis spectra on the introduction of calf thymus DNA and a small increase in fluorescence they do not appear to be intercalators, but appear to associate within one of the grooves. All of the reported bisbenzothiazole complexes show reasonable cytotoxicity against a range of human cancer cell lines. Show less

We herein report the synthesis, characterization and anticancer activity of BTPIP (2-(4-(benzo[b]thiophen-2-yl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) and its four ruthenium(II) polypyridyl complexes [Ru(NN)₂(BTPIP)](ClO₄)₂ (N-N = bpy = 2,2'-bipyridine, Ru(II)-1; phen = 1,10-phenanthroline, Ru(II)-2; dmb = 4,4'-dimethyl-2,2'-bipyridine, Ru(II)-3; dmp = 2,9-dimethyl-1,10-phenanthroline, Ru(II)-4). The DNA binding behaviors reveal that the complexes bind to calf thymus DNA by intercalation. Cytotoxicity of the complexes against A549, HepG-2, SGC-7901 and Hela cells were evaluated in vitro. Complexes Ru(II)-1, Ru(II)-2, Ru(II)-3, Ru(II)-4 show moderate activity on the cell proliferation in A549 cells with IC₅₀ values of 9.3 ± 1.2, 12.1 ± 1.6, 10.3 ± 1.6, 8.9 ± 1.2 μM, respectively. Apoptosis assessment, intracellular mitochondrial membrane potential (MMP), location in mitochondria, reactive oxygen species (ROS), cell invasion assay and cell cycle arrest were also performed to explore the mechanism of this action. When the concentration of the ruthenium(II) complexes is increased, the amount of reactive oxygen species increases obviously and the mitochondrial membrane potential decreases dramatically in A549 cells. Most importantly, the ruthenium(II) polypyridyl complexes could arrive the cytoplasm through the cell membrane and accumulate in the mitochondria. These results showed that the ruthenium(II) complexes could induce apoptosis in A549 cells through an ROS-mediated mitochondrial dysfunction pathway. Show less

Two 4-phenyl-3-thiosemicarbazone ligands, (E)-2-(2-chlorobenzylidene)-N-phenylhydrazinecarbothioamide (HL(1)) and (E)-2-(2-nitrobenzylidene)-N-phenylhydrazinecarbothioamide (HL(2)), and its ruthenium(II) complexes were synthesized and characterized by physico-chemical and spectroscopic methods. The Schiff bases act as bidentate, monobasic chelating ligands with S and N as the donor sites and are preferably found in the thiol form in all the complexes studied. The molecular structure of HL(1) and HL(2) were determined by single crystal X-ray diffraction method. DNA binding of the compounds was investigated by absorption spectroscopy which indicated that the compounds bind to DNA via intercalation. The oxidative cleavage of the complexes with CT-DNA inferred that the effects of cleavage are dose dependent. Antioxidant study of the ligands and complexes showed significant antioxidant activity against DPPH radical. In addition, the in vitro cytotoxicity of the ligands and complexes assayed against HeLa and MCF-7 cell lines showed higher cytotoxic activity with the lower IC50 values indicating their efficiency in killing the cancer cells even at low concentrations. Show less

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