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Novel metal complexes have received great attention in the last decades due to their potential anticancer activity. Notably, ruthenium-based complexes have emerged as good alternative to the currently used platinum-based drugs for cancer therapy, providing less toxicity and side effects to patients. Glioblastoma is an aggressive and invasive type of brain tumor and despite of advances is the field of neurooncology there is no effective treatment until now. Therefore, we sought to investigate the potential antiproliferative activity of phosphine-ruthenium-based complexes on human glioblastoma cell lines. Due to its octahedral structure as opposed to the square-planar geometry of platinum(II) compounds, ruthenium(II) complexes exhibit different structure-function relationship probably acting through a different mechanism from that of cisplatin beyond their ability to bind DNA. To better improve the pharmacological activity of metal complexes we hypothesized that neutron activation of ruthenium in the complexes would allow to decrease the effective concentration of the compound needed to kill tumor cells. Herein we report on the effect of unmodified and neutron activated phosphine ruthenium II complexes on glioblastoma cell lines carrying wild-type and mutated p53 tumor suppressor gene. Induction of apoptosis/authophagy as well as generation of reactive oxygen species were determined. The phosphine ruthenium II complexes tested were highly active against glioblastoma cell lines inducing cell death both through apoptosis and autophagy in a p53 independent fashion. Neutron activation of ruthenium compounds rendered them more active than their original counterparts suggesting a new strategy to improve the antitumor activity of these compounds. Show less

Guanidinium-functionalized molecules are commonly studied for their use as pharmaceutically active compounds and drugs carriers. Herein, four cyclometalated iridium(III) complexes containing guanidinium ligands have been synthesized and characterized as potential anticancer agents. These complexes exhibit moderate antitumor activity in HeLa, MCF-7, HepG2, CNE-2, and A549 human tumor cells. Interestingly, all complexes showed higher cytotoxicity than cisplatin against a cisplatin-resistant cell line A549R, and less cytotoxicity on the nontumorigenic LO2 cells. Intracellular distribution studies suggest that these complexes are selectively localized in the mitochondria. Mechanism studies indicate that these complexes arrested the cell cycle in the G0/G1 phase and can influence mitochondrial integrity, inducing cancer cell death through reactive oxygen species (ROS)-dependent pathways. Show less

There iridium(III) complexes, [Ir(3-MeO-Phtpy)Cl₃] (1), [Ir(2-MeO-Phtpy)Cl₃] (2) and [Ir(4-MeO-Phtpy)Cl₃] (3) with 4'-(3-methoxyphenyl)-2,2':6',2″-terpyridine (3-MeO-Phtpy), 4'-(2-methoxyphenyl)-2,2':6',2″-terpyridine (2-MeO-Phtpy) and 4'-(4-methoxyphenyl)-2,2':6',2″-terpyridine (4-MeO-Phtpy) as ligands, respectively, were synthesized and evaluated for their antiproliferative activities. In these complexes, the iridium(III) center adopts a six-coordinate distorted octahedral geometry. Among them, complex 1 exhibited the most potent activity, with IC₅₀ values of 3.19-27.77 μM against four cancer cell lines (BEL-7404, Hep-G2, NCI-H460 and MGC80-3 cells). Cellular mechanism studies suggested that complexes 1-3 directly targeted c-myc promoter elements and inhibited the telomerase activity. In addition, complexes 1-3 may trigger cell apoptosis via a mitochondrial dysfunction pathway. We postulated that the difference in the in vitro antitumor activities of complexes 1-3 is mainly dependent on the position of the methoxy group on the phenyl ring of the iridium ligand. Show less

An iridium (III) complex [Ir(ppy)₂(BDPIP)]PF₆ (Ir-1) was reported to show high anticancer activity and may be used as a potent anticancer drug. In the current study, we designed and synthesized a novel iridium (III) complex and evaluated its potential inhibitory effect on the cancer cell growth in vitro and in vivo. This complex was found to display high cytotoxic activity in vitro and in vivo against A549 cell with a low IC₅₀ value of 3.6 ± 0.3 μM and inhibiting percentage of tumor growth is 63.84% compared with the control. The complex also exhibited potencies superior to that of cisplatin toward A549 cell in vitro and in vivo. Further studies revealed that the complex can induce apoptosis and autophagy, enhance the ROS level, cause a decrease in the mitochondrial membrane potential and inhibit the cell invasion. Our findings indicated that the complex induced apoptosis in A549 through mitochondria dysfunction and PI3K/AKT/mTOR signaling pathways. Show less

A new ligand THPDP (THPDP = 11-(6,7,8,9-tetrahydrophenazin-2-yl)dipyrido[3,2-a:2',3'-c]phenazine) and its iridium(III) complex [Ir(ppy)₂(THPDP)]PF₆ (Ir-1) was synthesized and characterized by elemental analysis, IR, ESI-MS, ¹H NMR and ¹³C NMR. The cytotoxicity in vitro of the complex against cancer cells B16, A549, Eca-109, SGC-7901, BEL-7402 and normal NIH 3T3 cell lines was evaluated using MTT method. The IC₅₀ values of the complex toward B16, A549 and Eca-109 cells are 1.0 ± 0.02, 1.4 ± 0.03 and 1.6 ± 0.06 μM, respectively. The apoptosis was investigated with AO/EB and DAPI staining methods. The complex shows strong ability to inhibit the cell growth in B16, A549 and Eca-109 cells. Ir-1 can induce apoptosis, increase the intracellular ROS level, and cause a decrease in the mitochondrial membrane potential. The intracellular Ca²⁺ level and the release of cytochrome c were studied under a fluorescent microscope. The cell invasion and autophagy were also performed, and the cell cycle arrest was assayed by flow cytometry. The expression of Bcl-2 family proteins, PI3K, AKT, mTOR, P-mTOR was investigated by western blot. The results show that the complex induces apoptosis through ROS-mediated mitochondria dysfunction and inhibition of AKT/mTOR pathways. These findings are helpful for design and synthesis of iridium(III) complexes as potent anticancer drugs. Show less

Many phosphorescent iridium complexes are potent candidates as photodynamic therapeutic agents. In this work, a series of mixed-ligand phosphorescent iridium complexes (Ir1: [Ir(L₁)(bpy)Cl](PF₆)₂; Ir2: [Ir(L₁)(ppy)Cl](PF₆); Ir3: [Ir(L₂)(bpy)Cl](PF₆)₂; Ir4: [Ir(L₂)(ppy)Cl](PF₆). L₁ = 2,6-bis(2-benzimidazolyl)pyridine; bpy = 2,2'-bipyridine; L₂ = 2,6-bis(1-methyl-benzimidazol-2-yl)pyridine; ppy = 2-phenylpyridine) have been synthesized and characterized. These complexes display high luminescence quantum yields and long phosphorescence lifetimes. All the complexes are resistant to hydrolysis in aqueous solutions, and can produce singlet oxygen (¹O₂) effectively upon irradiation. Ir1 and Ir2 show pH-sensitive emission properties. Interestingly, higher cellular uptake efficiency is observed for Ir2 and Ir4 with the cyclometalated ppy ligand in human lung adenocarcinoma A549 cells. Ir2 with pH-sensitive emission properties can selectively image lysosomes, and Ir4 can specifically target mitochondria. Both Ir2 and Ir4 exhibit potent photodynamic therapy (PDT) effects, with Ir2 displaying a higher phototoxicity index (PI) especially in A549 cells (PI > 54). Mechanism studies indicate that Ir2 and Ir4 can induce apoptosis through reactive oxygen species (ROS) generation and caspase activation upon visible light (425 nm) irradiation. As expected, Ir2 can damage lysosomes more effectively with a pH-sensitive singlet oxygen (¹O₂) yield, while Ir4 tends to impair mitochondrial function. Nevertheless, the practical application of Ir2 and Ir4 for PDT may be limited to superficial tumors due to the short excitation wavelength (425 nm). Our study gives insights into the design and anticancer mechanisms of new metal-based PDT anticancer agents. Show less

Six cyclometalated iridium(iii) complexes bearing different numbers of fluorine atoms were synthesized. These complexes demonstrated much better anti-proliferation activities towards five tumour cell lines than the widely used clinical chemotherapeutic agent cisplatin. Moreover, the anti-proliferation activities were correlated to the number of substituted fluorine atoms. Colocalization and inductively coupled plasma-mass spectrometry (ICP-MS) indicated that this series of complexes could penetrate cell membranes rapidly and preferentially target mitochondria. Manifesting high selectivity between tumour cells and normal cells and remarkable sensitivity to a cisplatin-resistant cell line (A549R), complex Ir6 was successfully developed as a novel anticancer agent (with IC₅₀ values of 0.5 ± 0.1 μM for HeLa, 1.1 ± 0.2 μM for HepG2, 1.5 ± 0.3 μM for BEL-7402, 0.8 ± 0.1 μM for A549, and 0.7 ± 0.2 μM for A549R cell lines). Further mechanism studies including mitochondrial membrane potential depolarization and caspase 3/7 activation revealed that Ir6 induced apoptosis via mitochondrial pathways. These results demonstrated that complex Ir6 might be a promising candidate as a mitochondria-targeted theranostic anticancer agent. Show less

Seven novel half-sandwich Ir^III cyclopentadienyl complexes, [(η⁵-Cp^x)Ir(N^N)Cl]PF₆, have been prepared and characterized, where Cp^x is Cp* or the biphenyl derivative Cp^xbiph (C₅Me₄C₆H₄C₆H₅), and the N^N-chelating ligands are imino-pyridyl Schiff-bases. The X-ray crystal structures of complexes 2A, 2B, and 3A have been determined. Excitingly, most of the complexes show potent antiproliferative activity towards A549 and HeLa cancer cells, except for Cp* complex 1A towards HeLa cells. Cp^xbiph complex 2B displayed the highest potency, about 19 and 6 times more active than the clinically used drug cisplatin toward A549 and HeLa cells, respectively. These complexes undergo hydrolysis, and the kinetics data have been calculated. DNA binding has been studied by interaction with nucleobases 9-ethylguanine and 9-methyladenine, cleavage of plasmid DNA, and interaction with ctDNA. Interaction with DNA does not appear to be the major mechanism of action. Protein binding (bovine serum albumin, BSA) has been established by UV-Vis, fluorescence and synchronous spectroscopic studies. The stability of complex 2B in the presence of GSH was evaluated. The complexes catalytically convert coenzyme NADH to NAD⁺via hydride transfer. Cp^xbiph complexes 2B and 4B induce cell apoptosis and arrest cell cycles at the S and G₂/M phases towards A549 cancer cells and increase the reactive oxygen species dramatically, which appear to contribute to the remarkable anticancer activity. Show less

Half-sandwich pseudo-octahedral pentamethylcyclopentadienyl Ir^III complexes of the type [(η⁵-Cp^x)Ir(C^C)Cl]PF₆, where Cp^x is pentamethylcyclopentadienyl (Cp*), or its phenyl (Cp^xph = C₅Me₄C₆H₅) or biphenyl (Cp^xbiph = C₅Me₄C₆H₄C₆H₅) derivatives, and the C^C-chelating ligands are different N-heterocyclic carbene (NHC) ligands, have been synthesized and characterized. Three X-ray crystal structures have been determined. Except for Cp* complex 1A, the other eleven complexes 1B-4C all showed potent cytotoxicity, with IC₅₀ values ranging from 2.9 to 46.3 μM toward HeLa human cervical cancer cells. The potency toward HeLa cells increased with additional phenyl substitution on Cp*: Cp^xbiph > Cp^xph > Cp*, and increased with the size of chain substitution on the C^C-ligand in the order: ph > butyl > ethyl > methyl. Complex [(η⁵-C₅Me₄C₆H₄C₆H₅)Ir(L4)Cl]PF₆ (4C) displayed the highest potency, and was about 3 times more active than the clinical platinum drug cisplatin. Complexes 1A-4C all undergo hydrolysis and their kinetics was studied. DNA binding appears not to be the major mechanism of action. The ability of these iridium complexes to catalyze hydride transfer from the coenzyme NADH to NAD⁺ was studied. Complexes [(η⁵-C₅Me₄C₆H₄C₆H₅)Ir(L2)Cl]PF₆ (2C) and [(η⁵-C₅Me₄C₆H₄C₆H₅)Ir(L3)Cl]PF₆ (3C) cause cell apoptosis and arrest the cell cycle at the G₁ phase and G₂/M phase when HeLa cancer cells are treated with different IC₅₀ concentrations of the complexes, and increase the amount of reactive oxygen species (ROS) dramatically, which appears to contribute to the anticancer activity. This class of organometallic Ir complexes has unusual features worthy of further exploration in the design of novel anticancer drugs. Show less

Metal N-heterocyclic carbene (NHC) complexes represent a promising class of anticancer therapeutic agents. In this work, four cyclometalated iridium(iii) complexes (Ir1-Ir4) containing N-heterocyclic carbene ligands have been explored as mitochondrial anticancer and photodynamic agents. These complexes are more cytotoxic than cisplatin against the cancer cells screened, can quickly penetrate into A549 cells and are mainly localized in the mitochondria. Mechanism studies show that these complexes exert their anticancer efficacy by increasing the intracellular ROS level, reducing the mitochondrial membrane potential (MMP) and inducing apoptosis. Additionally, Ir1-Ir4 exhibited two orders of magnitude higher cytotoxicity upon irradiation at 450 nm LED light. Our work provides a strategy for the design of highly effective anticancer photodynamic therapeutic agent based phosphorescent iridium complexes. Show less

Synthesis of terpyridyl based ligands 3-([2,2':6',2''-terpyridin]-4'-yl)-7-methoxy-2-(methylthio)-quinolone, (L1); 3-([2,2':6',2''-terpyridin]-4'-yl)-6-methoxyquinolin-2(1H)-one, (L2); 3-([2,2'-:6',2''-terpyridin]-4'-yl)-6-methylquinolin-2(1H)-one (L3) and cyclometalated iridium(iii) complexes [[Ir(ppy)₂L1]⁺PF₆^- (1), [Ir(ppy)₂L2]⁺PF₆^- (2), [Ir(ppy)₂L3]⁺PF₆^- (3) (2-phenylpyridine = Hppy)] involving these ligands has been described. The ligands L1-L3 and complexes 1-3 have been thoroughly characterized by elemental analyses, spectral studies (IR, ¹H, ¹³C NMR, UV/vis and fluorescence) ESI-MS, and the structure of 3 has been unambiguously authenticated by single crystal X-ray analyses. UV/vis, fluorescence and circular dichroism spectroscopic studies showed rather efficient binding of 1 with CT-DNA (calf thymus DNA) and BSA (bovine serum albumin) relative to 2 and 3. Molecular docking studies unveiled binding of 1-3 with minor groove of CT-DNA via van der Waal's forces and electrostatically with the hydrophobic moiety of HSA (human serum albumin). The ligands and complexes exhibited moderate cytotoxicity towards MDA-MB-231 (breast cancer cell line) and significant influence on HeLa (cervical cancer cell line) cells. Cytotoxicity, morphological changes, and apoptosis have been followed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) assay, Hoechst 33342/PI (PI = propidium iodide) staining, cell cycle analysis by FACS (fluorescence activated cell sorting), and ROS (reactive oxygen species) generation by DCFH-DA (dichlorodihydrofluorescein diacetate) dye. Confocal microscopy images revealed that the drug efficiently initiates apoptosis in the cell cytosol. The IC₅₀ values showed superior cytotoxicity of 1-3 against the HeLa cell line relative to cisplatin, and their ability to induce apoptosis is in the order 1 > 2 > 3. Show less

Organometallic ruthenium complexes as potential anticancer agents have been explored due to their suitable properties, such as stability in the solid state and in solution, water solubility and low toxicity. In this study, eight metal complexes of this class were synthesized, characterized and their important biological activities against a human breast tumor cell line (MDA-MB-231) were studied. Complexes 1-8 were obtained in good yields and have been characterized by satisfactory elemental analyses, IR, 1D and 2D ¹H and ¹³C{¹H} NMR, UV-Vis spectroscopy, cyclic voltammetry, ESI-MS and X-ray diffractometry (1, 2, 3 and 6). All complexes exhibit growth inhibition on human breast and lung tumor cell lines, with IC₅₀ values ranging from 6.0 to 45.0 μM in 48 h. Four compounds were selected to evaluate the changes in the morphology, clonogenic, migration, cell cycle arrest and cell death in MDA-MB-231 cells. The complexes are able to induce morphological changes and inhibit the size, number of colonies and cell migration, and induce cell cycle arrest in the sub-G1 phase and apoptosis cell death. The interaction of the complexes with DNA was determined by performing spectroscopic titration, a competitive assay with thiazole orange, circular dichroism, gel electrophoresis and interactions with guanosine or guanosine monophosphate by ¹H NMR, indicating the non-covalent interaction. The HSA binding affinity measured by spectrophotometric titration, revealed the hydrophobic and spontaneous association with the human protein. Overall, the studies indicated that these metal complexes are potential agents against MDA-MB-231 cells, encouraging us to continue studies of these types of compounds. Show less

The successful design, synthesis, characterization, photophysical properties and anticancer mechanistic studies of a series of half-sandwich cyclopentadienyl iridium(iii) complexes of the type [Cp*Ir^III(LC)(L1)](PF₆), 1, and [Cp*Ir^III(LC)(L2)](PF₆), 2, in which Cp* = pentamethylcyclopentadienyl, L1 = 4-(pyren-10-yl)ethynyl-phenylcyanamide, L2 = 4'-(pyren-10-yl)ethynyl-4-cyanamidobiphenyl, and LC = lidocaine, are reported for their application as photodynamic therapy (PDT) agents. The DNA binding, DNA photocleavage, cellular uptake, and apoptosis of the complexes have also been studied. Show less

Three ruthenium(II) phosphine/diimine/picolinate complexes were selected aimed at investigating anticancer activity against several cancer cell lines and the capacity of inhibiting the supercoiled DNA relaxation mediated by human topoisomerase IB (Top 1). The structure-lipophilicity relationship in membrane permeability using the Caco-2 cells have also been evaluated in this study. SCAR 5 was found to present 45 times more cytotoxicity against breast cancer cell when compared to cisplatin. SCAR 4 and 5 were both found to be capable of inhibiting the supercoiled DNA relaxation mediated by Top 1. Interaction studies showed that SCAR 4 and 5 can bind to DNA through electrostatic interactions while SCAR 6 is able to bind covalently to DNA. The complexes SCAR were found to interact differently with bovine serum albumin (BSA) suggesting hydrophobic interactions with albumin. The permeability of all complexes was seen to be dependent on their lipophilicity. SCAR 4 and 5 exhibited high membrane permeability (P _app  > 10 × 10^-6 cm·s^-1) in the presence of BSA. The complexes may pass through Caco-2 monolayer via passive diffusion mechanism and our results suggest that lipophilicity and interaction with BSA may influence the complexes permeation. In conclusion, we demonstrated that complexes have powerful pharmacological activity, with different results for each complex depending on the combination of their ligands. Show less

Organometallic iridium complexes have emerged as potent anticancer agents in recent years. In this work, three cyclometalated iridium(iii) complexes Ir1-Ir3 containing monodentate five-membered heterocyclic ligands have been synthesized and characterized. Upon visible light (425 nm) irradiation, the five-membered heterocyclic ligands will dissociate from the metal centre. Moreover, Ir1-Ir3 can also act as effective singlet oxygen photosensitizers. Thus, Ir1-Ir3 can exert their light-mediated activation of anticancer effects by dual modes including ligand exchange reactions and generation of singlet oxygen (¹O₂) upon visible light irradiation. Notably, Ir1 displays a high phototoxicity index of 61.7 against human cancer cells. Further studies show that light-mediated anticancer properties exerted by Ir1-Ir3 occur through reactive oxygen species (ROS) generation, caspase activation, and eventually apoptosis induction. Our study demonstrates that these complexes can act as novel dual-mode light-mediated anticancer agents. Show less

Ruthenium(II) arene complexes of 1,4,7-triaza-9-phosphatricyclo[5.3.2.1]tridecane (CAP) were obtained. Cytotoxicity studies against cancer cell lines reveal higher activity than the corresponding PTA analogues and, in comparison to the effects on noncancerous cells, the complexes are endowed with a reasonable degree of cancer cell selectivity. Show less

Five heteroleptic tris-diimine ruthenium(II) complexes [RuL(N^N)₂](PF₆)₂ (where L is 3,8-di(benzothiazolylfluorenyl)-1,10-phenanthroline and N^N is 2,2'-bipyridine (bpy) (1), 1,10-phenanthroline (phen) (2), 1,4,8,9-tetraazatriphenylene (tatp) (3), dipyrido[3,2-a:2',3'-c]phenazine (dppz) (4), or benzo[i]dipyrido[3,2-a:2',3'-c]phenazine (dppn) (5), respectively) were synthesized. The influence of π-conjugation of the ancillary ligands (N^N) on the photophysical properties of the complexes was investigated by spectroscopic methods and simulated by density functional theory (DFT) and time-dependent DFT. Their ground-state absorption spectra were characterized by intense absorption bands below 350 nm (ligand L localized ¹π,π* transitions) and a featureless band centered at ∼410 nm (intraligand charge transfer (¹ILCT)/¹π,π* transitions with minor contribution from metal-to-ligand charge transfer (¹MLCT) transition). For complexes 4 and 5 with dppz and dppn ligands, respectively, broad but very weak absorption (ε < 800 M^-1 cm^-1) was present from 600 to 850 nm, likely emanating from the spin-forbidden transitions to the triplet excited states. All five complexes showed red-orange phosphorescence at room temperature in CH₂Cl₂ solution with decreased lifetimes and emission quantum yields, as the π-conjugation of the ancillary ligands increased. Transient absorption (TA) profiles were probed in acetonitrile solutions at room temperature for all of the complexes. Except for complex 5 (which showed dppn-localized ³π,π* absorption with a long lifetime of 41.2 μs), complexes 1-4 displayed similar TA spectral features but with much shorter triplet lifetimes (1-2 μs). Reverse saturable absorption (RSA) was demonstrated for the complexes at 532 nm using 4.1 ns laser pulses, and the strength of RSA decreased in the order: 2 ≥ 1 ≈ 5 > 3 > 4. Complex 5 is particularly attractive as a broadband reverse saturable absorber due to its wide optical window (430-850 nm) and long-lived triplet lifetime in addition to its strong RSA at 532 nm. Complexes 1-5 were also probed as photosensitizing agents for in vitro photodynamic therapy (PDT). Most of them showed a PDT effect, and 5 emerged as the most potent complex with red light (EC₅₀ = 10 μM) and was highly photoselective for melanoma cells (selectivity factor, SF = 13). Complexes 1-5 were readily taken up by cells and tracked by their intracellular luminescence before and after a light treatment. Diagnostic intracellular luminescence increased with increased π-conjugation of the ancillary N^N ligands despite diminishing cell-free phosphorescence in that order. All of the complexes penetrated the nucleus and caused DNA condensation in cell-free conditions in a concentration-dependent manner, which was not influenced by the identity of N^N ligands. Although the mechanism for photobiological activity was not established, complexes 1-5 were shown to exhibit potential as theranostic agents. Together the RSA and PDT studies indicate that developing new agents with long intrinsic triplet lifetimes, high yields for triplet formation, and broad ground-state absorption to near-infrared (NIR) in tandem is a viable approach to identifying promising agents for these applications. Show less

The design of Ru or other metal-based anticancer agents may achieve better and faster optimization if the ligands used are also designed to have standalone functions. In this scenario, even after dissociation from the metal complex under adverse conditions, the ligand would have anti-cancer properties. In our work, we have generated a bispyrazole-containing benzimidazole ligand with potency against vascular endothelial growth factor receptor 2 (VEGFR2), which is known to have roles in vasculogenesis/angiogenesis. This ligand was used to obtain ternary Ru(ii) p-cymene complexes with the formulations [(η⁶-p-cymene)Ru(HL)(Cl)](Cl) (1), [(η⁶-p-cymene)Ru(HL)(Br)](Br) (2) and [(η⁶-p-cymene)Ru(HL)(I)](I) (3). ¹H NMR data supports that hydrolysis of the complex is governed by halide substitution, and the extent of hydrolysis followed the trend 3 > 1 > 2. All the complexes have low affinity towards DNA bases (average K_b ∼ 10³ M^-1 for CT DNA); however, all the complexes are cytotoxic in nature, with IC₅₀ values less than 15 μM. The presence of excess glutathione (GSH) liberates HL from the complexes in solution. The ability of the Ru complex to impair mitochondrial function and reduce the cellular GSH pool is thought to be the reason that it retains activity in the presence of GSH despite the ability of GSH to degrade the complexes. The chloride analogue 1 shows the best in vitro cytotoxicity against a prostate cancer cell line (LNCaP), with an IC₅₀ of 6.4 μM. The complexes show anti-proliferative activity by the mitochondria-mediated intrinsic apoptotic pathway. Docking studies showed that HL has high affinity towards vascular endothelial growth factor receptor 2 (VEGFR2). The complexes show anti-metastatic activity (in vitro) at almost non-toxic dosages, and the effect is sustained even 48 h after removal of the complexes from the culture media. Show less

With the aim of assessing how the aromaticity of the inert chelating ligand can influence the activity of ruthenium(II) polypyridyl complexes, two new monofunctional ruthenium(II) complexes, [Ru(Cl-Ph-tpy)(phen)Cl]Cl (1) and [Ru(Cl-Ph-tpy)(o-bqdi)Cl]Cl (2) (where Cl-Ph-tpy = 4'-(4-chlorophenyl)-2,2':6',2″-terpyridine, phen = 1,10-phenanthroline, o-bqdi = o-benzoquinonediimine), were synthesized. All complexes were fully characterized by elemental analysis and spectroscopic techniques (IR, UV-Vis, 1D and 2D NMR, XRD). Their chemical behavior in aqueous solution was studied by UV-Vis and NMR spectroscopy showing that both compounds are relatively labile leading to the formation of the corresponding aqua species 1a and 2a. ¹H NMR spectroscopy studies performed on complexes 1 and 2 demonstrated that after the hydrolysis of the Cl ligand, they are capable to interact with guanine derivatives (i.e., 9-methylguanine (9MeG) and 5'-GMP) through the N7, forming monofunctional adduct. The kinetics and the mechanism of the reaction of complexes 1 and 2 with the biologically more relevant 5'-GMP ligand were studied by UV-Vis spectroscopy. DNA/protein interactions of the complexes have been examined by photophysical studies, which demonstrated a bifunctional binding mode of the complexes with DNA and the complexes strongly quench the fluorescence intensity of bovine serum albumin (BSA) through the mechanism of both static and dynamic quenching. Complexes 1 and 2 strongly induced apoptosis of treated cancer cells with high percentages of apoptotic cells and negligible percentage of necrotic cells. In addition, both ruthenium complexes decreased Bcl-2/Bax ratio causing cytochrome c mitochondrial release, the activation of caspase-3 and induction of apoptosis. Show less

A new ligand PFPIP (PFPIP=2-(2,3,4,5,6-pentafluorophenyl)[4,5-f]imadazo [1,10]phenanthroline) and its four ruthenium(II) polypyridyl complexes [Ru(NN)₂(PFPIP)](ClO₄)₂ (NN=dmb: 4,4'-dimethyl-2,2'-bipyridine, 1; bpy: 2,2'-bipyridine, 2; phen: 1,10-phenanthroline, 3; dmp: 2,9-dimethyl-1,10-phenanthroline, 4) were synthesized and characterized by elemental analysis, IR, ¹H NMR, ¹³C NMR and ESI-MS. The cytotoxic activity in vitro of the ligand and complexes toward BEL-7402, A549, HeLa, HepG2 and MG-63 cell lines was evaluated using MTT method (MTT=(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). Complexes 1, 3 and 4 show moderate cytotoxic effect on the cell growth in BEL-7402 cells with IC₅₀ values of 32.1±0.9, 37.9±1.7 and 42.1±3.0μM, respectively. The apoptosis in BEL-7402 cell was investigated with AO/EB and Hoechst 33,258 staining methods. The autophagy in BEL-7402 cell induced by complexes was assayed using MDC staining cell nuclei. The cell invasion, reactive oxygen species (ROS), mitochondrial membrane potential, cell cycle arrest, cellular uptake, comet assay and wound healing were studied under a fluorescent microscope. The complexes can cause autophagy and inhibit the cell invasion, and increase the ROS levels and induce a decrease in the mitochondrial membrane potential. The expression of the proteins related with apoptosis induced by the complexes was assayed by western blot analysis. Show less