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
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
Fine-tuning of the properties of a recently reported 1,3-indandione-based organoruthenium complex is attempted to optimize the stability under physiological conditions. Previous work has shown its cap Show more
Fine-tuning of the properties of a recently reported 1,3-indandione-based organoruthenium complex is attempted to optimize the stability under physiological conditions. Previous work has shown its capacity of inhibiting topoisomerase IIα; however, fast aquation leads to undesired reactions and ligand cleavage in the blood stream before the tumor tissue is reached. Exchange of the chlorido ligand for six different N-donor ligands resulted in new analogs that were stable at pH 7.4 and 8.5. Only a lowered pH level, as encountered in the extracellular space of the tumor tissue, was capable of aquating the complexes. The 50% inhibitory concentration (IC50) values in three human cancer cell lines differed only slightly, and their dependence on the utilized leaving group was smaller than what would be expected from their differences in cellular accumulation, but in accordance with the very minor variation revealed in measurements of the complexes' lipophilicity. Show less
Glioma stem cells (GSCs) are thought to be responsible for the recurrence and invasion of glioblastoma multiform (GBM), which have been evaluated and exploited as the therapeutic target for GBM. Cyclo Show more
Glioma stem cells (GSCs) are thought to be responsible for the recurrence and invasion of glioblastoma multiform (GBM), which have been evaluated and exploited as the therapeutic target for GBM. Cyclometalated iridium(III) complexes have been demonstrated as the potential anticancer agents, however, their antitumor efficacies against GSCs are still unknown. Herein, we investigated the antitumor activity of two cyclometalated iridium(III) complexes [Ir(ppy)2L](PF6) (Ir1) and [Ir(thpy)2L](PF6) (Ir2) (ppy = 2-phenylpyridine, thpy = 2-(2-thienyl)pyridine and L = 4,4'-Bis(hydroxymethyl)-2,2'-bipyridine) against GSCs. The results clearly indicate that Ir1 and Ir2 kill GSCs selectively with IC50 values ranging from 5.26-9.05 μM. Further mechanism research display that Ir1 and Ir2 can suppress the proliferation of GSCs, penetrate into GSCs efficiently, localize to mitochondria, and induce mitochondria-mediated apoptosis, including the loss of mitochondrial membrane (MMP), elevation of intracellular reactive oxygen species (ROS) and caspases activation. Moreover, Ir1 and Ir2 can destroy the GSCs self-renewal and unlimited proliferation capacity by affecting the GSCs colony formation. According our knowledge, this is the first study to investigate the anti-GSCs properties of cyclometalated iridium(III) complexes. Show less
The rational design by the introduction of fluorine into a compound has achieved success in the development of organic anticancer drugs. However, the fluorine effect in metal-based anticancer complexe Show more
The rational design by the introduction of fluorine into a compound has achieved success in the development of organic anticancer drugs. However, the fluorine effect in metal-based anticancer complexes has rarely been reported. In this contribution, we report the synthesis, characterization, chemical reactivity, and biological activity of a series of half-sandwich zwitterionic iridium(III) complexes containing different substituents in the η5-CpR ring. The molecular structures for complexes Ir1-Ir4 and Ir7 were determined by single-crystal X-ray crystallography techniques. Notably, the asymmetrically substituted fluoro complexes Ir4 and Ir6 in solution show two conformational isomers. These complexes have sufficient stability, exhibit fluorescence emission, and show potent catalytic activity in converting NADH to NAD+. The effect of the substituents in the η5-CpR ring for these zwitterionic complexes on their anticancer activity was systematically investigated. Surprisingly, the presence of fluorinated substituents gives rise to a significant increase in the anticancer activity. The lipophilicity and cellular uptake levels of these complexes appeared to be the primary factors for their cytotoxicity in this system. A microscopic mechanism study showed that the typical complex Ir4 entered A549 cancer cells through an energy-dependent pathway and was mainly located in lysosomes. Furthermore, an increase in ROS level, apoptosis induction, and cell-cycle perturbation together contribute to the anticancer potency of these zwitterionic complexes. Show less
Mammalian tissues are fuelled by circulating nutrients, including glucose, amino acids, and various intermediary metabolites. Under aerobic conditions, glucose is generally assumed to be burned fully Show more
Mammalian tissues are fuelled by circulating nutrients, including glucose, amino acids, and various intermediary metabolites. Under aerobic conditions, glucose is generally assumed to be burned fully by tissues via the tricarboxylic acid cycle (TCA cycle) to carbon dioxide. Alternatively, glucose can be catabolized anaerobically via glycolysis to lactate, which is itself also a potential nutrient for tissues and tumours. The quantitative relevance of circulating lactate or other metabolic intermediates as fuels remains unclear. Here we systematically examine the fluxes of circulating metabolites in mice, and find that lactate can be a primary source of carbon for the TCA cycle and thus of energy. Intravenous infusions of 13C-labelled nutrients reveal that, on a molar basis, the circulatory turnover flux of lactate is the highest of all metabolites and exceeds that of glucose by 1.1-fold in fed mice and 2.5-fold in fasting mice; lactate is made primarily from glucose but also from other sources. In both fed and fasted mice, 13C-lactate extensively labels TCA cycle intermediates in all tissues. Quantitative analysis reveals that during the fasted state, the contribution of glucose to tissue TCA metabolism is primarily indirect (via circulating lactate) in all tissues except the brain. In genetically engineered lung and pancreatic cancer tumours in fasted mice, the contribution of circulating lactate to TCA cycle intermediates exceeds that of glucose, with glutamine making a larger contribution than lactate in pancreatic cancer. Thus, glycolysis and the TCA cycle are uncoupled at the level of lactate, which is a primary circulating TCA substrate in most tissues and tumours. Show less
Sensitivity and resistance of cells to platinum drug chemotherapy are to a large extent determined by activity of the DNA damage response (DDR). Combining chemotherapy with inhibition of specific DDR Show more
Sensitivity and resistance of cells to platinum drug chemotherapy are to a large extent determined by activity of the DNA damage response (DDR). Combining chemotherapy with inhibition of specific DDR pathways could therefore improve treatment efficacy. Multiple DDR pathways have been implicated in removal of platinum-DNA lesions, but it is unclear which exact pathways are most important to cellular platinum drug resistance. Here, we used CRISPR/Cas9 screening to identify DDR proteins that protect colorectal cancer cells against the clinically applied platinum drug oxaliplatin. We find that besides the expected homologous recombination, Fanconi anemia and translesion synthesis pathways, in particular also transcription-coupled nucleotide excision repair (TC-NER) and base excision repair (BER) protect against platinum-induced cytotoxicity. Both repair pathways are required to overcome oxaliplatin- and cisplatin-induced transcription arrest. In addition to the generation of DNA crosslinks, exposure to platinum drugs leads to reactive oxygen species production that induces oxidative DNA lesions, explaining the requirement for BER. Our findings highlight the importance of transcriptional integrity in cells exposed to platinum drugs and suggest that both TC-NER and BER should be considered as targets for novel combinatorial treatment strategies. Show less
In this study we report the synthesis, characterization and a thorough biological evaluation of twelve organoruthenium-8-hydroxyquinolinato (Ru-hq) complexes. The chosen hqH ligands bear various halog Show more
In this study we report the synthesis, characterization and a thorough biological evaluation of twelve organoruthenium-8-hydroxyquinolinato (Ru-hq) complexes. The chosen hqH ligands bear various halogen atoms in different positions which enables to study effect of the substituents on physico-chemical and biological properties. The determined crystal structures of novel complexes expectedly show the cymene ring, a bidentately coordinated deprotonated hq and a halide ligand (chlorido or iodido) coordinated to the ruthenium central ion. In previous studies the anticancer potential of organoruthenium complex with 8-hydroxyquinoline ligand clioquinol was well established and we have decided to perform an extended biological evaluation (antibacterial and antitumor activity) of the whole series of halo-substituted analogs. Beside the cytotoxic potential of studied compounds also the effect of two selected complexes (9 and 10) on apoptosis induction in MG-63 and A549 cells was also studied via externalization of phosphatidylserine at the outer plasma membrane leaflet. Both selected complexes that gave best preliminary cytotoxicity results contain bromo substituted hq ligands. Apoptosis induction results are in agreement with the cell viability assays suggesting the higher and more selective anticancer activity of complex 10 in comparison to complex 9 on MG-63 cells. Show less
As hypoxia is an important factor to limit chemotherapeutic efficacy in tumors, we herein report three ruthenium(II)-arene complexes containing a hypoxia inducible factor-1α inhibitor (YC-1), which en Show more
As hypoxia is an important factor to limit chemotherapeutic efficacy in tumors, we herein report three ruthenium(II)-arene complexes containing a hypoxia inducible factor-1α inhibitor (YC-1), which endow the organometallic complexes with potential for hypoxia targeting. In vitro tests showed the resulting complexes had higher anticancer activities in hypoxia than in normoxia against the tested cancer cell lines. Western blot analysis revealed that complexes 1-3 blocked HIF-1α protein accumulation under hypoxic conditions. Moreover, these complexes displayed much less cytotoxicity toward the normal human umbilical vein endothelial cell line (HUVEC), indicating that complexes 1-3 may be selectively cytotoxic for human cancer cell lines. These findings proved that ligation with YC-1 endowed these organometallic ruthenium(II) complexes with potential for hypoxia targeting in addition to enhancing their anticancer activities. Show less
Three new bis(2,2'-bipyridine)-heteroleptic Ru(II) dyads incorporating thienyl groups (n = 1-3, compounds 1, 2 and 3, respectively) appended to 1,10-phenanthroline were synthesized and characterized t Show more
Three new bis(2,2'-bipyridine)-heteroleptic Ru(II) dyads incorporating thienyl groups (n = 1-3, compounds 1, 2 and 3, respectively) appended to 1,10-phenanthroline were synthesized and characterized to investigate the impact of n on the photophysical and photobiological properties within the series. All three complexes showed unstructured emission near 618 nm from a triplet metal-to-ligand charge transfer (3 MLCT) state with a lifetime (τem ) of approximately 1 μs. Transient absorption measurements revealed an additional excited state that was nonemissive and long-lived (τTA = 43 μs for 2 and 27 μs for 3), assigned as a triplet intraligand (3 IL) state that was accessible only in 2 and 3. All three complexes were strong singlet oxygen (1 O2 ) sensitizers, with quantum yields (Φ∆ ) for 2 and 3 being the largest (74-78%), and all three were photocytotoxic to cancer cells with visible light activation in the order: 3 > 2 > 1. Cell-free DNA photodamage followed the same trend, where potency increased with decreasing 3 IL energy. Compounds 2 and 3 also showed in vitro photobiological effects with red light (625 nm), where their molar absorptivities were <100 m-1 cm-1 . These findings highlight that Ru(II) dyads derived from α-oligothiophenes directly appended to 1,10-phenanthroline-namely 2 and 3-possess low-lying 3 IL states that are highly photosensitizing, and they may therefore be of interest for photobiological applications such as photodynamic therapy (PDT). Show less
Fluorescent 4-ethylthio-1,8-naphthalimides containing rhodium(I) N-heterocyclic carbene (NHC) and ruthenium (II) NHC fragments were synthesised and evaluated for their antiproliferative effects, cellu Show more
Fluorescent 4-ethylthio-1,8-naphthalimides containing rhodium(I) N-heterocyclic carbene (NHC) and ruthenium (II) NHC fragments were synthesised and evaluated for their antiproliferative effects, cellular uptake and DNA-binding activity. Both types of organometallics triggered ligand dependent efficient cytotoxic effects against tumor cells with the rhodium(I) NHC derivatives causing stronger effects than the ruthenium (II) NHC analogues. Antiproliferative effects could also be observed against several pathogenic Gram-positive bacterial strains, whereas the growth of Gram-negative bacteria was not substantially affected. Cellular uptake was confirmed by atomic absorption spectroscopy as well as by fluorescence microscopy indicating a general ligand dependent accumulation in the cells. An in-depth study on the interaction with DNA confirmed insertion of the naphthalimide moiety between the planar bases of B-DNA via an intercalation mechanism, as well as its stacking on top of the quartets of G-quadruplex structures. Furthermore, additional coordinative binding of the organometallic complexes to the model DNA base 9-ethylguanine could be detected. The studied compounds thus represent promising bioorganometallics featuring strong pharmacological effects in combination with excellent cellular imaging properties. Show less
Precise quantitative measurement of viscosity at the subcellular level presents great challenges. Two-photon phosphorescence lifetime imaging microscopy (TPPLIM) can reflect micro-environmental change Show more
Precise quantitative measurement of viscosity at the subcellular level presents great challenges. Two-photon phosphorescence lifetime imaging microscopy (TPPLIM) can reflect micro-environmental changes of a chromophore in a quantitative manner. Phosphorescent iridium complexes are potential TPPLIM probes due to their rich photophysical properties including environment-sensitive long-lifetime emission and high two-photon absorption (TPA) properties. In this work, a series of iridium(iii) complexes containing rotatable groups are developed as mitochondria-targeting anticancer agents and quantitative viscosity probes. Among them, Ir6 ([Ir(ppy-CHO)2(dppe)]PF6; ppy-CHO: 4-(2-pyridyl)benzaldehyde; dppe: cis-1,2-bis(diphenylphosphino)ethene) shows satisfactory TPA properties and long lifetimes (up to 1 μs). The emission intensities and lifetimes of Ir6 are viscosity-dependent, which is mainly attributed to the configurational changes in the diphosphine ligand as proved by 1H NMR spectra. Ir6 displays potent cytotoxicity, and mechanism investigations show that it can accumulate in mitochondria and induce apoptotic cell death. Moreover, Ir6 can induce mitochondrial dysfunction and monitor the changes in mitochondrial viscosity simultaneously in a real-time and quantitative manner via TPPLIM. Upon Ir6 treatment, a time-dependent increase in viscosity and heterogeneity is observed along with the loss of membrane potential in mitochondria. In summary, our work shows that multifunctional phosphorescent metal complexes can induce and precisely detect microenvironmental changes simultaneously at the subcellular level using TPPLIM, which may deepen the understanding of the cell death mechanisms induced by these metallocompounds. Show less
Lysine-specific demethylase 5A (KDM5A) has recently become a promising target for epigenetic therapy. In this study, we designed and synthesized metal complexes bearing ligands with reported demethyla Show more
Lysine-specific demethylase 5A (KDM5A) has recently become a promising target for epigenetic therapy. In this study, we designed and synthesized metal complexes bearing ligands with reported demethylase and p27 modulating activities. The Rh(III) complex 1 was identified as a direct, selective and potent inhibitor of KDM5A that directly abrogate KDM5A demethylase activity via antagonizing the KDM5A-tri-/di-methylated histone 3 protein-protein interaction (PPI) in vitro and in cellulo. Complex 1 induced accumulation of H3K4me3 and H3K4me2 levels in cells, causing growth arrest at G1 phase in the triple-negative breast cancer (TNBC) cell lines, MDA-MB-231 and 4T1. Finally, 1 exhibited potent anti-tumor activity against TNBC xenografts in an in vivo mouse model, presumably via targeting of KDM5A and hence upregulating p27. Moreover, complex 1 was less toxic compared with two clinical drugs, cisplatin and doxorubicin. To our knowledge, complex 1 is the first metal-based KDM5A inhibitor reported in the literature. We anticipate that complex 1 may be used as a novel scaffold for the further development of more potent epigenetic agents against cancers, including TNBC. Show less
Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence Show more
Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence of many pathologies, particularly chronic non-communicable diseases such as obesity and diabetes. Here, we examine decades of research identifying the complex immunometabolic signaling networks and the cellular and molecular events that occur in the setting of altered nutrient and energy exposures and offer a historical perspective. Furthermore, we describe recent advances such as the discovery that a broad complement of immune cells play a role in immunometabolism and the emerging evidence that nutrients and metabolites modulate inflammatory pathways. Lastly, we discuss how this work may eventually lead to tangible therapeutic advancements to promote health. Show less
Within this work we aimed to improve the pharmacodynamics and toxicity profile of organoruthenium and -rhodium complexes which had previously been found to be highly potent in vitro but showed unselec Show more
Within this work we aimed to improve the pharmacodynamics and toxicity profile of organoruthenium and -rhodium complexes which had previously been found to be highly potent in vitro but showed unselective activity in vivo. Different organometallic complexes were attached to a degradable poly(organo)phosphazene macromolecule, prepared via controlled polymerization techniques. The conjugation to hydrophilic polymers was designed to increase the aqueous solubility of the typically poorly soluble metal-based half-sandwich compounds with the aim of a controlled, pH-triggered release of the active metallodrug. The synthesized conjugates and their characteristics have been thoroughly studied by means of 31P NMR and UV-Vis spectroscopy, ICP-MS analyses and SEC coupled to ICP-MS. In order to assess their potential as possible anticancer drug candidates, the complexes, as well as their respective macromolecular prodrug formulations were tested against three different cancer cell lines in cell culture. Subsequently, the anticancer activity and organ distribution of the poly(organo)phosphazene drug conjugates were explored in vivo in mice bearing CT-26 colon carcinoma. Our investigations revealed a beneficial influence of this macromolecular prodrug by a significant reduction of adverse effects compared to the free metallodrugs. 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 Show more
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
Nanohybrids can in most cases kill cancer cells more efficiently as compared with free photosensitizers. In this work, we constructed nanohybrid Ru1@CDs composed of carbon nanodots (CDs) and a phospho Show more
Nanohybrids can in most cases kill cancer cells more efficiently as compared with free photosensitizers. In this work, we constructed nanohybrid Ru1@CDs composed of carbon nanodots (CDs) and a phosphorescent Ru(ii) complex (Ru1) for one- and two-photon photodynamic therapy of cancer. The photosensitizer and imaging agent Ru1 is decorated onto the nanocarrier CDs covalently. Ru1 and Ru1@CDs can penetrate into cancer cells through an energy-dependent mechanism and endocytosis, respectively. Both Ru1 and Ru1@CDs are capable of lysosome-targeted phosphorescence imaging and photodamage under either 450 nm (one-photon) or 810 nm (two-photon) excitation. Conjugation with CDs can increase the cellular uptake efficacy of Ru1. Mechanism investigations show that both Ru1 and Ru1@CDs can induce apoptosis through generation of reactive oxygen species and cathepsin-initiated apoptotic signaling pathways. Upon two-photon excitation, Ru1@CDs show better penetrability, as well as higher inhibitory effects on cancer cell growth in both 2D cell and 3D multicellular tumor spheroid models. Our work provides an effective strategy for the construction of multifunctional imaging and phototherapeutic nanohybrids for the treatment of cancer. Show less
Photodynamic therapy (PDT) is a promising anti-tumor treatment strategy. Photosensitizer is one of the most important components of PDT. In this work, the anticancer activities of P Show more
Background
Photodynamic therapy (PDT) is a promising anti-tumor treatment strategy. Photosensitizer is one of the most important components of PDT. In this work, the anticancer activities of PDT mediated by six new ruthenium porphyrin complexes were screened. The mechanisms of the most efficacious candidate were investigated.
Methods
Photocytotoxicity of the six porphyrins was tested. The most promising complex, Rup-03, was further investigated using Geimsa staining, which indirectly detects reactive oxygen species (ROS) and subcellular localization. Mitochondrial membrane potential (MMP), cell apoptosis, DNA fragmentation, c-Myc gene expression, and telomerase activities were also assayed.
Results
Rup-03 and Rup-04 had the lowest IC50 values. Rup-03 had an IC50 value of 29.5±2.3μM in HepG2 cells and 59.0±6.1μM in RAW264.7 cells, while Rup-04 had an IC50 value of 40.0±3.8μM in SGC-7901 cells. The complexes also induced cellular morphological changes and impaired cellular ability to scavenge ROS, and accumulated preferentially in mitochondria and endoplasmic reticulum. Rup-03 reduced MMP levels, induced apoptosis, and repressed both c-Myc mRNA expression and telomerase activity in HepG2 cells.
Conclusions
Among six candidates, Rup-03-mediated PDT is most effective against HepG2 and RAW264.7, with a similar efficacy as that of Rup-04-mediated PDT against SGC-7901 cells. Repression of ROS scavenging activities and c-Myc expression, which mediated DNA damage-induced cell apoptosis and repression of telomerase activity, respectively, were found to be involved in the anticancer mechanisms of Rup-03. Show less
Organometallic metal(arene) anticancer agents require ligand exchange for their anticancer activity and this is generally believed to confer low selectivity for potential cellular targets. However, us Show more
Organometallic metal(arene) anticancer agents require ligand exchange for their anticancer activity and this is generally believed to confer low selectivity for potential cellular targets. However, using an integrated proteomics-based target-response profiling approach as a potent hypothesis-generating procedure, we found an unexpected target selectivity of a ruthenium(arene) pyridinecarbothioamide (plecstatin) for plectin, a scaffold protein and cytolinker, which was validated in a plectin knock-out model in vitro. Plectin targeting shows potential as a strategy to inhibit tumor invasiveness as shown in cultured tumor spheroids while oral administration of plecstatin-1 to mice reduces tumor growth more efficiently in the invasive B16 melanoma than in the CT26 colon tumor model. Show less
An addressable single cell imaging strategy combining ToF-SIMS and confocal fluorescence microscopy imaging has been developed, and sucessfully applied to visualize the subcellular distribution of an Show more
An addressable single cell imaging strategy combining ToF-SIMS and confocal fluorescence microscopy imaging has been developed, and sucessfully applied to visualize the subcellular distribution of an organoruthenium anticancer complex, [(η6-benzene)Ru(N,N-L)Cl]+ (1; L: 4-anilinoquinazoline ligand), showing its accumulation in both cell membrane and nuclei, and verifying its dual-targeting feature. Show less
The reaction of [Ru(CO)6Cl2], 1, with N[combining low line]3-methylbenzimidazole (MBI) and 5,6-dimethylbenzimidazole (DMBI) afforded two new complexes with the general Show more
The reaction of [Ru(CO)6Cl2], 1, with N[combining low line]3-methylbenzimidazole (MBI) and 5,6-dimethylbenzimidazole (DMBI) afforded two new complexes with the general formula fac-[RuII(CO)3Cl2L], L = MBI (2) or DMBI (4). Crystals of cis,trans-[RuII(CO)2Cl2(N[combining low line]3-MBI)2], 3, were also obtained from the mother liquor that produced 2. In the presence of water, the dissociation of Ru-N, Ru-Cl and Ru-CO bonds occurred as a function of time, water content and pH. Density functional theory structure simulations/optimizations were carried out at the Becke3LYP level of theory for evaluating the relative stability of possible conformers. ESI-MS studies revealed the ability of the complexes to link model proteins, such as lysozyme, bovine pancreatic ribonuclease and cytochrome c, with the partial release of the heteroaromatic base, chlorido and carbonyl ligands. X-ray diffraction studies on crystals grown from a solution of HEWL and 2 showed the partial removal of chloride and CO. Cytotoxicity tests yielded two-digit micromolar IC50 values in CH1/PA-1 and SW480 cancer cells. In contrast to CORM-3 and 2, a significantly reduced tumor growth was observed with 4 in the murine colon cancer CT-26 model in vivo. Show less
Ruthenium coordination complexes have the potential to serve as novel theranostic agents for cancer. However, a major limitation in their clinical implementation is effective tumor accumulation. In th Show more
Ruthenium coordination complexes have the potential to serve as novel theranostic agents for cancer. However, a major limitation in their clinical implementation is effective tumor accumulation. In this study, we have developed a liposome-based theranostic nanodelivery system for [Ru(phen)2dppz](ClO4)2 (Lipo-Ru). This ruthenium polypyridine complex emits a strong fluorescent signal when incorporated in the hydrophobic lipid bilayer of the delivery vehicle or in the DNA helix, enabling visualization of the therapeutic agent in tumor tissues. Incubation of MDA-MB-231 breast cancer cells with Lipo-Ru induced double-strand DNA breaks and triggers apoptosis. In a mouse model of triple-negative breast cancer, treatment with Lipo-Ru dramatically reduced tumor growth. Biodistribution studies of Lipo-Ru revealed that more than 20% of the injected dose accumulated in the tumor. These results suggest that Lipo-Ru could serve as a promising theranostic platform for cancer. Show less
Half-sandwich pseudo-octahedral pentamethylcyclopentadienyl IrIII complexes of the type [(η5-Cpx)Ir(C^C)Cl]PF6, where Cpx is pentamethylcyclopent Show more
Half-sandwich pseudo-octahedral pentamethylcyclopentadienyl IrIII complexes of the type [(η5-Cpx)Ir(C^C)Cl]PF6, where Cpx is pentamethylcyclopentadienyl (Cp*), or its phenyl (Cpxph = C5Me4C6H5) or biphenyl (Cpxbiph = 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*: Cpxbiph > Cpxph > 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
Two luminescent iridium(iii) complexes, 1 and 2, were synthesized and evaluated for their ability to probe COX-2 in human cancer cells. This is the first application of iridium(iii) complexes as imagi Show more
Two luminescent iridium(iii) complexes, 1 and 2, were synthesized and evaluated for their ability to probe COX-2 in human cancer cells. This is the first application of iridium(iii) complexes as imaging agents for COX-2. We demonstrate that complex 1 differentiates cancer cells from normal cells with high stability and low cytotoxicity. Show less
Targeting protein-protein interactions (PPIs) offers tantalizing opportunities for therapeutic intervention for the treatment of human diseases. Modulating PPI interfaces with organic small molecules Show more
Targeting protein-protein interactions (PPIs) offers tantalizing opportunities for therapeutic intervention for the treatment of human diseases. Modulating PPI interfaces with organic small molecules has been found to be exceptionally challenging, and few candidates have been successfully developed into clinical drugs. Meanwhile, the striking array of distinctive properties exhibited by metal compounds renders them attractive scaffolds for the development of bioactive leads. Here, we report the identification of iridium(iii) compounds as inhibitors of the H-Ras/Raf-1 PPI. The lead iridium(iii) compound 1 exhibited potent inhibitory activity against the H-Ras/Raf-1 interaction and its signaling pathway in vitro and in vivo, and also directly engaged both H-Ras and Raf-1-RBD in cell lysates. Moreover, 1 repressed tumor growth in a mouse renal xenograft tumor model. Intriguingly, the Δ-enantiomer of 1 showed superior potency in the biological assays compared to Λ-1 or racemic 1. These compounds could potentially be used as starting scaffolds for the development of more potent Ras/Raf PPI inhibitors for the treatment of kidney cancer or other proliferative diseases. Show less
Dopamine receptor expression is correlated with certain types of cancers, including lung, breast and colon cancers. In this study, we report luminescent iridium(iii) complexes (11-14) as intrac Show more
Dopamine receptor expression is correlated with certain types of cancers, including lung, breast and colon cancers. In this study, we report luminescent iridium(iii) complexes (11-14) as intracellular dopamine receptor (D1R/D2R) cell imaging agents. Complexes 11 and 13, which are conjugated with a dopamine receptor agonist, showed superior cell imaging characteristics, high stability and low cytotoxicity (>100 μM) in A549 lung cancer cells. siRNA knockdown and dopamine competitive assays indicated that complexes 11 and 13 could selectively bind to dopamine receptors (D1R/D2R) in A549 cells. Fluorescence lifetime microscopy demonstrated that complex 13 has a longer luminescence lifetime at the wavelength of 560-650 nm than DAPI and other chromophores in biological fluids. The long luminescence lifetime of complex 13 not only provides an opportunity for efficient dopamine receptor tracking in biological media, but also enables the temporal separation of the probe signal from the intense background signal by fluorescence lifetime microscopy for efficient analysis. Complex 13 also shows high photostability, which could allow it to be employed for long-term cellular imaging. Furthermore, complex 13 could selectively track the internalization process of dopamine receptors (D1R/D2R) in living cells. To the best of our knowledge, complex 13 is the first metal-based compound that has been used to monitor intracellular dopamine receptors in living cells. Show less
Glucose metabolism has long been thought to operate with exquisite specificity and near-optimal efficiency. New findings show, however, that two glycolytic enzymes produce minor products that inhibit Show more
Glucose metabolism has long been thought to operate with exquisite specificity and near-optimal efficiency. New findings show, however, that two glycolytic enzymes produce minor products that inhibit other enzymes involved in central carbon metabolism unless they are further metabolized by a novel enzyme. Show less
Anticancer active metal complexes with biologically active ligands have the potential to interact with more than one biological target, which could help to overcome acquired and/or intrinsic resistanc Show more
Anticancer active metal complexes with biologically active ligands have the potential to interact with more than one biological target, which could help to overcome acquired and/or intrinsic resistance of tumors to small molecule drugs. In this paper we present the preparation of 2-hydroxy-[1,4]-naphthoquinone-derived ligands and their coordination to a Ru(II)(η(6)-p-cymene)Cl moiety. The synthesis of oxime derivatives resulted in the surprising formation of nitroso-naphthalene complexes, as confirmed by X-ray diffraction analysis. The compounds were shown to be stable in aqueous solution but reacted with glutathione and ascorbic acid rather than undergoing reduction. One-electron reduction with pulse radiolysis revealed different behavior for the naphthoquinone and nitroso-naphthalene complexes, which was also observed in in vitro anticancer assays. Show less
Four new ruthenium(II) polypyridyl complexes [Ru(dmb)2(DQTT)](ClO4)2 (1) (DQTT=12-(1,4-dihydroquinoxalin-6-yl)-4,5,9,14-tetraazabenzo[b]triphenylene, dmb=4,4'-dimethyl-2,2'-bipyridine), [Ru(bpy)2(DQTT Show more
Four new ruthenium(II) polypyridyl complexes [Ru(dmb)2(DQTT)](ClO4)2 (1) (DQTT=12-(1,4-dihydroquinoxalin-6-yl)-4,5,9,14-tetraazabenzo[b]triphenylene, dmb=4,4'-dimethyl-2,2'-bipyridine), [Ru(bpy)2(DQTT)](ClO4)2 (2) (bpy=2,2'-bipyridine), [Ru(phen)2(DQTT)](ClO4)2 (3) (phen=1,10-phenanthroline) and [Ru(dmp)2(DQTT)](ClO4)2 (4) (dmp=2,9-dimethyl-1,10-phenanthroline) were synthesized and characterized by elemental analysis, ESI-MS, (1)H NMR and (13)C NMR. The cytotoxic activity in vitro of the complexes was evaluated against human BEL-7402, A549, HeLa, HepG-2 and MG-63 cancer cell lines by MTT (3-(4,5-dimethylthiazole)-2,5-diphenyltetrazolium bromide) method. The IC50 values of complexes 1-4 against BEL-7402 cells are 31.8 ± 1.0, 35.8 ± 1.6, 29.0 ± 0.8 and 25.0 ± 0.9 μM, respectively. The morphological apoptosis was investigated with AO/EB (acridine orange/ethidium bromide) and Hoechst 33258 staining methods. The DNA damage was assayed by comet assay. The inhibition of cell migration was evaluated by the wound healing assay. The levels of ROS (reactive oxygen species) and the changes of mitochondrial membrane potential were studied under fluorescent microscope. The percentages in the cells of apoptotic and necrotic cells and the cell cycle arrest were determined by flow cytometry. The expression of Bcl-2 family proteins was investigated by western blot analysis. The results show that the complexes induce BEL-7402 cells apoptosis through a ROS-mediated mitochondrial dysfunction pathway, which was accompanied by regulation of the expression of Bcl-2 family proteins. Show less
Four new ruthenium(II) polypyridyl complexes [Ru(dmb)2(dqtbt)](ClO4)2 (1) (dqtbt=12-(2,3-diphenyl-quinoxalin-6-yl)-4,5,10,13-tetraazabenzo[b]triphenylene, dmb=4,4'-dimethyl-2,2'-bipyridine), [Ru(bpy)2 Show more
Four new ruthenium(II) polypyridyl complexes [Ru(dmb)2(dqtbt)](ClO4)2 (1) (dqtbt=12-(2,3-diphenyl-quinoxalin-6-yl)-4,5,10,13-tetraazabenzo[b]triphenylene, dmb=4,4'-dimethyl-2,2'-bipyridine), [Ru(bpy)2(dqtbt)](ClO4)2 (2) (bpy=2,2'-bipyridine), [Ru(phen)2(dqtbt)](ClO4)2 (3) (phen=1,10-phenanthroline) and [Ru(dmp)2(dqtbt)](ClO4)2 (4) (dmp=2,9-dimethyl-1,10-phenanthroline) were synthesized and characterized. The cytotoxicity in vitro of the complexes was evaluated against human BEL-7402, A549, HeLa, HepG-2 and MG-63 cancer cell lines. These complexes are sensitive to BEL-7402 cells, the IC50 values are 4.9±0.5, 4.6±0.4, 7.7±1.8 and 1.9±0.3μM toward BEL-7402 cells. The complexes can increase the levels of reactive oxygen species and induce the decrease of mitochondrial membrane potential. Morphological and comet assay studies show that the complexes can effectively induce apoptosis in BEL-7402 cells. Complexes 1-4 inhibit the cell growth at G0/G1 phase in BEL-7402 cell line. The complexes can downregulate the expression of Bcl-2 and Bcl-x proteins and upregulate the levels of Bid protein in BEL-7402 cells. The results show that the complexes induce BEL-7402 cell apoptosis through a ROS-mediated mitochondrial dysfunction pathway. In addition, the complexes show strong protein-binding affinities. Show less