👤 Pandya C

The cancer stem cell (CSC) toxicity and mechanism of action of a series of iridium(III) complexes bearing polypridyl and charged 1-methyl-2-(2-pyridyl)pyridinium ligands, 1-4 is reported. The most effective complex (containing 1,10-phenanthroline), 3, kills CSCs and bulk cancer cells with equal potency (in the micromolar range), indicating that it could potentially remove heterogenous tumour populations with a single dose. Encouragingly, 3 also inhibits mammopshere formation to a similar extent as salinomycin, a well-established anti-CSC agent. This complex induces CSC apoptosis by mitochondrial membrane depolarization, inhibition of mitochondrial metabolism, and intracellular reactive oxygen species (ROS) generation. To the best of our knowledge, this is the first study to investigate the anti-CSC properties of iridium complexes. Show less

Two pairs of Rh(III) and Ir(III) biscyclometallated complexes with thiabendazole (L¹), named [Ir-a]Cl and [Rh-a]Cl, and N-benzyl-thiabendazole (L²), named [Ir-b]Cl and [Rh-b]Cl, have been designed and synthesized to explore the photophysical and biological effects that arise from changing both the metal center and the ancillary ligand. In the dark, the four metal complexes exhibit greater cytotoxicity than cisplatin against human colon (SW480) and human lung (A549) adenocarcinoma cell lines. Moreover, the pair of complexes bearing the ligand L² is markedly more cytotoxic and present higher uptake values than complexes with L¹, thereby their biological properties were studied further to determine their mechanism of action. Interestingly, in spite of the different metal center both the [Ir-b]Cl and [Rh-b]Cl complexes are responsible for the loss of mitochondrial functionality and the activation of apoptotic cell death pathways. Moreover, the photodynamic activity of the four complexes, [Ir-a,b]Cl and [Rh-a,b]Cl, was tested using visible blue light (460 nm) under soft irradiation conditions (20 min, 5.5 mW cm^-2). While the Rh complexes are not photopotentiated, the phototoxicity index (IC₅₀ non-irradiated/IC₅₀ irradiated) of [Ir-a]Cl and [Ir-b]Cl complexes was 15.8 and 3.6, respectively. We also demonstrate that only the Ir derivatives are capable of photocatalyzing the oxidation of S-containing l-amino acids under blue light irradiation, [Ir-a]Cl being more active than [Ir-b]Cl, which provides a reasonable mechanism for their biological action (oxidative stress could be selectively promoted through a photocatalytic action) upon irradiation. This different PDT behaviour depending on the metal center and the ancillary substituent may be useful for future rational design of metal-based photosensitizers. Show less

Two new biscyclometalated complexes [Ir(ptzR)2(dppz)]+ (dppz = dipyridophenazene; ptzRH = 4-phenyl-1-benzyl-1,2,3-triazole (1+) and 4-phenyl-1-propyl-1,2,3-triazole (2+)) have been prepared. The hexafluorophosphate salts of these complexes have been fully characterized and, in one case, the X-ray structure of a nitrate salt was obtained. The DNA binding properties of the chloride salts of the complexes were investigated, as well as their cellular uptake by A2780 and MCF7 cell lines. Both complexes display an increase in the intensity of phosphorescence upon titration with duplex DNA, indicating the intercalation of the dppz ligand and, given that they are monocations, the complexes exhibit appreciable DNA binding affinity. Optical microscopy studies reveal that both complexes are taken up by live cancer cell lines displaying cytosol based luminescence. Colocalization studies with commercial probes show high Pearson coefficients with mitotracker dyes confirming that the new complexes specifically localize on mitochondria. Show less

Nitric oxide (NO) is an intra- and extracellular messenger with important functions during human physiology process. A long-lived luminescent iridium(III) complex probe 1 has been designed and synthesized for the monitoring of NO controllably released from sodium nitroprusside (SNP). Probe 1 displayed a 15-fold switch-on luminescence in the presence of SNP at 580 nm. The probe exhibited a linear response towards SNP between 5 to 25 μM with detection limit at 0.18 μM. Importantly, the luminescent switch-on detection of NO in HeLa cells was demonstrated. Overall, complex 1 has the potential to be applied for NO tracing in complicated cellular environment. Show less

A panel of iridium(iii) porphyrin complexes containing axial N-heterocyclic carbene (NHC) ligand(s) were synthesized and characterized. X-ray crystal structures of the bis-NHC complexes [Ir^III(ttp)(IMe)₂]⁺ (2a), [Ir^III(oep)(BIMe)₂]⁺ (2d), [Ir^III(oep)(I ⁱ Pr)₂]⁺ (2e) and [Ir^III(F₂₀tpp)(IMe)₂]⁺ (2f) display ruffled porphyrin rings with mesocarbon displacements of 0.483-0.594 Å and long Ir-C_NHC bonds of 2.100-2.152 Å. Variable-temperature ¹H NMR analysis of 2a reveals that the macrocycle porphyrin ring inversion takes place in solution with an activation barrier of 40 ± 1 kJ mol^-1. The UV-vis absorption spectra of Ir^III(por)-NHC complexes display split Soret bands. TD-DFT calculations and resonance Raman experiments show that the higher-energy Soret band is derived from the ¹MLCT dπ(Ir) → π*(por) transition. The near-infrared phosphorescence of Ir^III(por)-NHC complexes from the porphyrin-based ³(π, π*) state features broad emission bands at 701-754 nm with low emission quantum yields and short lifetimes (Φ _em < 0.01; τ < 4 μs). [Ir^III(por)(IMe)₂]⁺ complexes (por = ttp and oep) are efficient photosensitizers for ¹O₂ generation (Φ _so = 0.64 and 0.88) and are catalytically active in the light-induced aerobic oxidation of secondary amines and arylboronic acid. The bis-NHC complexes exhibit potent dark cytotoxicity towards a panel of cancer cells with IC₅₀ values at submicromolar levels. The cytotoxicity of these complexes could be further enhanced upon light irradiation with IC₅₀ values as low as nanomolar levels in association with the light-induced generation of reactive oxygen species (ROS). Bioimaging of [Ir^III(oep)(IMe)₂]⁺ (2c) treated cells indicates that this Ir complex mainly targets the endoplasmic reticulum. [Ir^III(oep)(IMe)₂]⁺ catalyzes the photoinduced generation of singlet oxygen and triggers protein oxidation, cell cycle arrest, apoptosis and the inhibition of angiogenesis. It also causes pronounced photoinduced inhibition of tumor growth in a mouse model of human cancer. Show less

Oncosis is a non-apoptotic form of programmed cell death (PCD), which differs from apoptosis in both morphological changes and inner pathways, and might hold the key to defeating a major obstacle in cancer therapy - drug-resistance, which is often a result of the intrinsic apoptosis resistance of tumours. However, despite the fact that the term "oncosis" was coined and used much earlier than apoptosis, little effort has been made to discover new drugs which can initiate this form of cell death, in comparison to drugs inducing apoptosis or any other type of PCD. So herein, we present the synthesis of a series of mitochondria-targeting cyclometalated Ir(iii) complexes, which activated the oncosis-specific protein porimin and calpain in cisplatin-resistant cell line A549R, and determined their cytotoxicity against a wide range of drug-resistant cancer types. To the best of our knowledge, these complexes are the very first metallo-components to induce oncosis in drug-resistant cancer cells. Show less

Investigating the role of lysosome dysfunction in cancer requires the development of efficient probes for lysosomes. We report herein a cyclometalated iridium(iii) complex (Ir-Ly) as a luminescent probe for visualizing lysosomes in cancer cells. The morpholine and hydroxy moieties within Ir-Ly provide suitable hydrophilicity and responsiveness to pH. Importantly, Ir-Ly exhibits a large Stokes shift, long lifetime and high photostability, which are important advantages for lysosome tracking in living cells. Show less

A series of six osmium(ii) complexes of the type [(η6-p-cymene)Os(C^N)X] (X = chlorido or acetato) containing benzimidazole C^N ligands with an ester group as a handle for further functionalization have been synthesized. They exhibit IC50 values in the low micromolar range in a panel of cisplatin (CDDP)-resistant cancer cells (approximately 10× more cytotoxic than CDDP in MCF-7), decrease the levels of intracellular ROS and reduce the NAD+ coenzyme, and inhibit tubulin polymerization. This discovery could open the door to a new large family of osmium(ii)-based bioconjugates with diverse modes of action. 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 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

Looking for new metal-based anticancer treatments, in recent years many ruthenium complexes have been proposed as effective and safe potential drugs. In this context we have recently developed a novel approach for the in vivo delivery of Ru(III) complexes, preparing stable ruthenium-based nucleolipidic nanoaggregates endowed with significant antiproliferative activity. Herein we describe the cellular response to our ruthenium-containing formulations in selected models of human breast cancer. By in vitro bioscreens in the context of preclinical studies, we have focused on their ability to inhibit breast cancer cell proliferation by the activation of the intrinsic apoptotic pathway, possibly via mitochondrial perturbations involving Bcl-2 family members and predisposing to programmed cell death. In addition, the most efficient ruthenium-containing cationic nanoaggregates we have hitherto developed are able to elicit both extrinsic and intrinsic apoptosis, as well as autophagy. To limit chemoresistance and counteract uncontrolled proliferation, multiple cell death pathways activation by metal-based chemotherapeutics is a challenging, yet very promising strategy for targeted therapy development in aggressive cancer diseases, such as triple-negative breast cancer with limited treatment options. These outcomes provide valuable, original knowledge on ruthenium-based candidate drugs and new insights for future optimized cancer treatment protocols. 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

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

Two new ligand PTTP (2-phenoxy-1,4,8,9-tetraazatriphenylene) and FTTP (2-(3-fluoronaphthalen-2-yloxy)-1,4,8,9-tetraazatriphenylene) and their six ruthenium(II) polypyridyl complexes [Ru(N-N)₂(PTTP)](ClO₄)₂ and [Ru(N-N)₂(FTTP)](ClO₄)₂ (N-N=dmb: 4,4'-dimethyl-2,2'-bipiridine; dmp: 2,9-dimethyl-1,10-phenanthroline; ttbpy: 4,4'-ditertiarybutyl-2,2'-bipyridine) were synthesized and characterized. The cytotoxic activity of the complexes against cancer cells HeLa, BEL-7402, A549, HepG-2, HOS and normal cell LO2 was evaluated by MTT method. The IC₅₀ values range from 1.5±0.1 to 55.9±7.5μM. Complex 3 shows the highest cytotoxic activity toward BEL-7402 cells (IC₅₀=1.5±0.1μM). Complex 5 displays most effective inhibition of the cell growth in A549 and HOS cells with low IC₅₀ values of 2.5±0.6 and 2.6±0.1μM, respectively. The apoptosis, reactive oxygen species, mitochondrial membrane potential, DNA damage, autophagy and anti-metastasis assay were investigated under a fluorescent microscope. The cell cycle arrest was assayed by flow cytometry, and the expression of caspases and Bcl-2 family proteins was studied by western blot. The results obtained show that the complexes induce apoptosis in BEL-7402 cells through a ROS-mediated mitochondrial dysfunction pathway. Show less

Two novel series of (salen)ruthenium(iii) complexes bearing guanidine and amidine axial ligands were synthesized, characterized, and evaluated for anticancer activity. In vitro cytotoxicity tests demonstrate that these complexes are cytotoxic against various cancer cell lines and the leading complexes have remarkable cancer-cell selectivity. A detailed study of the guanidine complex 7 and the amidine complex 13 reveals two distinguished modes of action. Complex 7 weakly binds to DNA and induces DNA damage, cell cycle arrest, and typical apoptosis pathways in MCF-7 cells. In contrast, complex 13 induces paraptosis-like cell death hallmarked by massive vacuole formation, mitochondrial swelling, and ER stress, resulting in significant cytotoxicity against human breast cancer cells. Our results provide an extraordinary example of tuning the mechanism of action of (salen)ruthenium(iii) anticancer complexes by modifying the structure of the axial ligands. Show less

Synergistic photodynamic therapy (PDT) that combines photosensitizers (PSs) to attack different key sites in cancer cells is very attractive. However, the use of multiple PSs may increase dark cytotoxicity. Additionally, realizing the multiple vein passage of several PSs through dosing could be a challenge in clinical treatment. To address these issues, a novel strategy that enables a single PS to ablate two key sites (i.e., cytomembranes on the outside and mitochondria on the inside) of cancer cells synergistically was proposed. Five new fluorinated ruthenium (II) complexes (Ru1-Ru5), which possessed excellent two-photon properties and good singlet oxygen quantum yields, were designed and synthesized. When incubated with HeLa cells, the complexes were observed on the cytomembranes at first. With an extension of the treatment time, both the cytomembranes and mitochondria were lit up by the complexes. Under two-photon laser irradiation, the mitochondria and cytomembranes were ablated simultaneously, and the HeLa cells were destroyed effectively by the complexes, whether the cells were in a monolayer or in multicellular spheroids. With the largest phototoxicity index under the two-photon laser, Ru4 was used for two-photon PDT of in vivo xenograft tumors and successfully inhibited the growth of the tumors. Our results emphasized that the strategy of attacking two key sites with a single PS is an efficient method for PDT. Show less

A glutathione (GSH)-activatable ruthenium(ii)-azo photosensitizer was prepared. The complex had low toxicity towards cells under dark conditions. It exhibited excellent phototoxicity under two-photon excitation (810 nm) and thus was developed as a two-photon photodynamic anticancer agent for cancer therapy. Show less

Multidrug resistance is a major impediment to chemotherapy and limits the efficacies of conventional anticancer drugs. A strategy to bypass multidrug resistance is to develop new drug candidates capable of inducing apoptosis-independent programmed cell death. However, cellular pathways implicated in alternative programmed cell death are not well-elucidated and multifactorial, making a target-based discovery approach a challenge. Here, we show that a coordination-directed three-component assembly and phenotypic screening strategy could be employed as a viable alternative for the identification of apoptosis-independent organoruthenium anticancer agents. Through an on-plate synthesis and screening of 195 organoruthenium complexes against apoptosis-sensitive and -resistant cancers, we identified two apoptosis-independent hits. Subsequent validation of the two hits showed a lack of induction of apoptotic biomarkers, a caspase-independent activity and an equal efficacy in both apoptosis-sensitive and -resistant colorectal cancers. This validated their apoptosis-independent modes-of-action, paving the way as potential candidates for the treatment of highly-refractory cancer phenotypes. Show less

A series of novel ruthenium(ii) 2,2'-bipyridyl (bpy) and 1,10-phenanthroline (phen) derivatives containing PTA (1,3,5-triaza-7-phosphaadamantane) or mPTA (N-methyl-1,3,5-triaza-7-phosphaadamantane cation) have been synthesized and fully characterized. Three types of complexes have been obtained, neutral [Ru(N-N)(PTA)₂Cl₂] (1, N-N = bpy and 4, N-N = phen), monocationic [Ru(N-N)(PTA)₃Cl][Cl] (2, N-N = bpy and 5, N-N = phen) and dicationic [Ru(N-N)(mPTA)Cl₂][BF₄]₂ (3, N-N = bpy and 6, N-N = phen). The solid-state structures of four complexes have been determined by single-crystal X-ray diffraction. The cytotoxicity of the complexes has been evaluated in vitro against U266 and RPMI human multiple myeloma cells. Show less

The synthesis and characterization of Pt(II) (1 and 2) and Ru(II) arene (3 and 4) or polypyridine (5 and 6) complexes is described. With the aim of having a functional group to form bioconjugates, one uncoordinated carboxyl group has been introduced in all complexes. Some of the complexes were selected for their potential in photodynamic therapy (PDT). The molecular structures of complexes 2 and 5, as well as that of the sodium salt of the 4'-(4-carboxyphenyl)-2,2':6',2″-terpyridine ligand (cptpy), were determined by X-ray diffraction. Different techniques were used to evaluate the binding capacity to model DNA molecules, and MTT cytotoxicity assays were performed against four cell lines. Compounds 3, 4, and 5 showed little tendency to bind to DNA and exhibited poor biological activity. Compound 2 behaves as bonded to DNA probably through a covalent interaction, although its cytotoxicity was very low. Compound 1 and possibly 6, both of which contain a cptpy ligand, were able to intercalate with DNA, but toxicity was not observed for 6. However, compound 1 was active in all cell lines tested. Clonogenic assays and apoptosis induction studies were also performed on the PC-3 line for 1. The photodynamic behavior for complexes 1, 5, and 6 indicated that their nuclease activity was enhanced after irradiation at λ = 447 nm. The cell viability was significantly reduced only in the case of 5. The different behavior in the absence or presence of light makes complex 5 a potential prodrug of interest in PDT. Molecular docking studies followed by molecular dynamics simulations for 1 and the counterpart without the carboxyl group confirmed the experimental data that pointed to an intercalation mechanism. The cytotoxicity of 1 and the potential of 5 in PDT make them good candidates for subsequent conjugation, through the carboxyl group, to "selected peptides" which could facilitate the selective vectorization of the complex toward receptors that are overexpressed in neoplastic cell lines. Show less

Elucidation of the communication between metal complexes and cell membrane may provide useful information for rational design of metal-based anticancer drugs. Herein we synthesized a novel class of ruthenium (Ru) complexes containing phtpy derivatives (phtpy = phenylterpyridine), analyzed their structure-activity relationship and revealed their action mechanisms. The result showed that, the increase in the planarity of hydrophobic Ru complexes significantly enhanced their lipophilicity and cellular uptake. Meanwhile, the introduction of nitro group effectively improved their anticancer efficacy. Further mechanism studies revealed that, complex (2c), firstly accumulated on cell membrane and interacted with death receptors to activate extrinsic apoptosis signaling pathway. The complex was then transported into cell cytoplasm through transferrin receptor-mediated endocytosis. Most of the intracellular 2c accumulated in cell plasma, decreasing the level of cellular ROS, inducing the activation of caspase-9 and thus intensifying the apoptosis. At the same time, the residual 2c can translocate into cell nucleus to interact with DNA, induce DNA damage, activate p53 pathway and enhance apoptosis. Comparing with cisplatin, 2c possesses prolonged circulation time in blood, comparable antitumor ability and importantly, much lower toxicity in vivo. Taken together, this study uncovers the role of membrane receptors in the anticancer actions of Ru complexes, and provides fundamental information for rational design of membrane receptor targeting anticancer drugs. 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 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

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

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

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

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

Herein we present a series of DCA-Ir(iii) co-drug complexes that preferentially accumulate in mitochondria and selectively cause cancer cell metabolic alterations and were found to act in synergy by sensitizing cancer cells for PDT to achieve cancer-specific enhanced two-photon PDT in the hypoxic environment of multicellular tumor spheroids. Show less

Mitochondria generate energy but malfunction in many cancer cells, hence targeting mitochondrial metabolism is a promising approach for cancer therapy. Here we have designed cyclometallated iridium(iii) complexes, containing one TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) spin label [C₄₃H₄₃N₆O₂Ir₁·PF₆]˙ (Ir-TEMPO1) and two TEMPO spin labels [C₅₂H₅₈N₈O₄Ir₁·PF₆]˙ (Ir-TEMPO2). Electron paramagnetic resonance (EPR) spectroscopy revealed spin-spin interactions between the TEMPO units in Ir-TEMPO2. Both Ir-TEMPO1 and Ir-TEMPO2 showed bright luminescence with long lifetimes (ca. 35-160 ns); while Ir-TEMPO1 displayed monoexponential decay kinetics, the biexponential decays measured for Ir-TEMPO2 indicated the presence of more than one energetically-accessible conformation. This observation was further supported by density functional theory (DFT) calculations. The antiproliferative activity of Ir-TEMPO2 towards a range of cancer cells was much greater than that of Ir-TEMPO1, and also the antioxidant activity of Ir-TEMPO2 is much higher against A2780 ovarian cancer cells when compared with Ir-TEMPO1. Most notably Ir-TEMPO2 was particularly potent towards PC3 human prostate cancer cells (IC₅₀ = 0.53 μM), being ca. 8× more active than the clinical drug cisplatin, and ca. 15× more selective towards cancer cells versus normal cells. Confocal microscopy showed that both Ir-TEMPO1 and Ir-TEMPO2 localise in the mitochondria of cancer cells. Show less

Herein a series of mitochondria-targeted AIE (aggregation-induced emission)-active Ir(iii) complexes were designed to selectively exert one-/two-photon photodynamic activities in mitochondria to address the issues which current PDT are confronted with (i.e., shallow penetration depth of routinely used irradiation; systematic toxicity associated with effective drug concentration; concentration-quenched photodynamic activity at the target, etc.). Show less

In this article, we report on the development of new metal-based anticancer agents with imaging, chemotherapeutic and photosensitizing properties. Hence, a new heterobimetallic complex (Pt-LQ-Re) was prepared by connecting a non-conventional trans-chlorido Pt(ii) complex to a photoactive Re tricarbonyl unit (LQ-Re), which can be replaced by ^99mTc to allow for in vivo imaging. We describe the photophysical and biological properties of the new complexes, in the dark and upon light irradiation (DNA interaction, cellular localization and uptake, and cytotoxicity). Furthermore, planar scintigraphic images of mice injected with Pt-LQ-Tc clearly showed that the radioactive compound is taken up by the excretory system organs, namely liver and kidneys, without significant retention in other tissues. All in all, the strategy of conjugating a chemotherapeutic compound with a PDT photosensitizer endows the resulting complexes with an intrinsic cytotoxic activity in the dark, driven by the non-classical platinum core, and a selective activity upon light irradiation. Most importantly, the possibility of integrating a SPECT imaging radiometal (^99mTc) in the structure of these new heterobimetallic complexes might allow for in vivo non-invasive visualization of their tumoral accumulation, a crucial issue to predict therapeutic outcomes. Show less

IID (Integrated Interactions Database) is the first database providing tissue-specific protein-protein interactions (PPIs) for model organisms and human. IID covers six species (S. cerevisiae (yeast), C. elegans (worm), D. melonogaster (fly), R. norvegicus (rat), M. musculus (mouse) and H. sapiens (human)) and up to 30 tissues per species. Users query IID by providing a set of proteins or PPIs from any of these organisms, and specifying species and tissues where IID should search for interactions. If query proteins are not from the selected species, IID enables searches across species and tissues automatically by using their orthologs; for example, retrieving interactions in a given tissue, conserved in human and mouse. Interaction data in IID comprises three types of PPI networks: experimentally detected PPIs from major databases, orthologous PPIs and high-confidence computationally predicted PPIs. Interactions are assigned to tissues where their proteins pairs or encoding genes are expressed. IID is a major replacement of the I2D interaction database, with larger PPI networks (a total of 1,566,043 PPIs among 68,831 proteins), tissue annotations for interactions, and new query, analysis and data visualization capabilities. IID is available at http://ophid.utoronto.ca/iid. Show less