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Title: Modulating Excited State Properties and Ligand Ejection Kinetics in Ruthenium Polypyridyl Complexes Designed to Mimic Photochemotherapeutics. Abstract: Ruthenium(II) polypyridyl complexes have gained significant interest as photochemotherapeutics (PCTs) due to their synthetic viability, strong light absorption, well understood excited state properties, and high phototoxicity indexes. Herein, we report the synthesis, characterization, electrochemical, spectrochemical, and preliminary cytotoxicity analyses of three series of ruthenium(II) polypyridyl complexes designed to mimic PCTs. The three series have the general structure of [Ru(bpy)2(N-N)]2+ (Series 1), [Ru(bpy)(dmb)(N-N)]2+ (Series 2), and [Ru(dmb)2(N-N)]2+ (Series 3, where N-N is a bidentate polypyridyl ligand, bpy = 2,2'-bipyridine, and dmb = 6,6'-dimethyl-2,2'-bipyridine). In the three series, the N-N ligand was systematically modified to incorporate increased conjugation and/or electronegative heteroatoms to increase dπ-π* backbonding, red-shifting the lowest energy metal-to-ligand charge transfer (MLCT) absorptions from λmax = 454 to λmax = 580 nm, nearing the therapeutic window for PCTs (600-1100 nm). In addition, steric bulk was systematically introduced through the series, distorting the Ru(II) octahedra, making the dissociative 3dd* state thermally accessible at room and body temperatures. This resulted in a 4 orders of magnitude increase in photoinduced ligand ejection kinetics, and demonstrates the ability to modulate both the MLCT* and dd* manifolds in the complexes, which is critical in PCT drug design. Preliminary cell viability assays suggest that the increased steric bulk to lower the 3dd* states may interfere with the cytotoxicity mechanism, limiting photoinitiated toxicity of the complexes. This work demonstrates the importance of understanding both the MLCT* and dd* manifolds and how they impact the ability of a complex to act as a PCT agent. Show less

Light-activated treatments, such as photodynamic therapy (PDT), provide temporal and spatial control over a specific cytotoxic response by exploiting toxicity differences between irradiated and dark conditions. In this work, a novel strategy for developing near infrared (NIR)-activatable Ru(II) polypyridyl-based photosensitizers (PSs) was successfully developed through the incorporation of symmetric heptamethine cyanine dyes in the metal complex via a phenanthrimidazole ligand. Owing to their strong absorption in the NIR region, the PSs could be efficiently photoactivated with highly penetrating NIR light (770 nm), leading to high photocytotoxicities towards several cancer cell lines under both normoxic and hypoxic conditions. Notably, our lead PS (Ru-Cyn-1), which accumulated in the mitochondria, exhibited a good photocytotoxic activity under challenging low-oxygen concentration (2 % O₂ ) upon NIR light irradiation conditions (770 nm), owing to a combination of type I and II PDT mechanisms. The fact that the PS Protoporphyrin IX (PpIX), the metabolite of the clinically approved 5-ALA PS, was found inactive under the same challenging conditions positions Ru-Cyn-1 complex as a promising PDT agent for the treatment of deep-seated hypoxic tumours. Show less

Photodynamic therapy (PDT) is a medical technique for the treatment of cancer. It is based on the use of non-toxic molecules, called photosensitizers (PSs), that become toxic when irradiated with light and produce reactive oxygen specious (ROS) such as singlet oxygen (¹O₂). This light-induced toxicity is rather selective since the physician only targets a specific area of the body, leading to minimal side effects. Yet, a strategy to improve further the selectivity of this medical technique is to confine the delivery of the PS to cancer cells only instead of spreading it randomly throughout the body prior to light irradiation. To address this problem, we present here novel sulfonamide-based monopodal and dipodal ruthenium and osmium polypyridyl complexes capable of targeting carbonic anhydrases (CAs) that are a major target in cancer therapy. CAs are overexpressed in the membrane or cytoplasm of various cancer cells. We therefore anticipated that the accumulation of our complexes in or outside the cell prior to irradiation would improve the selectivity of the PDT treatment. We show that our complexes have a high affinity for CAs, accumulate in cancer cells overexpressing CA cells and importantly kill cancer cells under both normoxic and hypoxic conditions upon irradiation at 540 nm. More importantly, Os(ii) compounds still exhibit some phototoxicity under 740 nm irradiation under normoxic conditions. To our knowledge, this is the first description of ruthenium/osmium-based PDT PSs that are CA inhibitors for the selective treatment of cancers. Show less

Title: A Ru(II) complex-based COX-2 targeting type I photosensitizer evokes ferroptosis and apoptosis. Abstract: Photodynamic therapy (PDT) often faces challenges such as oxygen dependence and limited tumour specificity. We report a tumour-targeting photosensitizer (PS), RuCXB, which enhances uptake by cancer cells by targeting overexpressed cyclooxygenase-2 enzyme in tumours. RuCXB also reduces oxygen dependence via a type I PDT mechanism and achieves a strong therapeutic effect through the synergistic induction of ferroptosis and apoptosis. This work presents a reliable strategy for developing potent PSs with enhanced PDT efficacy, tumour selectivity, and diminished oxygen dependence. Show less

Two novel strained ruthenium(II) polypyridyl complexes containing a 2,3-dihydro-1,4-dioxino[2,3-f]-1,10-phenanthroline (dop) ligand selectively ejected a methylated ligand when irradiated with >400 nm light. The best compound exhibited a 1880-fold increase in cytotoxicity in human cancer cells upon light-activation and was 19-fold more potent than the well-known chemotherapeutic, cisplatin. Show less

The combination of more than one bioactive moiety in a multitargeted anticancer agent may result in synergistic activity of its components. Using this concept, bioorganometallic compounds were designed to feature a metal center, a 2-pyridinecarbothioamide (PCA), and a hydroxamic acid, which is found in the anticancer drug vorinostat (SAHA). The organometallics showed inhibitory activity in the nanomolar range against histone deacetylases (HDACs) as the key target for SAHA. In particular, the Rh complex was a potent inhibitor of HDAC6 over HDAC1 and HDAC8. Whereas this complex was highly cytotoxic in human cancer cells, it showed low toxicity in hemolysis studies and zebrafish, demonstrating the role of the metal center. For this complex a slightly reduced expression of vascular endothelial growth factor receptor 2 (VEGFR2) was established, which was upregulated by SAHA. This finding indicates that the new organometallics display different modes of action than their bioactive components. Show less

The promise of the metal(arene) structure as an anticancer pharmacophore has prompted intensive exploration of this chemical space. While N-heterocyclic carbene (NHC) ligands are widely used in catalysis, they have only recently been considered in metal complexes for medicinal applications. Surprisingly, a comparatively small number of studies have been reported in which the NHC ligand was coordinated to the Ru^II(arene) pharmacophore and even less with an Os^II(arene) pharmacophore. Here, we present a systematic study in which we compared symmetrically substituted methyl and benzyl derivatives with the nonsymmetric methyl/benzyl analogues. Through variation of the metal center and the halido ligands, an in-depth study was conducted on ligand exchange properties of these complexes and their biomolecule binding, noting in particular the stability of the M-C_NHC bond. In addition, we demonstrated the ability of the complexes to inhibit the selenoenzyme thioredoxin reductase (TrxR), suggested as an important target for anticancer metal-NHC complexes, and their cytotoxicity in human tumor cells. It was found that the most potent TrxR inhibitor diiodido(1,3-dibenzylbenzimidazol-2-ylidene)(η⁶-p-cymene)ruthenium(II) 1b^I was also the most cytotoxic compound of the series, with the antiproliferative effects in general in the low to middle micromolar range. However, since there was no clear correlation between TrxR inhibition and antiproliferative potency across the compounds, TrxR inhibition is unlikely to be the main mode of action for the compound type and other target interactions must be considered in future. Show less

Two ruthenium(II) complexes [Ru(IP)2(PIP)](ClO4)2·2H2O (1) and [Ru(PIP)2(IP)](ClO4)2·2H2O (2) (IP=imidazole [4, 5-f] [1,10] phenanthroline, PIP=2-phenylimidazo-[4, 5-f][1,10] phenanthroline) have been synthesized and characterized. The quadruplex binding of the compounds was evaluated by emission spectrum, CD spectroscopy, Visual detection assay and FRET (fluorescence resonance energy transfer)-melting assay. The results show that both complexes can induce the stabilization of quadruplex DNA, while complex 1 is a better G-quadruplex binder than complex 2. Furthermore, polymerase chain reaction-stop assay, electrophoretic mobility shift assay, telomerase repeat amplification protocol and MTT (3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay demonstrate that complex 1 not only can stabilize dimer forms of the G-quadruplex at low concentrations but also exhibit better inhibitory activity for telomerase and cancer cells. Show less

Four new luminescent cyclometallated iridium(III) bis(quinolylbenzaldehyde) diimine complexes [Ir(qba)(2)(N⁁N)](PF(6)) (Hqba = 4-(2-quinolyl)benzaldehyde, N⁁N = 2,2'-bipyridine, bpy (1); 1,10-phenanthroline, phen (2); 3,4,7,8-tetramethyl-1,10-phenanthroline, Me(4)-phen (3); 4,7-diphenyl-1,10-phenanthroline, Ph(2)-phen (4)) have been synthesised and characterised, and their electronic absorption, emission and electrochemical properties investigated. The X-ray crystal structures of complexes 1 and 2 have been determined. Upon irradiation, complexes 1-4 exhibited intense and long-lived orange-yellow emission in fluid solutions at 298 K and in alcohol glass at 77 K. The emission has been assigned to a triplet intra-ligand ((3)IL) excited state associated with the qba ligand, probably with mixing of some triplet metal-to-ligand charge-transfer ((3)MLCT) (dπ(Ir) →π*(qba)) character. Reductive amination reactions of complexes 1-4 with the protein bovine serum albumin (BSA) afforded the bioconjugates 1-BSA-4-BSA, respectively. Upon photoexcitation, these bioconjugates displayed intense and long-lived (3)MLCT (dπ(Ir) →π*(N⁁C)) emission in aqueous buffer at 298 K. The cross-linked nature of the Ir-BSA bioconjugates has been verified by SDS-PAGE. Additionally, the cytotoxicity of the complexes towards human cervix epithelioid carcinoma (HeLa) cells has been examined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assays, and the cellular uptake of complex 4 has been investigated by laser-scanning confocal microscopy and flow cytometry. Show less

9-Anthracenecarboxylic acid (9-Ac) was reported early as a chloride channel inhibitor and was found to exhibit significant anti-proliferative activity on leukemic cells, but has not been researched in solid tumor cells. Herein, a 9-anthraceneic acid derivative was introduced into the cyclometalated Iridium (III) species to construct a novel Iridium (Ir) complex Ir-9-Ac, [Ir(ppy)₂(9-Ac-L)]PF₆ (ppy = 2-phenylpyridine, 9-Ac-L = N-((4'-methyl-[2,2'-bipyridin]-4-yl)methyl)anthracene-9-carboxamide), which could accumulated in lysosomes. Ir-9-Ac showed good cytotoxic activity against several tumor cell lines, notably on A549 cells. Besides Ir-9-Ac could inhibit the cell colony formation and growth of the 3D cell spheroids, demonstrating the potential to suppress tumors in vivo. This design provided a platform for the design of cyclometalated Iridium (III) anticancer complexes. Show less

Improvement of antineoplastic activity and selectivity is a main goal in the development of antineoplastic agents. Herein, we synthesized three new iridium (III) complexes: [Ir(ppy)₂(FTTP)](PF₆) (Ir1, ppy = 2-phenylpyridine, FTTP = 2-(3-fluoronaphthalen-2-yloxy)-1,4,8,9-tetraazatriphenylene), [Ir(bzq)₂(FTTP)](PF₆) (Ir2, bzq = benzo[h]quinolone), [Ir(piq)₂(FTTP)](PF₆) (Ir3, piq = 1-phenylisoquinoline). Ir1-3 exhibit excellent cytotoxicity against various cancer cells particularly towards human cervical carcinoma HeLa cells while remaining non-toxic to normal cell lines. Assays on 2D cell colony formation and 3D multicellular tumor spheroid model confirm that Ir1-3 can effectively inhibit the colony-forming and penetrate deeply into HeLa 3D multicellular tumor spheroid model exhibiting a notable cytotoxic effect, which was consistent with the results from the viability assays. Meanwhile, confocal microscopy shows a rapid uptake of Ir1-3 and co-localization experiments with subcellular markers reveal that Ir1-3 locate mainly at the mitochondria. Further investigation of the mechanism indicated the complexes Ir1-3 promote the excessive generation of ROS, inhibit glutathione and thioredoxin reductase that effectively interferes with the intracellular redox balance, induce oxidative stress and result in caspase-dependent apoptosis. Moreover, the ROS-mediated inactivation of the PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin) pathway, DNA damage combing with suppression of the cyclin D1/CDK4/6 activity arrested cell cycle in the G0/G1 phase are involved in complexes-induced cell apoptosis. Finally, assays on xenografted cervical carcinoma mouse model confirm the excellent biocompatibility and antineoplastic efficiency of Ir3 in vivo. Collectively, this work offers building blocks for developing iridium (III) complexes as clinical application potential. Show less

In this work, we report on the development of fluorescent half-sandwich iridium complexes using a fluorophore attachment strategy. These constructs consist of pentamethylcyclopentadienyl (Cp*) iridium units ligated by picolinamidate donors conjugated to green-emitting boron-dipyrromethene (bodipy) dyes. Reaction studies in H₂O/THF mixtures showed that the fluorescent Ir complexes were active as catalysts for transfer hydrogenation, with activities similar to that of their non-fluorescent counterparts. The iridium complexes were taken up by NIH-3T3 mouse fibroblast cells, with 50% inhibition concentrations ranging from ~20-70 μM after exposure for 3 h. Visualization of the bodipy-functionalized Ir complexes in cells using fluorescence microscopy revealed that they were localized in the mitochondria and lysosome but not the nucleus. These results indicate that our fluorescent iridium complexes could be useful for future biological studies requiring intracellular catalyst tracking. Show less

The synthesis and characterisation of iridium(III) bis(2-(2,4-difluorophenyl)pyridinato-N, C2')-2(4-carboxylphenyl)imidazo[4,5-f][1,10]phenanthroline perchlorate, [Ir(dfpp)(2)(picCOOH)](+) and its octaarginine conjugate [Ir(dfpp)(2)(picCONH-Arg(8))](9+) are reported. Both complex and conjugate exhibit intense and long-lived luminescence, which is O(2) and pH sensitive. Conjugation to the polyarginine peptide renders the complex very water soluble. The uptake of the parent iridium(III) complex and conjugate are compared in two mammalian cell lines; SP2 myeloma and Chinese hamster ovary (CHO). Both complexes internalise into the cytoplasm, however dye uptake rate and distribution vary with peptide conjugation and with cell identity. Whereas transmembrane transport is thought to have been facilitated by the dimethyl sulfoxide (DMSO) used as co-solvent (0.05% v/v) for the parent complex, the octaarginine, the dye-conjugate (iridium-R(8)) is membrane permeable in water only. Both complexes exhibit high cytotoxicity, evident through blebbing and vacuole formation within living cells, indicative of apoptosis, within 30min of exposure to the probe. The IC(50) recorded for the cells in the dark was independent, in the case of the parent complex, of the identity of the cell, with IC(50) of 84.8μM and 88μM respectively for SP2 and CHO cells. The IC(50) approximately doubled for the polyarginine conjugate and displayed a significant dependence on cell type with IC(50) of 35μM and 54.1μM respectively for SP2 and CHO cells. These IC(50) values were recorded in the dark. However under irradiation cell death is considerably faster. Evidence from imaging suggests that the conjugate penetrates the nucleus whereas the parent does not, indicating that nuclear penetration may play a role in cytotoxicity. Show less

Four neutral cyclometalated iridium(III) (Ir^III) dithioformic acid complexes ([(ppy)₂Ir(S^S)], Ir1-Ir4) were designed and synthesized. Toxicity assay revealed that these complexes showed favorable anticancer activity, especially for human non-small cell lung cancer cells (A549). Ir1 exhibited the best anticancer activity (11.0 ± 0.4 μM) was about twice that of cisplatin, meanwhile, which could availably restrain A549 cells migration. Complexes could target mitochondria, induce a decrease in mitochondrial membrane potential (MMP), result in an increase of intracellular reactive oxygen species (ROS) and disruption of the cell cycle, and ultimately generate apoptosis. Western blotting experiment indicated that complexes could inhibit the expression of B cell CLL/lymphoma-2 protein (Bcl-2), induce the expression of BCL2-associated X protein (Bax) and lead to a massive release of Cytochrome C (Cyt-c), which amplified apoptosis signals by activating downstream pathway to promote apoptosis. All these confirmed the existence of mitochondrial anticancer channels for these complexes. Above all, cyclometalated iridium(III) dithioformic acid complexes possess the prospect of becoming a multifunctional cancer therapeutic platform, including mitochondria-targeted imaging, anti-migration, and anticancer agents. Show less

In this paper, two new iridium(III) complexes [Ir(ppy)₂(CBIP)](PF₆) (ppy = 2-phenylpyridine, CBIP = 2-(4'-chloro-(1,1'-biphenyl))-1H-imidazo[4,5-f][1,10]phenanthroline) (Ir1) and [Ir(piq)₂(CBIP)](PF₆) (piq = 1-phenylisoquinoline) (Ir2) were synthesized and characterized. The anticancer activity of the complexes against cancer A549, HepG2, SGC-7901, BEL-7402, HeLa and LO2 cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Unexpectedly, the complexes exhibit no or low cytotoxic activity toward the selected cancer cells. To increase the anticancer activity, complexes Ir1 and Ir2 were encapsulated into the liposome to form Ir1lipo and Ir2lipo, while Ir1lipo and Ir2lipo show high cytotoxic efficacy against BEL-7402, SGC-7901 and HeLa cells and Ir2lipo displays moderate cytotoxic activity against A549 and HepG2. The anticancer mechanism was explored through wound healing, cell cycle arrest, apoptosis, the change of mitochondrial membrane potential and antitumor activity in vivo. The antitumor in vivo showed that Ir1Lipo (3.9 mg/kg) exhibited significant antitumor activity with an inhibitory rate of 62.16%. Additionally, the expression of B-cell lymphoma-2 family proteins was studies by western blotting analysis. The results demonstrate that Ir1lipo and Ir2lipo induce apoptosis in BEL-7402 cells via endoplasmic reticulum stress-mitochondrial pathway. Show less

Combining the ligand NPIP (2-(2-nitrophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) with piq (1-phenylisoquinoline) and bzq (benzo[h]quinolone) gave [Ir(piq)₂(NPIP)](PF₆) (Ir1), and [Ir(bzq)₂(NPIP)](PF₆) (Ir2). The newly synthesized complexes were characterized by high-resolution mass spectrometry (HRMS), ¹H NMR and ¹³C NMR. The complexes showed high antiproliferative activity against B16 cells. Three-dimensional (3D) cell model in vitro was used to evaluate the inhibitory effect of iridium (III) complex on B16 cells. The cellular uptake, mitochondrial localization, and intracellular distribution of the drugs confirmed that the iridium (III) complexes targeted the mitochondria, and the complexes can lead to the loss of mitochondrial membrane potential (MMP), increases the intracellular ROS content, further induces apoptosis. We also found that Ir1 and Ir2 can trigger the release of damage-associated molecular patterns (DAMPs) (cell surface calreticulin (CRT), heat-shock protein 70 (HSP70) and high mobility group box 1 (HMGB1)). In addition, Ir1 and Ir2 inhibited glutathione (GSH) synthesis and thus induced oxidative stress, Ir1 and Ir2 promoted malondialdehyde (MDA) production which is the stable metabolite of lipid peroxidation products. Finally, mice xenograft assay was performed to demonstrate that the complex shows higher antitumor activity in vivo than cisplatin. The inhibitory rates for cisplatin and Ir1 are 38.95% and 69.67%, respectively. Show less

Despite their outstanding properties as potential photosensitizers for photodynamic therapy (PDT), Ir(III) biscyclometalated complexes need both further developments to overcome remaining limitations and in-depth investigations into their mechanisms of action to reach clinic application in the treatment of cancer. This work describes the synthesis of a family of Ir(III) complexes of general formula [Ir(C^N)₂(N^N')]Cl (N^N' = thiabendazole-based ligands; C^N = ppy (2-phenylpyridinate) (Series A), or dfppy (2-(2,4-difluorophenyl)pyridinate) (Series B)) and their evaluation as potential PDT agents. These complexes are partially soluble in water and exhibit cytotoxic activity in the absence of light irradiation versus several cancer cell lines. Furthermore, the cytotoxic activity of derivatives of Series A is enhanced upon irradiation, particularly for complexes [1a]Cl and [3a]Cl, which show phototoxicity indexes (PI) above 20. Endocytosis was established as the uptake mechanism for [1a]Cl and [3a]Cl in prostate cancer cells by flow cytometry. These derivatives mainly accumulate in the mitochondria as shown by colocalization confocal microscopy experiments. Presumably, [1a]Cl and [3a]Cl induce death on cancer cells under irradiation through apoptosis triggered by a multimodal mechanism of action, which likely involves damage over mitochondrial DNA and mitochondrial membrane depolarization. Both processes seem to be the result of photocatalytic oxidation processes. Show less

In this report, a new ligand TFBIP (TFBIP = 2-(4'-trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) and its three iridium (III) complexes [Ir(ppy)₂(TFBIP)](PF₆) (Ir1, ppy = 2-phenylpyridine), [Ir(bzq)₂(TFBIP)](PF₆) (Ir2, bzq = benzo[h]quinolone) and [Ir(piq)₂(TFBIP)](PF₆) (Ir3, piq = 1-phenylisoquinoline) were synthesized and characterized. The cytotoxicity in vitro of the complexes toward several cancer cells was evaluated by 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) methods. The complexes show no cytotoxicity (IC₅₀ > 100 μM) against these cancer cells. To enhance anticancer activity, these complexes were trapped in liposomes to form Ir1Lipo, Ir2Lipo and Ir3Lipo. The liposomes Ir1Lipo, Ir2Lipo and Ir3Lipo exhibit high or moderate cytotoxic activity. In particular, Ir1Lipo can effectively inhibit the cell growth with a low IC₅₀ value (< 10 μM) toward A549, HepG2, BEL-7402, B16, HeLa and SGC-7901 cells. Surprisingly, Ir1Lipo has no cytotoxic activity against the normal cell LO2 (IC₅₀ > 100 μM). The apoptosis and pyroptosis were investigated. Ir3Lipo induces apoptosis with a high early apoptotic number of 37%. The reactive oxygen species (ROS) levels, mitochondrial permeability transition pore open and mitochondrial membrane potential were detected. The intracellular Ca²⁺ concentration and release of cytochrome c were investigated. The expression of Bcl-2 (B-cell lymphoma-2) family proteins was explored by western blot. The antitumor activity in vivo of Ir1Lipo was evaluated with an inhibitory rate of 53%. Show less

Two iridium (III) polypyridine complexes [Ir(ppy)₂(BIP)]PF₆ (ppy = 2-phenylpyridine, BIP = 2-biphenyl-1H-imidazo[4,5-f][1,10]phenanthroline, Ir1), [Ir(piq)₂(BIP)]PF₆ (piq = 1-phenylisoquinoline, Ir2) and their liposomes Ir1lipo and Ir2lipo were synthesized and characterized. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate cytotoxic activity against several cancer cells (A549, HepG2, SGC-7901, Bel-7402, HeLa) and non-cancer cell (mouse embryonic fibroblast, NIH3T3). The results showed that Ir1lipo displays the high cytotoxicity toward SGC-7901 with IC₅₀ value of 5.8 ± 0.2 μM, while the complexes have no cytotoxicity toward A549, HepG2, Bel-7402 and HeLa cells. The cell colony demonstrated that the iridium (III) complexes-loaded liposomes can inhibit cell proliferation, induce cell cycle arrest at G0/G1 phase. Moreover, they also cause autophagy, induce a decrease of mitochondrial membrane potential and increase intracellular reactive oxygen species (ROS) content. These results suggest that the complexes encapsulated liposomes Ir1lipo and Ir2lipo inhibit the growth of SGC-7901 cells through a ROS-mediated mitochondrial dysfunction and activating the PI3K (phosphoinositide-3 kinase)/ AKT (protein kinase B) signaling pathways. Show less

Eight half-sandwich iridium^III (Ir^III) complexes of the general formula [(η⁵-Cp^xbiph)Ir(O^N)Cl] (Cp^xbiph is tetramethyl(biphenyl)cyclopentadienyl, and the O^N is α-picolinic acid chelating ligand and its derivatives) were synthesized and characterized. Compared with cis-platin widely used in clinic, target Ir^III complexes showed at most five times more potent antitumor activity against A549 cells by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Ir^III complexes could be transported by serum albumin, bind with DNA, catalyze the oxidation of nicotinamide-adenine dinucleotid (NADH) and induce the production of reactive oxygen species, which confirmed the antitumor mechanism of oxidation. Ir^III complexes could enter A549 cells followed by an energy-dependent cellular uptake mechanism, meanwhile, target the mitochondria and lysosomes with the Pearson's colocalization coefficient of 0.33 and 0.74, respectively, lead to the lysosomal destruction and the change of mitochondrial membrane potential (ΔΨm), and eventually induce apoptosis. Show less

A range of phosphorescent Ir(III) complexes containing four diverse P^P-chelating ligands of the type [Ir(ppy)₂(L)][PF₆], (ppy = 2‑phenylpyridine) where L is 1,2‑bis(diphenylphosphino)benzene (L1), 1,2‑bis(diphenylphosphino)ethane (L2), 1,2‑bis(diphenylphosphino)propane(L3) and 1,8‑bis(diphenylphosphino)naphthalene (L4) were synthesized respectively. The iridium complexes possessed excellent antiproliferative properties, which was a substantial improvement over cisplatin, especially complex Ir1. Generally, the order of in vitro antiproliferative activity of the complexes is Ir1 > Ir2 = Ir3 > Ir4 > CDDP (Cisplatin). Two X-ray crystal structures were determined. The best complex, Ir1, was chosen to further study the mechanism of action. The self-luminescence of complex Ir1 was also successfully used to elucidate the subcellular localization. Complex Ir1 was specifically targeted to lysosomes in A549 cancer cells. This targeting caused lysosomal damage and the induction of ROS (reactive oxygen species) production in cancer cells. Flow cytometry studies confirmed that this complex induced apoptosis, especially late apoptosis. Our results suggested that changes in the mitochondrial membrane potential were responsible for apoptosis. The chemistry and biological studies showed that this class of metal complexes is worthy of further exploration to design novel anticancer drugs. Show less

Four triphenylamine (TPA)-appended cyclometallated iridium(III) complexes were designed and synthesized. Photophysical properties of these complexes were studied, and density functional theory (DFT) was utilized to analyze the influence of the ancillary ligands (TPA-modified bipyridine) to these complexes. The introduction of TPA units could effectively adjust the lipid solubility of complexes (logP), and endowed complexes with potential bioactivity (anticancer, antibacterial and bactericidal activity), especially in the field of anticancer (the best value of IC₅₀ is 4.34±0.01μM). Interestingly, complexe 4 show some selectivity for cancer cells versus normal cells. Meanwhile, complexes could effectively prevent the metastasis of cancer cells. Complexes can be transported by serum albumin and followed by the static quenching mechanism (K_q: 10¹³M^-1s^-1), disturb cell cycle at G₀/G₁ phase, and induce apoptosis. The favorable fluorescence property confirmed these complexes followed by an energy-dependent cellular uptake mechanism, effectively accumulated in lysosomes (PCC: >0.95) and induced lysosomal damage, and eventually leaded to cell death. Our study demonstrates that these complexes are potential anticancer agents with dual functions, including metastasis inhibition and lysosomal damage. Show less

The studies of iridium (III) complexes as potent anticancer reagents have attracted great attention. Here, a new iridium (III) complex [Ir(bzq)₂(PYIP)](PF₆) (Ir1, bzq = benzo[h]quinoline, PYIP = 2-(pyren-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) was synthesized and its liposomes (Ir1Lipo) was prepared. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method was used to detect the cytotoxic activity of Ir1 and Ir1Lipo on HepG2, SGC-7901, BEL-7402, HeLa, B16, A549 and normal NIH3T3 cells. The complex Ir1 displays no obvious inhibitory effect on the growth of BEL-7402 cells, while the Ir1Lipo shows significant cytotoxic activity on BEL-7402 cells (IC₅₀ = 2.6 ± 0.03 μM). In further studies, Ir1Lipo induced apoptosis by the mitochondrial pathways, such as increasing intracellular reactive oxygen species (ROS) content and intracellular Ca²⁺ level, decreasing the mitochondrial membrane potential (MMP). In addition, after incubation with Ir1Lipo, the colony formation of BEL-7402 cells was significantly inhibited. Moreover, flow cytometry was used to detect the impact of Ir1Lipo on cell cycle distribution, and western blot was used to detect the expression of caspases and Bcl-2 (B-cell lymphoma-2) family proteins. Furthermore, Ir1Lipo exhibited significant antitumor activity in vivo with an inhibitory rate of 65.8%. These results indicated that Ir1Lipo induces apoptosis in BEL-7402 cells through intrinsic mitochondrial pathway. Show less

In this report, we synthesized three new iridium(III) complexes: [Ir(piq)₂(apip)]PF₆ (Ir1, piq = 1-phenylisoquinoline, apip = 2-aminophenyl-1H-imidazo[4,5-f][1,10]phenanthroline), [Ir(piq)₂(maip)]PF₆ (Ir2, maip = 3-aminophenyl-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ir(piq)₂(paip)]PF₆ (Ir3, paip = 4-aminophenyl-1H-imidazo[4,5-f][1,10]phenanthroline). The DNA binding was investigated. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method was used to detect the cytotoxic activity of Ir1, Ir2 and Ir3, the complexes show highly active against B16 cells with IC₅₀ values of 0.3 ± 0.2 μM, 3.7 ± 0.2 μM and 4.6 ± 1.1 μM, respectively. Subsequently, cellular uptake suggested that the cytotoxicity of the complexes is attributed to their differences in cellular uptake levels. In addition, complexes Ir1, Ir2 and Ir3 induce cell cycle arrest at the G0/G1 phase and regulate the cell cycle mediators such as cyclin D1, CDK6 (cyclin-dependent kinase 6), CDK4 and p21, leading to the inhibition of B16 cells proliferation. The autophagy was investigated by monodansylcadaverine (MDC) staining. The complexes can promote the change from LC3-I to LC3-II, up-regulate levels of Beclin-1 and down-regulate expression of p62. The complexes induced apoptosis by regulating the expression levels of related indicators such as PARP (poly ADP-ribose polymerase), PI3K (phosphoinositide-3 kinase), AKT (protein kinase B), Caspase, Bcl-2 (B-cell lymphoma-2), Bad (Bcl2 associated death promoter), Bax (Bcl2-associated X) and Cyto C (cytochrome C). Additionally, Ir1 exerted significant antitumor activity in the suppression of malignant melanoma proliferation in vivo. As indicated in the above results, these complexes were highly effective for malignant melanoma treatment through the intrinsic pathway and provided much insight into anticancer drugs for tumor therapy. Show less

The new ligand BBIP (BBIP = 2-(7-bromo-2H-benzo[d]imidazole-4-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) with its iridium(III) complexes: [Ir(ppy)₂(BBIP)](PF₆) (ppy = 2-phenylpyridine, Ir1), [Ir(bzq)₂(BBIP)](PF₆) (bzq = benzo[h]quinolone, Ir2) and [Ir(piq)₂(BBIP)](PF₆) (piq = 1-phenylisoquinoline, Ir3) were synthesized and characterized by elemental analysis, High Resolution Mass Spectrometer (HRMS), ¹H NMR and ¹³C{1H} NMR. The cytotoxicity of the complexes against A549, HepG2, SGC-7901, BEL-7402, HeLa and normal LO2 was evaluated through 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) method. The results show that Ir1 exhibits high cytotoxic activity against A549 cells with a low IC₅₀ value of 4.9 ± 0.5 μM. A series of biological activities such as cell cycle arrest, endoplasmic reticulum localization assay, apoptosis, western blotting, cellular uptake determination and in vivo antitumor activity were investigated. The assays implied that the complexes inhibit cancer cell migration through blocking mitotic progress. Cell cycle distribution stated that the complexes depress cell growth at G0/G1 phase. Additionally, the complexes acted on the endoplasmic reticulum and induce apoptosis through endoplasmic reticulum stress pathway. Especially, the western blotting showed that the complexes activated Bcl-2 (B-cell lymphoma-2) family and decreased PI3K (phosphoinositide-3 kinase) and AKT (protein kinase B), up-regulated the expression of mTOR (mammalian target of rapamycin) and p-mTOR (phosphorylated mammalian target of rapamycin). Therefore, the complexes induce apoptosis through activating PI3K-AKT-mTOR pathway. Antitumor in vivo demonstrated that Ir1 can effectively prevent the tumor growth with an inhibitory rate of 48.89%. Show less

Cisplatin and its analogs have been used for the treatment of various cancers, but their serious side effect has limited clinical application. Presently, scientists are developing other metal drugs as an alternative of cisplatin. In this paper, three new iridium(III) complexes [Ir(ppy)₂(adppz)](PF₆) (adppz = 7-aminodipyrido[3,2-a:2',3'-c]phenazine; ppy = 2-phenylpyridine 1), [Ir(bzq)₂(adppz)](PF₆) (bzq = benzo[h]quinolone 2) and [Ir(piq)₂(adppz)](PF₆) (piq = 1-phenylisoquinoline 3) were synthesized and characterized. The complexes can effectively inhibit the cell colonies. The cytotoxicity in vitro of the complexes against A549, HepG2, SGC-7901, BEL-7402 and normal NIH3T3 cells was evaluated by 3-(4,5-dimethylthiazole)-2,5-diphenyltetraazolium bromide (MTT) methods. The intracellular reactive oxygen species (ROS) levels and Ca²⁺ concentrations were assayed. The mitochondrial membrane potential, a release of cytochrome c and the expression of B-cell lymphoma/leukemia-2 (Bcl-2) family protein have been investigated. The data reveal that the complexes 1-3 can effectively inhibit the cell proliferation in A549 cells with low IC₅₀ value of 3.2 ± 0.4 μM, 4.8 ± 0.5 μM and 1.2 ± 0.2 μM, respectively. The antitumor in vivo shows that complex 3 can inhibit tumor growth with an inhibitory rate of 76.34%. The studies on the mechanism indicate that these complexes cause apoptosis in A549 cell via a ROS-mediated lysosomal-mitochondrial dysfunction pathway. In addition, the interaction of the complexes with BSA was explored. Show less