📚 BiometalDB

Organelle-targeted photosensitizers have been reported to be effective photodynamic therapy (PDT) agents. In this work, we designed and synthesized two iridium(III) complexes that specifically stain the mitochondria and lysosomes of living cells, respectively. Both complexes exhibited long-lived phosphorescence, which is sensitive to oxygen quenching. The photocytotoxicity of the complexes was evaluated under normoxic and hypoxic conditions. The results showed that HeLa cells treated with the mitochondria-targeted complex maintained a slower respiration rate, leading to a higher intracellular oxygen level under hypoxia. As a result, this complex exhibited an improved PDT effect compared to the lysosome-targeted complex, especially under hypoxia conditions, suggestive of a higher practicable potential of mitochondria-targeted PDT agents in cancer therapy. Show less

To investigate the antitumor effect of iridium complexes, three iridium (III) complexes [Ir(ppy)₂(dcdppz)]PF₆ (ppy = 2-phenylpyridine, dcdppz = 11,12-dichlorodipyrido[3,2-a:2',3'-c]phenazine) (Ir1), [Ir(bzq)₂(dcdppz)]PF₆ (bzq = benzo[h]quinoline) (Ir2) and [Ir(piq)₂(dcdppz)]PF₆ (piq = 1-phenylisoquinoline) (Ir3) were synthesized and characterized. Geometry optimization, molecular dynamics simulation and docking studies have been performed to further explore the antitumor mechanism. The cytotoxicity of Ir1-3 toward cancer cells was studied by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The localization of complexes Ir1-3 in the mitochondria, intracellular accumulation of reactive oxygen species (ROS) levels, the changes of mitochondrial membrane potential and morphological changes in apoptosis were investigated. Flow cytometry was applied to quantify fluorescence intensity and determine cell cycle distribution. Western blotting was used to detect the expression of apoptosis-related proteins. The anti-tumor effect of Ir1 in vivo was evaluated. The results showed that Ir1-3 had high cytotoxicity to most tumor cells, especially to SGC-7901 cells with a low IC₅₀ value. Ir1-3 can increase the intracellular ROS levels, reduce the mitochondrial membrane potential. Additionally, the complexes induce an increase of apoptosis-related protein expression, enhance the percentage of apoptosis. The complexes inhibit the cell proliferation at G0/G1 phase. The results obtained from antitumor in vivo indicate that Ir1 can significantly inhibit the growth of tumors with an inhibitory rate of 54.08%. The docking studies show that complexes Ir1-3 interact with DNA through minor-groove intercalation, which increases the distance of DNA base pairs, leading to a change of DNA helix structure. These experimental and theoretical findings indicate that complexes Ir1-3 can induce apoptosis in SGC-7901 cells through the mitochondrial dysfunction and DNA damage pathways, and then exerting anti-tumor activity in vitro and vivo. Show less

Photodynamic therapy (PDT) is a cancer treatment still bearing enormous prospects of improvement. Within the toolbox of PDT, developing photosensitizers (PSs) that can specifically reach tumor cells and promote the generation of high concentration of reactive oxygen species (ROS) is a constant research goal. Mitochondria is known as a highly appealing target for PSs, thus being able to assess the biodistribution of the PSs prior to its light activation would be crucial for therapeutic maximization. Bifunctional Ir(III) complexes of the type [Ir(C^N)₂(N^N-R)]⁺, where N^C is either phenylpyridine (ppy) or benzoquinoline (bzq), N^N is 2,2'-dipyridylamine (dpa) and R either anthracene (1 and 3) or acridine (2 and 4), have been developed as novel trackable PSs agents. Activation of the tracking or therapeutic function could be achieved specifically by irradiating the complex with a different light wavelength (405 nm vs. 470 nm respectively). Only complex 4 ([Ir(bzq)₂(dpa-acr)]⁺) clearly showed dual emissive pattern, acridine based emission between 407-450 nm vs. Ir(III) based emission between 521 and 547 nm. The sensitivity of A549 lung cancer cells to 4 evidenced the importance of involving the metal center within the activation process of the PS, reaching values of photosensitivity over 110 times higher than in dark conditions. Moreover, complex 4 promoted apoptotic cell death and possibly the paraptotic pathway, as well as higher ROS generation under irradiation than in dark conditions. Complexes 2-4 accumulated in the mitochondria but species 2 and 4 also localizes in other subcellular organelles. Show less

Cancer stem cells (CSCs) represent a difficult to treat cellular niche within tumours due to their unique characteristics, which give them a high propensity for resistance to classical anti-cancer treatments and the ability to repopulate the tumour mass. An attribute that may be implicated in the high rates of recurrence of certain tumours. However, other characteristics specific to these cells, such as their high dependence on mitochondria, may be exploited for the development of new therapeutic agents that are effective against the niche. As such, a previously described phosphorescent N-heterocyclic carbene iridium(III) compound which showed a high level of cytotoxicity against classical tumour cell lines with mitochondria-specific effects was studied for its potential against CSCs. The results showed a significantly higher level of activity against several CSC lines compared to non-CSCs. Mitochondrial localisation and superoxide production were confirmed. Although the cell death involved caspase activation, their role in cell death was not definitive, with a potential implication of other, non-apoptotic pathways shown. A cytostatic effect of the compound was also displayed at low mortality doses. This study thus provides important insights into the mechanisms and the potential for this class of molecule in the domain of anti-CSC therapeutics. Show less

Heteroleptic C^N cyclometalated iridium(iii) complexes incorporating a monostyryl/distyryl BODIPY ligand via acetylide bonds of 2,2'-bipyridine (bpy) with both absorption (ca. ε = 8.96 × 10⁴ M^-1 cm^-1, 9.89 × 10⁴ M^-1 cm^-1, and 7.89 × 10⁴ M^-1 cm^-1 at 664 nm, 644 nm, and 729 nm for Ir-2, Ir-3 and Ir-4, respectively) and fluorescence emission bands (ca. 624-794 nm for Ir-1, Ir-2, Ir-3 and Ir-4) in the near infra-red region (NIR) and exceptionally long-lived triplet excited states (τ = 156.5 μs for Ir-2) have been reported. Ir(ppy)₃ (Ir-0; ppy = 2-phenylpyridine) was used as reference, which gives the typical weak absorption in visible range (ε = 1.51 × 10⁴ M^-1 cm^-1 M^-1 cm^-1 at 385 nm). The nanosecond time-resolved transient absorption and DFT calculations proposed that styryl BODIPY-localized long lived ³IL states were populated for Ir-1, Ir-2, Ir-3 and Ir-4 (τ_T = 106.6 μs, 156.5 μs, 92.5 μs and 31.4 μs, respectively) upon photoexcitation. The complexes were used as triplet photosensitizers for singlet oxygen (¹O₂) mediated photooxidation of 1,5-dihydronaphthalene to produce juglone. The ¹O₂ quantum yields (Φ_Δ) of Ir-1 (0.53) and Ir-2 (0.81) are ca. 9-fold of Ir-3 (0.06) and 40-fold of Ir-4 (0.02), respectively. Ir-2 has high molar absorption coefficient at 664 nm, moderate fluorescence in the NIR region, and high singlet oxygen quantum yield (Φ_Δ = 0.81), exhibits predominate photocytotoxicity over dark cytotoxicity in LLC cells (lung cancer cells) upon irradiation, making it potentially suitable for use in in vivo photodynamic therapy (PDT). Our results are useful for preparation of transition metal complexes that show strong absorption of visible light in the NIR region with long-lived triplet excited states and for the application of these complexes in photocatalysis and theranostics such as simultaneous photodynamic therapy (PDT) and luminescent bioimaging. Show less

Title: Synthesis, physicochemical characterization and antiproliferative activity of phosphino Ru(II) and Ir(III) complexes. Abstract: Herein, we present the synthesis of new complexes based on ruthenium(II) (Ru(η6-p-cymene)Cl2PPh2CH2OH (RuPOH) and Ru(η6-p-cymene)Cl2P(p-OCH3Ph)2CH2OH (RuMPOH)) and iridium(III) (Ir(η5-Cp*)Cl2P(p-OCH3Ph)2CH2OH (IrMPOH) and Ir(η5-Cp*)Cl2PPh2CH2OH (IrPOH)) containing phosphine ligands with/without methoxy motifs on phenyl rings (P(p-OCH3Ph)2CH2OH (MPOH) and PPh2CH2OH (POH)). The complexes were characterized by mass spectrometry, NMR spectroscopy (1D: 1H, 13C{1H}, and 31P{1H} and 2D: HMQC, HMBC, and COSY NMR) and elemental analysis. All the complexes were structurally identified by single-crystal X-ray diffraction analysis. The Ru(II) and Ir(III) complexes have a typical piano-stool geometry with an η6-coordinated arene (RuII complexes) or η5-coordinated (IrIII compounds) and three additional sites of ligation occupied by two chloride ligands and the phosphine ligand. Oxidation of NADH to NAD+ with high efficiency was catalyzed by complexes containing P(p-OCH3Ph)2CH2OH (IrMPOH and RuMPOH). The catalytic property might have important future applications in biological and medical fields like production of reactive oxygen species (ROS). Furthermore, the redox activity of the complexes was confirmed by cyclic voltamperometry. Biochemical assays demonstrated the ability of Ir(III) and Ru(II) complexes to induce significant cytotoxicity in various cancer cell lines. Furthermore, we found that RuPOH and RuMPOH selectively inhibit the proliferation of skin cancer cells (WM266-4; IC50, after 24 h: av. 48.3 μM; after 72 h: av. 10.2 μM) while Ir(III) complexes were found to be moderate against prostate cancer cells (DU145). Show less

The organelle-specific localization of mononuclear and trinuclear iridium(III) complexes and their photodynamic behavior within the cells are described herein, emphasizing their structure-activity relationship. Both the IrA2 and IrB2 complexes possess a pair of phenyl-benzothiazole derived from the -CHO moieties of mononuclear organometallic iridium(III) complexes IrA1 and IrB1, which chelates IrCp*Cl (Cp* = 1,2,3,4,5-pentamethylcyclopentadiene) to afford trinuclear complexes IrA3 and IrB3. Insights into the photophysical and electrochemical parameters of the complexes were obtained by a time-dependent density functional theory study. The synthesized complexes IrA2, IrA3, IrB2, and IrB3 were found to be nontoxic to human MCF7 breast carcinoma cells. However, the photoexcitation of complexes using LED light could effectively trigger intracellular reactive oxygen species (ROS) generation, leading to cell death. Furthermore, to check the organelle-specific localization of IrA2 and IrB2, we observed that both complexes could selectively localize in the endoplasmic reticulum. In contrast, trinuclear IrA3 and IrB3 accumulate in the nuclei. The photoexcitation of complexes using LED light could effectively trigger intracellular reactive oxygen species (ROS) generation, leading to cell death. Show less

Photodynamic therapy (PDT) is a non-invasive, light-activated treatment approach that has been broadly employed in cancer. Cyclometallic iridium (Ш) complexes are candidates for ideal photosensitizers due to their unique photophysical and photochemical features, such as high quantum yield, large Stokes shift, strong resistance to photobleaching, and high cellular permeability. We evaluated a panel of iridium complexes and identified PC9 as a powerful photosensitizer to kill cancer cells. PC9 shows an 8-fold increase of cytotoxicity to HeLa cells under light irradiation. Further investigation discloses that PC9 has a strong mitochondrial-targeting ability and can inhibit the antioxidant enzyme thioredoxin reductase, which contributes to improving PDT efficacy. Our data indicate that iridium complexes are efficient photosensitizers with distinct physicochemical properties and cellular actions, and deserve further development as promising agents for PDT. Show less

Anti-PD-L1 immunotherapy, a new lung cancer treatment, is limited to a few patients due to low PD-L1 expression and tumor immunosuppression. To address these challenges, the upregulation of PD-L1 has the potential to elevate the response rate and efficiency of anti-PD-L1 and alleviate the immunosuppression of the tumor microenvironment. Herein, we developed a novel usnic acid-derived Iridium(III) complex, Ir-UA, that boosts PD-L1 expression and converts "cold tumors" to "hot". Subsequently, we administered Ir-UA combined with anti-PD-L1 in mice, which effectively inhibited tumor growth and promoted CD4⁺ and CD8⁺ T cell infiltration. To our knowledge, Ir-UA is the first iridium-based complex to stimulate the expression of PD-L1 by explicitly regulating its transcription factors, which not only provides a promising platform for immune checkpoint blockade but, more importantly, provides an effective treatment strategy for patients with low PD-L1 expression. Show less

Owing to the safety and low toxicity, photodynamic therapy (PDT) for cancer treatment has received extensive attention. However, the excess H₂S in cancer cells reduces the PDT efficiency, because H₂S indirectly depletes the reactive oxygen species (ROS). To improve anticancer efficiency, a mitochondria-targeted iridium(III) complex Ir-MMB has been developed as H₂S consumer and photo-oxidation anticancer agent. On the one hand, complex Ir-MMB can consume H₂S with sensitive phosphorescence turn-on, which has been successfully applied to exogenous and endogenous H₂S response imaging in living cells. On the other hand, Ir-MMB can enhance its anticancer activity and cause photo-oxidation damage via catalyzing the oxidation of reduced form of nicotinamide-adenine dinucleotide (NADH) to NAD⁺ and producing H₂O₂ under light, and ultimately results in cell apoptosis through mitochondrial depolarization and ROS production. Show less

Title: Ligand Dictated Photosensitization of Iridium(III) Dithiocarbamate Complexes for Photodynamic Therapy. Abstract: Organelle-targeted photosensitizers (PSs) for photodynamic therapy (PDT) are considered as an effective therapeutic strategy for the development of next generation PSs with the least side effects and high therapeutic efficacy. However, multiorganelle targeted PSs eliciting PDT via both type I and type II mechanisms are scarce. Herein, a series of cyclometalated iridium(III) complexes were formulated [Ir(C∧N)2(S∧S)] (C∧N = 2-phenylpyridine (ppy) and 2-(thiophen-2-yl)pyridine (thpy); S∧S = diethyldithiocarbamate (DEDTC), morpholine-N-dithiocarbamate (MORDTC) and methoxycarbonodithioate (MEDTC)) and the newly designed complexes Ir2@DEDTC and Ir1@MEDTC were characterized by single crystal X-ray crystallography. Complexes containing thpy as C∧N ligand exhibit excellent photophysical properties such as red-shifted emission, high singlet oxygen quantum yield (ϕΔ) and longer photoluminescence lifetime when compared with complexes containing ppy ligands. Ir2@DEDTC exhibits the highest ϕΔ and photoluminescence lifetimes among the synthesized complexes. Therefore, Ir2@DEDTC was chosen to evaluate the photosensitizing ability to produce reactive oxygen species (ROS). Upon blue light irradiation (456 nm), it efficiently produces ROS, i.e., hydroxy radical (•OH) and singlet oxygen (1O2), which was confirmed by electron paramagnetic resonance (EPR) spectroscopy. In vitro photocytotoxicity toward HCT116, HeLa, and PC3 cell lines showed that out of all the synthesized complexes, Ir2@DEDTC has the highest photocytotoxic index (PI > 400) value. Ir2@DEDTC is efficiently taken up by the HCT116 cell line and accumulated mainly in the lysosome and mitochondria of the cells, and after PDT treatment, it elicits cell shrinkage, membrane blebbing, and DNA fragmentation. The phototherapeutic efficacy of Ir2@DEDTC has been investigated against 3D spheroids considering its ability to mimic some of the basic features of solid tumors. The morphology was drastically altered in the Ir2@DEDTC treated 3D spheroid after the light irradiation unleashed the potential of the Ir(III) dithiocarbamate complex as a superior PS for PDT. Hence, mitochondria and lysosome targeted photoactive cyclometalated Ir(III) dithiocarbamate complex exerting oxidative stress via both type I and type II PDT can be regarded as a dual-organelle targeted two-pronged approach for enhanced PDT. Show less

Ligand HMSPIP (2-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) and its iridium(III) complexes [Ir(ppy)₂(HMSPIP)]PF₆ (ppy = 2-phenylpyridine, Ir1) and [Ir(bzq)₂(HMSPIP)]PF₆ (bzq = benzo[h]quinoline, Ir2) were synthesized. The complexes were characterized by ¹H NMR, ¹³C NMR, and UV/Vis spectra. The cytotoxicity of the complexes toward cancer cells were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, the scratch wound healing and colony-forming were also investigated. MTT assay certificated that the complexes show high toxic effect on the HeLa cells. The cell cycle assay illustrated that the complexes blocked cell growth at G₀/G₁ phase in HeLa cells. A series of subsequent experiments showed that the complexes first enter the endoplasmic reticulum (ER) and then enter the mitochondria, leading to an increase in intracellular Ca²⁺ and reactive oxygen species (ROS) content, depolarizing mitochondrial membrane potential (MMP), and ultimately resulting in apoptosis. In addition, the experimental results revealed that the complexes not only increase the level of ROS but also inhibit the production of GSH and eventually produce large amounts of MDA and further leading to cell death. Taken together, we consider that the complexes can be used as potential candidate drugs for HeLa cancer treatment. Show less

While the phenomenal clinical success of blockbuster platinum (Pt) drugs is highly encouraging, the inherent and acquired resistance and dose-limiting side effects severely limit their clinical application. To find a better alternative with translational potential, we synthesized a library of six organo-Ir^III half-sandwich [(η⁵-Cp^X)Ir(N∧N)Cl]⁺-type complexes. In vitro screening identified two lead candidates [(η⁵-Cp^XPh)Ir(Ph₂Phen)Cl]⁺ (5, Cp^XPh = tetramethyl-phenyl-cyclopentadienyl and Ph₂Phen = 4,7-diphenyl-1,10-phenanthroline) and [(η⁵-Cp^XBiPh)Ir(Ph₂Phen)Cl]⁺ (6, Cp^XBiPh = tetramethyl-biphenyl-cyclopentadienyl) with nanomolar IC₅₀ values. Both 5 and 6 efficiently overcame Pt resistance and presented excellent cancer cell selectivity in vitro. Potent antiangiogenic properties of 6 were demonstrated in the zebrafish model. Satisfyingly, 6 and its nanoliposome Lipo-6 presented considerably higher in vivo antitumor efficacy as compared to cisplatin, as well as earlier reported Ir^III half-sandwich complexes in mice bearing the A549 non-small lung cancer xenograft. In particular, complex 6 is the first example of this class that exerted dual in vivo antiangiogenic and antitumor properties. Show less

Cancers are driven by multiple genetic mutations but evolve to evade treatments targeting specific mutations. Nonetheless, cancers cannot evade a treatment that targets mitochondria, which are essential for tumor progression. Iridium complexes have shown anticancer properties, but they lack specificity for their intracellular targets, leading to undesirable side effects. Herein we present a systematic study on structure-activity relationships of eight arylbenzazole-based Iridium(III) complexes of type [IrCl(Cp*)], that have revealed the role of each atom of the ancillary ligand in the physical chemistry properties, cytotoxicity and mechanism of biological action. Neutral complexes, especially those bearing phenylbenzimidazole (HL1 and HL2), restrict the binding to DNA and albumin. One of them, complex 1[C,NH-Cl], is the most selective one, does not bind DNA, targets exclusively the mitochondria, disturbs the mitochondria membrane permeability inducing proton leak and increases ROS levels, triggering the molecular machinery of regulated cell death. In mice with orthotopic lung tumors, the administration of complex 1[C,NH-Cl] reduced the tumor burden. Cancers are more vulnerable than normal tissues to a treatment that harnesses mitochondrial dysfunction. Thus, complex 1[C,NH-Cl] characterization opens the way to the development of new compounds to exploit this vulnerability. Show less

Photodynamic therapy (PDT) has long been receiving increasing attention for the minimally invasive treatment of cancer. The performance of PDT depends on the photophysical and biological properties of photosensitizers (PSs). The always-on fluorescence signal of conventional PSs makes it difficult to real-time monitor phototherapeutic efficacy in the PDT process. Therefore, functional PSs with good photodynamic therapy effect and self-reporting properties are highly desired. Here, two nonemissive iridium(III) solvent complexes, [(dfppy)₂Ir(DMSO)]Cl (Ir-DMSO, dfppy = 2,4-difluorophenyl)pyridine, DMSO = dimethyl sulfoxide) and [(dfppy)₂Ir(ACN)]Cl (Ir-ACN, ACN = acetonitrile) as PSs, were synthesized. Both of them exhibit intense high-energy absorption bands, low photoluminescence (PL) emission, and low dark toxicity. Thanks to the lower dark toxicity of Ir-DMSO, we chose it as a PS for further PDT. In this work, Ir-DMSO functions as a specific PL "signal on" PS for self-reporting therapeutic efficacy during its own PDT process. Colocalization experiments indicated that Ir-DMSO accumulated in the endoplasmic reticulum and mitochondria. Under light irradiation, Ir-DMSO not only exhibited the ability to kill cancer cells but also presented a "signal on" PL response toward cell death. During Ir-DMSO-induced PDT, cell death modality was further investigated and immunogenic cell death was revealed, in which main hallmarks, including ROS generation, upregulation of surface-exposed calreticulin, high-mobility group box 1, and adenosine triphosphate secretion, were observed. Thanks to the specific coordination reaction between Ir-DMSO and histidine (His)/His-containing proteins, the phototherapeutic efficacy can be monitored in real time without other signal probes. This work provides a new and promising strategy for the development of PSs with self-reporting ability, which is of great importance for imaging-guided PDT. Show less

Identification of intracellular targets of anticancer drug candidates provides key information on their mechanism of action. Exploiting the ability of the anticancer (C∧N)-chelated half-sandwich iridium(III) complexes to covalently bind proteins, click chemistry with a bioorthogonal azido probe was used to localize a phenyloxazoline-chelated iridium complex within cells and profile its interactome at the proteome-wide scale. Proteins involved in protein folding and actin cytoskeleton regulation were identified as high-affinity targets. Upon iridium complex treatment, the folding activity of Heat Shock Protein HSP90 was inhibited in vitro and major cytoskeleton disorganization was observed. A wide array of imaging and biochemical methods validated selected targets and provided a multiscale overview of the effects of this complex on live human cells. We demonstrate that it behaves as a dual agent, inducing both electrophilic and oxidative stresses in cells that account for its cytotoxicity. The proposed methodological workflow can open innovative avenues in metallodrug discovery. Show less

Title: Functional Upgrading of an Organo-Ir(III) Complex to an Organo-Ir(III) Prodrug as a DNA Damage-Responsive Autophagic Inducer for Hypoxic Lung Cancer Therapy. Abstract: The efficiency of nitrogen mustards (NMs), among the first chemotherapeutic agents against cancer, is limited by their monotonous mechanism of action (MoA). And tumor hypoxia is a significant obstacle in the attenuation of the chemotherapeutic efficacy. To repurpose the drug and combat hypoxia, herein, we constructed an organo-Ir(III) prodrug, IrCpNM, with the composition of a reactive oxygen species (ROS)-inducing moiety (Ir-arene fragment)-a hypoxic responsive moiety (azo linker)-a DNA-alkylating moiety (nitrogen mustard), and realized DNA damage response (DDR)-mediated autophagy for hypoxic lung cancer therapy for the first time. Prodrug IrCpNM could upregulate the level of catalase (CAT) to catalyze the decomposition of excessive H2O2 to O2 and downregulate the expression of the hypoxia-inducible factor (HIF-1α) to relieve hypoxia. Subsequently, IrCpNM initiates the quadruple synergetic actions under hypoxia, as simultaneous ROS promotion and glutathione (GSH) depletion to enhance the redox disbalance and severe oxidative and cross-linking DNA damages to trigger the occurrence of DDR-mediated autophagy via the ATM/Chk2 cascade and the PIK3CA/PI3K-AKT1-mTOR-RPS6KB1 signaling pathway. In vitro and in vivo experiments have confirmed the greatly antiproliferative capacity of IrCpNM against the hypoxic solid tumor. This work demonstrated the effectiveness of the DNA damage-responsive organometallic prodrug strategy with the microenvironment targeting system and the rebirth of traditional chemotherapeutic agents with a new anticancer mechanism. Show less

Although reactive aldehyde species (RASP) are associated with the pathogenesis of many major diseases, there are currently no clinically approved treatments for RASP overload. Conventional aldehyde detox agents are stoichiometric reactants that get consumed upon reacting with their biological targets, which limits their therapeutic efficiency. To achieve longer-lasting detoxification effects, small-molecule intracellular metal catalysts (SIMCats) were used to protect cells by converting RASP into non-toxic alcohols. It was shown that SIMCats were significantly more effective in lowering cell death from the treatment with 4-hydroxynon-2-enal than aldehyde scavengers over a 72 h period. Studies revealed that SIMCats reduced the aldehyde accumulation in cells exposed to the known RASP inducer arsenic trioxide. This work demonstrates that SIMCats offer unique benefits over stochiometric agents, potentially providing new ways to combat diseases with greater selectivity and efficiency than existing approaches. Show less

Cyclometalated iridium complexes with mitochondrial targeting show great potential as substitutes for platinum-based complexes because of their strong anti-cancer properties. Three novel cyclometalated iridium(III) compounds were synthesized and evaluated in five different cell lines as part of the ongoing systematic investigations of these compounds. The complexes were prepared using 4,7-dichloro-1,10-phenanthroline ligands. The cytotoxicity of complexes Ir1-Ir3 towards HeLa cells was shown to be high, with IC₅₀ values of 0.83±0.06, 4.73±0.11, and 4.95±0.62 μM, respectively. Complex Ir1 could be ingested by HeLa cells in 3 h and has shown high selectivity toward mitochondria. Subsequent investigations demonstrated that Ir1 triggered apoptosis in HeLa cells by augmenting the generation of reactive oxygen species (ROS), reducing the mitochondrial membrane potential, and depleting ATP levels. Furthermore, the movement of cells was significantly suppressed and the progression of the cell cycle was arrested in the G0/G1 phase following the administration of Ir1. The Western blot analysis demonstrated that the induction of apoptosis in HeLa cells by Ir1 involves the activation of the mitochondria-dependent channel and the PI3K/AKT signaling pathway. No significant cytotoxicity was observed in zebrafish embryos at concentrations less than or equal to 16 µM, e.g., survival rate and developmental abnormalities. In vivo, antitumor assay demonstrated that Ir1 suppressed tumor growth in mice. Therefore, our work shows that complex Ir1 could be a promising candidate for developing novel antitumor drugs. Show less

Installing proton-coupled electron transfer (PCET) in Ir-complexes is indeed a newly explored phenomenon, offering high quantum efficiency and tunable photophysics; however, the prospects for its application in various fields, including interrogating biological systems, are quite open and exciting. Herein, we developed various organelle-targeted Ir(iii)-complexes by leveraging the photoinduced PCET process to see the opportunities in phototherapeutic application and investigate the underlying mechanisms of action (MOAs). We diversified the ligands' nature and also incorporated a H-bonded benzimidazole-phenol (BIP) moiety with π-conjugated ancillary ligands in Ir(iii) to study the excited-state intramolecular proton transfer (ESIPT) process for tuning dual emission bands and to tempt excited-state PCET. These visible or two-photon-NIR light activatable Ir-catalysts generate reactive hydroxyl radicals (˙OH) and simultaneously oxidize electron donating biomolecules (1,4-dihydronicotinamide adenine dinucleotide or glutathione) to disrupt redox homeostasis, downregulate the GPX4 enzyme, and amplify oxidative stress and lipid peroxide (LPO) accumulation. Our homogeneous photocatalytic platform efficiently triggers organelle dysfunction mediated by a Fenton-like pathway with spatiotemporal control upon illumination to evoke ferroptosis poised with the synergistic action of apoptosis in a hypoxic environment leading to cell death. Ir2 is the most efficient photochemotherapy agent among others, which provided profound cytophototoxicity to 4T1 and MCF-7 cancerous cells and inhibited solid hypoxic tumor growth in vitro and in vivo. Show less

Aggregation-induced phosphorescence emission (AIPE) materials based on transition metal Ir(III) complexes have significant advantages in bioimaging and photodynamic therapy (PDT) due to the long lifetime, the reduced photobleaching and the good reactive oxygen species (ROS) generation. Herein, four cationic Ir(III) complexes (Ir1-Ir4) have been synthesized and studied. Tunable phosphorescence from green to red with the excellent properties of AIPE and long lifetimes can be achieved by varying the substituents. Moreover, these phosphorescence Ir(III) complexes exhibited dual-mode PDT potential (type I and type II). Complex Ir4 showed great prospect in bioimaging and PDT with the large Stokes shift (259 nm), the long lifetime (9.85 μs) and the high ROS yield (0.73). Confocal microscopy demonstrated that Ir4 accumulated in the mitochondria selectively and possessed remarkable photostability (reduced photobleaching up to 600 s). The results indicate that Ir4 may be used in dual-mode PDT guided by mitochondria-targeted imaging. This work provides an in-depth understanding of the relationship between structure and photophysical properties and facilitates the study in PDT applications. Show less

By rational altering the structure of CN auxiliary ligand, Near-infrared (NIR) phosphorescent cyclometalated platinum (II) and iridium (III) complexes with metformin (Met) have been successfully obtained and characterized. The dissociation of Met in aqueous solution can be accelerated by addition of Glutathione (GSH) and alleviated by drop of histidine, accompanied with a significant decay change of deep red phosphorescence. Besides, Pt3 and Ir1 with moiety of btpq mainly selectively targeted and located in Mitochondrial, while Pt1 of ppy and Pt2 with thpy mainly accumulated in endoplasmic reticulum. Moreover, Pt1-3 and Ir1 with metformin moiety all exert a significant enhanced anticancer activity, among them, Pt3 displays ca.66-fold, ca.147-fold and ca.588-fold higher cytotoxicity than cisplatin, Met-free analogue Pt3a and Met. Their relative anticancer mechanism was further investigated, both Pt2 and Pt3 could form covalent interaction with bovine serum albumin (BSA) and effectively induce reactive oxygen species (ROS) generation, arrest of cell cycle, loss of Mitochondrial membrane potential (MMP), display effective anti-metastasis activity and eventually induce apoptosis of cancer cell. Show less

To enhance the cytoselective behavior of the complexes, we intended to develop a CuAAC "click"-derived synthetic protocol for the preparation of 2-(2-(4-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)butoxy)phenyl)benzo[d]thiazole-based Ru(II)/Ir(III)/Re(I) complexes, and their cytotoxicity against three different cancer cell lines (MCF-7, HeLa, and U87MG) in consort with one normal cell line (HEK-293) was evaluated. In our detailed investigations, the significant cytotoxic nature of the Ru(II) complex 7a compared to Ir(III) and Re(I) complexes (7b and 7c, respectively) was observed. Complex 7a was capable of MCF-7 cell apoptosis via the inhibition of both S- and G2/M-phase cell cycle arrest in association with a substantial quantity of ROS production and DNA intercalation. Show less