📚 BiometalDB

Title: Triphenylphosphine-modified cyclometalated iridium Abstract: This study presents the development and evaluation of triphenylphosphine-modified cyclometalated iridiumIII complexes as selective anticancer agents targeting mitochondria. By leveraging the mitochondrial localization capability of the triphenylphosphine group, these complexes displayed promising cytotoxicity in the micromolar range (3.12-7.24 μM) against A549 and HeLa cancer cells, these complexes exhibit significantly higher activity compared to their unmodified counterparts lacking the triphenylphosphine moiety. Moreover, they demonstrate improved specificity for cancer cells over normal cells, achieving selectivity index in the range of 5.46-14.83. Mechanistic studies confirmed that these complexes selectively target mitochondria rather than DNA, as shown by confocal microscopy and flow cytometry, where they accumulate to induce mitochondrial dysfunction. This disruption leads to mitochondrial membrane depolarization (MMP), elevated reactive oxygen species (ROS) levels, and activation of intrinsic apoptosis pathways. Furthermore, the complexes induce cell cycle arrest at the G2/M phase and suppress the migration of A549 cells. Show less

Modulating mitochondrial activity to regulate cancer cell homeostatic recycling presents a promising approach to overcome tumor resistance. Consequently, there is an urgent need for novel mitochondria-targeting agents and innovative strategies. We have developed [((η⁵-Cp∗)Ir(rhod)]²⁺2PF₆^- (Ir-rhod), a new mitochondria-targeted iridium complex that exhibits greater cytotoxicity towards A549R (cisplatin-resistant human lung cancer) cells compared to the ligand rhod. Ir-rhod's mitochondrial targeting ability stems from both rhodamine's inherent mitochondrial affinity and the complex's positive bivalent nature. The positively charged Ir-rhod enters cells and is drawn to mitochondria due to the high transmembrane potential in tumor cells. Notably, rhodamine enables real-time observation of Ir-rhod's dynamic distribution in vivo. Ir-rhod influences mitochondrial function, triggering tumor cell ferroptosis and apoptosis by modulating ACSL4 and GPX4. The targeting effect of Ir-rhod reduces its systemic toxicity in vivo, enhancing its biosafety profile. To our knowledge, Ir-rhod is an effective mitochondria-targeted Ir complex capable of inducing tumor cell death by disrupting mitochondrial function, offering a potent strategy to suppress cisplatin resistance in non-small cell lung cancer. Show less

Site-specific bioconjugation techniques are extensively utilized in biological and biomedical fields to precisely label biomolecules with luminescent tags for direct visualization of their intracellular dynamics or with cytotoxic agents for the development of novel anticancer therapeutics. In this work, a series of cyclometalated iridium-(III) polypyridine complexes featuring a thioester moiety was designed as novel phosphorogenic probes for labeling N-terminal cysteine (N-Cys)-containing biomolecules. These thioester complexes were weakly emissive in solutions due to the presence of a low-lying nonradiative distorted triplet intraligand (³IL) state localized on the thioester unit, as elucidated by computational analyses. However, their emission intensities and singlet oxygen (¹O₂)-photosensitization efficiencies substantially increased upon reaction with l-Cys due to the conversion of the quenching thioester moiety to a nonquenching amide unit. Additionally, the thioester complexes exhibited high selectivity toward N-Cys and displayed significantly enhanced reactivity due to the electron-withdrawing iridium-(III) polypyridine moiety. The remarkable aminothiol-induced emission and ¹O₂-photosensitization turn-on of the thioester complexes were exploited for the development of intracellular Cys sensors and Cys-activatable photosensitizers for cancer-targeted photodynamic therapy. Furthermore, one of the thioester complexes was selected to react with various N-Cys-modified tumor-targeting peptides, yielding photofunctional iridium-(III)-peptide conjugates with high ¹O₂ generation efficiencies. These conjugates retained the tumor-targeting capabilities of the original peptides and showed high specificity for MDA-MB-231 cells compared to MCF-7 and HEK-293 cells, resulting in selective photocytotoxicity toward this triple-negative breast cancer cell line. We believe that our design approach will inspire the development of novel luminogenic thioester-based reagents for bioconjugation, bioimaging, and therapeutic applications. Show less

Title: Mitochondrial-targeted iridium(III) complexes suppress tumor growth through inducting immunogenic cell death to activate immune response. Abstract: A new ligand, 2-(2-hydroxyl-4-methyl)phenyl-1H-imidazo[4,5-f][1,10]phenanthroline (IPMP), and [Ir(ppy)2(IPMP)]PF6 (7a), [Ir(bzq)2(IPMP)]PF6 (7b), and [Ir(piq)2(IPMP)]PF6 (7c) have been prepared and characterized by HRMS, NMR spectra. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays revealed that 7b exhibited excellent activity (IC50 = 4.5 ± 0.4 μM), while 7a and 7c showed good cytotoxicity (IC50 = 8.5 ± 0.9 μM and 8.9 ± 2.2 μM) against non-small cell lung cancer A549 cells. The experiments of cellular uptake and mitochondrial localization demonstrate that these new iridium(III) complexes are readily taken up by A549 cells and accumulate in the mitochondria and damage the structure of the mitochondria, which results in the loss of mitochondrial membrane potential (MMP), elevated lipid peroxidation, as well as DNA damage, the inhibition of microtubule polymerization, hindrance of the cell cycle in the G0/G1 phase, and release of cytochrome c, collectively leading to apoptosis. Furthermore, upregulation of Beclin-1, overexpression of NF-κB and downregulation of GPX4 protein were observed, which resulted in the activation of autophagy, pyroptosis and ferroptosis, respectively. In the C57BL/6 mouse model, the 7b demonstrated promising in vivo antitumor efficacy, with a tumor inhibitory rate of 66.9 %. Additionally, the complexes induce an immunogenic cell death to activate immune response, further enhance CD8+ T cells and efficiently inhibit tumor growth. Collectively, we consider that the complexes may be utilized as potential candidate agents for the treatment of A549 cancer. Show less

Title: Mitochondrial Viscosity Probes: Iridium(III) Complexes Induce Apoptosis in HeLa Cells. Abstract: Mitochondrial viscosity has emerged as a promising biomarker for diseases such as cancer and neurodegenerative disorders, yet accurately measuring viscosity at the subcellular level remains a significant challenge. In this study, we synthesized and characterized three cyclometalated iridium(III) complexes (Ir1-Ir3) containing 5-fluorouracil derivatives as ligands. Among these, Ir1 selectively induced apoptosis in HeLa cells by increasing mitochondrial production of reactive oxygen species (ROS), which triggered a cascade of events leading to mitochondrial dysfunction. Additionally, the fluorescence lifetime of Ir1 demonstrated high sensitivity to intracellular viscosity changes, enabling real-time fluorescence lifetime imaging microscopy (FLIM) of cellular micro-viscosity during apoptosis. These findings underscore the potential of cyclometalated Ir(III) complexes for both therapeutic and diagnostic applications at the subcellular level. Show less

Photoactivatable systems have received considerable attention in the development of diagnostics and therapeutics due to their noninvasive nature and precise spatiotemporal control. Of particular interest is the 3,6-dithio-1,2,4,5-tetrazine (S,S-tetrazine) unit, which can not only act as a photolabile protecting group for constructing photoactivatable systems but also as a bioorthogonal scaffold that enables the inverse electron-demand Diels-Alder (IEDDA) cycloaddition reaction with strained alkynes. In this study, we designed and synthesised a cyclometallated iridium(iii) complex modified with a 3-chloro-6-thio-1,2,4,5-tetrazine moiety (1) for cysteine conjugation. The complex was conjugated with an integrin-targeting peptide c(RGDfC) to afford a tumour-targeting conjugate (1-RGD) for bioimaging and photoactivated therapy. An RGD-free analogue (2) was also prepared for comparison studies. Unlike common iridium(iii) complexes, excitation of conjugate 1-RGD and complex 2 resulted in weak emission and negligible singlet oxygen (¹O₂) generation due to the quenching effect of the tetrazine unit. Upon continuous light irradiation, the S,S-tetrazine moiety in conjugate 1-RGD and complex 2 underwent efficient photodissociation, yielding thiocyanate (3) and amide (4) complexes as photoproducts with increased emission intensities and enhanced ¹O₂ generation efficiencies. Interestingly, the IEDDA cycloaddition reaction of the S,S-tetrazine-containing conjugate 1-RGD and complex 2 with (1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN-OH) led to significant emission enhancement. Notably, conjugate 1-RGD showed higher cellular uptake and (photo)cytotoxicity (IC_50,dark = 26 μM, IC_50,light = 0.08 μM) in U87-MG cells, which overexpress integrin, compared to MCF-7 (IC_50,dark = 52 μM, IC_50,light = 0.22 μM) and HEK293 cells (IC_50,dark > 50 μM, IC_50,light = 1.3 μM) with lower integrin levels. This work will contribute to the development of photoactivatable transition metal complexes for cancer-targeted imaging and therapy. Show less

Colon cancer is one of the most commonly diagnosed cancers and is recognized as the most aggressive tumor of the digestive system. Aberrant activation of signal transducer and activator of transcription 3 (STAT3) is associated with proliferation, metastasis and immunosuppression of the tumor cells. Here, to inhibit the STAT3 pathway and suppress metastasis in colon cancer cells, the half-sandwich iridium complex Ir-ART containing an artesunate-derived ligand was synthesized. The complex showed remarkable antiproliferative activity against human colon cancer HCT-116 cells and exhibited a concentration-dependent reduction in STAT3 protein expression. Mechanism study demonstrates that Ir-ART is located mainly in the nucleus and mitochondria, causing γ-H2AX and cyclin B1 reduction and reactive oxygen species accumulation and mitochondrial membrane potential loss, ultimately leading to autophagic cell death. The migration of cancer cells was also inhibited via metalloproteinase 9 downregulation. Furthermore, Ir-ART could initiate antitumor immune responses by eliciting immunogenic cell death and downregulating immunosuppressive cytokine cyclooxygenase-2. Taken together, Ir-ART is expected to be further applied to chemotherapy and immunotherapy for colon cancer. Show less

Title: Designing novel tridentate iridium(III) complexes comprising functionalized benzothiazole ligands to improve anticancer activity by targeting mitochondria. Abstract: In recent years, organo‑iridium anticancer agents have shown promising antitumor activity toward cancer cells. In this paper, two benzothiazole-based tridentate ligands, 2,2'-(5-(tert-butyl)-1,3-phenylene)bis(benzo[d]thiazole) (L1) and 2,2'-(5-(methyl)-1,3-phenylene)bis(benzo[d]thiazole) (L2), have been designed and synthesized, and then combined with 2,2'-bipyridine (bipy) and 1,10-phenanthroline (phen) ancillary ligands to form a series of novel [Ir(N^C^N)(N^N)Cl]+-type iridium(III) complexes (Ir1-Ir4). The phosphorescence properties of these complexes facilitate the visualization of their subcellular localization and interactions with other biomolecules. Among them, complex Ir2 has the best cytotoxicity activity toward A549 cells and its antitumor activity was further evaluated. Laser confocal assay reveals that Ir2 followed an energy-dependent cellular uptake mechanism and specifically accumulates in mitochondria (Pearson colocalization coefficient: 0.89). The anticancer mechanism has been explored through apoptosis, cell cycle arrest, western blotting (WB), reactive oxygen species (ROS) levels and mitochondrial membrane potential (MMP) changes. The antitumor activity in vivo confirms that Ir2 could effectively inhibit tumor growth with an inhibitory rate of 71.60 %, which is superior to cisplatin. To the best of our knowledge, Ir2 is a rare example of [Ir(N^C^N)(N^N)Cl]+-type complexes as potential anticancer agents. Show less

Title: Endocytic Uptake of Self-Assembled Iridium(III) Nanoaggregates for Holistic Treatment of Metastatic 3D Triple-Negative Breast Tumor Spheroids. Abstract: Triple-negative breast cancer (TNBC) presents a formidable challenge due to its aggressive behavior and limited array of treatment options available. This study focuses on employing nanoaggregate material of organometallic Ir(III) complexes for treating TNBC cell line MDA-MB-231. In this approach, Ir(III) complexes with enhanced cellular permeability are strategically designed and achieved through the incorporation of COOMe groups into their structure. The lead compound, IrL1, exhibits promiscuous nanoscale aggregation in RPMI cell culture media, characterized by a stable hydrodynamic effective diameter ranging from 190 to 202 nm over 48 h. With excellent photo-responsive contrast-enhanced cell imaging properties IrL1 exhibits an outstanding IC50, 48h value of 36.05± 0.03 nm when irradiated with 390 nm light in MDA-MB-231 (IC50, 48 h of Cisplatin is 5.29 µµ). In cell, investigation confirms that IrL1 nanoaggregates internalization via energy-dependent endocytosis undergo ferroptosis and ROS mediated cell death in MDA-MB-231 cells. Further, these in vivo studies using NOD-SCID mice confirmed that IrL1 exhibits a tendency to ablate tumors inoculated in mice models at therapeutically relevant doses. Thus, this comprehensive approach holds promise for expanding the repertoire of organometallic Ir(III) nanoaggregates with adaptable characteristics, thereby advancing their clinical utility of nanomedicine in the holistic treatment of metastatic 3D triple-negative breast tumor spheroids. Show less

Title: Monomer Versus Dimer of Cationic Ir(III) Complexes for Photodynamic Therapy by Two-Photon Activation: A Comparative Study. Abstract: Iridium(III) complexes have been recognized as promising candidates for two-photon sensitized photodynamic therapy (PDT). In this context, we report on the study of two complexes: a monomer (IrL1) and a dimer (Ir2L2). Both complexes possess 2-phenylpyridine cyclometallating ligands and a pyridylbenzimidazole derivative as an ancillary ligand. In the dimer, the two Ir(III) centers are connected by a non-conjugated bridged bis(pyridylbenzimidazole). We compare the photophysical properties of these complexes. Both display phosphorescent emission in the orange-red part of the visible spectrum, with emissions centered at 610 nm for IrL1 and 625 nm for Ir2L2, both exhibiting quantum yields of ∼24%. However, Ir2L2 proves to be much brighter than the monomer, making the dimer four times brighter than IrL1. This trend is consistent under two-photon excitation (TPE), and the singlet oxygen generation quantum yields, with the dimer displaying a figure of merit (σTPA × ΦΔ) of 40, compared to only 5 for the monomer. Both complexes generate intracellular ROS and exhibit strong phototoxicity upon blue light activation (λ = 420 nm), achieving submicromolar IC50 values in HT29 and A549 cell lines after 24 h of incubation. Moreover, with TPE (λ = 800 nm), both complexes also generate intracellular ROS and induce cancer cell death. Show less

Title: Cyclometalated iridium(III) complexes induce immunogenic cell death in HepG2 cells via paraptosis. Abstract: Immunotherapy has been shown to provide superior antitumor efficacy by activating the innate immune system to recognize, attack and eliminate tumor cells without seriously harming normal cells. Herein, we designed and synthesized three new cyclometalated iridium(III) complexes (Ir1, Ir2, Ir3) then evaluated their antitumor activity. When co-incubated with HepG2 cells, the complex Ir1 localized in the lysosome, where it induced paraptosis and endoplasmic reticulum stress (ER stress). Notably, Ir1 also induced immunogenic cell death (ICD), promoted dendritic cell maturation that enhanced effector T cell chemotaxis to tumor tissues, down-regulated proportions of immunosuppressive regulatory T cells within tumor tissues and triggered activation of antitumor immunity throughout the body. To date, Ir1 is the first reported iridium(III) complex-based paraptosis inducer to successfully induce tumor cell ICD. Furthermore, Ir1 induced ICD of HepG2 cells without affecting cell cycle or reactive oxygen species levels. Show less

The development of anticancer drugs to treat triple-negative breast cancer (TNBC) is an ongoing challenge. Immunogenic cell death (ICD) has garnered considerable interest worldwide as a promising synergistic modality for cancer chemoimmunotherapy. However, only few drugs or treatment modalities can trigger an ICD response and none of them exert a considerable clinical effect against TNBC. Therefore, new agents with potentially effective chemoimmunotherapeutic response are required. In this study, five new cyclometalated Ir(III) complexes containing isoquinoline alkaloid CˆN ligands were designed and synthesized. Among them, Ir-1 exhibited the highest in vitro cytotoxicity. Mechanistically, Ir-1 could trigger autophagy-dependent ferroptosis and a subsequent ferroptosis-dependent ICD response as well as indoleamine 2,3-dioxygenase (IDO) inhibition via reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress in MDA-MB-231 cells. When immunocompetent BALB/c mice were vaccinated with Ir-1-treated dying TNBC cells, antitumor CD8⁺ T-cell response and Foxp3⁺ T-cell depletion were induced, resulting in long-lasting antitumor immunity in TNBC cells. Moreover, combination therapy with Ir-1 and anti-PD1 could substantially augment in vivo therapeutic effects. Based on these results, Ir-1 is a promising candidate for chemoimmunotherapy against TNBC and its effects are mediated synergistically via ICD induction and IDO blockage. Show less

Title: Synthesis, biological evaluation of novel iridium(III) complexes targeting mitochondria toward melanoma B16 cells. Abstract: A new ligand 2-(1E,3E,5E,7E)-2,6-dimethyl-8-(2,6,6-trimethylcyclohex-1-yl)octa-1,2,5,7-tetraen-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (DTOIP) was synthesized and combined with [Ir(ppy)2Cl]2·2H2O (ppy = deprotonated Hppy: 2-phenylpyridine), [Ir(piq)2Cl]2·2H2O (piq = deprotonated Hpiq: 1-phenylisoquinoline) and [Ir(bzq)2Cl]2·2H2O (bzq = deprotonated Hbzq: benzo[h]quinolone) to form [Ir(ppy)2(DTOIP)](PF6) (Ir1), [Ir(piq)2(DTOIP)](PF6) (Ir2), and [Ir(bzq)2(DTOIP)](PF6) (Ir3), respectively. The complexes were characterized by elemental analysis, high-resolution mass spectrometry (HRMS), 1H NMR and 13C NMR. The antiproliferative activity of the complexes toward B16, BEL-7402, Eca-109 and normal LO2 cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Complexes Ir1, Ir2 and Ir3 showed high antiproliferative activity against B16 cells with a low IC50 values of 0.4 ± 0.1, 2.0 ± 0.1 and 1.4 ± 0.09 μM, respectively. Three-dimensional (3D) in vitro cell models also demonstrated that the iridium(III) complexes have a remarkable cytotoxicity to B16 cells. The experiments of cellular uptake, mitochondrial localization, and intracellular distribution of the drugs proved that the three iridium(III) complexes can enter the mitochondria, leading to the loss of mitochondrial membrane potential (MMP), decreased glutathione (GSH) levels, causing an increase of intracellular ROS content, and DNA damage, finally inducing apoptosis. RNA-sequence and bioinformatics analyses were used to analyze the differentially expressed genes and enriched biology processes. Antitumor in vivo demonstrated that complex Ir1 (5 mg/kg) exhibits a high efficacy to inhibit the tumor growth with an inhibitory rate of 71.67%. These results show that the complexes may be potent anticancer candidate drugs. Show less

Natural coumarin derivatives and cyclometallic iridium (Ⅲ) (Ir^Ⅲ) complexes have attracted much attention in the field of anticancer. In this study, six coumarin-modified cyclometallic Ir^Ⅲ salicylaldehyde Schiff base complexes ([(ppy)₂Ir(O^N)]/[(ppy-CHO)₂Ir(O^N)]) were designed and synthesized. Compared with coumarin and Ir^Ⅲ complex monomers, target complexes exhibited favorable cytotoxic activity toward A549 and BEAS-2B cells. These complexes could induce extensive apoptosis of A549 cell (late apoptosis), which was represented by the disturbance of cell cycle (G₁-phase) and the accumulation of intracellular reactive oxygen species, exhibiting an anticancer mechanism of oxidation. With the help of suitable fluorescence of these complexes, no conflict with the probes, confocal detection confirmed that complexes showed an energy-dependent cellular uptake mechanism and triggered lysosome-mediated apoptosis in A549 cell line. Above all, our findings reveal the design of a lysosomal targeting cyclometallic Ir^Ⅲ Schiff base complexes and provide a new idea for the design of integrated drugs for diagnosis and treatment. Show less

Title: A new family of luminescent iridium complexes: synthesis, optical, and cytotoxic studies. Abstract: By using N,N-dibutyl-2,2'-bipyridine-4,4'-dicarboxamide as a diimine (dbbpy) and distinctive cyclometalated groups, this work reports a new family of cationic phosphorescent Ir(III) cyclometalated [Ir(C^N)2(N^N)]X compounds [C^N = difluorophenylpyridine (dfppy) a, 2,6-difluoro-3-(pyridin-2-yl)benzaldehyde (CHO-dfppy) b, and 2,6-difluoro-3-pyridin-2-yl-benzoic acid (COOH-dfppy) c; X = Cl-2a,b,c-Cl; X = PF6-2b,c-PF6]. For comparative purposes, the related complex [Ir(dfppy)2(H2dcbpy)]+ (3a-PF6) incorporating 3,3'-dicarboxy-2,2'-bipyridine as an auxiliary ligand (N^N = H2dcbpy) is also presented. All complexes have been fully characterized and their photophysical properties were investigated in detail. The theoretically calculated results obtained by density functional theory (DFT) and time-dependent density functional theory (TD-DFT) studies indicate that luminescence is derived from mixed 3ML'CT (Ir → N^N)/3LL'CT (C^N → N^N) excited states with the predominant metal-to-diimine charge transfer character. Their antineoplastic activity against tumour cell lines A549 (lung carcinoma) and HeLa (cervix carcinoma), as well as the nontumor BEAS-2B (bronchial epithelium) cell line was assessed and fluorescence microscopy studies were performed for their cellular localization. Among them, 2a-Cl exhibited the most potent anticancer activity, being higher than cisplatin. However, 2b-Cl and 2c-Cl,-PF6 were the least toxic, while 2b-PF6 and 3a-PF6 exhibited only moderate activity. Confocal microscopy studies for 2a-Cl suggest that complexes localize preferentially in the lysosomes and to a lesser extent in the cytoplasm, but ultimately causing damage to the mitochondria. Finally, the potential photodynamic behaviour of scarcely toxic complexes 2b-Cl, 2b-PF6, 2c-Cl and 3a-PF6 was also studied. Show less

Title: Two near-infrared phosphorescent iridium(III) complexes for the detection of GSH and photodynamic therapy. Abstract: GSH is one of the most important reducing agents in biological systems. The depletion of GSH in the human body is linked to many diseases. Therefore, it is necessary to develop suitable and efficient probes for detecting GSH concentrations in real samples. In this work, we designed and synthesized two near-infrared emitting iridium(III) complex probes containing a novel ligand functionalized with an α,β-unsaturated ketone for the rapid and sensitive detection of GSH. The molecular structure of Ir2 was determined by X-ray crystallography. Due to their large Stokes shift, long luminescence lifetime and NIR emission, these probes were successfully applied in the imaging of GSH in living cells. In addition, two iridium(III) complexes have strong singlet oxygen generation ability which can be used for photodynamic therapy (PDT) upon visible light irradiation. On the basis of these findings, our iridium(III) complexes may serve as GSH probes for HeLa cell imaging and as photosensitizers for PDT. Show less

Title: Exploring the phototoxicity of GSH-resistant 2-(5,6-dichloro-1 Abstract: Metal complexes play a crucial role in photo-activated chemotherapy (PACT), which has recently been used to treat specific disorders. Triple-negative breast cancer has an enormously high rate of relapse due to the existence and survival of cancer stem cells (CSCs) characterized by increased amounts of glutathione (GSH). Hence, designing a phototoxic molecule is an enticing area of research to combat triple-negative breast cancer (TNBC) via GSH depletion and DNA photocleavage. Herein, we focus on the application of PTA and non-PTA Ir(III) complexes for phototoxicity in the absence and presence of GSH against MDA-MB-231 TNBC cells. Between these two complexes, [Cp*IrIII(DD)PTA]·2Cl (DDIRP) exhibited better phototoxicity (IC50 ∼ 2.80 ± 0.52 μM) compared to the non-PTA complex [Cp*IrIII(DD)Cl]·Cl (DDIR) against TNBC cells because of the high GSH resistance power of the complex DDIRP. The significant potency of the complex DDIRP under photo irradiation in both normoxia and hypoxia conditions can be attributed to selective transportation, high cellular permeability and uptake towards the nucleus, GSH depletion by GSH-GSSG conversion, the ability of strong DNA binding including intercalation, and oxidative stress. The strong affinity to serum albumin, which serves as a carrier protein, aids in the transport of the complex to its target site while preventing glutathione (GSH) deactivation. Consequently, the complex DDIRP was developed as a suitable phototoxic complex in selective cancer therapy, ruling over the usual chemotherapeutic drug cisplatin and the PDT drug Photofrin. The ability of ROS generation under hypoxic conditions delivers this complex as a hypoxia-efficient selective metallodrug for the treatment of TNBC. Show less

Title: Lysosome-targeted cyclometalated iridium(III) complexes: JMJD inhibition, dual induction of apoptosis, and autophagy. Abstract: A series of cyclometalated iridium(III) complexes with the formula [Ir(C^N)2 L](PF6) (C^N = 2-phenylpyridine (ppy, in Ir-1), 2-(2-thienyl)pyridine (thpy, in Ir-2), 2-(2,4-difluorophenyl)pyridine (dfppy, in Ir-3), L = 2-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)quinolin-8-ol) were designed and synthesized, which utilize 8-hydroxyquinoline derivative as N^N ligands to chelate the cofactor Fe2+ of the Jumonji domain-containing protein (JMJD) histone demethylase. As expected, the results of UV/Vis titration analysis confirm the chelating capabilities of Ir-1-3 for Fe2+, and molecular docking studies also show that Ir-1-3 can interact with the active pocket of JMJD protein, and treatment of cells with Ir-1-3 results in significant upregulation of trimethylated histone 3 lysine 9 (H3K9Me3), indicating the inhibition of JMJD activity. Meanwhile, Ir-1-3 exhibit much higher cytotoxicity against the tested tumor cell lines compared with the clinical chemotherapeutic agent cisplatin. And Ir-1-3 can block the cell cycle at the G2/M phase and inhibit cell migration and colony formation. Further studies show that Ir-1-3 can specifically accumulate in lysosomes, damage the integrity of lysosomes, and induce apoptosis and autophagy. Reduction of mitochondrial membrane potential and elevation of reactive oxygen species also contribute to the antitumor effects of Ir-1-3. Finally, Ir-1 can inhibit tumor growth effectively in vivo and increase the expression of H3K9Me3 in tumor tissues. Our study demonstrates that these iridium(III) complexes are promising anticancer agents with multiple functions, including the inhibition of JMJD and induction of apoptosis and autophagy. Show less

Title: Mitochondria-targeted neutral and cationic iridium(III) anticancer complexes chelating simple hybrid sp Abstract: Most platinum group-based cyclometalated neutral and cationic anticancer complexes with the general formula [(C^N)2Ir(XY)]0/+ (neutral complex: XY = bidentate anionic ligand; cationic complex: XY = bidentate neutral ligand) are notable owing to their intrinsic luminescence properties, good cell permeability, interaction with some biomolecular targets and unique mechanisms of action (MoAs). We herein synthesized a series of neutral and cationic amine-imine cyclometalated iridium(III) complexes using Schiff base ligands with sp2-N/sp3-N N^NH2 chelating donors. The cyclometalated iridium(III) complexes were identified by various techniques. They were stable in aqueous media, displayed moderate fluorescence and exhibited affinity toward bovine serum albumin (BSA). The complexes demonstrated promising cytotoxicity against lung cancer A549 cells, cisplatin-resistant lung cancer A549/DDP cells, cervical carcinoma HeLa cells and human liver carcinoma HepG2 cells, with IC50 values ranging from 9.98 to 19.63 μM. Unfortunately, these complexes had a low selectivity (selectivity index: 1.62-1.98) towards A549 cells and BEAS-2B normal cells. The charge pattern of the metal center (neutral or cationic) and ligand substituents showed little influence on the cytotoxicity and selectivity of these complexes. The study revealed that these complexes could target mitochondria, cause depolarization of the mitochondrial membrane, and trigger the production of intracellular ROS. Additionally, the complexes were observed to induce late apoptosis and perturb the cell cycle in the G2/M or S phase in A549 cells. Based on these results, it appears that the anticancer efficacy of these complexes was predominantly attributed to the redox mechanism. Show less

Title: Lysosome-targeted cyclometalated Ir(III) complexes as photosensitizers/photoredox catalysts for cancer therapy. Abstract: A novel lysosome-targeted photosensitizer/photoredox catalyst based on cyclometalated Ir(III) complex IrL has been designed and synthesized, which exhibited excellent phosphorescence properties and the ability to generate single oxygen (1O2) and photocatalytically oxidize 1,4-dihydronicotinamide adenine dinucleotide (NADH) under light irradiation. Most importantly, the aforementioned activities are significantly enhanced due to protonation under acidic conditions, which makes them highly attractive in light-activated tumor therapy, especially for acidic lysosomes and tumor microenvironments. The photocytotoxicity of IrL and the mechanism of cell death have been investigated. Additionally, the tumor-killing ability of IrL under light irradiation was evaluated using a 4T1 tumor-bearing mouse model. This work provides a strategy for the development of lysosome-targeted photosensitizers/photoredox catalysts to overcome hypoxic tumors. Show less

Title: Anticancer activity and mechanism studies of photoactivated iridium(III) complexes toward lung cancer A549 cells. Abstract: Cyclometalated iridium(III) compounds have been widely explored due to their outstanding photo-physical properties and multiple anticancer activities. In this paper, three cyclometalated iridium(III) compounds [Ir(ppy)2(DBDIP)]PF6 (5a), [Ir(bzq)2(DBDIP)]PF6 (5b), and [Ir(piq)2(DBDIP)]PF6 (5c) (ppy: 2-phenylpyridine; bzq: benzo[h]quinoline; piq: 1-phenylisoquinoline, and DBDIP: 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) were synthesized and the mechanism of antitumor activity was investigated. Compounds photoactivated by visible light show strong cytotoxicity against tumor cells, especially toward A549 cells. Biological experiments such as migration, cellular localization, mitochondrial membrane potential and permeability, reactive oxygen species (ROS) and calcium ion level detection were performed, and they demonstrated that the compounds induced the apoptosis of A549 cells through a mitochondrial pathway. At the same time, oxidative stress caused by ROS production increases the release of damage-related molecules and the expression of porogen gasdermin D (GSDMD), and the content of LDH released from damaged cell membranes also increased. Besides, the content of the lipid peroxidation product, malondialdehyde (MDA), increased and the expression of GPX4 decreased. These indicate that the compounds promote cell death by combining ferroptosis and pyroptosis. The results reveal that cyclometalated iridium(III) compounds 5a-5c may be a potential chemotherapeutic agent for photodynamic therapy of cancers. Show less

Title: Cationic N,S-chelate half-sandwich iridium complexes: synthesis, characterization, anticancer and antiplasmodial activity. Abstract: A series of pyrazole-based ligands and their corresponding cationic N,S-chelate half-sandwich iridium complexes were successfully synthesized. All iridium complexes exhibited good anticancer activity against the MCF-7 and MDA-MB-231 human breast cancer cells. The cytotoxic activity of unsubstituted iridium complex 1 is greater than that of cisplatin against MCF-7 cells. In addition, the cationic half-sandwich iridium complexes are also efficient in antiplasmodial study and complex 1 displayed the best activity as its IC50 was observed to be approximately 0.11 μM against the CQS-NF54 strain. These iridium complexes generally exhibited enhanced activity against the CQS-NF54 strain in comparison with that against the CQR-K1 strain. An "IC50 speed assay" investigation against the CQS-NF54 strain indicated complexes 1-3 to be fast-acting complexes that reach their lowest IC50 values within 16 hours. All complexes were fully characterized by IR spectroscopy, NMR spectroscopy, and elemental analysis, and the structure of the iridium complex was confirmed by single-crystal X-ray diffraction. Show less

Title: Cyclometalated iridium(III) tetrazine complexes for mitochondria-targeted two-photon photodynamic therapy. Abstract: The fast-moving field of photodynamic therapy (PDT) has provided fresh opportunities to expand the potential of metallodrugs to combat cancers in a light-controlled manner. As such, in the present study, a series of cyclometalated Ir(III) complexes modified with a tetrazine functional group (namely, Ir-ppy-Tz, Ir-pbt-Tz, and Ir-dfppy-Tz) are developed as potential two-photon photodynamic anticancer agents. These complexes target mitochondria but exhibit low toxicity towards HLF primary lung fibroblast normal cells in the dark. When receiving a low-dose one- or two-photon PDT, they become highly potent towards A549 lung cancer cells (with IC50 values ranging from 24.0 nM to 96.0 nM) through the generation of reactive oxygen species (ROS) to induce mitochondrial damage and subsequent apoptosis. Our results indicated that the incorporation of tetrazine with cyclometalated Ir(III) matrices would increase the singlet oxygen (1O2) quantum yield (ΦΔ) and, meanwhile, enable a type I PDT mechanism. Ir-pbt-Tz, with the largest two-photon absorption (TPA) cross-section (σ2 = 102 GM), shows great promise in serving as a two-photon PDT agent for phototherapy. Show less

Title: Towards efficient Ir(III) anticancer photodynamic therapy agents by extending π-conjugation on N^N ligands. Abstract: In this work we disclose a new family of biscyclometallated Ir(III) complexes of the general formula [Ir(C^N)2(N^N)]Cl (IrL1-IrL5), where HC^N is 1-phenyl-β-carboline and N^N ligands (L1-L5) are different diimine ligands that differ from each other in the number of aromatic rings fused to the bipyridine scaffold. The photophysical properties of IrL1-IrL5 were thoroughly studied, and theoretical calculations were performed for a deeper comprehension of the respective variations along the series. All complexes exhibited high photostability under blue light irradiation. An increase in the number of aromatic rings led to a reduction in the HOMO-LUMO band gap causing a red-shift in the absorbance bands. Although all the complexes generated singlet oxygen (1O2) in aerated aqueous solutions through a photocatalytic process, IrL5 was by far the most efficient photosensitizer. Consequently, IrL5 was highly active in the photocatalytic oxidation of NADH. The formation of aggregates in DMSO at a high concentration (25 mM) was confirmed using different techniques, but was proved to be negligible in the concentration range of biological experiments. Moreover, ICP-MS studies proved that the cellular uptake of IrL2 and IrL3 is much better relative to that of IrL1, IrL4 and IrL5. The antiproliferative activity of IrL1-IrL5 was investigated in the dark and under blue light irradiation against different cancer cell lines. Complexes IrL1-IrL4 were found to be cytotoxic under dark conditions, while IrL5 turned out to be weakly cytotoxic. Despite the low cellular uptake of IrL5, this derivative exhibited a high increase of cytotoxicity upon blue light irradiation resulting in photocytotoxicity indexes (PI) up to 38. IrL1-IrL4 showed lower photocytotoxicity indexes ranging from 1.3 to 17.0. Haemolytic experiments corroborated the compatibility of our complexes with red blood cells. Confocal microscopy studies proved their accumulation in mitochondria, leading to mitochondrial membrane depolarization, and ruled out their localization in lysosomes. Overall, the mitochondria-targeted activity of IrL5, which inhibits considerably the viability of cancer cells upon blue light irradiation, allows us to outline this PS as a new alternative to traditional chemotherapeutic agents. Show less

Title: Mitochondria-targeted cyclometalated iridium-β-carboline complexes as potent non-small cell lung cancer therapeutic agents. Abstract: Natural products and metals play a crucial role in cancer research and the development of antitumor drugs. We designed and synthesized three new carboline-based cyclometalated iridium complexes [Ir(C-N)2(PPβC)](PF6), where PPβC = N-(1,10-phenanthrolin-5-yl)-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxamide, C-N = 2-phenylpyridine (ppy, Ir1), 2-(2,4-difluorophenyl) pyridine (dfppy, Ir2), 7,8-benzoquinoline (bzq, Ir3), by combining iridium with β-carboline derivative. These iridium complexes exhibited high potential antitumor effects after being promptly taken up by A549 cells. Accumulating in mitochondria rapidly and preferentially, Ir1-3 caused a series of changes in mitochondrial events, including the loss of mitochondrial membrane potential, the depletion of cellular ATP, and the elevation of reactive oxygen species, leading to significant death of A549 cells. Moreover, the activation of intracellular caspase pathway and apoptosis was further validated to contribute to iridium complexes-induced cytotoxicity. These novel iridium complexes exerted a prominent inhibitory effect on tumor growth in a three-dimensional multicellular tumor spheroid model. Show less

Organoiridium picolinamidate complexes are promising for intracellular applications because of their biocompatibility, activity in living systems, and ease of derivatization. To shield their metal centers from inhibition by biological nucleophiles (e.g., glutathione), attempts were made to increase the steric bulk of the supporting N-(2,6-R₂-phenyl)picolinamidate ligand. It was found that when R = H (Ir1) or methyl (Ir2), the ligand adopts N,N'-coordination to iridium, whereas when R = isopropyl (Ir3) or phenyl (Ir4), N,O-coordination was observed. Based on experimental measurements and density functional theory calculations, it was revealed that the carbon chemical shift of the C(O)NR group can be used as a diagnostic handle to distinguish between the N,N'- and N,O-isomers in solution. Computational studies indicate that the former is favored thermodynamically but the latter is preferred when the R group is overly bulky. Complexes Ir1-Ir4 exhibit differences in lipophilicity, cellular uptake, cytotoxicity, and the propensity to generate reactive oxygen species in living cells. Reaction studies showed that Ir1/Ir2 are more efficient than Ir3/Ir4 in promoting the reduction of aldehydes to alcohols via transfer hydrogenation but both isomer types were susceptible to catalyst poisoning by glutathione. This work has led to new insights into structural isomerism in organoiridium picolinamidate complexes and suggests that steric tuning alone is insufficient to protect the Ir center from poisoning by biological nucleophiles. Show less

Title: Iridium(III) complexes conjugated with naproxen exhibit potent anti-tumor activities by inducing mitochondrial damage, modulating inflammation, and enhancing immunity. Abstract: A series of Ir(III)-naproxen (NPX) conjugates with the molecular formula [Ir(C^N)2bpy(4-CH2ONPX-4'-CH2ONPX)](PF6) (Ir-NPX-1-3) were designed and synthesized, including C^N = 2-phenylpyridine (ppy, Ir-NPX-1), 2-(2-thienyl)pyridine (thpy, Ir-NPX-2) and 2-(2,4-difluorophenyl)pyridine (dfppy, Ir-NPX-3). Cytotoxicity tests showed that Ir-NPX-1-3 exhibited excellent antitumor activity, especially in A549R cells. The cellular uptake experiment showed that the complexes were mainly localized in mitochondria, and induced apoptosis in A549R cells by damaging the structure and function of mitochondria. The main manifestations are a decrease in the mitochondrial membrane potential (MMP), an increase in reactive oxygen species (ROS) levels, and cell cycle arrest. Furthermore, Ir-NPX-1-3 could inhibit the migration and colony formation of cancer cells, demonstrating potential anti-metastatic ability. Finally, the anti-inflammatory and immunological applications of Ir-NPX-1-3 were verified. The downregulation of cyclooxygenase-2 (COX-2) and programmed death-ligand 1 (PD-L1) expression levels and the release of immunogenic cell death (ICD) related signaling molecules such as damage-associated molecular patterns (DAMPs) (cell surface calreticulin (CRT), high mobility group box 1 (HMGB1), and adenosine triphosphate (ATP)) indicate that these Ir(III) -NPX conjugates are novel ICD inducers with synergistic effects in multiple anti-tumor pathways. Show less

Title: Synthesis, photophysical characterisation, quantum-chemical study and Abstract: In this paper, we present the synthesis of four new complexes: the dimeric precursor [Ir(dmppz)2(μ-Cl)]2 (1) (Hdmppz - 3,5-dimethyl-1-phenyl-1H-pyrazole) and heteroleptic bis-cyclometalated complexes: [Ir(dmppz)2(Py2CO)]PF6·½CH2Cl2 (2), [Ir(dmppz)2(H2biim)]PF6·H2O (3), and [Ir(dmppz)2(PyBIm)]PF6 (4), with auxiliary N,N-donor ligands: 2-di(pyridyl)ketone (Py2CO), 2,2'-biimidazole (H2biim) and 2-(2'-pyridyl)benzimidazole (PyBIm). In the obtained complexes, SC-X-ray analysis revealed that Ir(III) has an octahedral coordination sphere with chromophores of the type {IrN2C2Cl2} (1) or {IrN4C2} (2-4). The complexes obtained, which have been fully characterised by physicochemical methods (CHN, TG, FTIR, UV-Vis, PL and 1H, 13C, 15N NMR), were used to continue our studies on the factors influencing the cytotoxic properties of potential chemotherapeutic agents (in vitro). To this end, the following studies are presented: (i) comparative analysis of the effects on the biological properties of N,N-donor ligands and C,N-donor ligands in the studied complexes, (ii) studies of the interactions of the compounds with the selected molecular target: DNA and BSA (UV-Vis, CD and PL methods), (iii) and the reactivity towards redox molecules: GSH, NADH (UV-Vis and/or ESI-MS methods), (iv) cytotoxic activity (IC50) of potential chemotherapeutics against MCF-7, K-562 and CCRF-CEM cell lines. Show less

Title: Mitochondrial-targeted cyclometalated Ir(III)-5,7-dibromo/dichloro-2-methyl-8-hydroxyquinoline complexes and their anticancer efficacy evaluation in Hep-G2 cells. Abstract: Both 8-hydroxyquinoline compounds and iridium (Ir) complexes have emerged as potential novel agents for tumor therapy. In this study, we synthesized and characterized two new Ir(III) complexes, [Ir(L1)(bppy)2] (Br-Ir) and [Ir(L2)(bppy)2] (Cl-Ir), with 5,7-dibromo-2-methyl-8-hydroxyquinoline (HL-1) or 5,7-dichloro-2-methyl-8-hydroxyquinoline as the primary ligand. Complexes Br-Ir and Cl-Ir successfully inhibited antitumor activity in Hep-G2 cells. In addition, complexes Br-Ir and Cl-Ir were localized in the mitochondrial membrane and caused mitochondrial damage, autophagy, and cellular immunity in Hep-G2 cells. We tested the proteins related to mitochondrial and mitophagy by western blot analysis, which showed that they triggered mitophagy-mediated apoptotic cell death. Remarkably, complex Br-Ir showed high in vivo antitumor activity, and the tumor growth inhibition rate was 63.0% (P < 0.05). In summary, our study on complex Br-Ir revealed promising results in in vitro and in vivo antitumor activity assays. Show less

Title: Photofunctional cyclometallated iridium(III) polypyridine methylsulfone complexes as sulfhydryl-specific reagents for bioconjugation, bioimaging and photocytotoxic applications. Abstract: We report herein near-infrared (NIR)-emitting cyclometallated iridium(III) complexes bearing a heteroaromatic methylsulfone moiety as sulfhydryl-specific reagents; one of the complexes was conjugated to cysteine and cysteine-containing peptides and proteins for bioimaging and photocytotoxic applications. Show less