📚 BiometalDB

The rational design by the introduction of fluorine into a compound has achieved success in the development of organic anticancer drugs. However, the fluorine effect in metal-based anticancer complexes has rarely been reported. In this contribution, we report the synthesis, characterization, chemical reactivity, and biological activity of a series of half-sandwich zwitterionic iridium(III) complexes containing different substituents in the η⁵-Cp^R ring. The molecular structures for complexes Ir1-Ir4 and Ir7 were determined by single-crystal X-ray crystallography techniques. Notably, the asymmetrically substituted fluoro complexes Ir4 and Ir6 in solution show two conformational isomers. These complexes have sufficient stability, exhibit fluorescence emission, and show potent catalytic activity in converting NADH to NAD⁺. The effect of the substituents in the η⁵-Cp^R ring for these zwitterionic complexes on their anticancer activity was systematically investigated. Surprisingly, the presence of fluorinated substituents gives rise to a significant increase in the anticancer activity. The lipophilicity and cellular uptake levels of these complexes appeared to be the primary factors for their cytotoxicity in this system. A microscopic mechanism study showed that the typical complex Ir4 entered A549 cancer cells through an energy-dependent pathway and was mainly located in lysosomes. Furthermore, an increase in ROS level, apoptosis induction, and cell-cycle perturbation together contribute to the anticancer potency of these zwitterionic complexes. Show less

A series of new organoiridium(III) complexes [Ir(N-C)(2)(N-S)]Cl (HN-C = 2-phenylpyridine (Hppy), N-S = methyl thiosemicarbazide (1), phenyl thiosemicarbazide (2) and naphtyl thiosemicarbazide (3)) have been synthesized and characterized. The crystal structure of (1) has been established by X-ray diffraction, showing the thiosemicarbazide ligand bound to the iridium atom as N,S-chelate. The cytotoxicity studies show that they are more active than cisplatin (about 5-fold) in T47D (breast cancer) at 48 h incubation time. On the other hand, very low resistance factors (RF) of 1-3 in A2780cisR (cisplatin-resistant ovarian carcinoma) at 48 h were observed (RF ≈ 1). Ir accumulation in T47D cell line after 48 h continuous exposure for complexes 1-3 are higher than that corresponding to cisplatin (about 10 times). The complexes 1-3 bind strongly to HSA with binding constants of about 10(4) M(-1) at 296 K, binding occurring at the warfarin site I for 2. Complexes 2 and 3 are also capable of binding in the minor groove of DNA as shown by Hoechst 33258 displacement experiments. Furthermore, complex 2 is also a good cathepsin B inhibitor (an enzyme implicated in a number of cancer related events), being the enzyme reactivated by cysteine. Show less

We, herein, report the synthesis, characterization, luminescence properties, anticancer, and antibacterial activities of a family of novel half-sandwich iridium(III) complexes of the general formula [(η⁵-Cp^x)Ir(C^N)Cl]PF₆^- [Cp^x = pentamethylcyclopentadienyl (Cp*) or tetramethyl(biphenyl)-cyclopentadienyl (Cp^xbiph)] bearing versatile imine-N-heterocyclic carbene ligands. In this complex framework, substituents on four positions could be modulated, which distinguishes this class of complex and provides a large amount of flexibility and opportunity to tune the cytotoxicity of complexes. The X-ray crystal structures of complexes 4 and 10 exhibit the expected "piano-stool" geometry. With the exception of 1, 2, and 11, each complex shows potent cytotoxicity, with IC₅₀ (half-maximum inhibitory concentration) values ranging from 1.99 to 25.86 μM toward A549 human lung cancer cells. First, the effect of four positions bearing different substituents in the complex framework on the anticancer activity, that is, structure-activity relationship, was systematically studied. Complex 8 (IC₅₀ = 1.99 μM) displays the highest anticancer activities, whose cytotoxicity is more than 10-fold higher than that of the clinical platinum drug cisplatin against A549 cancer cells. Second, their chemical reactivity including nucleobases binding, catalytic activity in converting coenzyme NADH to NAD⁺, reaction with glutathione (GSH), and bovine serum albumin (BSA) binding is investigated. No reaction with nucleobase is observed. However, these iridium(III) complexes bind rapidly to GSH and can catalyze oxidation of NADH to NAD⁺. In addition, they show moderate binding affinity to BSA and the fluorescence quenching of BSA by the iridium (III) complexes is due to the static quenching. Third, the mode of cell death was also explored through flow cytometry experiments, including cell cycle, apoptosis induction, reactive oxygen species (ROS) and mitochondrial membrane potential. It seems that cell cycle perturbation, apoptosis induction, increase of ROS level and loss of mitochondrial membrane potential together contribute to the anticancer potency of these complexes. Last, the use of confocal microscopy provides insights into the microscopic mechanism that the typical and most active complex 8 enters A549 lung cancer cells mainly through energy-dependent pathway and is located in lysosome. Furthermore, lysosome damage and nuclear morphology were detected by confocal microscopy. Nuclear condensation and apoptotic bodies may finally induce cells apoptosis. Interestingly, complex 8 also shows antibacterial activity against Gram-positive Staphylococcus aureus. This work may provide an alternative and effective strategy to smart design of potent organometallic half-sandwich iridium(III) anticancer drugs. Show less

Three iridium(III) complexes ([Ir(Hppy)₂(L)](PF₆) (Hppy = 2-phenylpyridine, L = 5-nitrophenanthroline, NP), 1; 5-nitro-6-amino-phenanthroline (NAP), 2; and 5,6-diamino-phenanthroline (DAP) 3 were synthesized and characterized. The cytotoxicities of Ir(III) complexes 1-3 against cancer cell lines SGC-7901, A549, HeLa, Eca-109, HepG2, BEL-7402, and normal NIH 3T3 cells were investigated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide (MTT) method. The results showed that the three iridium(III) complexes had moderate in vitro anti-tumor activity toward SGC-7901 cells with IC₅₀ values of 3.6 ± 0.1 µM for 1, 14.1 ± 0.5 µM for 2, and 11.1 ± 1.3 µM for 3. Further studies showed that 1-3 induce cell apoptosis/death through DNA damage, cell cycle arrest at the S or G0/G1 phase, ROS elevation, increased levels of Ca²⁺, high mitochondrial membrane depolarization, and cellular ATP depletion. Transwell and Colony-Forming assays revealed that complexes 1-3 can also effectively inhibit the metastasis and proliferation of tumor cells. These results demonstrate that 1-3 induce apoptosis in SGC-7901 cells through ROS-mediated mitochondrial damage and DNA damage pathways, as well as by inhibiting cell invasion, thereby exerting anti-tumor cell proliferation activity in vitro. Show less

Despite the clinical success of photodynamic therapy (PDT), the application of this medical technique is intrinsically limited by the low oxygen concentrations found in cancer tumors, hampering the production of therapeutically necessary singlet oxygen (¹O₂). To overcome this limitation, we report on a novel mitochondria-localized iridium(III) endoperoxide prodrug (2-O-IrAn), which, upon two-photon irradiation in NIR, synergistically releases a highly cytotoxic iridium(III) complex (2-IrAn), singlet oxygen, and an alkoxy radical. 2-O-IrAn was found to be highly (photo-)toxic in hypoxic tumor cells and multicellular tumor spheroids (MCTS) in the nanomolar range. To provide cancer selectivity and improve the pharmacological properties of 2-O-IrAn, it was encapsulated into a biotin-functionalized polymer. The generated nanoparticles were found to nearly fully eradicate the tumor inside a mouse model within a single treatment. This study presents, to the best of our knowledge, the first example of an iridium(III)-based endoperoxide prodrug for synergistic photodynamic therapy/photoactivated chemotherapy, opening up new avenues for the treatment of hypoxic tumors. Show less

Among all molecules developed for anticancer therapies, photodynamic therapeutic agents have a unique profile. Their maximal activity is specifically triggered in tumors by light, and toxicity of even systemically delivered drug is prevented in nonilluminated parts of the body. Photosensitizers exert their therapeutic effect by producing reactive oxygen species via a light-activated reaction with molecular oxygen. Consequently, the lowering of pO₂ deep in solid tumors limits their treatment and makes essential the design of oxygen-independent sensitizers. In this perspective, we have recently developed Ir(III)-based molecules able to oxidize biomolecules by type I processes under oxygen-free conditions. We examine here their phototoxicity in relevant biological models. We show that drugs, which are mitochondria-accumulated, induce upon light irradiation a dramatic decrease of the cell viability, even under low oxygen conditions. Finally, assays on 3D tumor spheroids highlight the importance of the light-activation step and the oxygen consumption rate on the drug activity. Show less

Protein inactivation by reactive oxygen species (ROS) such as singlet oxygen ((1)O2) and superoxide radical (O2(•-)) is considered to trigger cell death pathways associated with protein dysfunction; however, the detailed mechanisms and direct involvement in photodynamic therapy (PDT) have not been revealed. Herein, we report Ir(III) complexes designed for ROS generation through a rational strategy to investigate protein modifications by ROS. The Ir(III) complexes are effective as PDT agents at low concentrations with low-energy irradiation (≤ 1 J cm(-2)) because of the relatively high (1)O2 quantum yield (> 0.78), even with two-photon activation. Furthermore, two types of protein modifications (protein oxidation and photo-cross-linking) involved in PDT were characterized by mass spectrometry. These modifications were generated primarily in the endoplasmic reticulum and mitochondria, producing a significant effect for cancer cell death. Consequently, we present a plausible biologically applicable PDT modality that utilizes rationally designed photoactivatable Ir(III) complexes. Show less

A nonemissive cyclometalated iridium(III) solvent complex, without conjugation with a cell-penetrating molecular transporter, [Ir(ppy)(2)(DMSO)(2)](+)PF(6)(-) (LIr1), has been developed as a first reaction-based fluorescence-turn-on agent for the nuclei of living cells. LIr1 can rapidly and selectively light-up the nuclei of living cells over fixed cells, giving rise to a significant luminescence enhancement (200-fold), and shows very low cytotoxicity at the imaging concentration (incubation time <10 min, LIr1 concentration 10 μM). More importantly, in contrast to the reported nuclear stains that are based on luminescence enhancement through interaction with nucleic acids, complex LIr1 as a nuclear stain has a reaction-based mode of action, which relies on its rapid reaction with histidine/histidine-containing proteins. Cellular uptake of LIr1 has been investigated in detail under different conditions, such as at various temperatures, with hypertonic treatment, and in the presence of metabolic and endocytic inhibitors. The results have indicated that LIr1 permeates the outer and nuclear membranes of living cells through an energy-dependent entry pathway within a few minutes. As determined by an inductively coupled plasma atomic emission spectroscopy (ICP-AEC), LIr1 is accumulated in the nuclei of living cells and converted into an intensely emissive adduct. Such novel reaction-based nuclear staining for visualizing exclusively the nuclei of living cells with a significant luminescence enhancement may extend the arsenal of currently available fluorescent stains for specific staining of cellular compartments. Show less

Seven novel half-sandwich Ir^III cyclopentadienyl complexes, [(η⁵-Cp^x)Ir(N^N)Cl]PF₆, have been prepared and characterized, where Cp^x is Cp* or the biphenyl derivative Cp^xbiph (C₅Me₄C₆H₄C₆H₅), and the N^N-chelating ligands are imino-pyridyl Schiff-bases. The X-ray crystal structures of complexes 2A, 2B, and 3A have been determined. Excitingly, most of the complexes show potent antiproliferative activity towards A549 and HeLa cancer cells, except for Cp* complex 1A towards HeLa cells. Cp^xbiph complex 2B displayed the highest potency, about 19 and 6 times more active than the clinically used drug cisplatin toward A549 and HeLa cells, respectively. These complexes undergo hydrolysis, and the kinetics data have been calculated. DNA binding has been studied by interaction with nucleobases 9-ethylguanine and 9-methyladenine, cleavage of plasmid DNA, and interaction with ctDNA. Interaction with DNA does not appear to be the major mechanism of action. Protein binding (bovine serum albumin, BSA) has been established by UV-Vis, fluorescence and synchronous spectroscopic studies. The stability of complex 2B in the presence of GSH was evaluated. The complexes catalytically convert coenzyme NADH to NAD⁺via hydride transfer. Cp^xbiph complexes 2B and 4B induce cell apoptosis and arrest cell cycles at the S and G₂/M phases towards A549 cancer cells and increase the reactive oxygen species dramatically, which appear to contribute to the remarkable anticancer activity. Show less

Five mononuclear cyclometalated iridium complexes [1](PF6)-[5](PF6) were prepared using imidazole-based ligands of varying alkyl chain length. The complexes were characterised by various analytical techniques. The single crystal X-ray structures of [2](PF6), [3](PF6) and [4](PF6) revealed the expected distorted Oh structures around the metal centre; however, the chain length was found to play a crucial role in deciding the overall geometry. Theoretical investigations demonstrated that the HOMOs were mainly contributed by iridium and cyclometalated ligands, whereas the LUMOs were constituted from bpy/phen units. The complexes were found to be luminescent with a moderate emission quantum yield and lifetime in CH3CN. The in vitro growth inhibition assay of the complexes with a shorter alkyl chain ([4]+ and [5]+) displayed higher anticancer activity (IC50 < 0.5 μM) compared to the complexes with a longer alkyl chain ([1]+-[3]+) (IC50 < 30 μM) against human breast cancer (MCF-7) cells. The complexes [4]+ and [5]+ also displayed moderate cancer cell selectivity (∼3 times) over normal breast (MCF-10) cells. The flow cytometry assay and fluorescence microscopy analysis suggested that cellular accumulation was primarily responsible for the variation in anticancer activity. Interestingly, without possessing any anticancer activity or toxicity ((IC50 > 50 μM), the complex [1]+ mainly accumulated near the cell membrane outside the cell and displayed a clear image of the cell membrane. The light microscopy images and western blot analysis reveal that complex [4]+ induced combined apoptosis and paraptosis. Thus, tuning the anticancer activity and cellular imaging property mediated by the alkyl chain would be of great importance and would be useful in anticancer research. Show less

Half-sandwich pseudo-octahedral pentamethylcyclopentadienyl Ir^III complexes of the type [(η⁵-Cp^x)Ir(C^C)Cl]PF₆, where Cp^x is pentamethylcyclopentadienyl (Cp*), or its phenyl (Cp^xph = C₅Me₄C₆H₅) or biphenyl (Cp^xbiph = C₅Me₄C₆H₄C₆H₅) derivatives, and the C^C-chelating ligands are different N-heterocyclic carbene (NHC) ligands, have been synthesized and characterized. Three X-ray crystal structures have been determined. Except for Cp* complex 1A, the other eleven complexes 1B-4C all showed potent cytotoxicity, with IC₅₀ values ranging from 2.9 to 46.3 μM toward HeLa human cervical cancer cells. The potency toward HeLa cells increased with additional phenyl substitution on Cp*: Cp^xbiph > Cp^xph > Cp*, and increased with the size of chain substitution on the C^C-ligand in the order: ph > butyl > ethyl > methyl. Complex [(η⁵-C₅Me₄C₆H₄C₆H₅)Ir(L4)Cl]PF₆ (4C) displayed the highest potency, and was about 3 times more active than the clinical platinum drug cisplatin. Complexes 1A-4C all undergo hydrolysis and their kinetics was studied. DNA binding appears not to be the major mechanism of action. The ability of these iridium complexes to catalyze hydride transfer from the coenzyme NADH to NAD⁺ was studied. Complexes [(η⁵-C₅Me₄C₆H₄C₆H₅)Ir(L2)Cl]PF₆ (2C) and [(η⁵-C₅Me₄C₆H₄C₆H₅)Ir(L3)Cl]PF₆ (3C) cause cell apoptosis and arrest the cell cycle at the G₁ phase and G₂/M phase when HeLa cancer cells are treated with different IC₅₀ concentrations of the complexes, and increase the amount of reactive oxygen species (ROS) dramatically, which appears to contribute to the anticancer activity. This class of organometallic Ir complexes has unusual features worthy of further exploration in the design of novel anticancer drugs. Show less

Organometallic iridium complexes have emerged as potent anticancer agents in recent years. In this work, three cyclometalated iridium(iii) complexes Ir1-Ir3 containing monodentate five-membered heterocyclic ligands have been synthesized and characterized. Upon visible light (425 nm) irradiation, the five-membered heterocyclic ligands will dissociate from the metal centre. Moreover, Ir1-Ir3 can also act as effective singlet oxygen photosensitizers. Thus, Ir1-Ir3 can exert their light-mediated activation of anticancer effects by dual modes including ligand exchange reactions and generation of singlet oxygen (¹O₂) upon visible light irradiation. Notably, Ir1 displays a high phototoxicity index of 61.7 against human cancer cells. Further studies show that light-mediated anticancer properties exerted by Ir1-Ir3 occur through reactive oxygen species (ROS) generation, caspase activation, and eventually apoptosis induction. Our study demonstrates that these complexes can act as novel dual-mode light-mediated anticancer agents. Show less

The successful design, synthesis, characterization, photophysical properties and anticancer mechanistic studies of a series of half-sandwich cyclopentadienyl iridium(iii) complexes of the type [Cp*Ir^III(LC)(L1)](PF₆), 1, and [Cp*Ir^III(LC)(L2)](PF₆), 2, in which Cp* = pentamethylcyclopentadienyl, L1 = 4-(pyren-10-yl)ethynyl-phenylcyanamide, L2 = 4'-(pyren-10-yl)ethynyl-4-cyanamidobiphenyl, and LC = lidocaine, are reported for their application as photodynamic therapy (PDT) agents. The DNA binding, DNA photocleavage, cellular uptake, and apoptosis of the complexes have also been studied. Show less

The novel steroidal conjugates [M(η(5)-C(5)Me(5))Cl(LEV-ppy)] (M = Rh (1) and Ir (2)) bearing the lipophilic levonorgestrel group 17-α-[2-phenylpyridyl-4-ethynyl]-19-nortestosterone (LEV-ppy), where the chelating ligand is N and C-bound, have been prepared and characterized. Both compounds are more active than cisplatin (about 6-fold) in T47D (breast cancer) at 48 h incubation time. On the other hand, very low resistance factors (RF) of 1 and 2 in A2780cisR (cisplatin-resistant ovarian carcinoma) at 48 h were observed (RF = 0.9 and 1.1, respectively). The iridium steroidal compound 2 is twice as active as the non-steroidal analogue 2', whose promising anticancer activity has recently been reported by Sadler. Theoretical DFT calculations on complexes 1 and 2 at the B3LYP-D/def2-TZVP-ecp level of theory show that the strongest bond to the metal atom is the η(5)-interaction to the Cp* ligand and that both of them feature a rather strong metal-chlorine bond. The new steroidal conjugates 1 and 2 are able to bind to DNA according to Hoechst 33258 displacement experiments and ESI-TOF MS spectrometry studies. Complexes 1 and 2 are also cathepsin B inhibitors, an enzyme implicated in a number of cancer related events. Show less

Synthesis of terpyridyl based ligands 3-([2,2':6',2''-terpyridin]-4'-yl)-7-methoxy-2-(methylthio)-quinolone, (L1); 3-([2,2':6',2''-terpyridin]-4'-yl)-6-methoxyquinolin-2(1H)-one, (L2); 3-([2,2'-:6',2''-terpyridin]-4'-yl)-6-methylquinolin-2(1H)-one (L3) and cyclometalated iridium(iii) complexes [[Ir(ppy)₂L1]⁺PF₆^- (1), [Ir(ppy)₂L2]⁺PF₆^- (2), [Ir(ppy)₂L3]⁺PF₆^- (3) (2-phenylpyridine = Hppy)] involving these ligands has been described. The ligands L1-L3 and complexes 1-3 have been thoroughly characterized by elemental analyses, spectral studies (IR, ¹H, ¹³C NMR, UV/vis and fluorescence) ESI-MS, and the structure of 3 has been unambiguously authenticated by single crystal X-ray analyses. UV/vis, fluorescence and circular dichroism spectroscopic studies showed rather efficient binding of 1 with CT-DNA (calf thymus DNA) and BSA (bovine serum albumin) relative to 2 and 3. Molecular docking studies unveiled binding of 1-3 with minor groove of CT-DNA via van der Waal's forces and electrostatically with the hydrophobic moiety of HSA (human serum albumin). The ligands and complexes exhibited moderate cytotoxicity towards MDA-MB-231 (breast cancer cell line) and significant influence on HeLa (cervical cancer cell line) cells. Cytotoxicity, morphological changes, and apoptosis have been followed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) assay, Hoechst 33342/PI (PI = propidium iodide) staining, cell cycle analysis by FACS (fluorescence activated cell sorting), and ROS (reactive oxygen species) generation by DCFH-DA (dichlorodihydrofluorescein diacetate) dye. Confocal microscopy images revealed that the drug efficiently initiates apoptosis in the cell cytosol. The IC₅₀ values showed superior cytotoxicity of 1-3 against the HeLa cell line relative to cisplatin, and their ability to induce apoptosis is in the order 1 > 2 > 3. Show less

Metal N-heterocyclic carbene (NHC) complexes represent a promising class of anticancer therapeutic agents. In this work, four cyclometalated iridium(iii) complexes (Ir1-Ir4) containing N-heterocyclic carbene ligands have been explored as mitochondrial anticancer and photodynamic agents. These complexes are more cytotoxic than cisplatin against the cancer cells screened, can quickly penetrate into A549 cells and are mainly localized in the mitochondria. Mechanism studies show that these complexes exert their anticancer efficacy by increasing the intracellular ROS level, reducing the mitochondrial membrane potential (MMP) and inducing apoptosis. Additionally, Ir1-Ir4 exhibited two orders of magnitude higher cytotoxicity upon irradiation at 450 nm LED light. Our work provides a strategy for the design of highly effective anticancer photodynamic therapeutic agent based phosphorescent iridium complexes. Show less

We report the synthesis and characterization of novel pentamethylcyclopentadienyl (Cp*) iridium(III) complexes [(Cp*)Ir(4-methyl-4'-carboxy-2,2'-bipyridine)Cl]PF6 (Ir-I), the product (Ir-II) from amide coupling of Ir-I to dibenzocyclooctyne-amine, and its conjugate (Ir-CP) with the cyclic nona-peptide c(CRWYDENAC). The familiar three-legged 'piano-stool' configuration for complex Ir-I was confirmed by its single crystal X-ray structure. Significantly, copper-free click strategy has been developed for site-specific conjugation of the parent complex Ir-I to the tumour targeting nona-cyclic peptide. The approach consisted of two steps: (i) the carboxylic acid group of the bipyridine ligand in complex Ir-I was first attached to an amine functionalized dibenzocyclooctyne group via amide formation to generate complex Ir-II; and (ii) the alkyne bond of dibenzocyclooctyne in complex Ir-II underwent a subsequent strain-promoted copper-free cycloaddition with the azide group of the modified peptide. Interestingly, while complex Ir-I was inactive towards A2780 human ovarian cancer cells, complex Ir-II exhibited moderate cytotoxic activity. Targeted complexes such as Ir-CP offer scope for enhanced activity and selectivity of this class of anticancer complexes. Show less

Group 9 transition metal complexes have been widely explored as therapeutic agents due to their unique geometry, their propensity to undergo ligand exchanges with biomolecules and their diverse steric and electronic properties. These metal complexes can offer distinct modes of action in living organisms compared to carbon-based molecules. In this study, we investigated the antimicrobial and anti-proliferative abilities of a series of cyclometallated iridium(III) complexes. The iridium(III) complex 1 inhibited the growth of S. aureus with MIC and MBC values of 3.60 and 7.19 μM, respectively, indicating its potent bactericidal activity. Moreover, complex 1 also exhibited cytotoxicity against a number of cancer cell lines, with particular potency against ovarian, cervical and melanoma cells. This cyclometallated iridium(III) complex is the first example of a substitutionally-inert, Group 9 organometallic compound utilized as a direct and selective inhibitor of S. aureus. Show less

Two luminescent iridium(iii) complexes, 1 and 2, were synthesized and evaluated for their ability to probe COX-2 in human cancer cells. This is the first application of iridium(iii) complexes as imaging agents for COX-2. We demonstrate that complex 1 differentiates cancer cells from normal cells with high stability and low cytotoxicity. Show less

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

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

Modulating the hypoxic microenvironment is the priority for tumor treatment. Cytometalated iridium(iii)-metformin conjugates were synthesized for treating hypoxic cancer cells for the first time, which alleviate hypoxia via mitochondria respiration inhibition, thus displaying 10-fold higher cytotoxicity, emerging anti-metastasis and anti-inflammatory activities than a metformin-free Ir(iii) complex and cisplatin against hypoxic cancer cells. Show less

Organometallic iridium complexes are potent anticancer candidates which act through different mechanisms from cisplatin-based chemotherapy regimens. Here, ten phosphorescent cyclometalated iridium(III) complexes containing 2,2'-bipyridine-4,4'-dicarboxylic acid and its diester derivatives as ligands are designed and synthesized. The modification by ester group, which can be hydrolysed by esterase, facilitates the adjustment of drug-like properties. The quantum yields and emission lifetimes are influenced by variation of the ester substituents on the Ir(III) complexes. The cytotoxicity of these Ir(III) complexes is correlated with the length of their ester groups. Among them, 4a and 4b are found to be highly active against a panel of cancer cells screened, including cisplatin-resistant cancer cells. Mechanism studies in vitro indicate that they undergo hydrolysis of ester bonds, accumulate in mitochondria, and induce a series of cell-death related events mediated by mitochondria. Furthermore, 4a and 4b can induce pro-death autophagy and apoptosis simultaneously. Our study indicates that ester modification is a simple and feasible strategy to enhance the anticancer potency of Ir(III) complexes. Show less

Two novel photoactivatable mitochondria-targeting luminescent iridium(III) poly(ethylene glycol) (PEG) complexes incorporated with a nitrobenzyl group were designed. They showed minimal cytotoxic activity in the dark, but became significantly cytotoxic upon irradiation due to the release of the PEG pendants. Show less

Synthetic anion transporters that can interfere with the intracellular pH homeostasis are gaining increasing attention for tumor therapy, however, the biological mechanism of anion transporters remains to be explored. In this work, two phosphorescent cyclometalated Ir(iii) complexes containing 2-phenylpyridine (ppy) as the cyclometalated ligand, and 2,2'-biimidazole (H₂biim, Ir1) or 2-(1H-imidazol-2-yl)pyridine (Hpyim, Ir2) as the ancillary ligands have been synthesized and characterized. Due to the protonation and deprotonation process of the N-H groups on H₂biim and Hpyim, Ir1 and Ir2 display pH-dependent phosphorescence and can specifically image lysosomes. Both Ir1 and Ir2 can act as anion transporters mainly through the anion exchange mechanism with higher potency observed for Ir1. Mechanism investigation shows that Ir1 and Ir2 can induce caspase-independent cell death through reactive oxygen species (ROS) elevation. As Ir1 and Ir2 can alkalinize lysosomes through anion disturbance, they can inhibit autophagic flux. Our work provides a novel anticancer mechanism of metal complexes, which gives insights into the innovative structure-based design of new metallo-anticancer agents. Show less

We report the synthesis, characterization, and antiproliferative activity of 15 iridium(III) half-sandwich complexes of the type [(η⁵-Cp*)Ir(2-(R'-phenyl)-R-pyridine)Cl] bearing either an electron-donating (-OH, -CH₂OH, -CH₃) or electron-withdrawing (-F, -CHO, -NO₂) group at various positions on the 2-phenylpyridine (2-PhPy) chelating ligand giving rise to six sets of structural isomers. The X-ray crystal structures of [(η⁵-Cp*)Ir(2-(2'-fluorophenyl)pyridine)Cl] (1) and [(η⁵-Cp*)Ir(2-(4'-fluorophenyl)pyridine)Cl] (2) exhibit the expected "piano-stool" configuration. DFT calculations showed that substituents caused only localized effects on the electrostatic potential surface of the chelating 2-PhPy ligand of the complexes. Hydrolysis of all complexes is rapid, but readily reversed by addition of NaCl. The complexes show preferential binding to 9-ethylguanine over 9-methyladenine and are active catalysts for the oxidation of NADH to NAD⁺. Antiproliferative activity experiments in A2780 ovarian, MCF-7 breast, A549 lung, and HCT116 colon cancer cell lines showed IC₅₀ values ranging from 1 to 89 μM, with the most potent complex, [(η⁵-Cp*)Ir(2-(2'-methylphenyl)pyridine)Cl] (13) (A2780 IC₅₀ = 1.18 μM), being 10× more active than the parent, [(η⁵-Cp*)Ir(2-phenylpyridine)Cl], and 2× more active than [(η⁵-Cp^xPh)Ir(2-phenylpyridine)Cl]. Intriguingly, contrasting biological activities are observed between structural isomers despite exhibiting similar chemical reactivity. For pairs of structural isomers both the nature and position of the functional group can affect the hydrophobicity of the complex. An increase in hydrophobicity resulted in enhanced cellular-iridium accumulation in A2780 ovarian cells, which generally gave rise to an increase in potency. The structural isomers [(η⁵-Cp*)Ir(2-(4'-fluorophenyl)pyridine)Cl] (2) and [(η⁵-Cp*)Ir(2-phenyl-5-fluoropyridine)Cl] (4) preferentially localized in the cytosol > membrane and particulate > nucleus > cytoskeleton. This work highlights the strong dependence of biological behavior on the nature and position of the substituent on the chelating ligand and shows how this class of organometallic anticancer complexes can be fine-tuned to increase their potency without using extended cyclopentadienyl systems. Show less

Luminescent cyclometallated iridium(III) complexes with a polyhedral oligomeric silsesquioxane (POSS) unit were designed as efficient theranostic agents that displayed tuneable organelle-targeting properties, minimal dark cytotoxicity and substantial photocytotoxicity even under hypoxic conditions. Show less

Precise quantitative measurement of viscosity at the subcellular level presents great challenges. Two-photon phosphorescence lifetime imaging microscopy (TPPLIM) can reflect micro-environmental changes of a chromophore in a quantitative manner. Phosphorescent iridium complexes are potential TPPLIM probes due to their rich photophysical properties including environment-sensitive long-lifetime emission and high two-photon absorption (TPA) properties. In this work, a series of iridium(iii) complexes containing rotatable groups are developed as mitochondria-targeting anticancer agents and quantitative viscosity probes. Among them, Ir6 ([Ir(ppy-CHO)₂(dppe)]PF₆; ppy-CHO: 4-(2-pyridyl)benzaldehyde; dppe: cis-1,2-bis(diphenylphosphino)ethene) shows satisfactory TPA properties and long lifetimes (up to 1 μs). The emission intensities and lifetimes of Ir6 are viscosity-dependent, which is mainly attributed to the configurational changes in the diphosphine ligand as proved by ¹H NMR spectra. Ir6 displays potent cytotoxicity, and mechanism investigations show that it can accumulate in mitochondria and induce apoptotic cell death. Moreover, Ir6 can induce mitochondrial dysfunction and monitor the changes in mitochondrial viscosity simultaneously in a real-time and quantitative manner via TPPLIM. Upon Ir6 treatment, a time-dependent increase in viscosity and heterogeneity is observed along with the loss of membrane potential in mitochondria. In summary, our work shows that multifunctional phosphorescent metal complexes can induce and precisely detect microenvironmental changes simultaneously at the subcellular level using TPPLIM, which may deepen the understanding of the cell death mechanisms induced by these metallocompounds. Show less

Organometallic half-sandwich Ir^III complexes of the type [(η⁵-Cp^x)Ir(N^N)Cl]PF₆ 1-6, where Cp^x = C₅Me₅ (Cp*), C₅Me₄C₆H₅ (Cp^xph), C₅Me₄C₆H₄C₆H₅ (Cp^xbiph), N^N is imionopyridine chelating ligand, were prepared and characterized. The X-ray crystal structure of complex 1 has been determined. Four compounds displayed higher anticancer potency than clinically used anticancer drug cisplatin against A549 cancer cells, especially complex 3 which is 8 times more active than cisplatin. No hydrolysis was observed by NMR and UV-Vis for complexes 3 and 6; however, these complexes show big differences in nucleobase binding, mainly decided by the imionopyridine chelating ligand. Complex 3 is stable in the presence of glutathione, but 6 reacted rapidly with glutathione. The octanol/water partition coefficients (log P) of 3 and 6 have been determined. In addition, these complexes display effective catalytic activity in converting coenzyme NADH to NAD⁺ by accepting hydride to form an Ir hydride adduct. The mechanism of actions of these complexes involves apoptosis induction, cell cycles arrest, and significant increase of reactive oxygen species levels in A549 cancer cells. Show less

Near-infrared (NIR) emitters are important probes for biomedical applications. Nanoparticles (NPs) incorporating mono- and tetranuclear iridium(iii) complexes attached to a porphyrin core have been synthesized. They possess deep-red absorbance, long-wavelength excitation (635 nm) and NIR emission (720 nm). TD-DFT calculations demonstrate that the iridium-porphyrin conjugates herein combine the respective advantages of small organic molecules and transition metal complexes as photosensitizers (PSs): (i) the conjugates retain the long-wavelength excitation and NIR emission of porphyrin itself; (ii) the conjugates possess highly effective intersystem crossing (ISC) to obtain a considerably more long-lived triplet photoexcited state. These photoexcited states do not have the usual radiative behavior of phosphorescent Ir(iii) complexes, and they play a very important role in promoting the singlet oxygen (¹O₂) and heat generation required for photodynamic therapy (PDT) and photothermal therapy (PTT). The tetranuclear 4-Ir NPs exhibit high ¹O₂ generation ability, outstanding photothermal conversion efficiency (49.5%), good biocompatibility, low half-maximal inhibitory concentration (IC₅₀) (0.057 μM), excellent photothermal imaging and synergistic PDT and PTT under 635 nm laser irradiation. To our knowledge this is the first example of iridium-porphyrin conjugates as PSs for photothermal imaging-guided synergistic PDT and PTT treatment in vivo. Show less