An iridium complex, preparation method and application thereof

Abstract

The application discloses an iridium complex and a preparation method and application thereof, and the iridium complex comprises a structure shown in the following formula: wherein X ‑ represents an anion. The compound of the application scheme has a spontaneous light emitting characteristic in an alkaline environment, can generate superoxide anions and singlet oxygen, and has catalytic oxidation ability on NADH / NADPH in tumor cells. The complex has good proliferation inhibition ability (IC 50 50 of 3.67 muM) on human non-small cell lung cancer cell lines (A549) under normal oxygen conditions, and also has proliferation inhibition ability (IC 50 50 of 6.85 muM) under anoxic conditions, which has important significance for researching the anti-tumor of the spontaneous light emitting metal iridium complex and provides a new idea for developing the photodynamic therapy of deep tumors in the clinic. In the complex of the application scheme, the donor and the acceptor are covalently attached, the covalent interaction is more stable, and the distance is closer, and therefore, higher transfer efficiency can be achieved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemistry, and in particular to an iridium complex and a preparation method and application thereof. BACKGROUND

[0002] In the treatment of diseases, photodynamic therapy (PDT) is increasingly valued for its non-invasive, high spatial selectivity, easy operation and excellent biocompatibility. As a highly potential strategy for cancer treatment, the core elements of PDT include photosensitizer, light source and molecular oxygen. However, the current high requirement for external excitation light source and the limitation of light penetration depth greatly hinder its application in the treatment of deep tissue diseases. Therefore, it is a great challenge to develop a new method of deep tissue light therapy that does not require external light source for activation, especially to develop a chemiluminescent agent that can be activated in situ for photodynamic therapy of deep tissue lesions.

[0003] Chemiluminescence, as a phenomenon of generating light through chemical excitation in the chemical reaction process, has become a promising tool in the field of biological imaging and in vivo therapy. Studies have shown that probes with chemiluminescence function can generate chemiluminescence in situ in diseased tissues, which is expected to replace traditional external light sources to achieve chemiluminescence-stimulated photodynamic therapy of tumors.

[0004] In most reported studies, PDT based on chemiluminescence usually relies on the mechanism of intermolecular chemiluminescence resonance energy transfer (CRET), that is, the energy of the chemiluminescence donor is transferred to the appropriate photosensitizer acceptor. However, the materials of these intermolecular CRET strategies are often self-assembled through non-covalent interactions such as π-π stacking, hydrophobic interaction and electrostatic interaction. These interactions not only have poor stability but also are sensitive to external interference, leading to easy leakage of molecules in nanomaterials. In addition, the distance between the donor and the acceptor is far, which seriously restricts the efficiency of CRET.

[0005] Therefore, it is of great significance to develop covalently linked self-luminescent photosensitizers for photodynamic therapy of deep tumors. SUMMARY

[0006] The present application aims to at least solve one of the problems in the prior art. To this end, the present application proposes an iridium complex, which can self-luminesce.

[0007] According to one aspect of the present application, an iridium complex is proposed, comprising the structure shown in the following formula:

[0008]

[0009] wherein X represents an anion. - represents an anion.

[0010] According to a preferred embodiment of the present application, at least the following advantages are achieved: the compound of the present application has a self-luminescent property in an alkaline environment, can generate superoxide anion and singlet oxygen, and has catalytic oxidation ability to NADH / NADPH in tumor cells. The complex has good proliferation inhibition ability (IC 50 50.67 μM) to human non-small cell lung cancer cell line (A549) under normoxic conditions, and also has proliferation inhibition ability (IC 50 50.67 μM) under hypoxic conditions, which is of great significance for the study of self-luminescent metal iridium complexes against tumors and provides a new idea for the clinical development of deep tumor photodynamic therapy. In the complex of the present application, the donor and the acceptor are covalently attached, the covalent interaction is more stable, and the distance is closer, so that higher transfer efficiency can be achieved.

[0011] In some embodiments of the present application, X - represents at least one of PF6 - , halide (preferably chloride), tetrafluoroborate, tetraphenylborate, triflate or tetrakis(3,5-di(trifluoromethyl)phenyl)borate. The anion has little effect on the luminescence process.

[0012] According to another aspect of the present application, a preparation method of the above-mentioned complex is provided, comprising the following steps:

[0013] S1, esterifying 9-acridine formyl chloride with an imidazole ligand to obtain an acridine-esterified imidazole ligand;

[0014] S2, reacting the acridine-esterified imidazole ligand with a phenylpyridine iridium dichloride bridge precursor to obtain an acridine-esterified iridium complex;

[0015] S3, reacting the acridine-esterified iridium complex with methyl triflate, and then performing ion replacement with a compound containing X - to obtain the iridium complex;

[0016] wherein, the structure formula of the imidazole ligand is as follows:

[0017] According to the preparation method of a preferred embodiment of the present application, at least the following advantages are achieved: the preparation method of the present application is simple to operate and has good industrial application prospects.

[0018] In some embodiments of the present application, the step S1 specifically comprises: esterifying 9-acridine formyl chloride with an imidazole ligand in the presence of a protective atmosphere, 4-dimethylaminopyridine and triethylamine to obtain an acridine-esterified imidazole ligand.

[0019] In some embodiments of the present application, the step S1 specifically comprises: dissolving 9-acridine formyl chloride, imidazole ligand and 4-dimethylamino pyridine in solvent I, adding triethylamine under a protective atmosphere, stirring at 20-35°C for 18-36h.

[0020] In some embodiments of the present application, the step S1 further comprises: after the reaction is completed, spin-drying the solvent, and purifying the crude product by silica gel column chromatography to obtain the acridine esterified imidazole ligand.

[0021] In some embodiments of the present application, the reaction formula of the step S1 is as follows:

[0022]

[0023] In some embodiments of the present application, the solvent I comprises at least one of anhydrous dichloromethane, anhydrous DMF and anhydrous acetonitrile.

[0024] In some embodiments of the present application, the molar ratio of 9-acridine formyl chloride, imidazole ligand, 4-dimethylamino pyridine and triethylamine in the step S1 is 1:1-1.1:0.14-0.18:28-32.

[0025] In some embodiments of the present application, the molar ratio of 9-acridine formyl chloride, imidazole ligand, 4-dimethylamino pyridine and triethylamine in the step S1 is 1:1:0.16:30.

[0026] In some embodiments of the present application, the reaction temperature in the step S1 is 25°C, and the reaction time is 26h.

[0027] In some embodiments of the present application, the step S1 further comprises a preparation step of 9-acridine formyl chloride: reacting 9-acridine carboxylic acid with thionyl chloride under heating.

[0028] In some embodiments of the present application, the reaction temperature under heating is 80-120°C.

[0029] In some embodiments of the present application, the reaction time under heating is 1-4h.

[0030] In some embodiments of the present application, the step S1 further comprises a preparation step of 9-acridine formyl chloride: dissolving 9-acridine carboxylic acid in thionyl chloride, stirring at 80-120°C for 1-4h. After the reaction is completed, cooling to room temperature, spin-drying the solvent to obtain bright yellow crystals of 9-acridine formyl chloride, and the reaction formula of this step is as follows:

[0031]

[0032] It can also be directly purchased.

[0033] In some embodiments of the present application, the molar ratio of 9- acridinecarboxylic acid to thionyl chloride in step S1 is 1:70.

[0034] In some embodiments of the present application, the heating reflux temperature in step S1 is 110°C, and the reaction time is 3h.

[0035] In some embodiments of the present application, the protective atmosphere comprises an inert gas atmosphere or a nitrogen atmosphere.

[0036] In some embodiments of the present application, the inert gas comprises argon.

[0037] In some embodiments of the present application, step S2 specifically comprises dissolving the phenylpyridine iridium dichloride bridge precursor and the acridine esterified imidazole ligand in solvent II, stirring at 50-80°C for 18-36h.

[0038] In some embodiments of the present application, the solvent II comprises at least one of a mixed solution of methanol and dichloromethane, a mixed solution of chloroform and methanol, ethylene glycol, and a mixed solution of ethylene glycol and diethyl ether.

[0039] In some embodiments of the present application, the molar ratio of the phenylpyridine iridium dichloride bridge precursor to the acridine esterified imidazole ligand in step S2 is 1:2-2.2.

[0040] In some embodiments of the present application, the molar ratio of the phenylpyridine iridium dichloride bridge precursor to the acridine esterified imidazole ligand in step S2 is 1:2.

[0041] In some embodiments of the present application, the reaction temperature in step S2 is 60°C, and the time is 24h.

[0042] In some embodiments of the present application, step S2 specifically comprises dissolving the phenylpyridine iridium dichloride bridge precursor and the acridine esterified imidazole ligand in methanol / dichloromethane (v / v = 3 / 1), stirring at 50-80°C for 18-36h. After the reaction is completed, the solvent is rotary evaporated, and the crude product is purified by silica gel column chromatography to obtain the acridine esterified metal iridium complex. The reaction formula of this step is as follows:

[0043]

[0044] In some embodiments of the present application, step S3 specifically comprises dissolving the acridine esterified metal iridium complex and methyl triflate in solvent III, reacting at 40-80°C for 48-96h, and then adding an aqueous solution of ammonium hexafluorophosphate, to obtain the iridium complex after the reaction.

[0045] In some embodiments of the present application, the solvent III comprises dichloromethane.

[0046] In some embodiments of the present application, the molar ratio of the acridine esterified metal iridium complex to methyl triflate in step S3 is 1:20.

[0047] In some embodiments of the present application, the reaction temperature in step S3 is 60°C and the reaction time is 72h.

[0048] In some embodiments of the present application, step S3 is specifically as follows: the acridine esterified metal iridium complex and methyl triflate are dissolved in anhydrous dichloromethane, and stirred at 40-80°C for 48-96h. After the reaction is completed, the solution is cooled to room temperature, and the solvent is removed by rotary evaporation. Then, saturated ammonium hexafluorophosphate aqueous solution is added to precipitate the product. The precipitate is collected by filtration and dried. The dried product is purified by silica gel column chromatography to obtain the metal iridium complex. The reaction formula of this step is as follows:

[0049]

[0050] According to another aspect of the present application, the above-mentioned iridium complex is used in the preparation of an anti-tumor drug.

[0051] According to the application of a preferred embodiment of the present application, at least the following beneficial effects are achieved: the complex of the present application can generate superoxide anion under light irradiation. Superoxide anion is usually associated with oxidative stress in vivo, and it can act as a signal molecule involved in various physiological and pathological processes. Therefore, it can kill tumor cells or inhibit their growth by inducing oxidative stress. The complex of the present application has strong ability to generate superoxide anion after light irradiation, which can cause oxidative stress in tumor cells. Therefore, it has good anti-tumor potential, which indicates that it has good application prospects in the field of anti-tumor drugs.

[0052] In some embodiments of the present application, the tumor is lung cancer.

[0053] In some embodiments of the present application, the tumor is non-small cell lung cancer. The complex of the present application has strong inhibitory effect on the proliferation of non-small cell lung cancer cells, and has good application prospects in the treatment of non-small cell lung cancer.

[0054] In some embodiments of the present application, the cell line of lung cancer is human non-small cell lung cancer cell line (A549).

[0055] In some embodiments of the present application, the drug further comprises a pharmaceutically acceptable carrier and / or excipient. That is, the drug or photosensitizer uses the metal ruthenium complex as the main active ingredient, which is mixed with a pharmaceutically acceptable carrier and / or excipient to prepare a composition, and is prepared into a clinically acceptable dosage form.

[0056] In some embodiments of the present application, the excipients refer to diluents, binders, lubricants, disintegrants, co-solvents, stabilizers and other pharmaceutical bases used in the pharmaceutical field.

[0057] In some embodiments of the present application, different pharmaceutical excipients for the pharmaceutical dosage form can vary depending on the specific medical application. The pharmaceutical excipients can be used to adjust the solubility and bioavailability of the photocatalyst, increase its stability, adjust the host's immune response and act as emulsifiers, antioxidants, aerosol propellants, tablet binders, tablet disintegrants. Preferred pharmaceutical excipients include, but are not limited to, binders / fillers, coating agents, disintegrants, lubricants and sweeteners compatible with the use of photosensitizers.

[0058] In some embodiments of the present application, the carriers are functional pharmaceutical auxiliaries acceptable in the pharmaceutical field, including surfactants, suspending agents, emulsifiers and some pharmaceutical high molecular materials prepared in the embodiments of the present application, such as cyclodextrin, chitosan, polylactic acid (PLA), polylactic acid glycolic acid copolymer (PLGA), hyaluronic acid, etc.

[0059] In some embodiments of the present application, the pharmaceutical dosage form of the present application is not particularly limited, and the active substance can be administered together with assimilable edible carriers, inert diluents or directly combined with food. The pharmaceutical dosage form includes, but is not limited to, hard or soft gelatin capsules, tablets, pills, powder injections, solutions, suspensions, elixirs, syrups, wafers, gels, buccal or sublingual tablets, films, suppositories and enemas, etc.

[0060] In some other embodiments of the present application, the photocatalyst of the present application can be prepared without any formulation adjuvant or using other existing technology known pharmaceutical delivery systems, such as liposome forming components, vectored and non-vectored proteins, organic and inorganic nanoparticles, nanoemulsions and microemulsions, nanocrystals, single solvents or appropriate solvent mixtures, components such as lactose, polyvinylpyrrolidone (PVP), etc.

[0061] In some embodiments of the present application, the prepared pharmaceuticals can be administered orally, involving any part of the gastrointestinal tract (such as the mouth, pharynx, esophagus, stomach, small intestine (duodenum, jejunum, ileum), large intestine (cecum, colon, rectum) and anus) or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically), and if certain drugs are not stable under stomach conditions, they can be prepared into enteric-coated tablets.

[0062] According to another aspect of the present application, an anti-tumor metal photosensitizer is provided, wherein the active ingredient of the anti-tumor metal photosensitizer comprises the iridium complex described above. Other ingredients can also be included. The donor and the acceptor of the present application have the function of self-luminescence through covalent linkage, and it is of great significance to prepare the photosensitizer for deep tumor photodynamic therapy.

[0063] According to another aspect of the present application, a reagent or kit for biomedical imaging is provided, comprising the iridium complex described above. By introducing these complexes into cells, the concentration change of hydrogen peroxide in the cells can be monitored in real time, so as to understand the physiological state or disease progression of the cells.

[0064] According to another aspect of the present application, a chemical sensor is provided, comprising the iridium complex described above. As a chemical sensor, it is used for detecting hydrogen peroxide or other related chemicals in the environment. These sensors have high sensitivity and high selectivity, and can accurately and quickly respond to the concentration change of the target substance in a complex environment.

[0065] Other features and advantages of the present application will be set forth in the following description, and in part will become apparent from the description, or can be learned by practice of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0066] The above and / or additional aspects and advantages of the present application will become apparent and be readily understood from the following description, taken in conjunction with the accompanying drawings, in which:

[0067] Figure 1 Nuclear magnetic resonance hydrogen spectrum of the acridine esterified imidazole ligand prepared for the embodiment of the present application;

[0068] Figure 2 Nuclear magnetic resonance hydrogen spectrum of the acridine esterified metal iridium complex prepared for the embodiment of the present application;

[0069] Figure 3 Nuclear magnetic resonance hydrogen spectrum of the self-luminescent metal iridium complex prepared for the embodiment of the present application;

[0070] Figure 4 Luminescence process diagram of the self-luminescent metal iridium complex prepared for the embodiment of the present application under alkaline conditions and hydrogen peroxide activation;

[0071] Figure 5 Ultraviolet-visible absorption spectrum diagram of the self-luminescent metal iridium complex prepared for the embodiment of the present application in different solvents;

[0072] Figure 6 Fluorescence excitation spectrum diagram and fluorescence emission spectrum diagram of the self-luminescent metal iridium complex prepared for the embodiment of the present application;

[0073] Figure 7The fluorescence emission spectrum diagram of the self-luminescent metal iridium complex prepared in the embodiment of the present application in different solvents is shown in the following figure:

[0074] Figure 8 The test result diagram of the ability of the self-luminescent metal iridium complex prepared in the embodiment of the present application to produce superoxide anion by photocatalysis is shown in the following figure:

[0075] Figure 9 The test result diagram of the ability of the self-luminescent metal iridium complex prepared in the embodiment of the present application to produce singlet oxygen by photocatalysis is shown in the following figure:

[0076] Figure 10 The test result diagram of the ability of the self-luminescent metal iridium complex prepared in the embodiment of the present application to oxidize NADH and NADPH by photocatalysis is shown in the following figure:

[0077] Figure 11 The test result diagram of the cytotoxicity of the self-luminescent metal iridium complex prepared in the embodiment of the present application to human non-small cell lung cancer cell line (A549) under normoxic and hypoxic conditions is shown in the following figure. DETAILED DESCRIPTION

[0078] The concept and technical effects of the present application will be described below in combination with embodiments so as to fully understand the purpose, features and effects of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, but not all the embodiments. Based on the embodiments of the present application, other embodiments obtained by those skilled in the art without creative labor are within the protection scope of the present application. The test methods used in the embodiments are conventional methods unless otherwise specified. The materials and reagents used are commercially available unless otherwise specified. The same parameters are used in the same way in each embodiment unless otherwise specified. The following described embodiments are exemplary and are used to explain the present application, but cannot be understood as limiting the present application.

[0079] In the description of the present application, the description of the terms “one embodiment”, “some embodiments”, “illustrative embodiment”, “example”, “specific example” or “some examples” means that the specific features, structures, materials or characteristics described in combination with the embodiment or example are included in at least one embodiment or example of the present application. In the present specification, the illustrative description of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner.

[0080] In the present application, “room temperature” refers to 25±5℃, and in the embodiments, it is specifically 25℃.

[0081] EMBODIMENT

[0082] In this example, a metal iridium complex having self-luminous performance is prepared, and the structural formula of the complex is as follows:

[0083]

[0084] The preparation process is specifically as follows:

[0085] (1) 9-acridine carboxylic acid is used to generate 9-acridine formyl chloride

[0086] 9-acridine carboxylic acid (228 mg, 1 mmol) is dissolved in 5 mL of thionyl chloride, and stirred at 110°C for 3 h. After the reaction is completed, the solution is cooled to room temperature, and bright yellow crystals after the solvent is spun dry, which is 9-acridine formyl chloride (237 mg, 98%).

[0087] The chemical reaction equation is as follows:

[0088]

[0089] (2) 9-acridine formyl chloride is used to generate acridine esterified imidazole ligand with imidazole ligand

[0090] 9-acridine formyl chloride (243 mg, 1 mmol), imidazole ligand (389 mg, 1 mmol), and 4-dimethylaminopyridine (20 mg, 0.16 mmol) are dissolved in 20 mL of anhydrous dichloromethane, 4 mL of triethylamine is added in an argon (or other inert gas or nitrogen) atmosphere, and stirred at 25°C for 26 h. After the reaction is completed, the solvent is spun dry, and the crude product is purified by silica gel column chromatography to obtain light yellow acridine esterified imidazole ligand (475 mg, 80%).

[0091] The chemical reaction equation is as follows:

[0092]

[0093] The nuclear magnetic resonance hydrogen spectrum of the product is as shown in Figure 1 Specifically, the nuclear magnetic resonance hydrogen spectrum data is measured as follows: 1 HNMR (500 MHz, DMSO-d6) δ 9.12 (d, J = 4.2 Hz, 1H), 9.07 (d, J = 8.0 Hz, 1H), 8.98 (d, J = 4.2 Hz, 1H), 8.30 (d, J = 8.7 Hz, 4H), 7.99 (t, J = 7.7 Hz, 2H), 7.91 (dd, J = 8.3, 4.3 Hz, 1H), 7.86 (d, J = 7.0 Hz, 2H), 7.84-7.77 (m, 7H), 7.70 (d, J = 8.4 Hz, 2H), 7.51 (dd, J = 8.3, 4.2 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H). It is indicated that the correct structure of the target compound is prepared by the above operation.

[0094] (3) Generation of phenylpyridine iridium dichloro-bridge precursor from 2-phenylpyridine and iridium trichloride hydrate

[0095] 2-phenylpyridine (389 mg, 2.5 mmol) and iridium trichloride hydrate (318 mg, 1 mmol) were dissolved in 40 mL of ethylene glycol ethyl ether / water (v / v = 3 / 1) and stirred at 120 °C for 12 h. After the reaction was completed, it was cooled to room temperature, suction filtered, the filter cake was washed with water and methanol, and dried under vacuum at reduced pressure to obtain the phenylpyridine iridium dichloro-bridge precursor (474 mg, 44%).

[0096] The above chemical reaction equation is shown below:

[0097]

[0098] (4) Generation of acridylated metal iridium complex from phenylpyridine iridium dichloro-bridge precursor and acridylated imidazole ligand

[0099] phenylpyridine iridium dichloro-bridge precursor (536 mg, 0.5 mmol) and acridylated imidazole ligand (593 mg, 1 mmol) were dissolved in 20 mL of methanol / dichloromethane (v / v = 3 / 1) and stirred at 60 °C for 24 h. After the reaction was completed, it was cooled to room temperature, the solvent was evaporated, and the crude product was purified by silica gel column chromatography to obtain the acridylated metal iridium complex (550 mg, 84%).

[0100] The above chemical reaction equation is shown below:

[0101]

[0102] The nuclear magnetic resonance hydrogen spectrum of the product is shown in Figure 2 Specifically, the nuclear magnetic resonance hydrogen spectrum data measured were as follows: 1 HNMR (500 MHz, DMSO-d6) δ 9.35 (d, J = 8.2 Hz, 1H), 8.28 (q, J = 8.0 Hz, 6H), 8.17 (t, J = 6.9 Hz, 1H), 8.12 (d, J = 5.1 Hz, 1H), 8.01-7.70 (m, 19H), 7.52 (t, J = 5.4 Hz, 3H), 7.06 (dq, J = 13.5, 7.0, 6.4 Hz, 4H), 6.96 (dt, J = 13.9, 7.6 Hz, 2H), 6.31 (dd, J = 15.3, 7.5 Hz, 2H). Thus, it was confirmed that the target compound having the correct structure was obtained by the above operation.

[0103] (5) Generation of metal iridium complex having self-light emitting function from acridylated metal iridium complex and methyl trifluoromethanesulfonate

[0104] The acridinium ester metal iridium complex (223 mg, 0.2 mmol) was dissolved in 6 mL of anhydrous dichloromethane with methyl trifluoromethanesulfonate (455 mg, 2 mmol) and stirred at 60 °C for 72 h. After the reaction was completed, it was cooled to room temperature, and the solvent was evaporated. Then, a saturated aqueous solution of ammonium hexafluorophosphate was added to precipitate the product, which was filtered and dried. The product was purified by column chromatography on silica gel to obtain the metal iridium complex (65.7 mg, 23 %). The above chemical reaction is shown in the following equation:

[0105]

[0106] The mass spectrum of the product was ESI-MS (CH3OH): [M-2PF6 - ] 2+ calcd. for [C 62 H 42 IrN7O2] 2+ : 554.5, found: 554.4.

[0107] The nuclear magnetic hydrogen spectrum of the product is shown in the following equation: Figure 3 Specifically, the nuclear magnetic hydrogen spectrum data measured were as follows: 1 HNMR (500 MHz, DMSO-d6) δ 9.73 (d, J = 8.6 Hz, 1H), 8.49 (d, J = 5.0 Hz, 1H), 8.39 (dd, J = 8.6, 5.2 Hz, 1H), 8.36-8.28 (m, 7H), 8.09-7.96 (m, 9H), 7.95-7.89 (m, 4H), 7.85-7.75 (m, 5H), 7.58-7.46 (m, 3H), 7.15-6.94 (m, 6H), 6.31 (dd, J = 23.9, 7.5 Hz, 2H), 4.58 (s, 3H). Thus, it was shown that the above operation produced the target compound with a correct structure.

[0108] Test Example

[0109] To verify the application effect of the above complex, its performance was tested as follows:

[0110] 1. Spontaneous light detection of the metal iridium complex

[0111] The metal iridium complex synthesized by the above operation has an acridinium ester structure in its structure, and C-9 on the acridine ring thereof can form unstable dioxymethane with H2O2 (hydrogen peroxide) under alkaline conditions. The dioxymethane can rapidly decompose into CO2 and an electronically excited N-methyl acridinone, and the N-methyl acridinone emits photons in the process of returning to the ground state.

[0112] The metal iridium complex was dissolved in methanol, then diluted with 10 wt% NaOH, and 30 wt% H2O2 (hydrogen peroxide) was added to the diluted solution. As shown in Figure 4 , the metal iridium complex produced a chemiluminescence phenomenon after the addition of hydrogen peroxide.

[0113] 2. UV-Vis absorption spectrum and fluorescence spectrum determination of the metal iridium complex in different solvents

[0114] (1) UV-Vis absorption spectrum of the metal iridium complex in different solvents

[0115] The metal iridium complex prepared by the above operation was dissolved in phosphate buffered saline (PBS), dichloromethane (DCM), and methanol (MeOH), respectively, to prepare a 10 μM sample solution. Then, a double-beam UV-Vis spectrophotometer was used to record the UV-Vis absorption spectrum of the metal iridium complex to characterize its absorbance in different solvents, and the results are shown in Figure 5 . The results in the figure show that the maximum absorption of the compound is near 365 nm, and the absorption wavelength can extend to 500 nm in phosphate buffered saline.

[0116] (2) Fluorescence excitation spectrum and emission spectrum of the metal iridium complex

[0117] The metal iridium complex prepared by the above operation was dissolved in dichloromethane to prepare a 10 μM sample solution. A fluorescence spectrophotometer was used to record the fluorescence emission spectrum of the metal iridium complex with a fixed EX wavelength of 392 nm, and similarly, the fluorescence excitation spectrum of the metal iridium complex was recorded with a fixed EM wavelength of 608 nm to characterize its excitation spectrum and emission spectrum in dichloromethane, and the results are shown in Figure 6 . As can be seen from the results in the figure, the optimal excitation wavelength of the metal iridium complex in dichloromethane is 392 nm, and the optimal emission wavelength is 608 nm.

[0118] (3) Fluorescence emission spectrum of the metal iridium complex in different solvents

[0119] The metal iridium complex prepared by the above operation was dissolved in phosphate buffered saline (PBS), dichloromethane (DCM), and methanol (MeOH), respectively, to prepare a 10 μM sample solution. A fluorescence spectrophotometer was used to record the fluorescence emission spectrum of the metal iridium complex with a fixed EX wavelength of 392 nm to characterize its fluorescence emission intensity in different solvents, and the results are shown in Figure 7 . The results in the figure show that the fluorescence emission intensity of the compound in dichloromethane is stronger, and in phosphate buffered saline, it is weaker.

[0120] 3. Determination of the ability of the metal iridium complex to generate superoxide anion

[0121] To detect the ability of the above-mentioned operation to produce superoxide anion by the synthesized metal iridium complex, dihydro rhodamine 123 (DHR123) was used to determine the ability of the new metal iridium complex to produce superoxide anion. When superoxide anion is produced in the solution, DHR123 will immediately capture superoxide anion in the solution, and DHR123 is oxidized to generate fluorescent derivative rhodamine 123, which emits bright green fluorescence (Ex / Em=500 / 536 nm). The increase in fluorescence intensity indicates the generation of superoxide anion in the solution. The fluorescence spectrum of the mixed solution of the sample to be tested and DHR123 was monitored by a fluorescence spectrophotometer at different light irradiation times, which can reflect the production ability of superoxide anion.

[0122] The PBS solution containing the metal iridium complex (5 μM) and the DHR123 reagent (10 μM) was placed in a cuvette, and the superoxide anion production ability under light irradiation was determined as shown in Figure 8 From the figure, it can be seen that the metal iridium complex has the ability to produce superoxide anion after light irradiation.

[0123] 4. Ability of metal iridium complex to produce singlet oxygen

[0124] To detect the ability of the above-mentioned operation to produce singlet oxygen by the synthesized metal iridium complex, singlet oxygen probe Singlet Oxygen Sensor Green (SOSG) was used to determine the ability of the new metal iridium complex to produce singlet oxygen. When singlet oxygen is produced in the solution, SOSG will immediately capture singlet oxygen in the solution, and the generated SOSG endoperoxide (SOSG-EP) emits green fluorescence similar to that of fluorescein. The fluorescence emission spectrum of the mixed solution of the sample to be tested and SOSG was monitored by a fluorescence spectrophotometer at different light irradiation times, which can reflect the production ability of singlet oxygen.

[0125] The PBS solution containing the metal iridium complex (5 μM) and the SOSG reagent (5 μM) was placed in a cuvette, and the singlet oxygen production ability under light irradiation was determined as shown in Figure 9 From the figure, it can be seen that the metal iridium complex has the ability to produce singlet oxygen after light irradiation.

[0126] 5. Ability of metal iridium complex to photocatalyze oxidation of NADH / NADPH

[0127] Under light irradiation, the metal complex can oxidize reduced coenzyme I (NADH) and reduced coenzyme II (NADPH) to their oxidized states NAD + and NADP +So the mixture of metal iridium complex (5 μM) and NADH or NADPH (A 339nm =1.0) in a cuvette can be irradiated to determine its ability to oxidize NADH / NADPH, respectively, and the results are shown in Figure 10 Fig. 1. As can be seen from the figure, the metal iridium complex has the ability to photocatalyze the oxidation of NADH and NADPH.

[0128] 6. Therapeutic effect of metal iridium complex on human non-small cell lung cancer cell line

[0129] MTT colorimetric method was used to analyze the anti-proliferation effect of metal iridium complex on human non-small cell lung cancer cell line (A549 cells). MTT, the Chinese name is thiazolyl blue, is a kind of tetrazolium salt. In living cells, succinate dehydrogenase in mitochondria can reduce MTT to generate a blue-violet crystal-forming formazan (soluble in dimethyl sulfoxide), and the product has an absorption peak at 490 nm, so the enzyme-linked immunoassay instrument can be used to analyze the cell proliferation.

[0130] The MTT experiment procedure is as follows:

[0131] (1) First, resuscitate 1 tube of A549 tumor cells, and culture with fresh complete culture medium (DMEM culture medium + 10 vol% fetal bovine serum + 1 vol% penicillin-streptomycin mixture). After 2 passages, start the experiment.

[0132] (2) When the cells reach the logarithmic growth phase, seed them at a cell density of 80000 cells / mL into 2 96-well plates, and culture the cells in each well with 100 μL of culture medium. One plate is for the normoxic group, and the other plate is for the hypoxic group. The normoxic group is sent into a 37°C, 5% CO2 incubator for culture, and the hypoxic group is sent into a 37°C, 3% O2, 5% CO2 incubator for culture.

[0133] (3) After adhering, aspirate the original culture medium, and add 100, 50, 10, 1, 0.1, and 0.01 μM of metal iridium complex 100 μL into each well, respectively, and gently shake. Continue to incubate in the corresponding condition for 24 h in the dark.

[0134] (4) After 24 h of incubation, add 10 μL of MTT (5 mg / mL) into each well, and continue to incubate in a 37°C incubator for 4 h. Then aspirate the supernatant, add 100 μL of dimethyl sulfoxide (DMSO) into each well, and detect A 490nm using an enzyme-linked immunoassay instrument. Calculate the cell proliferation inhibition rate, and obtain the IC 50 value (the drug concentration when the inhibition rate is equal to 50%).

[0135] The results are shown in Figure 11The killing effect of the metal iridium complex of different concentrations on human non-small cell lung cancer cell line (A549 cells) under normoxic and hypoxic treatment conditions was detected by MTT method. As can be seen from the figure, the killing effect of the metal iridium complex of different concentrations on human non-small cell lung cancer cell line (A549 cells) under normoxic and hypoxic treatment conditions was different. Under normoxic condition, the IC 50 was 3.67 μM, which was better than that of cisplatin (IC 50 was 8.64 μM), and under hypoxic condition, the IC 50 of human non-small cell lung cancer cell line was 6.85 μM, which was also better than that of cisplatin (IC 50 was 22.3 μM). Thus, it is shown that the complex with the scheme structure of the present application has a strong tumor proliferation inhibition effect.

[0136] The above has made a detailed description of the embodiments of the present application, but the present application is not limited to the above embodiments, and various changes can be made within the knowledge range possessed by those skilled in the art without departing from the purpose of the present application.

Claims

1. An iridium complex, characterized in that: It includes the structure shown in the following formula: Among them, X - Represents anions.

2. The iridium complex according to claim 1, characterized in that: X - Represents PF6 - At least one of the following: halide ions, tetrafluoroborate group, tetraphenylborate group, trifluoromethanesulfonic acid group or tetra(3,5-bis(trifluoromethyl)phenyl)borate group.

3. The method for preparing the iridium complex according to claim 1 or 2, characterized in that: Includes the following steps: S1. 9-Acridine formyl chloride undergoes an esterification reaction with an imidazole ligand to obtain an acridine-esterified imidazole ligand; S2. The acridine-esterified imidazole ligand and the phenylpyridine iridium dichlorobridge precursor are reacted to obtain the acridine-esterified iridium complex; S3, reacting the acridine esterified iridium complex with methyl trifluoromethanesulfonate, followed by reaction with X-containing... - The iridium complex was obtained by ion substitution of the compound. The imidazole ligand has the following structural formula: .

4. The preparation method according to claim 3, characterized in that: Step S1 specifically includes: 9-acridine formyl chloride and imidazole ligand undergo esterification reaction in a protective atmosphere and in the presence of 4-dimethylaminopyridine and triethylamine to obtain acridine-esterified imidazole ligand.

5. The preparation method according to claim 3, characterized in that: Step S2 specifically includes: dissolving the phenylpyridine iridium dichlorobridge precursor and the acridine esterified imidazole ligand in solvent II and stirring at 50-80°C for 18-36 hours. Solvent II includes at least one of the following: a mixed solution of methanol and dichloromethane, a mixed solution of chloroform and methanol, ethylene glycol, and a mixed solution of ethylene glycol and diethyl ether.

6. The preparation method according to claim 3, characterized in that: Step S3 specifically includes: dissolving the acridine esterified iridium metal complex and methyl trifluoromethanesulfonate in solvent III, reacting at 40-80°C for 48-96 h, and then adding an aqueous solution of ammonium hexafluorophosphate to obtain the iridium complex after the reaction.

7. The use of the iridium complex as described in claim 1 or 2 in the preparation of antitumor drugs, characterized in that: The tumor is non-small cell lung cancer.

8. An antitumor metal photosensitizer, characterized in that: The active ingredient of the antitumor metal photosensitizer is the iridium complex as described in claim 1 or 2.

9. A reagent or kit for biomedical imaging, characterized in that: It contains an iridium complex as described in claim 1 or 2.

10. A chemical sensor, characterized in that: It contains an iridium complex as described in claim 1 or 2.

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