A lichenic acid-modified cyclometallated iridium (III) complex, its synthesis method and application

Abstract

The present invention discloses a lichenic acid-modified cyclometallated iridium (III) complex, a synthesis method thereof, and an application thereof. The complex is obtained by connecting the natural small molecule lichenic acid with cyclometallated iridium to obtain a product with high anti-cancer activity and low toxic side effects. The compound of the present invention has good cellular uptake ability and the ability to target mitochondria in tumor cells. Secondly, the compound of the present invention induces the production of reactive oxygen species in cancer cells, reduces mitochondrial membrane potential, and ultimately induces autophagy inhibition of tumor cells (mitochondria), thereby achieving good anti-tumor activity. The compound of the present invention can also induce overexpression of PD-L1 in cancer cells by upregulating the level of ATF3, thereby enhancing the immunotherapy effect of anti-PD-L1.

Description

Technical Field

[0001] The present invention relates to a lichenic acid modified cyclometalated iridium (III) complex, and also relates to a synthesis method and application of the metal complex. Technical Background

[0002] Lung cancer is one of the most common malignant tumors worldwide, severely impacting individual health worldwide. Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer, accounting for 85% of all lung cancer cases. Currently, the main clinical treatments for NSCLC are surgery, radiotherapy, and chemotherapy. However, these treatments do not significantly improve patient survival. There is an urgent need to explore more effective treatments for NSCLC.

[0003] Tumor immunotherapy has developed rapidly in recent years and has become a hot topic in the treatment of non-small cell lung cancer. In particular, immune checkpoint blockade (ICB) therapy has shown significant clinical benefits and brought great hope to patients. Since 2016, atezolizumab (anti-PD-L1 antibody) has been approved by the FDA for first-line treatment of lung cancer patients. It can bind to PD-L1 and block the binding of PD-L1 to PD-1 on the surface of T cells, thereby activating T cells to kill tumor cells. However, due to poor immunogenicity and insufficient T cell infiltration, the popularization of this immunotherapy has been hindered by poor patient efficacy, and atezolizumab may only benefit patients with PD-L1-positive cancers. Therefore, stimulating PD-L1 expression is expected to improve the therapeutic effect of ICB.

[0004] Natural products or their derivatives possess diverse biological activities, and many anticancer drugs currently used in clinical treatment are derived from natural product scaffolds, such as vinblastine and paclitaxel. Lichenic acid (UA), a well-known dibenzofuran derivative, is a secondary metabolite of lichen. UA can upregulate ATF3, a factor that transcribes PD-L1, and has the potential to stimulate PD-L1 overexpression. However, UA suffers from poor water solubility, low bioavailability, and high dosage requirements, which limit its application as a candidate anticancer drug or anticancer drug component. Summary of the Invention

[0005] Purpose of the invention: The present invention aims to provide a lichenic acid-modified cyclometallated iridium (III) complex. On the one hand, the complex can solve the problems of poor water solubility and low bioavailability of lichenic acid as an anti-tumor drug or anti-tumor drug component. On the other hand, it can upregulate the expression of PD-L1 in tumor cells, thereby enhancing the effect of PD-L1 antibody immunotherapy. Another purpose of the present invention is to provide a synthesis method of the above-mentioned lichenic acid-modified cyclometallated iridium (III) complex and its application in the preparation of anti-tumor drugs or anti-tumor drug components.

[0006] Technical solution: The lichenic acid-modified cyclometallated iridium (III) complex of the present invention has the following structural formula:

[0007]

[0008] Cyclometalated iridium (III) complexes have good lipid solubility. Combining them with lichenic acid can increase the uptake of lichenic acid by tumor cells, thereby avoiding the defect of large dosage. At the same time, cyclometalated iridium (III) complexes have excellent photophysical properties and can be used for cell imaging.

[0009] The synthesis method of the lichenic acid-modified cyclometalated iridium (III) complex comprises: heating a lichenic acid-modified bipyridine ligand and a cyclometalated iridium dimer in a mixed solution of dichloromethane and methanol under reflux under an inert atmosphere, removing the solvent by reduced pressure distillation, displacing the solvent with NH4PF6 to obtain a crude product, and separating and purifying the crude product by column chromatography to obtain the lichenic acid-modified cyclometalated iridium (III) complex;

[0010] The structural formula of the lichenic acid-modified bipyridine ligand is as follows:

[0011]

[0012] The structural formula of the cyclometallated iridium dimer is shown below:

[0013]

[0014] Among them, the preparation method of the lichenic acid-modified bipyridine ligand is specifically as follows: under an inert atmosphere, lichenic acid and the bridging ligand 4-methyl-4'-aminomethyl-2,2'-bipyridine are dissolved in anhydrous ethanol, the mixture is reacted at room temperature for 24 hours to obtain a crude product, and the crude product is separated and purified by column chromatography.

[0015] Wherein, the inert atmosphere utilizes nitrogen or argon as a protective gas.

[0016] The reaction molar ratio of the lichenic acid-modified bipyridine ligand to the cyclometallated iridium dimer is 2:1.

[0017] Wherein, the volume ratio of dichloromethane to methanol in the mixed solution is 2:1.

[0018] The reflux reaction time is 12 h and the reaction temperature is 45°C.

[0019] Application of the lichenic acid-modified cyclometallated iridium (III) complex in the preparation of antitumor drugs and antitumor drug components.

[0020] Wherein, the tumor refers to human lung cancer cells.

[0021] Beneficial effects: Compared with the existing technology, the present invention has the following significant effects: The present invention is based on a cyclometallated iridium (III) complex modified with the natural product lichenic acid. The complex has good lipid solubility and anti-tumor cell proliferation ability, can effectively inhibit tumor cell proliferation, induce ROS production, and induce autophagy blockade in tumor cells. At the same time, it can also upregulate the expression of ATF3, and ultimately significantly increase the level of PD-L1 in tumor cells, thereby helping to enhance the immunotherapy effect of PD-L1 antibodies. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the localization map of the complex of Example 1 in A549 cells;

[0023] Figure 2 The laser confocal fluorescence imaging and flow cytometry images of Example 1 complex promoting the generation of intracellular reactive oxygen species in A549 cells are shown; wherein, Figure 2 a is a confocal fluorescence imaging image. Figure 2 b is the cell flow cytometry graph;

[0024] Figure 3 The following are the flow cytometry images and confocal fluorescence imaging images of the changes in mitochondrial membrane potential induced by the complex in Example 1 in A549 cells; wherein, Figure 3 a is a confocal fluorescence imaging image; Figure 3 b is the flow cytometry graph of cells at different concentrations;

[0025] Figure 4 This is an immunoblot protein image of the complex of Example 1 inducing (mitochondrial) autophagy inhibition in A549 cells;

[0026] Figure 5 This is an immunoblot protein image of ATF3 and PD-L1 proteins induced by the complex in Example 1 in A549 cells;

[0027] Figure 6 Graph showing the tumor inhibition rate and body weight of mice administered with the complex of Example 1, anti-PD-L1, and their combination. DETAILED DESCRIPTION

[0028] Example 1

[0029] The preparation method of the lichenic acid-modified cyclometallated iridium (III) complex (abbreviated as Ir-UA) of the present invention comprises the following steps:

[0030]

[0031] Step 1: Preparation of lichenic acid-modified bipyridine ligand: Under argon atmosphere, weigh lichenic acid (86.0 mg, 0.25 mmol) and 4-methyl-4'-aminomethyl-2,2'-bipyridine (0.3 mmol, 59.8 mg) in a two-necked flask, evacuate, introduce argon, and heat under reflux at 70°C with stirring for 24 h; after the reaction, the solvent was distilled off under reduced pressure, and the crude product was further purified by flash chromatography to obtain an off-white solid with a yield of 64%; 1H NMR(400MHz, DMSO-d6)δ(ppm):13.41(d,J=2.9Hz,2H),12.18(s,1H),8.70(d,J=5.0Hz,1H),8.53(d,J=4.9Hz,1H),8.42–8.36(m,1H),8.26(s,1H),7. 43(dd,J=5.1,1.8Hz,1H),7.30(d,J=4.8Hz,1H),5.92(s,1H),5.01(d,J=5. 7Hz,2H),2.64(s,3H),2.61(s,3H),2.42(s,3H),1.97(s,3H),1.68(s,3H).

[0032] Step 2: Under an argon atmosphere, the lichenic acid-modified bipyridine ligand (42.0 mg, 0.08 mmol) and the cyclometallated iridium dimer (42.8 mg, 0.04 mmol) were dissolved in a mixed solvent of anhydrous dichloromethane and anhydrous methanol (the volume ratio of anhydrous dichloromethane to anhydrous methanol in the mixed solution was 2:1). The mixture was heated under reflux and stirred at 45°C for 12 hours. After the reaction, the solvent was removed by distillation under reduced pressure, and a saturated methanol solution of NH4PF6 was added. After stirring for 2 hours, the solid was collected by centrifugation and further purified by column chromatography to obtain a yellow solid Ir-UA with a yield of 55%. NMR (400MHz, CDCl3) δ (ppm): 13.37 (s, 1H), 11.72 (s, 1H), 8.78–8.72 (m, 1H), 8.57 (s, 1H), 7.97–7.90 (m, 3H) ,7.82–7.76(m,3H),7.69(d,J=7.4Hz,2H),7.55(dd,J=8.4,4.1Hz,3H),7.39–7.35(m,1H),7.23(s,1H),7.1 3–7.08(m,1H),7.07–7.01(m,3H),6.92(tdd,J=7.4,3.4,1.3Hz,2H),6.31(d,J=7.6Hz,2H),5.77(s,1H),5. 06(dd,J=12.5,6.2Hz,2H),2.67(s,3H),2.61(d,J=9.2Hz,6H),2.08(s,3H),1.70(s,3H).ESI-MS(positive mode,m / z):calcd.1026.28,found1026.3

[0033] The structural formula of the complex Ir-NH2 without lichenic acid modification is:

[0034]

[0035] The complex Ir-NH2 was prepared by the following method:

[0036] Under an argon atmosphere, 4-methyl-4'-aminomethyl-2,2'-bipyridine (15.9 mg, 0.08 mmol) and cyclometallated iridium dimer (42.8 mg, 0.04 mmol) were dissolved in a mixed solvent of anhydrous dichloromethane and anhydrous methanol (the volume ratio of anhydrous dichloromethane to anhydrous methanol in the mixed solution was 2:1), and the mixture was heated under reflux and stirred at 45°C for 12 h. After the reaction, the solvent was distilled off under reduced pressure, and a saturated methanol solution of NH4PF6 was added. The mixture was stirred for 2 h and then centrifuged to collect the solid. The crude product was further purified by column chromatography to obtain a yellow solid Ir-NH2 with a yield of 67%. 1H NMR (400MHz, d6-DMSO) δ (ppm): 8.81 (s, 1H), 8.75 (s, 1H), 8.27 (d, J = 7.8Hz, 2H), 7 .93(t,J=8.0Hz,4H),7.74(d,J=5.4Hz,1H),7.69(d,J=5.5Hz,1H),7.65-7.59(m, 3H),7.53(d,J=5.3Hz,1H),7.17(t,J=6.5Hz,2H),7.02(t,J=7.4Hz,2H),6.90(t, J=7.4Hz,2H),6.20(d,J=7.5Hz,2H),3.94(s,2H),2.54(s,3H).ESI-MS(positive mode,m / z):calcd.699.86,found700.5

[0037] The following experiment was conducted on the complex Ir-UA prepared in Example 1 and the cyclometallated iridium (III) complex Ir-NH2 that did not contain lichenic acid:

[0038] Cytotoxicity to human lung cancer cells A549 and human lung fibroblast-like cells HLF:

[0039] The MTT colorimetric method was used to analyze the antiproliferative effects of lichenic acid-modified cyclometallated iridium (III) complex Ir-UA, lichenic acid, lichenic acid-free cyclometallated iridium (III) complex Ir-NH2, and cisplatin CDDP. MTT (thiazolyl blue) is a tetrazolium salt that can be reduced by succinate dehydrogenase in the mitochondria of living cells to produce a blue-purple product, formazan (the product is soluble in DMSO), and this product has an absorption peak at 570nm, so it can be used as an A 570 nm To analyze cell proliferation.

[0040] The specific experimental steps are as follows:

[0041] (1) First, thaw a tube of tumor cells and culture them in fresh culture medium (DMEM medium + 10% fetal bovine serum + 1% penicillin and streptomycin). Passage them twice before use.

[0042] (2) When the cells reached the logarithmic growth phase, they were seeded into 96-well plates at a density of 5000 cells / well (100 μL of culture medium per well) and then placed in an incubator (37°C, 5% CO2) for culture;

[0043] (3) After the cells adhered to the wall, 100 μL of fresh culture medium containing different concentration gradients of compound Ir-UA, different concentration gradients of lichenic acid, different concentration gradients of compound Ir-NH2, and different concentration gradients of cisplatin CDDP was added to each well, and then the cells were placed in an incubator for further incubation.

[0044] (4) After incubation for 48 hours, 20 μL of MTT (5 mg / mL) was added to each well and incubated in a 37°C incubator for another 4 hours. The supernatant was removed and 150 μL of dimethyl sulfoxide (DMSO) was added to each well. A was detected using an enzyme-linked immunosorbent assay (ELISA). 570nm , calculate the cell proliferation inhibition rate and find IC 50 The MTT test results of the compounds lichenic acid, Ir-NH2, Ir-UA and cisplatin CDDP are shown in Table 1.

[0045] Table 1

[0046]

[0047]

[0048] The results showed that the complex Ir-UA had a higher proliferation inhibitory activity against A549 than the natural small molecule lichenic acid, compound Ir-NH2 and CDDP, indicating that the anti-tumor activity of the complex Ir-UA modified with lichenic acid was improved; at the same time, the complex Ir-UA had lower toxicity to normal cells.

[0049] Example 2

[0050] Localization of the cyclometallated iridium (III) complex Ir-UA prepared in Example 1 in cells.

[0051] Methods: A549 cells were seeded in 35mm Corning laser confocal culture dishes. When the cell density grew to 70%, 10μM Ir-UA was added and treated for 6h. The culture medium was aspirated and the cells were washed twice with PBS. 500μL of the prepared mitochondrial green fluorescent probe was added and incubated in a 37℃ incubator for 30min. The probe was aspirated and the cells were washed twice with PBS. Fresh preheated serum-free culture medium was replaced and the cells were immediately observed under a confocal microscope.

[0052] Example 1 Synthesized cyclometallated iridium (III) complex Ir-UA intracellular localization Figure 1 As shown, the results showed that the cyclometallated iridium (III) complex Ir-UA can be taken up by A549 cells through the cell membrane in a large amount in a short period of time, and is mainly distributed in the mitochondria with a colocalization coefficient of 0.91, indicating that Ir-UA has excellent ability to target mitochondria.

[0053] Example 3

[0054] Application of the cyclometallated iridium (III) complex Ir-UA prepared in Example 1 to induce the generation of intracellular reactive oxygen species:

[0055] Method 1: Confocal microscopy was used to detect ROS in cancer cells. A549 cells were seeded in 35 mm Corning laser confocal culture dishes. When the cell density reached 70%, they were treated with 10 μM Ir-UA and Ir-NH2, respectively, for 24 hours. The cells were then stained with 10 μM H2DCFH-DA in serum-free medium at 37°C for 30 minutes in the dark and immediately observed using a confocal microscope with an excitation wavelength of 488 nm and an emission wavelength of 530 ± 20 nm.

[0056] Method 2: Flow cytometry was used to detect ROS in tumor cells. A549 cells were treated with 10 μM Ir-UA and 10 μM Ir-NH2 for 24 hours. The cells were then stained with 10 μM H2DCFH-DA in serum-free medium at 37°C for 30 minutes in the dark. The cells were centrifuged and the supernatant discarded. The cells were washed three times with serum-free medium to remove H2DCFH-DA that had not entered the cells. Within half an hour of harvesting the cells, green fluorescence intensity was measured by flow cytometry using an excitation wavelength of 488 nm and an emission wavelength of 530 ± 20 nm. The mean green fluorescence intensity was analyzed using FlowJo 7.6 software (Tree Star, OR, USA).

[0057] The results of the cyclometalated iridium (III) complex Ir-UA on the generation of intracellular reactive oxygen species are as follows Figure 2 The results showed that compared with the control group, both flow cytometry and confocal microscopy showed that green fluorescence was significantly enhanced after Ir-UA treatment, indicating that the complex Ir-UA effectively induced an increase in the content of intracellular reactive oxygen species.

[0058] Example 4

[0059] Application of the cyclometallated iridium (III) complex Ir-UA prepared in Example 1 to induce changes in intracellular mitochondrial membrane potential:

[0060] Method 1: Confocal microscopy was used to examine changes in mitochondrial membrane potential in tumor cells. A549 cells were seeded in 35 mm Corning laser confocal microscopy dishes. When the cell density reached 70%, they were treated with 10 μM Ir-UA and 10 μM Ir-NH2 for 24 hours. The cells were then stained with pre-prepared JC-1 working solution at 37°C in the dark for 30 minutes and immediately observed using a confocal microscope.

[0061] Method 2: Flow cytometry was used to examine changes in mitochondrial membrane potential in tumor cells. Cell culture medium containing 5, 10, and 15 μM Ir-UA and 15 μM Ir-NH2 was added to 6-well plates containing well-formed and normally growing A549 cells. After 24 hours of drug treatment, the cells were harvested, washed with PBS, and then stained with the prepared JC-1 working solution for 30 minutes. The cells were then washed with buffer and resuspended. The samples were immediately analyzed using a BD FACSverse flow cytometer, and the results were processed and analyzed using FlowJo 7.6 software. The fluorescence channels used for detection were λex = 488 nm, λem = 530 ± 30 nm; and λex = 488 nm, λem = 590 ± 30 nm.

[0062] The results of the cyclometallated iridium (III) complex Ir-UA on the changes in mitochondrial membrane potential in cells are as follows Figure 3 The results showed that, compared with the control group, green fluorescence was significantly enhanced and red fluorescence was significantly weakened after treatment with the Ir-UA complex, indicating that the Ir-UA complex can effectively induce a decrease in mitochondrial membrane potential. Flow cytometry also showed the same results.

[0063] Example 5

[0064] Application of the cyclometallated iridium (III) complex Ir-UA prepared in Example 1 to inducing autophagy inhibition in A549 cells:

[0065] Methods: Western blotting (WB) was used to detect changes in autophagy protein levels. Pre-prepared cell culture medium containing the complexes Ir-UA (5, 10, and 15 μM), lichenic acid (15 μM), and Ir-NH2 (15 μM) was added to adherent A549 cells in 100 mm culture dishes. After 24 hours of drug treatment, cells were harvested by centrifugation, washed with PBS to remove residual serum, and lysed with Biyuntian RIPA strong lysis buffer containing PMSF for 20 minutes. The cells were maintained at 4°C throughout the entire process to ensure protein denaturation. Following centrifugation at 13,400 rpm for 20 minutes, the supernatant was collected as the total protein sample required for the experiment. Protein concentrations in these samples were determined using a BCA protein assay kit. The expression levels of different proteins within the samples were determined by SDS-PAGE gel electrophoresis. After the gel is prepared, add the same volume of protein sample to each well for gel electrophoresis. Stop electrophoresis immediately after proper separation. Use a wet method to transfer the target protein to the PVDF membrane. After completion, place the membrane in a solution containing 5% skim milk powder for blocking for 2 hours. Dilute the primary antibody with skim milk powder according to the corresponding ratio according to the instructions for use of the antibody. Place the blocked membrane in the primary antibody incubation solution and incubate it at room temperature for a period of time to allow it to specifically bind to the target protein. After completion, wash with PBST (5×6min / time). Place the washed membrane in the pre-prepared secondary antibody incubation solution and incubate it for a period of time to allow it to bind to the primary antibody. Wash it with PBST as well. Prepare an equal volume of ECL developer, cover it on the PVDF membrane, and use a chemiluminescence imaging system to capture it after 2 minutes of treatment.

[0066] The experimental results of the cyclometalated iridium Ir-UA complex Ir-UA inducing the expression of autophagy-related proteins in A549 cells are as follows Figure 4 The results showed that compared with the untreated control group, the expression of mitochondrial autophagy-related proteins PINK1 and Parkin was significantly upregulated after cells were treated with the complex Ir-UA. At the same time, the levels of autophagy marker proteins LC3-II and p62 increased in a concentration-dependent manner, indicating that the complex Ir-UA can induce autophagy inhibition in A549 cells.

[0067] Example 6

[0068] Application of the cyclometallated iridium (III) complex Ir-UA prepared in Example 1 to inducing the expression of ATF3 and PD-L1 in A549 cells:

[0069] Method: Same as the method in Example 5

[0070] The experimental results of the cyclometallated iridium (III) complex Ir-UA on the induction of ATF3 and PD-L1 expression in A549 cells are as follows Figure 5 The results showed that compared with the control group without drug treatment, the expression of ATF3 and PD-L1 was significantly upregulated after cells were treated with the complex Ir-UA, indicating that the complex Ir-UA can induce the overexpression of PD-L1 in A549 cells.

[0071] Example 7

[0072] Anti-tumor application of the cyclometallated iridium (III) complex Ir-UA prepared in Example 1 in combination with anti-PD-L1 administration:

[0073] Methods: Mouse Lewis lung cancer (LLC) cells (approximately 2×10 7 / mL) were inoculated subcutaneously on the back of mice to establish a subcutaneous tumor model. 3 At the time of the study, LLC tumor-bearing mice were randomly divided into 4 groups (n=5): control group, anti-PD-L1, Ir-UA, Ir-UA + anti-PD-L1, of which PBS was injected as the control group. Each group was injected with PBS and Ir-UA at a dose of 5 mg / kg, once every 2 days, for a total of 5 doses. Subsequently, 75 μg of anti-PD-L1 was injected intraperitoneally on the same schedule. In addition, the tumor size and mouse weight were measured every 2 days. When the tumor volume of the control group mice reached approximately 1500 mm 3 At 4 hr, all mice were euthanized and their tumors were harvested. The tumor counts, tumor inhibition rates, and body weights of mice in each group were shown in Table 1. Figure 6 The results showed that the tumor inhibition effect of single anti-PD-L1 was poor, but when Ir-UA and anti-PD-L1 were administered simultaneously, the tumor inhibition effect was the best, indicating that the complex Ir-UA can enhance the efficacy of anti-PD-L1.

Claims

1. A lichenic acid-modified cyclometallated iridium (III) complex, characterized in that: The structural formula of the complex is shown below: 。 2. The method for synthesizing the lichenic acid-modified cyclometallated iridium (III) complex according to claim 1, characterized in that: Specifically, under an inert atmosphere, a lichenic acid-modified bipyridine ligand and a cyclometallated iridium dimer are heated under reflux in a mixed solution of dichloromethane and methanol, the solvent is removed by distillation under reduced pressure, and the crude product is replaced with NH4PF6 to obtain a crude product, which is then separated and purified by column chromatography to obtain a lichenic acid-modified cyclometallated iridium (III) complex; The structural formula of the lichenic acid-modified bipyridine ligand is as follows: ； The structural formula of the cyclometallated iridium dimer is shown below: 。 3. The method for synthesizing the lichenic acid-modified cyclometallated iridium (III) complex according to claim 2, characterized in that: The preparation method of the lichenic acid-modified bipyridine ligand is specifically as follows: under an inert atmosphere, lichenic acid and a bridging ligand 4-methyl-4'-aminomethyl-2,2'-bipyridine are dissolved in anhydrous ethanol, the mixture reacts at room temperature to obtain a crude product, and the crude product is separated and purified by column chromatography.

4. The method for synthesizing the lichenic acid-modified cyclometallated iridium (III) complex according to claim 3, characterized in that: The molar ratio of lichenic acid to 4-methyl-4'-aminomethyl-2,2'-bipyridine is 2.5-2.6:

3.

5. The method for synthesizing the lichenic acid-modified cyclometallated iridium (III) complex according to claim 2, characterized in that: The inert atmosphere utilizes nitrogen or argon as a protective gas.

6. The method for synthesizing the lichenic acid-modified cyclometallated iridium (III) complex according to claim 2, characterized in that: The reaction molar ratio of the lichenic acid-modified bipyridine ligand to the cyclometallated iridium dimer is 2:1-1.

2.

7. The method for synthesizing the lichenic acid-modified cyclometallated iridium (III) complex according to claim 2, characterized in that: In the mixed solution, the volume ratio of dichloromethane to methanol is 2:1~1.

5.

8. The method for synthesizing the lichenic acid-modified cyclometallated iridium (III) complex according to claim 2, characterized in that: The reflux reaction time is 12~13h; the reaction temperature is 45~48℃.

9. Use of the lichenic acid-modified cyclometallated iridium (III) complex according to claim 1 in the preparation of anti-tumor drugs.

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