A double Schiff base iron complex and its preparation method and application

Abstract

The present invention relates to the field of anti-tumor drugs, and in particular to a bis-Schiff base iron complex and a preparation method and application thereof. Five 5-halogenated salicylaldehyde diamine bis-Schiff base ligands are synthesized by condensation polymerization of 1,3-propylenediamine or its derivatives with 5-halogenated salicylaldehyde, and these ligands are reacted with Fe(II) to obtain Fe(III) complexes 1-5, and the complexes 1-5 have good anti-cancer activity and selectivity.

Description

Technical Field

[0001] The invention relates to the field of anti-tumor drugs, and in particular to a double Schiff base iron complex and a preparation method and application thereof. Background Art

[0002] Cancer is a disease caused by the loss of normal growth regulation mechanisms of cells in the human body. It is one of the diseases with the highest mortality rate in the world. Since tumor cells and normal cells have similar DNA and major metabolic pathways, traditional chemotherapy drugs will attack normal cells while preventing cancer cell DNA replication or cell division, resulting in serious toxic side effects. Although cisplatin is one of the earliest metal anticancer drugs used in clinical practice and is widely used in the treatment of various cancers, cisplatin-based therapies have serious defects such as low selectivity and large toxic side effects. In view of this embarrassing dilemma, the development of new, efficient and low-toxic metal-based anticancer drugs is imminent. In order to give full play to the synergistic effect of metal ions and ligands and reduce the toxic side effects of metal ions themselves, the selection of metal ions is very critical. Iron, as an essential trace element for the human body, plays a vital role in fully exerting the functions of human blood and various organs. However, the research and development of iron-based anticancer drugs is relatively lacking, and the effect is obviously insufficient. Therefore, in-depth research is needed to improve the efficacy of iron-based metal anticancer drugs and explore their mechanism of action. Summary of the invention

[0003] The purpose of the present invention is to provide a bis-Schiff base iron complex and a preparation method and application thereof in view of the above-mentioned problems. The bis-Schiff base iron complex has good anticancer activity and selectivity.

[0004] A bis-Schiff base iron complex, the complex is a 5-halogenated salicylaldehyde condensed 1,3-propylenediamine derivative bis-Schiff base Fe complex, the chemical formula of which is C 54 H 54 Br6Fe2N6O9, C 38 H 38 Cl4Fe2N4O6、C 38 H 38 Br4Fe2N4O6, C 34 H 26 Cl4Fe2N4O6 or C 34 H 25 Br4Fe2N4O6; 54 H 54 The structural formula of Br6Fe2N6O9 is (I), wherein C 38 H 38 Cl4Fe2N4O6、C 38 H 38The structural formula of Br4Fe2N4O6 is (II), wherein C 34 H 26 Cl4Fe2N4O6、C 34 H 25 The structural formula corresponding to Br4Fe2N4O6 is (III),

[0005]

[0006] In the structural formula (Ⅰ-Ⅲ), R 2 =Br or Cl.

[0007] The present invention provides a preparation method of the complex, comprising the following steps: weighing H2L and FeCl2·4H2O in a molar ratio of 1:1, dissolving them in a mixed solvent, and then reacting them under heating conditions, cooling them to room temperature after the reaction is completed, and collecting crystals to obtain a target product, namely the bis-Schiff base iron complex;

[0008] Wherein, the structural formula of H2L is shown in formula (IV):

[0009]

[0010] In formula (IV), R 1 =H, Me or OH; R 2 =Br or Cl;

[0011] The R 1 =H, R 2 =Br, recorded as H2L 1 ; or R 1 =Me, R 2 =Cl, recorded as H2L 2 ; or R 1 =Me, R 2 =Br is recorded as H2L 3 ; or R 1 =OH, R 2 =Cl, recorded as H2L 4 ; or R 1 =OH, R 2 =Br, recorded as H2L 5 ;

[0012] The mixed solvent is a composition in which N,N-dimethylformamide and anhydrous methanol are mixed in a volume ratio of 1:3; when H2L is H2L 1 、H2L 2 、H2L 3 When adding the mixed solvent, triethylamine is added to adjust the pH of the system to be alkaline, corresponding to Example 1-3.

[0013] In the above preparation method, the H2L is prepared by condensation reaction using 1,3-propylenediamine or its derivatives and 5-halogenated salicylaldehyde as raw materials.

[0014] Furthermore, the derivative of 1,3-propylenediamine is 2-methyl-1,3-propylenediamine or 2-hydroxy-1,3-propylenediamine; and the 5-halogenated salicylaldehyde is 5-chloro-salicylaldehyde or 5-bromo-salicylaldehyde.

[0015] In the above preparation method, the reaction temperature of the reaction is 80°C-85°C, and the reaction time is 48h-72h.

[0016] In addition, the present invention also provides the application of the bis-Schiff base iron complex in anti-tumor activity.

[0017] In summary, due to the adoption of the above technical solution, the present invention has the following beneficial effects:

[0018] 1. The present invention uses 1,3-propylenediamine or its derivatives to condense with 5-halogenated salicylaldehyde to synthesize five 5-halogenated salicylaldehyde diamine bis-Schiff base ligands, and reacts these ligands with Fe(II) to obtain Fe(III) complexes 1-5 respectively. The anticancer effects of the complexes 1-5 are adjusted by the halogen groups (-Cl and -Br) on the 5-halogenated salicylaldehyde and the 2-substituents (-H, -Me, -OH) on the 1,3-propylenediamine.

[0019] 2. In vitro cell experiments show that the complexes 1-5 prepared by the present invention have good anti-cancer activity, especially showing the best anti-tumor effect on Hep-G2 cell line. 50 The values ​​were 1.59±1.69μM, 8.34±0.52μM, 2.95±0.73μM, 10.97±2.01μM and 5.75±0.75μM, respectively. Complexes 1-5 had better antitumor effects on Hep-G2 cell lines than cisplatin.

[0020] 3. In vivo antitumor activity studies have shown that the relative tumor proliferation rate (T / C) of the complex prepared in Example 4 (complex 4) is 38.3%, and the T / C of cisplatin is 35.4%, that is, the antitumor activity of complex 4 on nude mice bearing Hep-G2 xenografts of human liver cancer cell line is equivalent to that of cisplatin, but no weight loss was observed in mice treated with the complex, while the weight of mice treated with cisplatin was significantly reduced, indicating that the treatment with the complex has good safety and few toxic side effects; compared with the control group, the tumor weight and volume after complex treatment were significantly reduced, and there was no obvious effect on the major organs in the body, indicating that the complex has a good tumor treatment effect, and at the same time has low toxicity to normal cells, reflecting excellent cancer cell selectivity, and has certain application prospects in the development of corresponding drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 It is a crystal structure diagram of the complex prepared in Examples 1-5 of the present invention.

[0022] Figure 2 This is a comparison chart of the anti-tumor effects of the complexes prepared in Example 1, Example 4, and Example 5 of the present invention on nude mouse Hep-G2 xenograft tumors.

[0023] Figure 3 This is a comparison of the histological morphology of the main organs of mice in each group after treatment. DETAILED DESCRIPTION

[0024] In order to express the present invention more clearly, the present invention is further described below through specific examples.

[0025] The present application provides a bis-Schiff base iron complex, which is a 5-halogenated salicylaldehyde condensed 1,3-propylenediamine derivative bis-Schiff base Fe complex, and its chemical formula is C 54 H 54 Br6Fe2N6O9, C 38 H 38 Cl4Fe2N4O6、C 38 H 38 Br4Fe2N4O6, C 34 H 26 Cl4Fe2N4O6 or C 34 H 25 Br4Fe2N4O6;

[0026] The C 54 H 54 The structural formula of Br6Fe2N6O9 is (I), wherein C 38 H 38 Cl4Fe2N4O6、C 38 H 38 The structural formula of Br4Fe2N4O6 is (II), wherein C 34 H 26 Cl4Fe2N4O6、C 34 H 25 The structural formula corresponding to Br4Fe2N4O6 is (III),

[0027]

[0028] In the structural formula (Ⅰ-Ⅲ), R 2 =Br or Cl.

[0029] The synthetic route of the complex is as follows:

[0030]

[0031] 1. Preparation Example

[0032] Example 1

[0033] Weigh H2L 1 (0.0221 g, 0.05 mmol) and FeCl2·4H2O (0.0099 g, 0.05 mmol) were placed in a round-bottom glass tube with a length of 190 mm and an inner diameter of 10 mm, and a mixed solvent consisting of 0.5 mL of N,N-dimethylformamide (DMF) and 1.5 mL of anhydrous methanol was added, and 30 μL of triethylamine was added. After ultrasonic dissolution, the round-bottom glass tube was sealed and placed in an oven at 80°C for 72 hours. After the reaction was completed, it was placed in an incubator to slowly cool to room temperature, and the precipitated black long strip crystals, namely C 51 H 42 Br6Fe2N6O6, yield 31.67%.

[0034] The H2L 1 It is prepared by condensation reaction of 1,3-propylenediamine and 5-bromo-salicylaldehyde, which is the existing technology.

[0035] After the obtained black long strip crystals were fully washed, clean and well-shaped crystals were selected for single crystal diffraction test, and the test results were analyzed for elements, as follows:

[0036] C 54 H 54 Br6Fe2N6O9:C,42.61;H,3.58;N,5.52%.Found:C,42.76;H,2.84;N,5.72%.IR(cm -1 ,KBr):3443s,2917w,1623s,1527m,1454s,1367m,1291s,1176w,1034m,823m,644w,531w.

[0037] Example 2

[0038] Weigh H2L 2(0.0183 g, 0.05 mmol) and FeCl2·4H2O (0.0099 g, 0.05 mmol) were placed in a round-bottomed glass tube with a length of 190 mm and an inner diameter of 10 mm, and a mixed solvent consisting of 0.5 mL of N,N-dimethylformamide (DMF) and 1.5 mL of anhydrous methanol was added, and 40 μL of triethylamine was added. After ultrasonic dissolution, the round-bottomed glass tube was sealed and placed in an oven at 85°C for 48 hours. After the reaction was completed, it was placed in an incubator to slowly cool to room temperature, and the precipitated black long strip crystals, namely C 38 H 38 Cl4Fe2N4O6, with a yield of 33.91%.

[0039] The H2L 2 The invention is prepared by condensation reaction of 2-methyl-1,3-propylenediamine and 5-chloro-salicylicaldehyde, which is the prior art.

[0040] After the obtained black long strip crystals were fully washed, clean and well-shaped crystals were selected for single crystal diffraction test, and the test results were analyzed for elements, as follows:

[0041] C 38 H 38 Cl4Fe2N4O6:C,50.70;H,4.25;N,6.22%.Found:C,50.59;H,4.46;N,6.03%.IR (cm -1 ,KBr):3455s,2918w,1624s,1533w,1453m,1301w,1171w,1031w,1034m,795w,708w,649w,538w.

[0042] Example 3

[0043] Weigh H2L 3 (0.0227 g, 0.05 mmol) and FeCl2·4H2O (0.0099 g, 0.05 mmol) were placed in a round-bottomed glass tube with a length of 190 mm and an inner diameter of 10 mm, and a mixed solvent consisting of 0.5 mL of N,N-dimethylformamide (DMF) and 1.5 mL of anhydrous methanol was added, and 50 μL of triethylamine was added. After ultrasonic dissolution, the round-bottomed glass tube was sealed and placed in an oven at 80°C for 72 hours. After the reaction was completed, it was placed in an incubator to slowly cool to room temperature, and the precipitated black long strip crystals, namely C 38 H 38 Br4Fe2N4O6, with a yield of 28.89%.

[0044] The H2L 3The invention is prepared by condensation reaction of 2-methyl-1,3-propanediamine and 5-bromo-salicylicaldehyde, which is prior art.

[0045] After the black long strip crystals were fully washed, clean crystals with good shapes were selected for single crystal diffraction test, and elemental analysis was performed on the test results, as follows:

[0046] C 38 H 38 Br4Fe2N4O6:C,42.34;H,3.55;N,5.20%.Found:C,42.17;H,3.71;N,5.47%.IR (cm -1 ,KBr):3428s,2910w,1617s,1527w,1453m,1373w,1288s,1171w,1040w,813w,698w,634w,538w.

[0047] Example 4

[0048] Weigh H3L 4 (0.0183 g, 0.05 mmol) and FeCl2·4H2O (0.0099 g, 0.05 mmol) were placed in a round-bottomed glass tube with a length of 190 mm and an inner diameter of 10 mm, and a mixed solvent consisting of 0.5 mL of N,N-dimethylformamide (DMF) and 1.5 mL of anhydrous methanol was added. After ultrasonic dissolution, the round-bottomed glass tube was sealed and placed in an oven at 80°C for 72 h. After the reaction was completed, it was placed in an incubator to slowly cool to room temperature, and the precipitated black long strip crystals, namely C 34 H 26 Cl4Fe2N4O6, with a yield of 24.62%.

[0049] The H2L 4 The invention is prepared by condensation reaction of 2-hydroxy-1,3-propylenediamine and 5-chloro-salicylicaldehyde, which is the prior art.

[0050] After the black long strip crystals were fully washed, clean crystals with good shapes were selected for single crystal diffraction test, and elemental analysis was performed on the test results, as follows:

[0051] C 36 H 32 Cl4Fe2N4O7: C, 48.79; H, 3.64; N, 6.32%. Found: C, 48.49; H, 3.38; N, 6.54%. IR (cm -1,KBr):3420w,2896w,1639s,1534s,1461m,1373m,315s,1178m,1041w,821w,708w,649w,545w.

[0052] Example 5

[0053] Weigh H3L 5 (0.0228 g, 0.05 mmol) and FeCl2·4H2O (0.0099 g, 0.05 mmol) were placed in a round-bottomed glass tube with a length of 190 mm and an inner diameter of 10 mm, and a mixed solvent consisting of 0.5 mL of N,N-dimethylformamide (DMF) and 1.5 mL of anhydrous methanol was added. After ultrasonic dissolution, the round-bottomed glass tube was sealed and placed in an oven at 80°C for 72 hours. After the reaction was completed, it was placed in an incubator to slowly cool to room temperature, and the precipitated black long strip crystals, namely C 34 H 25 Br4Fe2N4O6, yield 19.06%.

[0054] The H2L 5 The invention is prepared by condensation reaction of 2-hydroxy-1,3-propylenediamine and 5-bromo-salicylicaldehyde, which is the prior art.

[0055] After the black long strip crystals were fully washed, clean crystals with good shapes were selected for single crystal diffraction test, and elemental analysis was performed on the test results, as follows:

[0056] C 36 H 32 Br4Fe2N4O7:C,40.64;H,3.03;N,5.27%.Found:C,40.35;H,2.88;N,5.49%.IR (cm -1 ,KBr):3428w,2894w,1632s,1528w,1461m,1367m,1307s,1170m,1034m,914w,823m,719m,644m,546m.

[0057] The complexes prepared in Examples 1-5 are respectively referred to as Complexes 1-5. The crystal structures of Complexes 1-5 are as follows: Figure 1 Its crystallographic data are shown in Table 1.

[0058] Table 1 Crystallographic data of complexes 1-5

[0059]

[0060] Through the above characterization, it was determined that the above collected crystals were the complex described in the present invention.

[0061] 2. Antitumor Activity Experiment

[0062] In vitro antitumor activity experiments were conducted on complexes 1-5 and related ligands, and in vivo tumor inhibition experiments were conducted on complexes 1, 4 and 5. The details are as follows:

[0063] 1. Cell inoculation and culture

[0064] The tumor cell lines selected for the experiment by the present invention are: human bladder cancer T-24 cells, human liver cancer Hep-G2 cells, human cervical cancer Hela cells, gastric cancer cells MGC-803, non-small cell lung cancer A549 cells, ovarian cancer cells SK-OV-3, normal liver cells HL-7702 and normal lung cells Wi-38. Among them, Hela is grown in RPMI-1640 culture medium containing 10% fetal bovine serum and 1% penicillin-streptomycin double antibody. T-24, Hep-G2, A549, MGC-803, HL-7702, SK-OV-3, Wi-38 are grown in DMEM culture medium containing 10% fetal bovine serum and 1% penicillin-streptomycin double antibody. All cells were cultured in an incubator at 37°C and 5% CO2. When the cells grew to 80% to 90% of the area of ​​the culture flask, they were digested with trypsin and passaged 3 to 5 times. Cells with good growth conditions and in the logarithmic phase were used for experiments.

[0065] 2. Cell growth inhibition assay (MTT method)

[0066] The present invention adopts MTT method to carry out cell growth inhibition experiment, and MTT method is a method for detecting cell proliferation and vitality and drug cytotoxicity. MTT reagent can pass through the cell membrane and the inner membrane of the mitochondria of living cells, which may be due to its positive charge and its lipophilic structure, and is reduced to formazan by metabolically active cells. The color development characteristics of this redox chemical reaction provide a method for determining the intracellular formazan output based on colorimetry. MTT analysis is usually carried out after cells are incubated with MTT for several hours. The purple-blue precipitated formazan produced is then dissolved by DMSO. Subsequently, the absorbance (OD) at the wavelength (570nm and 630nm) where MTT produces the most formazan absorption is measured by a microplate reader, and finally the calculation of the cell proliferation inhibition rate is performed.

[0067] Specific experimental steps:

[0068] (1) Take cells in the logarithmic growth phase, discard the culture medium, wash twice with PBS, add 0.6-1.2 mL of trypsin for digestion, observe the cell morphology under a microscope, and wait until the cell morphology becomes round, indicating that digestion is complete. Then immediately add culture medium and blow off the attached cells.

[0069] (2) Add the diluted cell solution to the sample tank according to the ratio of 12 mL of culture medium and 2 mL of cell stock solution per 96-well plate, and mix well. Use a pipette to transfer 180 μL of cell solution to the 96-well plate. Add 200 μL of PBS to the wells around the 96-well plate. Then gently shake the 96-well plate to evenly distribute the cells, and finally place it in a cell culture incubator for incubation.

[0070] (3) After the cells grew to 80%, the diluted complexes prepared in Examples 1-5 were added at different concentrations. Six concentration gradients (including blank control) were set for each compound. Five experimental controls were performed in parallel. The cells were placed in the incubator and incubated for 48 h.

[0071] (4) After 48 h, add 10 μL of MTT to each well. After incubation for 4-6 h, pour out all the solution in the well plate. Use a spray gun to add 100 μL of DMSO to each well, and then place it on an oscillator for 5 min to fully dissolve the blue-purple formazan precipitate.

[0072] (5) Use an ELISA reader to measure the absorbance of the well plate at 570 nm and 630 nm, obtain the difference between the two, and finally calculate the IC value of the drug on the cells. 50 value.

[0073] The experimental results are shown in Table 2:

[0074] Table 2 The half-inhibitory concentration (IC) of complexes 1-5 and ligands on different tumor cell lines 50 , μM)

[0075]

[0076] As shown in Table 2, the ligand H2L 1 -H3L 5 The complexes 1-5 did not show good antitumor activity and selectivity on the tested cell lines. In contrast, the cytotoxicity of complexes 1-5 was much lower than that of normal cell lines, which means that these complexes 1-5 have obvious antitumor selectivity. In addition, complexes 1-5 showed the best antitumor effect on the Hep-G2 cell line, with an IC 50 The values ​​were 1.59±1.69, 8.34±0.52, 2.95±0.73, 10.97±2.01 and 5.75±0.75 μM, respectively. This indicates that complexes 1-5 have better antitumor effects on Hep-G2 cell lines than cisplatin and have good antitumor activity.

[0077] 3. In vivo tumor inhibition experiment

[0078] To establish a nude mouse subcutaneous tumor model, the injection site was selected at 0.3 cm from the back of the right forelimb armpit of the nude mouse. Before injection, the site was disinfected with iodine cotton balls, and then 200 μL of a 2×10 6 After mixing the cell suspension of 10 cells / mL, pierce the skin of the nude mouse with the syringe needle, slightly lift the needle and move it to the injection site, and slowly inject the cell suspension. After the injection, press the needle hole with a sterile cotton ball, and dispose of the experimental equipment and waste harmlessly.

[0079] Grouping and drug intervention: When the nude mouse tumor grows to about 100 mm 3 At the same time, nude mice with good growth and uniform size were selected and randomly divided into treatment group and control group (n=5 in each group). In the treatment group, the dosage of the drug was adjusted according to the IC50 value in the in vitro experiment and the effect of the in vivo experiment, and the dosage of complex 1 was determined to be 12.5 mg / kg, and the dosage of complex 4 and complex 5 was 30 mg / kg; and the dosage of cisplatin was 3 mg / kg according to the general standard, and intravenously injected once a day for 14 days. The control group was given 5% (v / v) DMSO saline.

[0080] Figure 2 (a) shows the effect of the complex on the tumor volume of nude mice, (b) shows the effect of the complex on the body weight of tumor-bearing nude mice, (c) shows the change of tumor weight in nude mice, and (d) shows the actual photos of tumor changes in the control group and the treatment group. (**P<0.01)

[0081] like Figure 2 As shown, the relative tumor proliferation rate (T / C) of complex 1 is 50.1%, the T / C of complexes 4 and 5 are 38.3% and 57.4% respectively, and the T / C of cisplatin is 35.4%. The tumor volume of the treatment group was significantly reduced. The antitumor activity of complex 4 on nude mice bearing Hep-G2 xenografts of human liver cancer cell line was almost equivalent to that of cisplatin. No weight loss was observed in mice treated with the complexes, while the weight of mice treated with cisplatin was significantly reduced, indicating that the complex treatment has good safety and few toxic side effects. Compared with the control group, the tumor weight and volume after complex treatment were significantly reduced, indicating that the complex has a good tumor treatment effect. In addition, Figure 3 It can be seen that after treatment with the complex, there was no obvious effect on the major organs of the mice.

[0082] The above test experiments indicate that the complex prepared by the present invention has a good tumor treatment effect, low toxicity to normal cells, and excellent cancer cell selectivity, and has a certain application prospect in the development of corresponding drugs.

[0083] The above description is a detailed description of the preferred feasible embodiments of the present invention, but the embodiments are not intended to limit the scope of the patent application of the present invention. All equivalent changes or modified changes completed under the technical spirit suggested by the present invention should fall within the patent scope covered by the present invention.

Claims

1. A bis-Schiff base iron complex, characterized in that: The complex is a Fe complex of a 5-halogenated salicylaldehyde condensed 1,3-propylenediamine derivative bis-Schiff base, and its chemical formula is C 54 H 54 Br6Fe2N6O9, C 38 H 38 Cl4Fe2N4O6、C 38 H 38 Br4Fe2N4O6, C 34 H 26 Cl4Fe2N4O6 or C 34 H 25 Br4Fe2N4O6; 54 H 54 The structural formula corresponding to Br6Fe2N6O9 is formula (I), wherein C 38 H 38 Cl4Fe2N4O6、C 38 H 38 The structural formula of Br4Fe2N4O6 is (II), wherein C 34 H 26 Cl4Fe2N4O6、C 34 H 25 The structural formula corresponding to Br4Fe2N4O6 is (III), In the structural formula (Ⅰ-Ⅲ), R 2 =Br or Cl.

2. The method for preparing a bis-Schiff base iron complex according to claim 1, characterized in that: Weigh H2L and FeCl2·4H2O in a molar ratio of 1:1, dissolve them in a mixed solvent, and then react them under heating conditions. After the reaction is completed, cool them to room temperature, collect crystals, and obtain the target product, i.e., the bis-Schiff base iron complex; Wherein, the structural formula of H2L is shown in formula (IV): In formula (IV), R 1 =H, Me or OH; R 2 =Br or Cl; The R 1 =H, R 2 =Br, recorded as H2L 1 ; or R 1 =Me, R 2 =Cl, recorded as H2L 2 ; or R 1 =Me, R 2 =Br is recorded as H2L 3 ; or R 1 =OH, R 2 =Cl, recorded as H2L 4 ; or R 1 =OH, R 2 =Br, recorded as H2L 5 ; The mixed solvent is a composition in which N,N-dimethylformamide and anhydrous methanol are mixed in a volume ratio of 1:3; when H2L is H2L 1 、H2L 2 、H2L 3 When adding the mixed solvent, triethylamine is added to adjust the pH of the system to be alkaline.

3. The preparation method according to claim 2, characterized in that: The H2L is prepared by condensation reaction using 1,3-propylenediamine or its derivatives and 5-halogenated salicylaldehyde as raw materials.

4. The preparation method according to claim 3, characterized in that: The derivative of 1,3-propylenediamine is 2-methyl-1,3-propylenediamine or 2-hydroxy-1,3-propylenediamine; the 5-halogenated salicylaldehyde is 5-chloro-salicylaldehyde or 5-bromo-salicylaldehyde.

5. The preparation method according to claim 2, characterized in that: The reaction temperature of the reaction is 80°C-85°C, and the reaction time is 48h-72h.

6. Use of the bis-Schiff base iron complex according to claim 1 in the preparation of drugs with anti-tumor activity.

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