CN107446002B - Nickel(II) nitrate chelate with 1-pyridine-6-methoxy-β-carboline as ligand and its synthesis method and application - Google Patents

Abstract

The invention discloses a nickel (II) nitrate chelate taking 1-pyridine-6-methoxyl- β -carboline as a ligand, a synthesis method and application thereof, wherein the structural formula of the nickel (II) nitrate chelate is shown as the following formula (I), and the preparation method comprises the following steps of dissolving a compound shown as the following formula (II) and nickel nitrate hexahydrate in a polar solvent for coordination reaction to obtain a target product.

Description

Nickel(II) nitrate chelate with 1-pyridine-6-methoxy-β-carboline as ligand and the same Synthetic methods and applications

technical field

The invention relates to the technical field of medicine, in particular to a nickel nitrate (II) chelate compound using 1-pyridine-6-methoxy-β-carboline as a ligand and a synthesis method and application thereof.

Background technique

Malignant tumors (commonly known as cancer) are one of the major diseases that endanger human health. The formation of cancer is a complex, multi-step process that involves mutations in a series of important regulatory genes that cause cancer cells to grow rapidly, cause damage to healthy organs, and spread throughout the patient's body at an advanced stage, eventually leading to the patient's death. More than 7 million people die from malignant tumors every year in the world, so it is urgent to prevent and treat cancer.

Chemotherapy for malignant tumors can be traced back to the 1940s, and it was found that Nitrogenmustard and the folic acid analog, Aminopterin, have significant tumor growth inhibitory activity. Carboline alkaloids are a class of tricyclic compounds with a pyridoindole structure. According to the different positions of the pyridine nitrogen atoms, carboline alkaloids are divided into three categories: α, β, γ, and δ, as shown in the following figure:

At present, the most studied are β-carboline alkaloid compounds. β-Carboline alkaloids are an active ingredient isolated from the Xinjiang medicinal plant Peganum harmala. It has broad-spectrum pharmacological activities, such as anti-anxiety, anti-depression, anti-spasmodic, anti-tumor, anti-malarial, anti-parasitic, anti-AIDS, etc. Camelina officinalis seeds have been used for a long time in Chinese herbal medicine formulations to treat cancer. The structural modification of β-carboline alkaloids has always attracted the attention of researchers. It is generally believed that the planar conjugated structure of most β-carboline alkaloids and the presence of different substituent groups (such as benzyl (-C ₆ H ₅ ), methoxy (-OCH ₃ )) are associated with their antitumor activity significant relationship. At present, the research on β-carboline alkaloids mainly includes the following aspects: firstly, based on the chemical research of natural products, they are found and purified from plants of different families and genera; Alkaloids undergo total synthesis or semi-synthesis, and their structures are modified. In addition, the molecular mechanism of its pharmacological activity (such as antitumor activity) is studied. Such as inserting DNA, inhibiting topoisomerase, inhibiting CDK, etc. However, from the current research progress, the content of β-carboline alkaloids in natural plants is generally relatively low, and the extraction is relatively complicated, which is not conducive to in-depth research on them. Although it has certain advantages, it is limited by the cost of preparation, so the current research on β-carboline alkaloids is still insufficient.

On the other hand, the research of medicinal inorganic chemistry based on medicinal active ligands has become a hot research field in recent years with the vigorous development of bio-inorganic chemistry. As cisplatin, carboplatin and oxaliplatin have become indispensable drugs in cancer chemotherapy, metal chelate antitumor drugs have gradually become a research hotspot. But so far, there are no reports on nickel(II) nitrate chelates using 1-pyridine-6-methoxy-β-carboline alkaloids as ligands and their synthesis methods and applications.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to provide a new nickel (II) nitrate chelate, namely a nickel (II) nitrate chelate using 1-pyridine-6-methoxy-β-carboline as a ligand , and its synthesis methods and applications.

The present invention relates to a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

The synthetic method of compound shown in above-mentioned formula (I) is: take compound shown in following formula (II) and nickel nitrate hexahydrate, dissolve in polar solvent, carry out coordination reaction, namely obtain target product;

The synthetic route of above-mentioned synthetic method is as follows:

The compound shown in the raw material formula (II) involved in the above-mentioned synthesis method participates in the reaction as a ligand, and its chemical name is 1-Pyridine-6-Methoxy-β-Carboline (1-Pyridine-6-Methoxy-β-Carboline ), referred to as LKL. The compound represented by the formula (II) can be prepared by designing a synthetic route by itself, preferably by the following method: using 5-methoxytryptamine and pyridine-2-carbaldehyde as raw materials, adding an acidic substance to catalyze ring closure (ie Pictet -Spengler condensation reaction), the obtained product is then oxidatively dehydrogenated with Pd/C to obtain. The specific synthetic route is as follows:

Reagents: (a) tetrahydrofuran or dichloromethane; (b) xylene or anisole.

The more concrete synthetic method of compound shown in above-mentioned formula (II), comprises the following steps:

①Dissolve 5-methoxytryptamine in tetrahydrofuran or dichloromethane, then add pyridine-2-carboxaldehyde, after mixing, add some acidic substances dropwise, and stir the reaction; after the reaction, adjust the reactant to neutral or Alkaline, extract with ethyl acetate or chloroform, collect the organic phase, and evaporate the solvent to obtain compound 1 as a yellow oily solid;

② Dissolve compound 1 in xylene or anisole, add Pd/C, react under heating conditions, filter the obtained reactant, wash the filter cake, collect the filtrate, spin dry to obtain the crude compound of the compound represented by formula (II) product (ie compound 2).

In the step 1. of the compound synthesis method shown in the above-mentioned formula (II), the ratio of the amount of the material of the raw material 5-methoxytryptamine and pyridine-2-carbaldehyde is usually 1:1.5 or 1:1, preferably pyridine-2-carbaldehyde The molar amount is slightly larger than the amount of 5-methoxytryptamine, so that the reaction proceeds fully. The pH value of the filtrate adopts lye to adjust, and the lye can be ammonia water, or is selected from any one or two or more alkaline substances in sodium acetate, sodium carbonate, sodium phosphate, sodium bicarbonate and potassium carbonate. aqueous solution. Preferably, a saturated sodium bicarbonate solution or an aqueous ammonia solution is used. Preferably, the reactants are adjusted to pH 7-9.

In step ① of the compound method for synthesizing the compound represented by the above formula (II), the acidic substance used may be trifluoroacetic acid, acetic acid, hydrochloric acid or sulfuric acid. The dosage of hydrochloric acid and trifluoroacetic acid is usually 4 to 5 times the volume of pyridine-2-carbaldehyde, if it is acetic acid, the amount added is 6 to 7 times the volume of pyridine-2-carbaldehyde, and if it is sulfuric acid, the amount added is pyridine-2 - 2 to 3 times the volume of formaldehyde, preferably trifluoroacetic acid in this application. The reaction after adding the acidic substance is preferably carried out at normal temperature.

In the step 1. of the compound synthesis method shown in the above formula (II), the raw material 5-methoxytryptamine and pyridine-2-formaldehyde undergo an aldol-amine condensation reaction under acid catalysis to form an intermediate Schiff base, and the Schiff base is in acid. Under the action of , a ring-closure reaction occurs to form compound 1. In the synthesis method, since trifluoroacetic acid is a strong fuming acid, the reaction is preferably carried out under ice bath conditions. Whether the reaction is complete can be detected by thin layer chromatography (TLC), and it is usually appropriate to control the reaction time to be 1 to 2 hours. After the reaction is completed, the solvent must be spin-dried under reduced pressure in the temperature range of 30 to 45°C to prevent side reactions from occurring. The amount of solvent tetrahydrofuran or dichloromethane is suitable for dissolving the raw materials participating in the reaction. Usually, it is calculated on the basis of dissolving 1 mmol 5-methoxytryptamine in 0.5-1 mL of tetrahydrofuran or 0.4-1 mL of dichloromethane.

In step 2 of the compound synthesis method shown in the above formula (II), the amount of Pd/C added is usually 1 to 2 times the amount of compound 1, and the Pd/C can be 5% Pd/C or 10% Pd/C, etc., 10% Pd/C is preferably used in this synthesis method; in this step, the reaction conditions are preferably carried out under the condition of 140-160 °C, and more preferably the reflux reaction is carried out under the condition of 140-160 °C in a reflux device . Whether the reaction is complete can be detected by TLC tracking. Usually, it is more appropriate to control the reaction time to be 12 to 24 hours.

In the step 2. of the compound synthesis method shown in the above-mentioned formula (II), methanol, chloroform and ethyl acetate are usually used to wash the filter cake multiple times, preferably 5 to 10 times; there is no requirement for its washing sequence, preferably methanol first, chloroform Second, ethyl acetate last.

What the above-mentioned method prepares is the crude product of the compound shown in formula (II), in order to further improve the purity of the compound shown in formula (II), it is more conducive to the carrying out of subsequent reactions, preferably the above-mentioned obtained crude product is purified, after the operation It is then used in the synthesis method of the target product of the present invention. The described purification operation is the same as the prior art, specifically, the crude product can be purified by using flash liquid chromatography to obtain the pure compound shown in formula (II); the reagents used in the purification process are composed of ethyl acetate and n-hexane. A mixed solvent composed of alkane in a volume ratio of 3:7 to 3:9, or a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 3:7 to 3:9.

In the synthesis method of the compound represented by the formula (I) of the present invention, the polar solvent is methanol and a compound selected from the group consisting of water, acetone, chloroform, dimethyl sulfoxide, N,N-dimethylformamide and acetonitrile One or a combination of any two or more. The preferred proportion of methanol in the polar solvent is 85-90 v/v%. When the polar solvent contains any two or more of water, acetone, chloroform, dimethyl sulfoxide, N,N-dimethylformamide and acetonitrile, on the premise that their total amount does not exceed 15% Under certain conditions, their ratio can be any ratio. The amount of the polar solvent can be determined according to needs, and usually, 1.5 mmol of nickel nitrate hexahydrate and 1 mmol of the compound represented by formula (II) are dissolved in 10-40 mL of polar solvent. In the specific dissolving step, generally the nickel nitrate hexahydrate and the compound represented by the formula (II) are mixed and then a polar solvent is added; the nickel nitrate hexahydrate and the compound represented by the formula (II) can also be dissolved with a polar solvent respectively, Then mix together to react.

In the method for synthesizing the compound represented by the formula (I) of the present invention, the molar ratio of the nickel nitrate hexahydrate and the compound represented by the formula (II) is a stoichiometric ratio, usually 1.5:1.

Specifically, the compound represented by the formula (I) of the present invention can be synthesized by a normal pressure solution method or a high pressure solvothermal method.

When using the normal pressure solution method, the synthesis method includes: taking the compound represented by formula (II) and nickel nitrate hexahydrate, dissolving in a polar solvent, reacting the obtained mixed solution under heating conditions, removing part of the solvent from the reactant, Set, separate out, and separate out the solid to obtain the target product.

In the above-mentioned normal pressure solution method, the reaction is preferably a reflux reaction, and the reaction is preferably carried out in the range of 35°C to the reflux temperature of the polar solvent, more preferably at 65-80°C. Whether the reaction is complete can be detected by thin-layer chromatography. Under the above-mentioned limited conditions, it is more appropriate to control the reaction time to 24-48h. The reactant is concentrated to remove part of the solvent, usually by concentration to remove 80-90% of the added amount of the polar solvent.

When high-pressure solvothermal method is adopted, its synthesis method includes: taking the compound shown in formula (II) and nickel nitrate hexahydrate, dissolving in a polar solvent, placing the obtained mixed solution in a container, and evacuating to a vacuum after freezing with liquid nitrogen , melted and sealed, and then reacted under heating conditions to obtain the target product.

In the above-mentioned high-pressure solvothermal method, the container is usually a thick-walled borosilicate glass tube, and the reaction is usually carried out at 35 to 80°C. The actual situation extended to more than 72h. Preferably, the reaction is carried out at 50 to 80°C.

The present invention also includes the use of the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof in the preparation of an antitumor drug.

The present invention also includes an antitumor drug prepared by using the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

Compared with the prior art, the present invention provides a new nickel (II) nitrate chelate, namely a nickel (II) nitrate chelate with 1-pyridine-6-methoxy-β-carboline as a ligand compound, and its synthetic method and application. The applicant investigated its inhibitory effect on various tumor cell lines, and the results showed that 1-pyridine-6-methoxy-β-carboline nickel (II) nitrate chelate showed stronger anti-tumor effect than its ligand. It has good potential medicinal value and is expected to be used in the preparation of various antitumor drugs.

Description of drawings

Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of the final product obtained in Example 1 of the present invention;

Fig. 2 is the carbon nuclear magnetic resonance spectrogram of the final product obtained in Example 1 of the present invention;

Fig. 3 is the electrospray mass spectrogram of the final product obtained in Example 1 of the present invention;

4 is an X-ray single crystal structure diagram of the final product obtained in Example 1 of the present invention;

FIG. 5 is an X-ray single crystal structure diagram of the final product prepared in Example 4 of the present invention.

FIG. 6 is the electrospray mass spectrogram of the final product prepared in Example 4 of the present invention.

Detailed ways

The present invention is described in further detail below in conjunction with specific embodiments to better understand the content of the present invention, but the present invention is not limited to the following embodiments.

Example 1: Synthesis of compound represented by formula (II), namely 1-pyridine-6-methoxy-β-carboline (LKL)

1) Dissolve 50 mg of 5-methoxytryptamine in 20 mL of tetrahydrofuran, stir and add 25 μL of pyridine-2-carbaldehyde dropwise, stir in an ice bath for 20 min, then add 110 μL of trifluoroacetic acid, and remove the ice bath after reacting for about 1 h. The reaction was continued at room temperature for about 1h; after the reaction, the obtained reactant was adjusted to neutrality with a sufficient amount of ammonia water, and the organic phase was separated with ethyl acetate, spin-dried under reduced pressure to obtain a yellow oily liquid, which was directly used in the next step without purification. ;

2) The yellow oily liquid was added to 50 mL of xylene, then 100 mg of 10% Pd/C was added, the temperature was raised to 140° C., and the reaction was refluxed overnight; The filtrate was washed 10 times with ethyl ester, the filtrate was collected, and the filtrate was spin-dried under reduced pressure to obtain a crude product, which was then purified by flash liquid chromatography (V _{ethyl acetate} :V _n-hexane =3:7) to obtain yellow crystals (yield approx. 70%).

The obtained yellow crystals were analyzed by H NMR, C NMR, electrospray mass spectrometry and single crystal diffraction analysis. The specific spectral characteristics are as follows:

(1) H NMR and C NMR spectra, their spectra are shown in Figures 1 and 2, respectively.

¹ H NMR (500MHz, CDCl3)δ:11.22(s,1H),8.82～8.74(m,2H),8.53(d,J=5.1Hz,1H),7.98(d,J=5.1Hz,1H), 7.90(td,J=7.8,1.8Hz,1H),7.60(d,J=2.4Hz,1H),7.54(d,J=8.8Hz,1H),7.37–7.32(m,1H),7.25(dd , J=8.8, 2.5Hz, 1H), 3.96 (s, J=4.0Hz, 3H).

¹³ C NMR(126MHz,CDCl3)δ:157.87,154.08,148.25,138.09,137.44,136.83,135.68,135.30,130.36,122.92,121.41,121.35,118.51,115.36,112.67,103.57,77.30,77.25,77.04,76.79, 56.02.

(2) Electrospray mass spectrometry, as shown in Figure 3, ESI-MS m/z: 276.11[M+H] ⁺ .

(3) X-ray single crystal diffraction analysis confirms that the single crystal structure is shown in FIG. 4 .

Therefore, it can be determined that the above-mentioned yellow solid product is 1-pyridine-6-methoxy-β-carboline, and its chemical structural formula is shown in the following formula (II):

Example 2: Synthesis of Ligand LKL

1) Dissolve 50 mg of 5-methoxytryptamine in 30 mL of dichloromethane, stir and add 30 μL of pyridine-2-carbaldehyde dropwise, stir evenly for 10 min, add 180 μL of acetic acid, and react at room temperature for about 2 h; The gained reactant is adjusted to neutrality with sufficient ammoniacal liquor, and the organic phase is separated with chloroform, and spin-dried under reduced pressure to obtain a yellow oily liquid, which is directly used in the next step without purification in this step;

2) The yellow oily liquid was added to 40 mL of anisole, then 50 mg of 10% Pd/C was added, the temperature was raised to 160 °C, and the reaction was refluxed for 20 h; after the reaction, the reactant was filtered, followed by chloroform, methanol, and ethyl acetate. Wash 5 times, collect the filtrate, spin dry the filtrate under reduced pressure to obtain a crude product, which is then purified by flash liquid chromatography (V _{ethyl acetate} :V _{petroleum ether} =3:9) to obtain yellow crystals (yield is about 55%). %).

The obtained yellow crystals were analyzed by H NMR, C NMR, electrospray mass spectrometry and single crystal diffraction, and it was determined to be the target product 1-pyridine-6-methoxy-β-carboline.

Example 3: Synthesis of Ligand LKL

1) Dissolve 50 mg of 5-methoxytryptamine in 30 mL of tetrahydrofuran, stir and add 20 μL of pyridine-2-carbaldehyde dropwise, stir in an ice bath for 15 min, then add 60 μL of sulfuric acid, remove the ice bath after the reaction for about 1 hour, and continue at room temperature The reaction was carried out for about 0.5h; after the reaction, the obtained reactant was adjusted to basicity with a sufficient amount of ammonia water, and the organic phase was separated with ethyl acetate, and was spin-dried under reduced pressure to obtain a yellow oily liquid, which was directly used in the next step without purification in this step;

2) The yellow oily liquid was added to 40 mL of anisole, then 120 mg of 5% Pd/C was added, the temperature was raised to 150 °C, and the reaction was refluxed for 24 h; after the reaction, the reactant was filtered, and the filter cake was sequentially washed with methanol, chloroform, and acetic acid. The ethyl ester was washed 8 times in turn, the filtrate was collected, and the filtrate was spin-dried under reduced pressure to obtain a crude product, which was then purified by flash liquid chromatography (V _{ethyl acetate} :V _{petroleum ether} =3:8) to obtain yellow crystals (yield about 45%).

The obtained yellow crystals were analyzed by H NMR, C NMR, electrospray mass spectrometry and single crystal diffraction, and it was determined to be the target product 1-pyridine-6-methoxy-β-carboline.

Example 4: Synthesis of chelate [Ni ^II (LKL) ₂ (NO ₃ )(CH ₃ OH)]·NO ₃

In a thick-walled borosilicate glass tube with one end open, directly add 0.15mmol nickel nitrate hexahydrate and 0.1mmol 1-pyridine-6-methoxy-β-carboline, and then add 1.5mL methanol/chloroform mixed solution (methanol and The volume ratio of chloroform is 13:1); after being frozen in liquid nitrogen, it is evacuated to vacuum, the open end is melted, and then fully reacted at 80 ° C for 72 hours; That is, a golden yellow rod-shaped crystalline solid product is precipitated, and the yield is 85%.

The structure of the yellow rod-shaped crystalline product obtained above was determined by electrospray mass spectrometry (as shown in Figure 6) and X-ray single crystal diffraction analysis (as shown in Figure 4), and it was determined to be 1-pyridine-6-methoxy- Nickel(II) nitrate chelate with β-carboline as the ligand, namely the target chelate [Ni ^II (LKL) ₂ (NO ₃ )(CH ₃ OH)]·NO ₃ , its structural formula is shown in the following figure:

Example 5: Synthesis of chelate [Ni ^II (LKL) ₂ (NO ₃ )(CH ₃ OH)]·NO ₃

Repeat Example 1, except:

The reaction temperature was changed to 35°C, and the reaction time was extended to 84h. After the reaction was completed, it was placed in an ice bath. A yellow powder was precipitated (80% yield).

The product was determined to be the target chelate [Ni ^II (LKL) ₂ (NO ₃ )(CH ₃ OH)]·NO ₃ by electrospray mass spectrometry and X-ray single crystal diffraction analysis.

Example 6: Synthesis of chelate [Ni ^II (LKL) ₂ (NO ₃ )(CH ₃ OH)]·NO ₃

Repeat Example 1, except:

The polar solvent was changed to methanol/acetone (the volume ratio of methanol and acetone was 13:2), the reaction temperature was still 80°C, and the reaction time was 72h. After the reaction, the temperature was lowered by 5°C every hour until it reached room temperature. A small amount of golden-yellow rod-like crystals was precipitated (yield 75%).

The product was determined to be the target chelate [Ni ^II (LKL) ₂ (NO ₃ )(CH ₃ OH)]·NO ₃ by electrospray mass spectrometry and X-ray single crystal diffraction analysis.

Example 7: Synthesis of chelate [Ni ^II (LKL) ₂ (NO ₃ )(CH ₃ OH)]·NO ₃

Weigh 1 mmol of 1-pyridine-6-methoxy-β-carboline and 1.2 mmol of nickel nitrate hexahydrate, respectively; dissolve 1-pyridine-6-methoxy-β-carboline in 60 mL of methanol, and dissolve 1-pyridine-6-methoxy-β-carboline in 60 mL of methanol. Nickel nitrate was dissolved in 3 mL of chloroform solvent, the two solutions were evenly mixed, reacted at 65°C for 24 hours, concentrated under reduced pressure to remove most of the solvent (80% of the solvent added), cooled to room temperature, and left to stand, and a yellow color was precipitated. The solid was isolated, washed with water, and dried to give the product as a yellow solid (75% yield).

The product was determined to be the target chelate [Ni ^II (LKL) ₂ (NO ₃ )(CH ₃ OH)]·NO ₃ by electrospray mass spectrometry and X-ray single crystal diffraction analysis.

Example 8: Synthesis of chelate [Ni ^II (LKL) ₂ (NO ₃ )(CH ₃ OH)]·NO ₃

Repeat Example 7, except:

The polar solvent was changed to a mixed solvent composed of methanol, water and dimethyl sulfoxide (the volume ratio of methanol, water and dimethyl sulfoxide was 8:1:1), the reaction temperature was 70 °C reflux, and the reaction time was After 12h, a yellow solid product was precipitated (70% yield).

The structure of the precipitated product was determined by electrospray mass spectrometry and X-ray single crystal diffraction analysis, and it was determined to be the target chelate [Ni ^II (LKL) ₂ (NO ₃ )(CH ₃ OH)]·NO ₃ .

In order to fully illustrate the application of the 1-pyridine-6-methoxy-β-carboline nickel (II) nitrate chelate in the present invention in pharmaceuticals, the applicant conducted an antitumor activity experiment.

Experimental Example 1: 1-Pyridine-6-methoxy-β-carboline nickel(II) nitrate chelate was used for in vitro inhibitory activity experiments on various human tumor strains

1. Cell lines and cell culture

In this experiment, T24 (human bladder cancer cells), NCI-H-460 (human large cell lung cancer cells), SK-OV-3 (human ovarian adenocarcinoma cell lines), Hep G (human liver cancer cells), and MGC803 (human gastric cancer cells) were contained in the 10% fetal bovine serum, 1% penicillin-streptomycin mixture in DMEM medium, and cultured in a 37°C incubator containing 5% CO ₂ by volume. SK-OV-3 (human ovarian adenocarcinoma cell line) in RPMI-1640 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin mixture, placed in a 37°C incubator containing 5% _CO by volume nourish.

2. Inhibition rate and IC ₅₀ measured by MTT method

Compounds were dissolved in DMSO as a 2mM stock solution, and diluted with serum-free medium to the final concentration of 200 μmol/L, 100 μmol/L, 50 μmol/L, 25 μmol/L, 12.5 μmol/L. The intermediate concentration liquid, take each intermediate concentration 20μL, ready to be added to the existing 180μL cell solution in a 96-well plate.

A series of tumor cell lines in logarithmic growth phase were inoculated in 96-well plates with 180 μL per well, and 200 μL of PBS (phosphate buffered saline powder solution) was added to the edge wells, the cell concentration was about 1×10 ⁴ /well, and cultured for 16 After 12 to 18 hours, after the cells adhered, change to serum-free DMEM and OS-RC-2 to RPMI-1640. After 12 to 18 hours, add 20 μL of intermediate concentration compound liquid, the final concentrations are 20 μmol/L, 10 μmol/L, 5 μmol/L , 2.5μmol/L, 1.25μmol/L. Five duplicate wells were set in parallel for each concentration of the compound, in which the final concentration of DMSO was less than or equal to 1%. At the same time, the corresponding negative control group (only cells and the same amount of DMSO in the culture medium, no drug) and blank control group (only the The same amount of drugs, no cells), each group was also set up 5 replicate wells in parallel, and the drug effect time was 48 hours. 4 hours before the end of the incubation, add 10 μL MTT to each well, and after continuing to culture for 4 hours, pour off the culture medium, add 100 μL DMSO/well, shake for 7 minutes with a plate shaker to fully dissolve the crystals, set the blank control group to zero, and use a microplate reader. The absorbance (A) value after removing the background light absorption value was measured at 570nm/630nm dual wavelength, and the inhibition rate was measured. The inhibition rate at 20μmol/L concentration was greater than 50%, which was consistent with the inhibition (or damage) of cells under the light microscope. If the morphology changes (such as cell shrinkage, fragmentation, floating, etc.), it is determined that the primary screening is effective, that is, the next step is to obtain IC ₅₀ , and the results are shown in Table 1 and Table 2 below:

Table 1:

Table 2:

Claims (9)

1. a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

2. the synthetic method of the compound described in claim 1 is characterized in that: get compound shown in following formula (II) and nickel nitrate hexahydrate, be dissolved in polar solvent, carry out coordination reaction, namely obtain target product;

Wherein, the polar solvent is methanol and one or any combination of two or more selected from water, acetone, chloroform, dimethyl sulfoxide, N,N-dimethylformamide and acetonitrile. 3. synthetic method according to claim 2 is characterized in that: get compound shown in formula (II) and nickel nitrate hexahydrate, be dissolved in polar solvent, gained mixed solution reacts under heating condition, and reactant removes part The solvent is left to stand for precipitation, and the solid is separated to obtain the target product. 4. synthetic method according to claim 3 is characterized in that: reaction is carried out in the reflux temperature range of 35 ℃ to polar solvent. 5. synthetic method according to claim 2 is characterized in that: get compound shown in formula (II) and nickel nitrate hexahydrate, be dissolved in polar solvent, gained mixed solution is placed in container, after liquid nitrogen freezing It is evacuated to vacuum, melted and sealed, and then reacted under heating conditions to obtain the target product. 6 . The synthetic method according to claim 5 , wherein the reaction is carried out at 35-80° C. 7 . 7. synthetic method according to claim 2 is characterized in that: compound shown in the described formula (II) is prepared by the following method: take 5-methoxytryptamine and pyridine-2-carbaldehyde as raw materials, add three Fluoroacetic acid is subjected to catalytic ring closure, and the obtained product is then oxidatively dehydrogenated with Pd/C to obtain. 8. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of antitumor drugs. 9. An antitumor drug prepared by using the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

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