CN107446002B - Nickel nitrate (II) chelate taking 1-pyridine-6-methoxy- β -carboline as ligand and synthetic method and application thereof - Google Patents

Nickel nitrate (II) chelate taking 1-pyridine-6-methoxy- β -carboline as ligand and synthetic method and application thereof Download PDF

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CN107446002B
CN107446002B CN201610377270.3A CN201610377270A CN107446002B CN 107446002 B CN107446002 B CN 107446002B CN 201610377270 A CN201610377270 A CN 201610377270A CN 107446002 B CN107446002 B CN 107446002B
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彭艳
朱艳宏
杨景枚
张国海
卢幸
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Guangxi Normal University
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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.
Figure DDA0002182201130000011

Description

Nickel nitrate (II) chelate taking 1-pyridine-6-methoxy- β -carboline as ligand and synthetic method and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a nickel (II) nitrate chelate taking 1-pyridine-6-methoxy- β -carboline as a ligand, and a synthesis method and application thereof.
Background
Malignant tumors (commonly known as cancers) are one of the major diseases that currently endanger human health. Cancer formation is a complex, multi-step process involving a series of mutations in important regulatory genes that lead to rapid growth of cancer cells, damage to healthy organs, and late spread throughout the patient's body, ultimately leading to death. The number of deaths caused by malignant tumors is over 700 thousands every year all over the world, so that the prevention and treatment of cancers are reluctant.
Chemotherapy of malignant tumors dates back to 40 th of the 20 th century, and mustard nitrogen (Nitrogenmustard) and the folic acid analog Aminopterin (Aminopterin) were found to have significant tumor growth inhibitory activity.
Figure GDA0002182201120000011
The most studied of the present time are β -carboline alkaloid compounds β -carboline alkaloids, an active ingredient isolated from the medicinal plant Peganum harmala, Xinjiang, have a broad spectrum of pharmacological activities such as anxiolytic, antidepressant, anticonvulsant, and antitumor, antimalarial, antiparasitic, anti-AIDS, etc. in herbal formulations, Peganum harmala seeds have been used for the treatment of cancer6H5) Methoxy (-OCH)3) β -carboline alkaloid research mainly includes the following aspects of discovering and separating and purifying from plants of different families based on natural product chemical research, fully synthesizing or semi-synthesizing β -carboline alkaloid through an organic synthesis method, modifying the structure of the carboline alkaloid, researching the molecular mechanism of the pharmacological activity (such as anti-tumor activity) of the carboline alkaloid, such as inserting DNA, inhibiting topoisomerase, inhibiting CDK and the like, but from the research progress at present, the β -carboline alkaloid content in natural plants is generally lower, and the extracted carboline alkaloid content is generally lowerThe organic semi-synthesis method has certain advantages in yield but is limited by preparation cost, so that the current extensive research on β -carboline alkaloids is still insufficient.
On the other hand, the research of medicinal inorganic chemistry based on medicinal active ligand is a hot research field along with the vigorous development of biological inorganic chemistry in recent years, and as cisplatin, carboplatin, oxaliplatin and the like become indispensable medicines in cancer chemotherapy, metal chelate antitumor medicines gradually become research hot.
Disclosure of Invention
The invention aims to provide a novel nickel (II) nitrate chelate, namely a nickel (II) nitrate chelate taking 1-pyridine-6-methoxyl- β -carboline as a ligand, and a synthetic method and application thereof.
The present invention relates to a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
Figure GDA0002182201120000021
the synthesis method of the compound shown in the formula (I) comprises the following steps: dissolving a compound shown as the following formula (II) and nickel nitrate hexahydrate in a polar solvent, and carrying out coordination reaction to obtain a target product;
Figure GDA0002182201120000022
the synthetic route of the synthetic method is as follows:
Figure GDA0002182201120000023
the compound shown in the formula (II) can be prepared by a self-designed synthetic route, preferably by the following method, wherein 5-methoxytryptamine and Pyridine-2-formaldehyde are used as raw materials, an acidic substance is added for carrying out catalytic ring closure (namely, a Pictet-Spengler condensation reaction), and the obtained product is subjected to Pd/C oxidative dehydrogenation, so that the specific synthetic route is as follows:
reagent: (a) tetrahydrofuran or dichloromethane; (b) xylene or anisole.
A more specific synthesis method of the compound represented by the formula (II) comprises the following steps:
① dissolving 5-methoxytryptamine in tetrahydrofuran or dichloromethane, adding pyridine-2-formaldehyde, mixing, adding part of acidic substance, stirring, reacting, adjusting the reactant to neutral or alkaline, extracting with ethyl acetate or chloroform, collecting organic phase, and evaporating to remove solvent to obtain yellow oily solid compound 1;
② dissolving compound 1 in xylene or anisole, adding Pd/C, reacting under heating, filtering the obtained reactant, washing the filter cake, collecting the filtrate, and spin-drying to obtain the crude product (compound 2) of the compound shown in formula (II).
In step ① of the method for synthesizing the compound represented by formula (II), the ratio of the amounts of the 5-methoxytryptamine and pyridine-2-carbaldehyde as raw materials is usually 1: 1.5 or 1:1, preferably the molar amount of pyridine-2-carbaldehyde is slightly larger than the amount of the 5-methoxytryptamine, so that the reaction is sufficiently performed, the pH value of the filtrate is adjusted by using an alkaline solution, wherein the alkaline solution may be ammonia water or an aqueous solution of one or more alkaline substances selected from sodium acetate, sodium carbonate, sodium phosphate, sodium bicarbonate and potassium carbonate, preferably a saturated sodium bicarbonate solution or an ammonia aqueous solution, and preferably the pH value of the reaction product is adjusted to 7-9.
In step ① of the method for synthesizing the compound represented by formula (II), the acidic substance used may be trifluoroacetic acid, acetic acid, hydrochloric acid or sulfuric acid, the amount of hydrochloric acid and trifluoroacetic acid is usually 4 to 5 times the volume of pyridine-2-carbaldehyde, the amount of hydrochloric acid and trifluoroacetic acid is 6 to 7 times the volume of pyridine-2-carbaldehyde in the case of acetic acid, and is 2 to 3 times the volume of pyridine-2-carbaldehyde in the case of sulfuric acid.
In the step ① of the method for synthesizing the compound represented by the formula (II), raw material 5-methoxytryptamine and pyridine-2-formaldehyde are subjected to an aldehyde-amine condensation reaction under acid catalysis to form intermediate Schiff base, and the Schiff base is subjected to a ring closing reaction under the action of acid to form the compound 1. in the method, trifluoroacetic acid is used as fuming strong acid, so the reaction is preferably carried out under an ice bath condition, whether the reaction is complete or not can be tracked and detected by Thin Layer Chromatography (TLC), usually, the reaction time is properly controlled to be 1-2 h, after the reaction is completed, the solvent needs to be dried by spinning under reduced pressure at the temperature of 30-45 ℃ to prevent side reaction, the dosage of the solvent tetrahydrofuran or dichloromethane is properly selected to dissolve the raw materials for the reaction, and usually, the dosage of 1mmol of 5-methoxytryptamine is calculated on the basis of 0.5-1 mL tetrahydrofuran or 0.4-1 mL dichloromethane.
In step ② of the method for synthesizing the compound represented by formula (II), the amount of Pd/C added is usually 1-2 times of the amount of the substance of compound 1, wherein the Pd/C can be 5% Pd/C or 10% Pd/C, etc., 10% Pd/C is preferably used in the method, in the step, the reaction conditions are preferably carried out at 140-160 ℃, more preferably the reflux reaction is carried out in a reflux device at 140-160 ℃, the completion of the reaction can be detected by TLC tracking, and the reaction time is usually controlled to be 12-24 h, which is suitable.
In step ② of the method for synthesizing the compound represented by formula (II), the filter cake is usually washed with methanol, chloroform and ethyl acetate for a plurality of times, preferably 5 to 10 times, and the order of washing is not required, preferably methanol first, chloroform second and ethyl acetate last.
In order to further improve the purity of the compound represented by the formula (II) and facilitate the subsequent reaction, the crude product obtained by the above method is preferably purified and then used in the synthesis method of the target product of the present invention. The purification operation is the same as the prior art, and specifically, the crude product can be purified by adopting a rapid liquid chromatography to obtain a pure compound shown in a formula (II); the reagents used in the purification process were prepared from ethyl acetate and n-hexane in a ratio of 3: 7-3: 9 or a mixed solvent composed of ethyl acetate and petroleum ether according to the volume ratio of 3: 7-3: 9, 9 in volume ratio.
In the synthesis method of the compound shown in the formula (I), the polar solvent is methanol and one or the combination of more than two of water, acetone, chloroform, dimethyl sulfoxide, N-dimethylformamide and acetonitrile. The preferable proportion of the 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-dimethylformamide and acetonitrile, the proportion of the polar solvent can be any proportion under the precondition that the total amount of the polar solvent does not exceed 15%. The amount of the polar solvent can be determined according to needs, and in general, 1.5mmol of nickel nitrate hexahydrate and 1mmol of the compound shown in the formula (II) are dissolved by 10-40 mL of the polar solvent. In the specific dissolving step, the nickel nitrate hexahydrate and the compound shown in the formula (II) are mixed and then added with a polar solvent; alternatively, nickel hexanitrate and the compound represented by the formula (II) may be dissolved in a polar solvent, respectively, and then mixed together to react.
In the method for synthesizing the compound represented by the formula (I), the molar ratio of the nickel nitrate hexahydrate to the compound represented by the formula (II) is a stoichiometric ratio, and is usually 1.5: 1.
The compound shown in the formula (I) can be synthesized by a normal-pressure solution method or a high-pressure solvothermal method during synthesis.
When the normal-pressure solution method is adopted, the synthesis method comprises the following steps: dissolving the compound shown in the formula (II) and nickel nitrate hexahydrate in a polar solvent, reacting the obtained mixed solution under a heating condition, removing part of the solvent from the reactant, standing, separating out, and separating out solids to obtain the target product.
In the normal pressure solution method, the reaction is preferably performed by a reflux reaction, and the reaction is preferably performed at a temperature ranging from 35 ℃ to the reflux temperature of the polar solvent, and more preferably at 65-80 ℃. Whether the reaction is complete or not can be detected by adopting thin-layer chromatography tracking, and the reaction time is controlled to be between 24 and 48 hours under the limited condition. And removing part of the solvent from the reactant by adopting a concentration mode, wherein the concentration is usually carried out to remove 80-90% of the addition amount of the polar solvent.
When the high-pressure solvothermal method is adopted, the synthesis method comprises the following steps: dissolving a compound shown in a formula (II) and nickel nitrate hexahydrate in a polar solvent, placing the obtained mixed solution in a container, freezing the mixed solution by liquid nitrogen, pumping the frozen mixed solution to vacuum, sealing the vacuum by melting, and then reacting under a heating condition to obtain a target product.
In the high-pressure solvothermal method, the container is usually a thick-walled borosilicate glass tube, the reaction is usually carried out at 35 to 80 ℃, and the reaction time is preferably controlled to be 36 to 72 hours under the temperature condition, and can be prolonged to be more than 72 hours according to actual conditions. Preferably, the reaction is carried out at 50-80 ℃.
The invention also discloses the application of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof in preparing antitumor drugs.
The invention also discloses an antitumor drug prepared by using the compound shown in the formula (I) or pharmaceutically acceptable salt thereof as an active ingredient.
The applicant researches the inhibition effect of the chelate on various tumor cell strains, and the result shows that the 1-pyridine-6-methoxy- β -carboline nickel (II) nitrate chelate has stronger antitumor activity than the ligand thereof, has better potential medicinal value and is expected to be used for preparing various antitumor drugs.
Drawings
FIG. 1 is a NMR spectrum of a final product obtained in example 1 of the present invention;
FIG. 2 is a NMR chart of a final product obtained in example 1 of the present invention;
FIG. 3 is an electrospray mass spectrum of a final product obtained in example 1 of the present invention;
FIG. 4 is a structural view of an X-ray single crystal of a final product obtained in example 1 of the present invention;
FIG. 5 is a structural view of an X-ray single crystal of a final product obtained in example 4 of the present invention.
FIG. 6 is an electrospray mass spectrum of the final product obtained in example 4 of the present invention.
Detailed Description
The present invention will be better understood from the following detailed description of specific examples, which should not be construed as limiting the scope of the present invention.
Example 1 Synthesis of Compound represented by formula (II), i.e., 1-pyridine-6-methoxy- β -carboline (LKL)
1) Dissolving 50mg of 5-methoxytryptamine in 20mL of tetrahydrofuran, stirring, dropwise adding 25 mu L of pyridine-2-formaldehyde, stirring in an ice bath for 20min, then adding 110 mu L of trifluoroacetic acid, reacting for about 1h, removing the ice bath, and continuing to react for about 1h at normal temperature; after the reaction is finished, adjusting the obtained reactant to be neutral by using enough ammonia water, separating an organic phase by using ethyl acetate, and performing reduced pressure spin drying to obtain yellow oily liquid, wherein the yellow oily liquid is directly used for the next reaction without purification;
2) adding the yellow oily liquid into 50mL of dimethylbenzene, then adding 100mg of 10% Pd/C, heating to 140 ℃, carrying out reflux reaction, and standing overnight; after the reaction is finished, the reactant is filtered, the filter cake is washed for 10 times by methanol, chloroform and ethyl acetate in sequence, the filtrate is collected, the filtrate is decompressed and dried in a spinning way to obtain a crude product, and then the crude product is purified by a rapid liquid chromatography (V)Ethyl acetate：VN-hexane3:7) to yield yellow crystals (yield about 70%).
Performing nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum, electrospray mass spectrum and single crystal diffraction analysis on the obtained yellow crystal, wherein the specific spectral characteristics are as follows:
(1) a hydrogen nuclear magnetic resonance spectrum and a carbon spectrum, the spectra of which are shown in fig. 1 and 2, respectively.
1H 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)。
13C 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 FIG. 3, ESI-MS M/z:276.11[ M + H ]]+.
(3) The single crystal structure was confirmed by X-ray single crystal diffraction analysis as shown in fig. 4.
Therefore, the yellow solid product can be determined to be 1-pyridine-6-methoxy- β -carboline, and the chemical structural formula of the yellow solid product is shown as the following formula (II):
Figure GDA0002182201120000061
example 2: synthesis of ligand LKL
1) Dissolving 50mg of 5-methoxytryptamine in 30mL of dichloromethane, stirring, dropwise adding 30 mu L of pyridine-2-formaldehyde, uniformly stirring for 10min, adding 180 mu L of acetic acid, and reacting at normal temperature for about 2 h; after the reaction is finished, adjusting the obtained reactant to be neutral by using enough ammonia water, separating an organic phase by using chloroform, and performing reduced pressure spin drying to obtain yellow oily liquid, wherein the yellow oily liquid is directly used for the next reaction without purification;
2) adding the yellow oily liquid into 40mL of anisole, then adding 50mg of 10% Pd/C, heating to 160 ℃, and carrying out reflux reaction for 20 h; after the reaction is finished, the reactant is filtered, washed for 5 times by chloroform, methanol and ethyl acetate in sequence, the filtrate is collected, the filtrate is decompressed and dried in a spinning way to obtain a crude product, and then the crude product is purified by a rapid liquid chromatography (V)Ethyl acetate：VPetroleum ether3:9) to yield yellow crystals (yield about 55%).
And (3) performing nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum, electrospray mass spectrum and single crystal diffraction analysis on the obtained yellow crystal to determine the yellow crystal to be the target product 1-pyridine-6-methoxy- β -carboline.
Example 3: synthesis of ligand LKL
1) Dissolving 50mg of 5-methoxytryptamine in 30mL of tetrahydrofuran, stirring, dropwise adding 20 mu L of pyridine-2-formaldehyde, stirring in an ice bath for 15min, then adding 60 mu L of sulfuric acid, removing the ice bath after reacting for about 1h, and continuing to react for about 0.5h at normal temperature; adjusting the obtained reactant to be alkaline by using enough ammonia water after the reaction is finished, separating an organic phase by using ethyl acetate, and performing reduced pressure spin drying to obtain yellow oily liquid, wherein the yellow oily liquid is directly used for the next reaction without purification;
2) adding the yellow oily liquid into 40mL of anisole, then adding 120mg of 5% Pd/C, heating to 150 ℃, and carrying out reflux reaction for 24 h; after the reaction is finished, the reactant is filtered, the filter cake is washed for 8 times by methanol, chloroform and ethyl acetate in turn, the filtrate is collected, the filtrate is decompressed and dried in a spinning way to obtain a crude product, and then the crude product is purified by a rapid liquid chromatography (V)Ethyl acetate：VPetroleum etherTo 3:8) to yield yellow crystals (yield about 45%).
And (3) performing nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum, electrospray mass spectrum and single crystal diffraction analysis on the obtained yellow crystal to determine the yellow crystal to be the target product 1-pyridine-6-methoxy- β -carboline.
Example 4: chelate [ Ni ]II(LKL)2(NO3)(CH3OH)]·NO3Synthesis of (2)
Directly adding 0.15mmol of nickel nitrate hexahydrate and 0.1mmol of 1-pyridine-6-methoxy- β -carboline into a thick-wall borosilicate glass tube with an opening at one end, adding 1.5mL of methanol/chloroform mixed solution (the volume ratio of methanol to chloroform is 13:1), freezing by liquid nitrogen, vacuumizing, sealing the opening end, fully reacting for 72 hours at 80 ℃, cooling for 5 ℃ per hour after the reaction is finished, and cooling to room temperature, so that a golden rod-shaped crystalline solid product is separated out, wherein the yield is 85%.
Determining the structure of the obtained yellow rod-shaped crystal product (shown in figure 4) by electrospray mass spectrometry (shown in figure 6) and X-ray single crystal diffraction analysis, and determining to be nickel (II) nitrate chelate with 1-pyridine-6-methoxy- β -carboline as ligand, namely target chelate [ Ni ] NiII(LKL)2(NO3)(CH3OH)]·NO3The structural formula is shown as the following figure:
Figure GDA0002182201120000071
example 5: chelate [ Ni ]II(LKL)2(NO3)(CH3OH)]·NO3Synthesis of (2)
Example 1 was repeated except that:
the reaction temperature was changed to 35 ℃ and the reaction time was extended to 84h, and after the reaction was completed, the reaction was placed in an ice bath. A yellow powder precipitated (yield 80%).
The product is determined to be a target chelate [ Ni ] by the structural determination of electrospray mass spectrum and X-ray single crystal diffraction analysisII(LKL)2(NO3)(CH3OH)]·NO3。
Example 6: chelate [ Ni ]II(LKL)2(NO3)(CH3OH)]·NO3Synthesis of (2)
Example 1 was repeated except that:
the polar solvent is changed into methanol/acetone (the volume ratio of methanol to acetone is 13:2), the reaction temperature is still 80 ℃, the reaction time is 72 hours, and after the reaction is finished, the temperature is reduced by 5 ℃ per hour until the temperature is reduced to the room temperature. A small amount of golden rod-like crystals precipitated (yield 75%).
The product is determined to be a target chelate [ Ni ] by the structural determination of electrospray mass spectrum and X-ray single crystal diffraction analysisII(LKL)2(NO3)(CH3OH)]·NO3。
Example 7: chelate [ Ni ]II(LKL)2(NO3)(CH3OH)]·NO3Synthesis of (2)
1mmol of 1-pyridine-6-methoxy- β -carboline and 1.2mmol of nickel nitrate hexahydrate are respectively weighed, 1-pyridine-6-methoxy- β -carboline is dissolved in 60mL of methanol, nickel nitrate hexahydrate is dissolved in 3mL of chloroform solvent, the two solutions are uniformly mixed, the mixture reacts for 24 hours at 65 ℃, after most of the solvent (80 percent of the added amount of the solvent) is removed through decompression and concentration, the mixture is cooled to room temperature and stands, yellow solid is separated out, the solid is separated out, washed by water and dried, and a yellow solid product is obtained (the yield is 75 percent).
The product is determined to be a target chelate [ Ni ] by the structural determination of electrospray mass spectrum and X-ray single crystal diffraction analysisII(LKL)2(NO3)(CH3OH)]·NO3。
Example 8: chelate [ Ni ]II(LKL)2(NO3)(CH3OH)]·NO3Synthesis of (2)
Example 7 was repeated, except that:
the polar solvent is changed into a mixed solvent consisting of methanol, water and dimethyl sulfoxide (the volume ratio of the methanol to the water to the dimethyl sulfoxide is 8: 1: 1), the reaction temperature is 70 ℃, the reflux is carried out, the reaction time is 12 hours, and a yellow solid product is separated out (the yield is 70%).
The precipitated product is determined to be a target chelate [ Ni ] by the structural determination of the product through electrospray mass spectrometry and X-ray single crystal diffraction analysisII(LKL)2(NO3)(CH3OH)]·NO3。
In order to fully illustrate the application of the 1-pyridine-6-methoxy- β -carboline nickel (II) nitrate chelate in pharmacy, the applicant performs an anti-tumor activity experiment on the chelate.
Experimental example 1 in vitro inhibitory Activity experiment of 1-pyridine-6-methoxy- β -carboline Nickel nitrate (II) chelate on various human tumor strains
1. Cell lines and cell cultures
In the experiment, T24 (human bladder cancer cells), NCI-H-460 (human large cell lung cancer) SK-OV-3 (human ovarian adenocarcinoma cell line), Hep G (human liver cancer cells) and MGC803 (human gastric cancer cells) are put into DMEM culture solution containing 10% of mixed solution of bovine fetal serum and 1% of streptomycin and then put into DMEM culture solution containing 5% of CO by volume concentration at 37 DEG C2Culturing in an incubator. SK-OV-3 (human ovarian adenocarcinoma cell line) is cultured in RPMI-1640 culture solution containing 10% of mixed solution of fetal bovine serum and 1% of streptomycin, and then placed in the RPMI-1640 culture solution at 37 ℃ and containing 5% of CO by volume concentration2Culturing in an incubator.
2. MTT method for measuring inhibition rate and IC50
Compounds were stored in DMSO-assisted solution as 2mM stock, diluted in serum-free medium to intermediate concentrations of 200. mu. mol/L, 100. mu. mol/L, 50. mu. mol/L, 25. mu. mol/L, 12.5. mu. mol/L, and 20. mu.L of each intermediate concentration was taken and prepared for addition to a conventional 180. mu.L cell sap 96-well plate.
Inoculating 180 μ L of each series of tumor cell strains in logarithmic growth phase to 96-well plate, adding 200 μ L of Phosphate Buffered Saline (LPBS) to the peripheral wells, and making the cell concentration about 1 × 104The cells are cultured for 16 hours per well, serum-free DMEM is replaced after the cells are attached to the wall, RPMI-1640 is replaced by OS-RC-2, and 20 mu L of compound liquid with intermediate concentration is added after 12 to 18 hours, wherein the final concentration is 20 mu mol/L, 10 mu mol/L, 5 mu mol/L, 2.5 mu mol/L and 1.25 mu mol/L. Each concentration of the compound is provided with 5 multiple wells in parallel, wherein the final concentration of DMSO is less than or equal to 1%, a corresponding negative control group (only cells and the same amount of DMSO in a culture solution without drugs) and a blank control group (only the same amount of drugs and no cells in the culture solution) are simultaneously provided, each group is also provided with 5 multiple wells in parallel, and the action time of the drugs is 48 hours. Adding 10 mu L MTT into each well 4 hours before the culture is finished, continuously culturing for 4 hours, pouring out the culture solution, adding 100 mu L DMSO into each well, oscillating for 7min by a plate oscillator to fully dissolve the crystal, adjusting the blank control group to zero, measuring the absorbance (A) value after removing the background light absorption value by using an enzyme-labeling instrument at a double wavelength of 570nm/630nm, measuring the inhibition rate, wherein the 20 mu mol/L concentration inhibition rate is more than 50%, and the inhibition rate accords with the morphological change (such as cell shrinkage, breakage, floating and the like) of the inhibited (or damaged) cells under a light mirror, judging that the primary screening is effective, and entering the next step to obtain IC50The results are shown in tables 1 and 2 below:
table 1:
Figure GDA0002182201120000091
table 2:
Figure GDA0002182201120000092

Claims (9)

1. a compound of the following formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0002182201110000011
2. a method of synthesizing the compound of claim 1, wherein: dissolving a compound shown as the following formula (II) and nickel nitrate hexahydrate in a polar solvent, and carrying out coordination reaction to obtain a target product;
Figure FDA0002182201110000012
wherein the polar solvent is methanol and one or the combination of more than two of water, acetone, chloroform, dimethyl sulfoxide, N-dimethylformamide and acetonitrile.
3. The method of synthesis according to claim 2, characterized in that: dissolving the compound shown in the formula (II) and nickel nitrate hexahydrate in a polar solvent, reacting the obtained mixed solution under a heating condition, removing part of the solvent from the reactant, standing, separating out, and separating out solids to obtain the target product.
4. The method of synthesis according to claim 3, characterized in that: the reaction is carried out at a temperature ranging from 35 ℃ to the reflux temperature of the polar solvent.
5. The method of synthesis according to claim 2, characterized in that: dissolving a compound shown in a formula (II) and nickel nitrate hexahydrate in a polar solvent, placing the obtained mixed solution in a container, freezing the mixed solution by liquid nitrogen, pumping the frozen mixed solution to vacuum, sealing the vacuum by melting, and then reacting under a heating condition to obtain a target product.
6. The method of synthesis according to claim 5, characterized in that: the reaction is carried out at 35-80 ℃.
7. The method of synthesis according to claim 2, characterized in that: the compound shown in the formula (II) is prepared by the following method: 5-methoxy tryptamine and pyridine-2-formaldehyde are taken as raw materials, trifluoroacetic acid is added for catalyzing and ring closing, and the obtained product is subjected to oxidative dehydrogenation by Pd/C to obtain the compound.
8. The use of a compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an anti-neoplastic drug.
9. An antitumor agent comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
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