CN114702441B - Cuprous complex with anti-tumor activity and preparation method and application thereof - Google Patents
Cuprous complex with anti-tumor activity and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the technical field of anticancer chemical drugs, in particular to a cuprous complex with antitumor activity and a preparation method and application thereof; of cuprous complexes has a chemical formula of [ CuL]ClO 4 Wherein L is 2- (alpha-quinoline methoxyl) benzaldehyde p-methylaniline Schiff base; the preparation method of the Schiff base cuprous complex comprises the following steps of preparing a ligand L and cupric salt Cu (ClO) 4 ) 2 Synthesizing, wherein the copper in the obtained complex is +1 valence. The cuprous schiff base complex has good cytotoxicity and broad-spectrum anticancer activity on four cancer cells HeLa, BGC-823, NCI-H460 and HepG-2, is likely to generate toxicity on cancer cells in a cell apoptosis inducing mode, has lower toxicity on normal cells than cisplatin, has potential medicinal value, and is expected to be developed into a new generation of anti-tumor candidate medicament.
Description
Technical Field
The invention relates to the technical field of anti-cancer chemical drugs, in particular to a cuprous complex with anti-tumor activity and a preparation method and application thereof.
Background
Metal anticancer drugs are receiving wide attention due to their superior properties and advantages in biomedical diagnosis and treatment. Since the discovery of cisplatin and related platinum drugs, there has been great interest in the development of metal anticancer drugs. The severe side effects exhibited by the currently used platinum complexes have prompted researchers to design and develop novel transition metal anticancer drugs with low toxicity. The transition metal complex has important application prospect in the aspect of developing and researching novel metal anti-cancer drugs due to the abundant coordination geometry and coordination number, various redox states and electronic properties, unique thermodynamic and kinetic characteristics and the inherent properties of cationic metal ions and ligands.
Copper (Cu) is used as a trace element necessary for a human body, plays a vital role in maintaining the health of the human body, has small toxic and side effects and good tolerance on the basis of endogenous metals in a natural biological way, has good water solubility and changeable coordination modes, generally shows better anticancer activity than other metal compounds and lower toxicity to normal cells, and is expected to become a novel metal anticancer drug replacing platinum. The main mechanism of copper-induced cytotoxicity is generally believed to be directly related to the redox nature between Cu (II)/Cu (I), which can be reduced to Cu (I) due to ROS (reactive oxygen) generation induced by copper (II), which can catalyze hydrogen peroxide (H) 2 O 2 ) Formation of free hydroxyl radicals radical (OH). Highly reactive hydroxyl radicals are capable of interacting with any biomolecule and can abstract hydrogens from amino-containing carbons to form carbon-centered protein radicals and hydrogens from unsaturated fatty acids to form lipid radicals, resulting in oxidative damage to cells. On the other hand, during uptake, cu (II) is reduced to Cu (I) by a membrane-like structure-bound metalloreductase, and taken up by cells via transmembrane transporters. Therefore, if the Cu (I) complex is directly used in an antitumor drug, the oxidation state of the Cu (I) complex is directly changed into Cu (I), so that hydroxyl free radicals are rapidly generated in cells, the uptake of copper by the cells is accelerated, and the Cu complex has important significance for enhancing the antitumor activity of the copper complex.
At present, the main way for synthesizing the cuprous complex is to react cuprous salt with corresponding ligand, and the research on synthesizing the cuprous complex from the cupric salt is very little. Cuprous salt is easily oxidized into cupric copper by oxygen in the air, so the cuprous complex is often synthesized under the protection of inert gas, and the synthesis of the cuprous complex and the research in the field of antitumor drugs are limited to a certain extent.
The Schiff base has good coordination capability and good physiological activities of antibiosis, anticancer, anti-inflammation and the like. The salicylaldehyde Schiff base has high activity in the aspects of bacteriostasis, sterilization, tumor resistance and the like, so that the salicylaldehyde Schiff base and the metal complex thereof have high potential in the medicine research and development industry. Quinolines are ubiquitous in nature and are often used as structural subunits of complex natural products. Quinoline drugs also have various pharmacological properties, and are heterocyclic compounds with very important biological activity in the field of medicinal chemistry. In addition, quinoline and metal complexes of derivatives thereof are expected to be developed into high-activity and low-toxicity antitumor drugs with new action mechanisms.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a cuprous complex with anti-tumor activity.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows: a cuprous schiff base complex, wherein the cuprous complex has a chemical formula of [ CuL]ClO 4 Wherein L is 2- (alpha-quinoline methoxyl) benzaldehyde p-methylaniline Schiff base; the structural formula of the cuprous complex is as follows:
further, the crystal structure of the cuprous complex is a monoclinic system, the structure of a P21/c space group is shown, and the unit cell parameters are as follows:
α =90 °, β =92.708 (11) °, γ =90 °, Z =4, cell volume £ is £ greater than @>
The whole structure consists of a Schiff base ligand L, a + 1-valent copper ion and a perchlorate ion outside, and the complex is yellow; in the crystal structure of the complex, copper ions are three-coordinated, three coordinating atoms are respectively an O atom in an ether bond, an N atom in a C = N bond and an N atom on a quinoline ring, and Cu is coordinated with threeThe atoms are in the same plane to form a T-shaped structure.
The invention also provides a preparation method of the cuprous schiff base complex, which comprises the following steps:
dissolving ligand L in anhydrous ethanol, heating to dissolve ligand completely, maintaining the solution temperature at 30-40 deg.C, and adding inorganic copper salt Cu (ClO) 4 ) 2 ·6H 2 O, after the metal salt is completely dissolved, the solution turns brown; filtering with filter paper rapidly, culturing the single crystal with filtrate by slow volatilization method, standing for one day, and separating yellow needle crystal from filtrate to obtain [ CuL]ClO 4 And (3) a complex.
The preparation method is characterized in that the used copper salt is bivalent copper, and in the obtained complex, the valence state of the copper metal center is positive and univalent. Such reactions are rare in current reports. The Cu (I) complex with positive valence is directly used for antitumor drugs, and the oxidation state of the Cu (I) complex is directly Cu (I), so that hydroxyl free radicals are rapidly generated in cells, the uptake of copper by the cells is accelerated, and the Cu complex has important significance for enhancing the antitumor activity of the copper complex.
Further, the synthesis method of the ligand L comprises the following steps: adding K to a solution of salicylaldehyde in acetonitrile 2 CO 3 Then adding 2-chloromethyl quinoline hydrochloride, heating and refluxing for 8-10 h, filtering the mixture, decompressing and desolventizing, completely dissolving the solid by dichloromethane, extracting by distilled water, collecting the organic phase and drying by anhydrous sodium sulfate. Drying, filtering, decompressing and desolventizing, recrystallizing the yellow solid for multiple times by using acetonitrile, decompressing and filtering to obtain an ether intermediate, heating and refluxing the ether intermediate and p-methylaniline in an ethanol solution for 5-6 h to obtain a ligand L, namely the 2- (alpha-quinolinylmethoxy) benzaldehyde p-methylaniline Schiff base.
Further, the ligand L is in contact with Cu (ClO) 4 ) 2 ·6H 2 The molar ratio of O is 1.
Further, salicylaldehyde and K 2 CO 3 And the molar ratio of the 2-chloromethyl quinoline hydrochloride to the 2-chloromethyl quinoline hydrochloride is 1 (2.5-3.5) to (1-1.1).
Further, the molar ratio of the ether intermediate to p-methylaniline is 1 to 1.2.
In addition, the invention also provides application of the cuprous schiff base complex in preparation of antitumor drugs.
Further, the tumor is cervical cancer, gastric adenocarcinoma, lung cancer and liver cancer.
Compared with the prior art, the invention has the following beneficial effects:
the cellular toxicity test experiment (MTT method) proves that the Schiff base cuprous complex prepared by the method of the invention has good cellular toxicity (IC) effect 50 Less than 20 mu M) and good broad-spectrum anticancer activity, and compared with the corresponding ligand activity, the addition of copper ions can obviously improve the cytotoxicity of the ligand; meanwhile, normal cell HUVEC is researched, and the toxic effect of the cuprous complex on normal cells is found to be smaller than that of cisplatin, so that the defect that the cisplatin has toxic and side effects on normal organisms is overcome to a certain extent, and the cuprous complex has one of the prerequisites of becoming an anti-tumor medicament. The Hoechst33342 staining experiment proves that the Schiff base cuprous complex can generate toxic action on cancer cells in a cell apoptosis inducing mode; the ROS level in the cells after being treated by the cuprous complex is detected by using a DCFH-DA probe, which indicates that the cuprous complex may induce cell death in the form of paraapoptosis.
The cuprous schiff base complex has the advantages of novel structure, simple and reliable preparation method, good product stability and low preparation cost, shows good cytotoxicity and broad-spectrum anticancer activity on four cancer cells HeLa, BGC-823, NCI-H460 and HepG-2, has toxicity less than that of cisplatin on normal cells, is likely to generate toxicity on cancer cells in a cell apoptosis induction mode, and can be used as an antitumor candidate drug.
Drawings
FIG. 1 is a crystal structure diagram of a cuprous schiff base complex in the invention.
FIG. 2 is a scheme showing the synthesis of ligand L according to the present invention.
FIG. 3 shows NMR of ligand L according to the invention: ( 1 H NMR) graph.
FIG. 4 shows NMR of ligand L according to the invention: ( 13 C NMR) graph.
FIG. 5 is a high resolution mass spectrum of the cuprous schiff base complex of the present invention.
FIG. 6 shows the effect of the cuprous schiff base complex prepared by the invention on HeLa cytotoxicity.
FIG. 7 shows the effect of the cuprous schiff base complex prepared by the present invention on the morphology of HeLa cells (100X).
FIG. 8 shows the result (100X) of the production of ROS in HeLa cells by the cuprous schiff base complex prepared by the present invention.
Detailed Description
The present invention is further illustrated by the following specific examples.
Example 1
Synthesis of ligand L (2- (alpha-quinolinylmethoxy) benzaldehyde p-methylaniline Schiff base)
As shown in FIG. 2, to a solution of 1.599mL (15.32 mmol) salicylaldehyde in 150mL acetonitrile was added 3.231g (15.83 mmol) 2-chloromethylquinoline hydrochloride, 6.560g (47.49 mmol) potassium carbonate and a catalytic amount of potassium iodide in N 2 Reflux was heated under atmosphere for 9h and the entire course of the reaction was followed by Thin Layer Chromatography (TLC) (the developing solvent was petroleum ether: ethyl acetate = 2. After the reaction was completed, the mixture was suction filtered, the residue and the inner wall of the flask were washed with a small amount of acetonitrile, and the washing solution was combined into the filtrate. The solution was removed under reduced pressure, an appropriate amount of methylene chloride was added to completely dissolve the solid, extracted three times with distilled water, and the organic phase was collected and dried over anhydrous sodium sulfate. Drying, filtration and desolventizing under reduced pressure gave a yellow solid which was recrystallized several times from acetonitrile and filtered under reduced pressure to give a pale yellow needle crystal (intermediate, 2.868g, yield: 71.1%).
2.868g (10.88 mmol) of the intermediate and 1.286g (12.00 mmol) of p-methylaniline are weighed, and then put into 150mL of anhydrous ethanol under N 2 Heating and refluxing for 5h under the atmosphere. After the reaction is finished, the reaction stock solution is concentrated and then is put into a freezing chamber of a refrigerator. After 15min, a large amount of flocculent solid is separated out from the concentrated solution, and light yellow solid is obtained after decompression and desolventization. By usingThe pale yellow solid was recrystallized from aqueous ethanol several times, and filtered under reduced pressure to give a white flocculent solid (L, 3.366g, yield: 87.8%) having a melting point of 81.2 to 81.7 ℃.
Fig. 3 and 4 show the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance of the ligand L, respectively.
FT-IR(KBr,v/cm -1 ):1596.49,1506.04,1446.67,1367.13,1260.58,1250.06,1224.60,1049.62,812.14,739.34.
1 H NMR(500MHz,CDCl 3 )δ9.08(s,1H),8.19(s,2H),8.08(s,1H),7.84(s,1H),7.75(s,1H),7.64(d,J＝8.5Hz,1H),7.56(s,1H),7.38(d,J＝0.8Hz,1H),7.19(d,J＝7.4Hz,4H),7.05(d,J＝14.5Hz,2H),5.48(s,2H),2.37(s,3H).
13 C NMR(125MHz,CDCl 3 )δ189.59,158.25,157.41,155.45,137.22,136.04,135.60,132.61,129.93,129.74,128.96,127.84,127.76,127.63,126.66,125.21,121.50,121.01,118.97,112.65,71.72,21.01.
Example 2
Cuprous schiff base complex [ CuL]ClO 4 Preparation of
Weighing 0.0705g (0.20 mmol) of ligand L, putting into 20mL of absolute ethyl alcohol, heating to completely dissolve the ligand, keeping the temperature of the solution at about 30-40 ℃, and then adding 0.0741g (0.20 mmol) of Cu (ClO) 4 ) 2 ·6H 2 And O. After the metal salt had completely dissolved, the solution turned brown. Filtering with filter paper, culturing the single crystal with the filtrate by slow solvent evaporation, standing for one day, and separating out yellow needle crystal from the filtrate. The infrared absorption spectrum (FT-IR) and High Resolution Mass Spectrum (HRMS) tests were carried out, and the results were as follows: FT-IR (KBr, v/cm) -1 ):1602.81,1586.04,1565.35,1401.46,1248.51,1093.63,828.76,751.94,622.73.HRMS(ESI-TOF)m/z[C 24 H 20 CuN 2 O] + Theoretical value is 415.0866, found 415.0866 (FIG. 5).
The complex is determined to be a monoclinic system through X-ray single crystal diffraction, the structure of a P21/c space group is determined, and the unit cell parameters are as follows:
α =90 °, β =92.708 (11) °, γ =90 °, Z =4, cell volume £ is £ greater than @>
The whole structure consists of a Schiff base ligand L, a copper ion and a perchlorate ion. In the crystal structure of the complex, copper ions are three-coordinated, and the three coordinating atoms are respectively an O atom in an ether bond, an N atom in N (1) -C (8), and an N atom on a quinoline ring. Quite interestingly, the copper ion in the complex is +1 valent. The reason is as follows: (1) The bond length of N (1) -C (8) is ^>
Therefore, N (1) -C (8) is a double bond, so that the coordinating atom of N (1) is neutral; (2) the O-coordinating atom in the ether linkage is neutral; (3) the N coordination atom in the quinoline ring is neutral; and (4) the external ions only have one perchlorate ion. In the complex, cu and the remaining three coordination atoms are in the same plane and form a T-shaped structure. The crystallographic and key angle data for the complexes are shown in tables 1 and 2, respectively.
TABLE 1 crystallographic data for the complexes
TABLE 2 partial bond length of the complexes
And key angle data (°) </or >>
Example 3
Cuprous schiff base complex [ CuL]ClO 4 Cytotoxicity test of
The cytotoxicity is detected by MTT (tetramethylazozolium, thiazole blue for short) method, and the basic steps are that a blank group (cell culture medium), a control group (drug dissolution medium with the same concentration) and an additive group are set. Cells were seeded in 96-well culture plates (5X 10) 3 One/well), 6 wells per group, the well plate was filled with sterile PBS around the periphery and placed in an incubator (37 ℃,5% CO) 2 ) After 24h of medium incubation, the complexes with different concentrations are respectively added into corresponding pore plates, and the culture medium is continuously placed in an incubator for incubation. After 48h, 20. Mu.L of MTT solution (5 mg/mL) was added to each well and incubation was continued for 4h, the supernatant was carefully aspirated off, dimethyl sulfoxide (100. Mu.L/well) was added, shaking was carried out gently, reaction was carried out at room temperature for 10min, absorbance at 492nm was measured with a microplate reader, and then data was analyzed, and each set of experiments was repeated three times. Usually also using half the inhibition ratio IC 50 The value is used to measure the cytotoxicity. IC (integrated circuit) 50 Defined as the concentration of drug required to kill half of the cells.
Cuprous schiff base complex [ CuL ]]ClO 4 In vitro cytotoxicity Studies
Investigation of cuprous Complex [ CuL]ClO 4 The in vitro antitumor activity of the compound takes cisplatin as a positive control, and an MTT colorimetric method is utilized to explore the cytotoxicity effect of the cuprous complex on four cancer cells HeLa, BGC-823, NCI-H460, hepG-2 and normal cells HUVEC. The results of the experiments are shown in Table 3 below, comparing the IC of cuprous compounds and cisplatin 50 The copper complex is found to show good cytotoxicity and broad-spectrum anticancer activity, and compared with the corresponding ligand activity, the addition of copper ions can obviously improve the cytotoxicity of the ligand. The research on normal cell HUVEC shows that the toxicity effect of the cuprous complex on normal cells is smaller than that of cisplatin, the defect that cisplatin has toxic and side effects on normal organisms is overcome to a certain extent, and the cuprous complex has one of the prerequisites of becoming an anti-tumor medicament. Table 3 lists the complex-to-cell IC 50 Value data.
TABLE 3 Complex-to-cell IC 50 Value of
Based on the good cytotoxicity of the cuprous complexes, the influence of time on the anticancer activity of the complexes was investigated, according to IC 50 We mainly treated HeLa cells and NCI-H460 cells. The results are shown in FIG. 6, and the complex has increasing toxicity to tumor cells with time, which shows that the complex has certain time dependence.
Example 4
Cuprous schiff base complex [ CuL]ClO 4 Apoptosis morphology detection assay
Apoptosis morphology detection assays utilize Hoechst33342 staining. Hoechst33342 is a blue fluorescent dye which can penetrate cell membranes, has low toxicity to cells, is commonly used for detecting apoptosis, and is detected by a fluorescence microscope or a flow cytometer after being dyed.
MTT experimental results show that cuprous complex has good toxic effect on HeLa and NCI-H460 cells. The induction of apoptosis is one of the main modes of cell death, and the apoptosis is characterized by a series of morphological changes, so that the corresponding morphological changes of HeLa and NCI-H460 cancer cells treated by the complexes are observed by a Hoechst33342 staining method, and the IC of each complex is determined according to the corresponding morphological changes of the HeLa and NCI-H460 cancer cells 50 The values set the corresponding concentrations for processing. The method comprises the following basic steps: a control group (a drug dissolution medium with the same concentration), a positive control group and a drug-adding group are arranged, and cisplatin is used as a positive control. The tumor cells were then seeded in 12-well culture plates (4X 10) 5 One/well) for 24h, adding a control, a positive control and a complex with a certain concentration into each well plate respectively, incubating for 24h, washing with precooled PBS, and adding Hoechst33342 (1 μ g.mL) -1 ) Staining was carried out at 37 ℃ for 15min in the dark. The cells were washed 2-3 times with pre-chilled PBS for 3 minutes each, and finally observed and photographed under a fluorescent microscope.
And detecting the morphological change of the cuprous complex on the cuprous complex by using HeLa cells. As shown in FIG. 7, in the control group, the cells remained in a normal growth state without any external influence, and the Hoechst33342 dye that entered the cells was excluded from the body, so that the cells appeared colorless or light blue; in the positive control group, due to the action of cisplatin, the cells show bright blue and a small part of bright blue generated by shrinkage of late-stage apoptosis cells; in the drug-adding group, due to the increase of apoptotic cells, the cells treated by the cuprous complex show bright blue and are accompanied by highlighted cells generated by cell shrinkage, and meanwhile, the cells also show characteristic apoptotic forms such as cell expansion, nuclear fragmentation, apoptotic bodies and the like.
Example 5
Cuprous schiff base complex [ CuL]ClO 4 Effect on intracellular ROS levels
According to the above experimental results, the cuprous complex may exert toxic effects on cancer cells by inducing apoptosis. Apoptosis is closely related to the production of intracellular ROS, and apoptosis of cells is often accompanied by an increase in ROS levels. Therefore, the DCFH-DA probe is used for detecting the ROS level in the cells after being treated by the cuprous complex, so that the cancer inhibition mechanism of the complex is explored.
As shown in fig. 8, the effect of cuprous complex on ROS levels in HeLa cells was explored using the DCFH-DA probe. Substantially no green fluorescence was evident in control cells; in the drug-added group, the green fluorescence in the HeLa cell is continuously enhanced along with the continuous increase of the concentration of the complex, which shows that the cuprous complex can cause apoptosis by up-regulating the ROS level in the cell and has certain concentration dependence. Meanwhile, cells treated by the cuprous complex all show a cell rounding and swelling form, and the staining result is similar to that of Hoechst 33342. This suggests that the cuprous complex may induce cell death in the form of paraapoptosis.
Claims (8)
1. A cuprous schiff base complex is characterized in that the cuprous complex has a chemical formula of [ CuL]ClO 4 Wherein L is 2- (alpha-quinolinylmethoxy) benzeneFormaldehyde condensation p-methylaniline schiff base; the structural formula of the cuprous complex is as follows:
the crystal structure of the cuprous complex is a monoclinic system, the structure of a P21/c space group is shown, and the unit cell parameters are as follows: a =7.0222 (8), b =18.549 (2), c =16.667 (3), a =90, β =92.708 (11), γ =90, Z =4, the unit cell volume V =2168.5 (5) a 3, the entire structure being composed of schiff base ligand L and one +1 valent copper ion, one perchlorate ion external, the complex being yellow; in the crystal structure of the complex, copper ions are three-coordinated, three coordinating atoms are respectively an O atom in an ether bond, an N atom in a C = N bond and an N atom on a quinoline ring, and Cu and the three coordinating atoms are in the same plane to form a T-shaped structure.
2. A process for the preparation of cuprous schiff base complex according to claim 1, comprising the steps of: dissolving ligand L in anhydrous ethanol, heating to dissolve ligand completely, maintaining the solution temperature at 30-40 deg.C, and adding inorganic copper salt Cu (ClO) 4 ) 2 ·6H 2 O, after the metal salt is completely dissolved, the solution turns brown; filtering with filter paper rapidly, culturing the single crystal with filtrate by slow volatilization method, standing for one day, and separating yellow needle crystal from filtrate to obtain [ CuL]ClO 4 And (3) a complex.
3. The preparation method of the cuprous schiff base complex according to claim 2, wherein the synthesis method of the ligand L comprises: adding K to a solution of salicylaldehyde in acetonitrile 2 CO 3 Then adding 2-chloromethyl quinoline hydrochloride, heating and refluxing for 8-10 h, carrying out suction filtration on the mixture, carrying out decompression and desolventizing, completely dissolving the solid by using dichloromethane, extracting by using distilled water, collecting an organic phase, and drying by using anhydrous sodium sulfate; drying, filtering, removing solvent under reduced pressure, recrystallizing the yellow solid with acetonitrile for several times, filtering under reduced pressure to obtain ether intermediate, and removing etherHeating and refluxing the intermediate and p-methylaniline in ethanol solution for 5-6 h to obtain a ligand L, namely the 2- (alpha-quinoline methoxyl) benzaldehyde p-methylaniline Schiff base.
4. A schiff base cuprous complex preparation method according to claim 2, wherein said ligand L is ligand L and Cu (ClO) 4 ) 2 ·6H 2 The molar ratio of O is 1.
5. A process for the preparation of cuprous schiff base complex according to claim 3, wherein said salicylaldehyde, K 2 CO 3 And 2-chloromethyl quinoline hydrochloride in a molar ratio of 1.
6. The preparation method of a schiff base cuprous complex according to claim 3, wherein the molar ratio of ether intermediate to p-methylaniline is 1.
7. Use of the cuprous schiff base complex of claim 1 in the preparation of an anti-tumor medicament.
8. The use according to claim 7, wherein the tumor is cervical cancer, gastric adenocarcinoma, lung cancer and liver cancer.
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| WO2022002104A1 (en) * | 2020-07-02 | 2022-01-06 | 长沙天赐生物医药科技有限公司 | Diazeniumdiolate schiff base copper complex, preparation method therefor and application thereof |
| CN113735781A (en) * | 2021-08-18 | 2021-12-03 | 广西师范大学 | Copper complex and preparation method and application thereof |
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