Polychlorinated aminophenol Schiff base derivative as well as preparation method and application thereof

Abstract

The invention discloses a polychlorinated aminophenol Schiff base derivative and a preparation method and application thereof, the structural formula of the polychlorinated aminophenol Schiff base derivative is # imgabs0, the polychlorinated aminophenol Schiff base derivative disclosed by the invention has a molecular structure which is totally different from that of an existing antitumor drug, and a brand new thought is opened up for research and development of the antitumor drug.

Description

Technical Field

[0001] The present invention belongs to the technical field of the application of Schiff base derivatives, and particularly relates to a polychlorinated aminophenol Schiff base derivative, a preparation method thereof, and an application thereof. Background Art

[0002] Cancer is a complex disease characterized by the uncontrolled division and growth of cancer cells, a process that not only disrupts the normal tissue structure of the body but also interferes with the physiological functions of organs.

[0003] In the research and development process of anti-cancer drugs, cisplatin, as the first-generation metal-based anti-tumor drug, has milestone significance. It inhibits the proliferation of cancer cells effectively by cross-linking with the DNA of cancer cells and interfering with its replication and transcription processes. Therefore, cisplatin is widely used in the clinical treatment of various malignant tumors, including testicular cancer, ovarian cancer, lung cancer, etc. However, the clinical application of cisplatin is also accompanied by some serious side effects. For example, nephrotoxicity may lead to renal failure, and ototoxicity may cause irreversible hearing loss. These side effects not only affect the quality of life of patients but also may limit the dosage and treatment course of the drug, thereby reducing the treatment effect. Therefore, searching for new anti-cancer drugs to improve the curative effect and reduce side effects has always been a hot topic in the fields of drug synthesis and biological mechanism research. Summary of the Invention

[0004] The purpose of the present invention is to overcome the defects of the prior art and provide a polychlorinated aminophenol Schiff base derivative.

[0005] Another purpose of the present invention is to provide a preparation method of the above-mentioned polychlorinated aminophenol Schiff base derivative.

[0006] Another purpose of the present invention is to provide an application of the above-mentioned polychlorinated aminophenol Schiff base derivative.

[0007] The technical solution of the present invention is as follows:

[0008] A polychlorinated aminophenol Schiff base derivative, the structural formula of which is

[0009] The preparation method of the above-mentioned polychlorinated aminophenol Schiff base derivative, the reaction route of which is

[0010]

[0011] The use of the above-mentioned polychlorinated aminophenol Schiff base derivative in the preparation of an anti-cancer composition.

[0012] An anti-cancer composition, the active ingredient of which comprises the above-mentioned polychlorinated aminophenol Schiff base derivative.

[0013] A nickel complex of a polychlorinated aminophenol Schiff base derivative, whose structural formula is

[0014]

[0015] The preparation method of the above nickel complex of the polychlorinated aminophenol Schiff base derivative, and its reaction route is

[0016]

[0017] The use of the above nickel complex of the polychlorinated aminophenol Schiff base derivative in the preparation of an anticancer composition.

[0018] In a preferred embodiment of the present invention, the anticancer composition has anticancer activity against breast cancer, non-small cell lung cancer, nasopharyngeal carcinoma and colon cancer.

[0019] An anticancer composition, whose active ingredient includes the above nickel complex of the polychlorinated aminophenol Schiff base derivative.

[0020] In a preferred embodiment of the present invention, it has anticancer activity against breast cancer, non-small cell lung cancer, nasopharyngeal carcinoma and colon cancer.

[0021] The beneficial effects of the present invention are:

[0022] 1. The polychlorinated aminophenol Schiff base derivative of the present invention has a molecular structure completely different from that of existing antitumor drugs, opening up a new idea for the research and development of antitumor drugs.

[0023] 2. The preparation method of the polychlorinated aminophenol Schiff base derivative of the present invention uses aminophenol derivatives and chloroaromatic aldehydes as raw materials under solvent conditions such as low temperature and absolute ethanol, and can prepare polychlorinated aminophenol Schiff base derivatives with high purity and high yield; this method has the advantages of simple process, pure product, high yield and convenient post-treatment.

[0024] 3. The nickel complex of the polychlorinated aminophenol Schiff base derivative of the present invention exhibits significant anticancer activity, which is of great significance for the effective development and utilization of a series of anticancer drugs.

[0025] 4. The preparation method of the nickel complex of the polychlorinated aminophenol Schiff base derivative of the present invention adopts a solvothermal preparation method, which has the characteristics of pure product, relatively high yield and convenient post-treatment. Description of the Drawings

[0026] Figure 1 It is the molecular structural formula of the Y2 nickel complex prepared in Example 2 of the present invention.

[0027] Figure 2MTT graphs of Y1, Y2 nickel complexes and cisplatin against SKBR3, MAD-MB-231, A549, CNE-2Z and HCT116 cancer cells in Example 3 of the present invention.

[0028] Figure 3 Showing the ultraviolet absorption spectrum of Y2 nickel complex in Tris-HCl-NaCl buffer solution in Example 5 of the present invention. Detailed implementation manners

[0029] The technical solutions of the present invention will be further described and illustrated below through specific implementation manners in conjunction with the accompanying drawings.

[0030] Example 1

[0031] The reaction formula of this example is:

[0032]

[0033] Specifically, it includes the following steps:

[0034] (1) Add 2-amino-4-chlorophenol (6.96 mmol) and 60 mL of absolute ethanol into a reactor equipped with a stirrer and a temperature control device. While controlling the temperature at 60 °C, slowly add 30 mL of an absolute ethanol solution of 3,5-dichlorosalicylaldehyde (6.96 mmol) with a total amount of 1.33 g in batches, mix evenly, and continuously stir and react for 5 h;

[0035] (2) After filtering the reaction product obtained in step (1), wash it with absolute ethanol to obtain an orange-red powder product of polychlorinated aminophenol Schiff base derivative Y1 with a purity of 99.5% and a yield of 84.52%.

[0036] The NMR results of the polychlorinated aminophenol Schiff base derivative Y1 are as follows: 1H NMR (400 MHz, d6-DMSO): δ 15.00 (s, 1H), 10.38 (s, 1H), 9.09 (s, 1H), 7.84–7.47 (m, 3H), 7.23 (dd, J = 8.7, 2.5 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H). 13C NMR (101 MHz, d6-DMSO): δ 160.57, 157.76, 150.14, 133.31, 132.31, 130.36, 128.31, 123.21, 122.37, 120.92, 119.94, 118.92, 117.96.

[0037] Example 2

[0038] The reaction formula of this example is

[0039]

[0040] Specifically, it includes the following steps:

[0041] (1) Put 0.01 g of the polychlorinated aminophenol Schiff base derivative Y1 prepared in Example 1, 8 mL of absolute ethanol, 0.03 mL of triethylamine, and 0.0075 g of nickel chloride hexahydrate into a reaction flask and mix evenly at room temperature;

[0042] (2) Transfer the material prepared in step (1) to the polytetrafluoroethylene inner liner in a 25 mL high-pressure reaction kettle, and carry out a solvothermal reaction for 72 h under the conditions of a filling degree of 80% and a reaction temperature of 65 °C, and cool to room temperature to obtain yellow-green square crystals.

[0043] (3) After solid-liquid separation of the material obtained in step (2), wash it with absolute ethanol 2-3 times to obtain the crystal of the polychlorinated aminophenol Schiff base nickel complex (Y2 nickel complex) as shown in Figure 1 Figure.

[0044] The crystal of this Y2 nickel complex belongs to the tetragonal system, the space group is I41 / a, the crystal size is 0.08×0.06×0.04 mm, and the unit cell parameters are: α = 90°, β = 90°, γ = 90°, D c = 1.683 g·cm -3 , Z = 4, μ = 1.668 mm -1 .

[0045] Example 3

[0046] In this example, the MTT colorimetric method was used to screen the cytotoxicity of Y1, Y2 nickel complexes and cisplatin. The specific operation process is as follows: Take a 96-well plate. To prevent edge effects, add 100 μL of PBS to each well around the plate for edge sealing. Then add 100 μL of cell suspension with a concentration of about 4×10 3 cells / well to the middle 5 rows.

[0047] Among them, the first row was set as the blank control group and the same volume of complete medium was added; the second row was the negative control containing 1% DMSO, and 100 μL of cell suspension was also added. Then place the culture plate in an incubator and culture for 24 h. Next, add 100 μL of the drug to be tested to each well and continue to culture for 48 h.

[0048] After the incubation was completed, 10 μL of MTT solution with a concentration of 0.5 mg / mL was added to each well, and then the culture plate was returned to the incubator for 4 h of incubation. At this time, purple formazan crystals could be seen in the wells. Then, 150 μL of DMSO was added to each well and incubated in a 37 °C incubator for 30 min until the formazan crystals were completely dissolved. Finally, the OD values of each well were measured using a microplate reader at a wavelength of 490 nm. For each sample concentration, 5 replicate wells were set, and the average value was taken to calculate the inhibition rate.

[0049] As shown in Table 1, after screening the cytotoxicity of Y1, Y2 nickel complexes and cisplatin by the above MTT method, it was found that the Y2 nickel complex showed a certain degree of inhibitory effect on four different cancer cells. From Table 1 and Figure 2 the data in it, it can be seen that the Y2 nickel complex showed anticancer activity against SKBR3, CNE-2Z, A549, MDA-MB-231 and HCT116 cells. Its IC 50 values were significantly lower than those of cisplatin, indicating that this Y2 nickel complex has broad anticancer activity, which is closely related to its unique molecular structure. These experimental results show that the nickel complex of polychlorinated aminophenol Schiff base has significant anticancer potential, and the formation of a metal complex with a specific structure by coordination with nickel ions can effectively enhance its anticancer activity.

[0050] Table 1 Anticancer activity of compounds against SKBR3, MAD-MB-231, A549, CNE-2Z and HCT116 cells (IC 50 )

[0051]

[0052] Example 4

[0053] "Synthesis, Crystal Structure and Anticancer Studies of Cubane-Type Ni(II) Complex Derived from 5-bromosalicylaldehyde-2-aminophenol Schiff Base" discloses a cubane-type nickel(II) complex with the structural formula Its structure is a cubane-type [Ni4O4] cluster and belongs to the tetragonal crystal system. In this example, its anticancer activity was compared with the Y2 nickel complex prepared in Example 2. The specific results are shown in Table 2 below (the detection method is also the MTT colorimetric method).

[0054] Table 2 Anticancer activity of compounds against different cells (IC 50 )

[0055] Cell line <![CDATA[Y2 nickel complex (IC 50 , μM)]]> <![CDATA[Cubic nickel(II) complex (IC 50 , μM)]]> CNE-2Z 7.78±0.51 9.31±0.73 MDA-MB-231 3.71±0.86 15.87±4.86 A549 9.81±1.65 15.58±0.38 SKBR3 7.58±0.46 Not tested HCT116 2.13±0.38 Not tested SMMC-7721 Not tested 10.24±1.07

[0056] As shown in Table 2, the Y2 nickel complex prepared in Example 2 has better broad-spectrum properties compared to the cubic nickel(II) complex, and among the co-tested cells (CNE-2Z, MDA-MB-231, and A549), the IC 50 of the Y2 nickel complex is significantly better than that of the cubic nickel(II) complex, that is, the Y2 nickel complex has better anti-cancer activities against nasopharyngeal carcinoma, triple-negative breast cancer, and non-small cell lung cancer.

[0057] Example 5

[0058] In this example, in order to deeply study the stability of the Y2 nickel complex prepared in Example 2 in Tris-HCl-NaCl buffer solution, the ultraviolet absorption peaks of the Y2 nickel complex were detected at 0 h, 24 h, and 48 h respectively. The experimental results are as Figure 3 shown. The Y2 nickel complex has absorption peaks at 291 nm and 428 nm, and at 24 h and 48 h, there is no obvious red shift or blue shift in the ultraviolet absorption peaks of the Y2 nickel complex. In addition, no new absorption peaks were detected during the whole experimental process. This indicates that the Y2 nickel complex is stable in Tris-HCl-NaCl buffer.

[0059] The above is only the preferred embodiment of the present invention, so the scope of implementation of the present invention cannot be limited thereby. That is, equivalent changes and modifications made according to the scope of the present invention patent and the content of the specification should still be within the scope covered by the present invention.

Claims

1. A polychlorinated aminophenol Schiff base derivative, characterized in that: Its structural formula is 2. The preparation method of a polychlorinated aminophenol Schiff base derivative according to claim 1, characterized in that: The reaction route is 3. Use of the polychlorinated aminophenol Schiff base derivative according to claim 1 in the preparation of an anticancer composition.

4. An anticancer composition, characterized in that: Its active ingredient includes the polychlorinated aminophenol Schiff base derivative according to claim 1.

5. A nickel complex of a polychlorinated aminophenol Schiff base derivative, characterized in that: Its structural formula is 6. The preparation method of a nickel complex of a polychlorinated aminophenol Schiff base derivative as claimed in claim 5, characterized in that: Its reaction route is 7. Use of the nickel complex of the polychlorinated aminophenol Schiff base derivative according to claim 5 in the preparation of an anticancer composition.

8. An anti-cancer composition according to claim 7, wherein: The said anticancer composition has anticancer activity against breast cancer, non-small cell lung cancer, nasopharyngeal carcinoma and colon cancer.

9. An anti-cancer composition, characterized in that: Its active ingredient includes the nickel complex of the polychlorinated aminophenol Schiff base derivative according to claim 5.

10. An anti-cancer composition according to claim 9, characterized in that: It has anticancer activity against breast cancer, non-small cell lung cancer, nasopharyngeal carcinoma and colon cancer.

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