Synthesis method of pyrazole aldehyde Schiff base with antitumor activity

Abstract

The invention discloses a synthesis method of pyrazole aldehyde Schiff base with anti-tumor activity, which comprises the following steps: by taking pyrazole aldehyde compounds and amino acid as initial raw materials, efficiently synthesizing a target product under mild reaction conditions through a one-step condensation reaction, mixing the pyrazole aldehyde compounds and the amino acid compounds by adopting a specific catalyst, and reacting to obtain the pyrazole aldehyde Schiff base with the anti-tumor activity. Refluxing at 65 DEG C and carrying out stirring reaction; after the reaction is completed, a crude product can be obtained through simple filtering, rotating and drying steps. The high-purity target pyrazole aldehyde Schiff base compound can be further obtained through purification means such as column chromatography or recrystallization. The synthesis method has the advantages that raw materials are easy to obtain, reaction conditions are mild, operation is easy and convenient, the yield is high and the like, the synthesis method is very suitable for industrial production, and through in-vitro anti-tumor activity tests, the synthesized pyrazole aldehyde Schiff base compound shows a remarkable anti-tumor effect, has an inhibiting effect on multiple tumor cell strains and has a good application prospect. The potential clinical application value is shown.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for synthesizing a pyrazole aldehyde Schiff base with anti-tumor activity. Background Art

[0002] Pyrazoles have two adjacent nitrogen atoms that can act as hydrogen donors or acceptors with different electronegativity and reactivity, which facilitates the synthesis and introduction of substituents, or improves the polarity or water solubility of the molecule, thus possessing broad-spectrum biological properties such as antibacterial, antimalarial, anti-inflammatory, antiviral, anti-tuberculosis, and anticancer activities. Mechanistically, pyrazole derivatives can act on various targets in cancer cells, such as EGFR (epidermal growth factor receptor), BRAF (B-Raf proto-oncogene, serine / threonine kinase) V600E, telomerase, Aurora A kinase, and receptor tyrosine kinases, and have the potential to inhibit cancer cell proliferation, arrest the cell cycle, induce apoptosis, and regulate autophagy. Notably, some commercially available anticancer drugs (such as crizotinib and darotamide) contain a pyrazole moiety. Therefore, pyrazoles are useful pharmacophores for the development of novel anticancer agents.

[0003] As a class of organic compounds containing pyrazole rings and Schiff base structures, pyrazole aldehyde Schiff bases have attracted extensive attention in the field of drug research and development due to their unique chemical structure and diverse biological activities. In particular, recent studies have shown that certain pyrazole aldehyde Schiff base compounds have significant anti-tumor activity, can inhibit the proliferation and migration of tumor cells, and are expected to become lead compounds for new anti-tumor drugs. However, most of the existing pyrazole aldehyde Schiff base synthesis methods have problems such as cumbersome steps, low yield, and difficulty in obtaining raw materials, which limits their further application and development. Summary of the invention

[0004] The purpose of the present invention is to overcome the defects of the prior art and provide a method for synthesizing a pyrazole aldehyde Schiff base with anti-tumor activity. Pyrazole aldehyde and an amino acid compound are used as raw materials, and a target product is directly generated through a one-step condensation reaction. The product exhibits good anti-tumor activity, is simple to operate, has readily available raw materials, and has a high yield.

[0005] The technical solution to achieve the above purpose is: a method for synthesizing a pyrazole aldehyde Schiff base with anti-tumor activity, and the synthetic route of the pyrazole aldehyde Schiff base is as follows:

[0006]

[0007] In the formula, R represents the general structural formula R group of an amino acid. The amino acid structure is composed of a chiral carbon atom connecting -H, -COOH, -N2H and an R group. The amino acids selected in the present invention are glycine, alanine, valine, leucine and phenylalanine, and the R groups represent H, CH3, C3H7, C4H9 or C7H7, respectively.

[0008] The above-mentioned method for synthesizing a pyrazole aldehyde Schiff base having antitumor activity comprises the following steps:

[0009] S1, raw material preparation: pyrazole aldehyde and amino acid are selected as initial raw materials;

[0010] S2, solvent selection: ethanol or methanol is selected as the reaction solvent. The reaction solvent needs to have good solubility for the initial raw materials and be able to promote the reaction;

[0011] S3, reaction conditions: adding pyrazole aldehyde and amino acid to the reaction solvent at room temperature to reflux temperature, and adding a catalyst, heating and stirring until the reaction is complete;

[0012] S4, product separation and purification: after the reaction is completed, cooling, filtering, washing, and rotary concentration steps are sequentially performed to obtain a crude product, and the crude product is purified by column chromatography or recrystallization to obtain the target product, pyrazolealdehyde Schiff base compound;

[0013] S5, biological activity test: The synthesized pyrazole aldehyde Schiff base compounds were tested for their in vitro antitumor activity to verify their ability to inhibit tumor cell proliferation.

[0014] The above-mentioned method for synthesizing a pyrazole aldehyde Schiff base with anti-tumor activity, wherein the pyrazole aldehyde is 3-pyrazole aldehyde; the amino acid is glycine, glutamic acid, alanine, valine, leucine, isoleucine, phenylalanine or aspartic acid; and the catalyst is NaOH.

[0015] The above-mentioned method for synthesizing a pyrazole aldehyde Schiff base with antitumor activity, in step S3, pyrazole aldehyde and amino acid are dissolved in a molar ratio of 1:1 to 1:2, an equimolar mass of catalyst is added, and a 50% mass fraction NaOH aqueous solution is prepared, the reaction time is 18-24h, and the reaction temperature is 50°C to 70°C.

[0016] The above-mentioned method for synthesizing a pyrazole aldehyde Schiff base with anti-tumor activity, wherein the molar ratio of pyrazole aldehyde to amino acid is 1:1.

[0017] The above-mentioned method for synthesizing a pyrazole aldehyde Schiff base with anti-tumor activity, wherein the reaction time is 24 hours.

[0018] The above-mentioned method for synthesizing a pyrazole aldehyde Schiff base with anti-tumor activity, wherein the reaction temperature is 65°C.

[0019] In the above-mentioned method for synthesizing a pyrazole aldehyde Schiff base with antitumor activity, methanol is used as the reaction solvent because it has good solubility for the raw materials and can promote the reaction.

[0020] The above-mentioned method for synthesizing a pyrazole aldehyde Schiff base with anti-tumor activity, wherein the pyrazole aldehyde Schiff base has an inhibitory effect on leukemia HL-60 cells, lung cancer A549 cells, liver cancer HepG2 cells, breast cancer MDA-MB-231 cells and colon cancer SW480 cells at a concentration of 10 μM.

[0021] The method for synthesizing the pyrazole aldehyde Schiff base with anti-tumor activity of the present invention uses pyrazole aldehyde and an amino acid compound as raw materials, directly generates the target product through a one-step condensation reaction, and has the following beneficial effects:

[0022] (1) Short synthetic route: The target product is directly generated through a one-step condensation reaction, which simplifies the synthetic steps and improves the synthetic efficiency;

[0023] (2) Raw materials are readily available: the raw materials used are all commercially available chemicals, which are easy to obtain and reduce production costs;

[0024] (3) High yield: The reaction conditions are mild, the yield is high, and it is suitable for large-scale production;

[0025] (4) Significant anti-tumor activity: The target product exhibits good in vitro anti-tumor activity and is expected to become a lead compound for new anti-tumor drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is a table showing the inhibitory effects of products No. 1-5 on cancer cells;

[0027] Figure 2 This is a graph showing the inhibitory effects of products No. 1-5 on cancer cells. DETAILED DESCRIPTION

[0028] In order to enable those skilled in the art to better understand the technical solution of the present invention, the specific implementation methods thereof are described in detail below in conjunction with the accompanying drawings:

[0029] In the following examples, each reagent used was analytically pure.

[0030] Example 1

[0031] The synthetic route of pyrazole aldehyde Schiff base compound 1 (referred to as product No. 1, 1g-1, YD696) is as follows:

[0032]

[0033] The synthesis method of the above-mentioned pyrazole aldehyde Schiff base 1 is as follows:

[0034] 3-Pyrazole aldehyde (5mmol) and glycine (5mmol) were dissolved in 50mL methanol, 0.2g NaOH was added as a catalyst, heated to 65 degrees Celsius for reflux, and heated and stirred for reflux for 24 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the filtrate was rotated to remove the solvent by a rotary evaporator, and the crude product was obtained after drying. It was further purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:3) to obtain a pure target pyrazole aldehyde Schiff base compound 1. The compound has a significant inhibitory effect on a variety of tumor cell lines in vitro antitumor activity test.

[0035] Example 2

[0036] The synthetic route of pyrazole aldehyde Schiff base compound 2 (referred to as product No. 2, lg-2, YD697) is as follows:

[0037]

[0038] The synthesis method of the pyrazole aldehyde Schiff base compound 2 is similar to that of Example 1, except that glycine is replaced by alanine.

[0039] Example 3

[0040] The synthetic route of pyrazole aldehyde Schiff base compound 3 (referred to as product No. 3, lg-3, YD698) is as follows:

[0041]

[0042] The synthesis method of the pyrazole aldehyde Schiff base compound 3 is similar to that of Example 1, except that glycine is replaced by valine.

[0043] Example 4

[0044] The synthetic route of pyrazole aldehyde Schiff base compound 4 (referred to as product No. 4, lg-4, YD699) is as follows:

[0045]

[0046] The synthesis method of the pyrazole aldehyde Schiff base compound 4 is similar to that of Example 1, except that glycine is replaced by leucine.

[0047] Example 5

[0048] The synthetic route of pyrazole aldehyde Schiff base compound 5 (referred to as product No. 5, lg-5, YD670) is as follows:

[0049]

[0050] The synthesis method of the pyrazole aldehyde Schiff base compound 5 is similar to that of Example 1, except that glycine is replaced by phenylalanine.

[0051] Biological activity test:

[0052] See also Figure 1 and Figure 2 The product No. 1-5 (pyrazole aldehyde Schiff base compound 1-5) synthesized in Example 1-5 was tested for its in vitro antitumor activity to verify its ability to inhibit tumor cell proliferation. Figure 1 and Figure 2 Among them, the numbers corresponding to products No. 1-5 are YD696-YD700 respectively.

[0053] Depend on Figure 1 and Figure 2 The results show that under the condition of 10uM concentration, products 1-5 have inhibitory effects on leukemia HL-60 cells, lung cancer A549 cells, liver cancer HepG2 cells, breast cancer MDA-MB-231 cells, colon cancer SW480 cells and other cells. Products 1-5 have significant inhibitory effects on leukemia HL-60 cells and breast cancer MDA-MB-231 cells, among which product 1 has a higher inhibitory effect on leukemia HL-60 cells than breast cancer MDA-MB-231 cells and other three types of cells; products 2-5 have a higher inhibitory effect on breast cancer MDA-MB-231 cells than leukemia HL-60 cells and other three types of cells. Products 1-5 have inhibitory effects on lung cancer A549 cells, liver cancer HepG2 cells, and colon cancer SW480, but the effect is not significant compared with the inhibitory effect on leukemia HL-60 cells and breast cancer MDA-MB-231 cells.

[0054] In summary, the method for synthesizing the pyrazole aldehyde Schiff base with anti-tumor activity of the present invention uses pyrazole aldehyde and an amino acid compound as raw materials, directly generates a target product through a one-step condensation reaction, and the product exhibits good anti-tumor activity, is simple to operate, has readily available raw materials, and has a high yield, has industrial application prospects, and provides new technical means and candidate molecules for the research and development and production of anti-tumor drugs.

[0055] Those skilled in the art should recognize that the above embodiments are only used to illustrate the present invention, and are not intended to limit the present invention. As long as they are within the spirit of the present invention, any changes or modifications to the above embodiments will fall within the scope of the claims of the present invention.

Claims

1. A method for synthesizing a pyrazole aldehyde Schiff base having antitumor activity, characterized in that: The synthetic route of pyrazole aldehyde Schiff base is as follows: Wherein, R is H, CH3, C3H7, C4H9 or C7H7.

2. The method for synthesizing a pyrazole aldehyde Schiff base having antitumor activity according to claim 1, characterized in that: The following steps are involved: S1, raw material preparation: pyrazole aldehyde and amino acid are selected as initial raw materials; S2, solvent selection: select ethanol or methanol as the reaction solvent; S3, reaction conditions: adding pyrazole aldehyde and amino acid to the reaction solvent at room temperature to reflux temperature, and adding a catalyst, heating and stirring until the reaction is complete; S4, product separation and purification: after the reaction is completed, cooling, filtering, washing, and rotary concentration steps are sequentially performed to obtain a crude product, and the crude product is purified by column chromatography or recrystallization to obtain the target product, pyrazolealdehyde Schiff base compound; S5, biological activity test: The synthesized pyrazole aldehyde Schiff base compounds were tested for their in vitro antitumor activity to verify their ability to inhibit tumor cell proliferation.

3. The method for synthesizing a pyrazole aldehyde Schiff base having antitumor activity according to claim 2, characterized in that: The pyrazole aldehyde is 3-pyrazole aldehyde; the amino acid is glutamic acid, alanine, valine, leucine, isoleucine, phenylalanine or aspartic acid; and the catalyst is NaOH.

4. The method for synthesizing a pyrazole aldehyde Schiff base having antitumor activity according to claim 2 or 3, characterized in that: In step S3, pyrazole aldehyde and amino acid are dissolved in a molar ratio of 1:1 to 1:2, and an equal molar mass of catalyst is added to prepare a 50% mass fraction NaOH aqueous solution. The reaction time is 18-24 hours and the reaction temperature is 50°C to 70°C.

5. The method for synthesizing a pyrazole aldehyde Schiff base having antitumor activity according to claim 4, characterized in that: The molar ratio of pyrazole aldehyde to amino acid dissolution was 1:

1.

6. The method for synthesizing a pyrazole aldehyde Schiff base having antitumor activity according to claim 4, characterized in that: The reaction time is 24h.

7. The method for synthesizing a pyrazole aldehyde Schiff base having antitumor activity according to claim 4, characterized in that: The reaction temperature was 65°C.

8. The method for synthesizing a pyrazole aldehyde Schiff base having antitumor activity according to claim 2, characterized in that: The reaction solvent used was methanol.

9. The method for synthesizing a pyrazole aldehyde Schiff base having antitumor activity according to claim 2, characterized in that: At a concentration of 10 μM, pyrazole aldehyde Schiff base has an inhibitory effect on leukemia HL-60 cells, lung cancer A549 cells, liver cancer HepG2 cells, breast cancer MDA-MB-231 cells and colon cancer SW480 cells.

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