CN105061409B - A kind of diphenyl pyrone class compound of 1,2,3- triazoles substitution and its preparation method and application - Google Patents

Abstract

The present invention relates to a kind of 1,2,3-triazole substituted bisphenylpyrone compounds, the general structural formula of which is as follows: Wherein the substituent R is a halogen, an alkyl group or an electron-withdrawing substituent, which can be located at the ortho, meta or para position of the benzene ring. The present invention also relates to the preparation of the above-mentioned 1,2,3-triazole-substituted biphenylpyrone compounds and their application in antitumor. The compound of the present invention has strong inhibitory activity on tumor cells, and this type of compound can be used for the treatment of tumors.

Description

A kind of 1,2,3-triazole substituted biphenylpyrone compound and its preparation method and application

technical field

The invention relates to the technical field of medicine, in particular to a 1,2,3-triazole-substituted bisphenylpyrone compound and a preparation method and application thereof.

Background technique

Tumor is one of the diseases that seriously endanger human health. According to data from the Chinese Medical Association in 2007, malignant tumors have become the number one killer among various diseases that endanger the lives of Chinese residents. In China, 2 million people die of tumors every year. Chemotherapy is one of the three major methods of cancer treatment. After years of hard work, some cancers can now be cured by drug chemotherapy. The currently used anti-tumor drugs have serious side effects: (1) The selectivity to tumor cells is not strong, and while killing tumor cells, it also damages normal cell nucleus tissue; (2) Tumor cells develop drug resistance to anti-tumor drugs . This is an urgent problem to be solved in tumor drug therapy.

The skeleton of diphenylpyrone is a simple tricyclic structure, and the tricyclic rings are in the same plane, forming π-π conjugation, which is similar to the chemical structure of anthrone antitumor drugs, and has significant antitumor activity. The Second Military Medical University of the Chinese People's Liberation Army, in May 2012, the master's degree thesis "Design, Synthesis and Biological Activity Research of Biphenylpyrone Derivatives", disclosed a class of bisphenylpyrone compounds with triazole rings, but Its structure is different from that of the present invention, and the involved compound has no obvious inhibitory effect on non-small cell lung cancer.

The present invention uses bisphenylpyrone as the basic core and introduces different nitrogen heterocycles at the 3-position: 1-hydroxyl-3-(1H-1,2,3-triazol-4-yl)bis Phenylpyrone compounds have good antitumor activity, but their structure and activity have not been reported so far.

Contents of the invention

The object of the present invention is to provide a 1,2,3-triazole-substituted bisphenylpyrone compound against the deficiencies in the prior art.

Another object of the present invention is to provide a preparation method of the above-mentioned bisphenylpyrone compounds.

Another object of the present invention is to provide the use of the above-mentioned bisphenylpyrone compounds.

For realizing above-mentioned object, the technical scheme that the present invention takes is:

A 1,2,3-triazole-substituted bisphenylpyrone compound, characterized in that the general structural formula of the 1,2,3-triazole-substituted bisphenylpyrone compound is as follows:

Wherein the substituent R is a halogen, an alkyl group or an electron-withdrawing substituent, and is located at the ortho, meta or para position of the benzene ring.

Preferably, the substituent R is halogen; the halogen is F, Cl or Br.

Preferably, the substituent R is an alkyl group; the alkyl group is an alkyl group with 1-4 carbon atoms.

Preferably, the substituent R is an electron-withdrawing substituent; the electron-withdrawing substituent is nitro, cyano, trifluoromethyl or trifluoromethoxy.

Preferably, the substituent R is CH ₃ , F, Cl, Br or CN.

Preferably, the substituent R is as follows:

serial number R IC50(μg/ml) 1c 2-CH3 27.87 1g 4-Cl 21.64 1h 3-Cl 19.06 1j 4-Br 15.15 1k 3-Br 33.37

For realizing above-mentioned second purpose, the technical scheme that the present invention takes is:

As mentioned above, the preparation method of 1,2,3-triazole substituted bisphenylpyrone compounds, the reaction scheme is as follows:

Scheme 1 Reagents and conditions: (a) P ₂ O ₅ /Ch ₃ SO ₃ H 85°C, 2.5h; (b) K ₂ CO ₃ , DMF, rt, 4h.

Scheme 2 Reagents and conditions:) a) DMSO, rt, 12h; (b) CuSO4.5H ₂ O, rt, 16h.

include:

(a) using 2-hydroxysalicylic acid and phloroglucinol as raw materials, stirring and reacting in Eaton's reagent to generate 1,3-dihydroxybisphenylpyrone (4);

(b) 1,3-dihydroxybisphenylpyrone, potassium carbonate, and propyne bromide are stirred and reacted in DMF to generate 1-hydroxy-3-(2-alkynyloxy)-bisphenylpyrone (5) ;

(c) sodium azide, intermediate, 1-hydroxyl-3-(2-alkynyloxy)-diphenylpyrone, copper sulfate, and sodium ascorbate react at room temperature in dimethyl sulfoxide to generate the target compound; Described intermediate structure is as follows:

Preferably, the stirring reaction temperature in the step (a) is 85° C., and the reaction time is 4 hours.

For realizing above-mentioned 3rd purpose, the technical scheme that the present invention takes is:

The application of the above-mentioned 1,2,3-triazole-substituted bisphenylpyrone compounds in the preparation of antitumor drugs.

Preferably, the tumor is lung cancer.

Preferably, the lung cancer is non-small cell lung cancer.

The drug for treating lung cancer contains the above-mentioned 1,2,3-triazole-substituted bisphenylpyrone compounds, pharmaceutically acceptable carriers and conventional drug carriers.

The present invention has the advantage that:

The present invention uses bisphenylpyrone as the basic core and introduces different nitrogen heterocycles at the 3-position to prepare 1-hydroxy-3-(1H-1,2,3-triazol-4-yl)bisphenyl Pyrone compounds, the experimental results show that the compounds of the present invention have better inhibitory activity on tumor cell proliferation, especially compounds 1c, 1g, 1h, 1j and 1k have a strong effect on human non-small cell lung cancer cells (A495). The inhibitory effect on cell proliferation, this type of compound can be used as a candidate drug for tumor treatment.

Description of drawings

Accompanying drawing 1 is the general structural formula of the compound of the present invention.

Detailed ways

The present invention will be further described below in combination with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the contents of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

The synthesis of embodiment 1 compound of the present invention

The preparation reaction scheme of compound of the present invention is as follows:

Scheme Reagents and conditions: (a) P ₂ O ₅ /CH ₃ SO ₃ H 85℃, 2.5h; (b) Propargylbronide, L ₂ CO ₃ , SMF, 4h; (c) Corresponding benzyl azide, DMSO, CuSO ₄ . _5H2O , rt, 16h.

The specific preparation method of the compound involved in the described reaction scheme route is as follows:

(1) Synthesis of 1,3-dihydroxybisphenylpyrone (4)

2-Hydroxysalicylic acid (6.9g, 0.05mol) and phloroglucinol (6.3g, 0.05mol) were dissolved in Eaton's reagent, stirred and reacted at 85°C for 4 hours, the reaction was complete, cooled to room temperature, and an appropriate amount of ice water was added Excessive acid was quenched, stirred for 2 hours and left to stand, filtered, dissolved in ethyl acetate, washed with water until neutral, dehydrated with anhydrous sodium sulfate, evaporated to dryness, mixed with a small amount of silica gel column chromatography (PE:EA=6:1 ).

(2) Synthesis of 1-hydroxy-3-(2-alkynyloxy)-biphenylpyrone (5)

Dissolve 1,3-dihydroxybisphenylpyrone (4) (2.33g, 0.0102mol) in DMF, then add potassium carbonate (2.82g, 0.0204mol) and propyne bromide (1.34g, 0.0114mmol), After stirring for 1.5 hours at 25°C, stir at room temperature for 4 hours. TLC detected that the reaction was complete. Pour into water, wash with ethyl acetate, remove water with anhydrous sodium sulfate, evaporate the solvent to dryness, mix a small amount of silica gel, and then perform column chromatography (PE:EA=8 :1).

(3) Synthesis of the target compound

Dissolve sodium azide (40mg, 0.65mmol) in DMSO, add p-methylbenzyl bromide (100mg, 0.54mmol) and stir overnight at room temperature, add 1-hydroxy-3-(2-alkynyloxy)-biphenyl Pyrone (5) (110mg, 0.41mmol), then dissolve copper sulfate pentahydrate (catalytic amount) in water, add sodium ascorbate (catalytic amount), quickly drop into the reaction solution, stir overnight, the reaction is complete, dichloro Methane was dissolved and extracted twice, water was removed with anhydrous sodium sulfate, the solvent was evaporated to dryness, and silica gel column chromatography (PE:EA=3:1) was used to obtain compound 1a.

It should be noted that, for compounds whose substituents R in the general formula are _CH3 , F, Cl, Br, CN, respectively located at the ortho, meta, or para positions of the benzene ring (i.e. 1b-1n), the corresponding R group Substitute benzyl bromide as a raw material, and the preparation method is the same as above. The numbers, structures and H NMR data of the prepared compounds are shown in Table 1.

Table 1 Proton NMR spectrum data of the target compound

The reagents used in the above examples are commercially available analytically pure. It should be understood that the above examples only use the substituent R as CH ₃ , Cl, Br, CN, but the implementation of the present invention is not limited to the above examples. Using different substituents R as synthetic raw materials, repeat the steps in the above examples, The desired compound can be synthesized.

The pharmacological experiment of embodiment 2 compounds of the present invention

(1) Experimental materials

1. Test sample

After the target compounds were dissolved in DMSO (Merck), PBS (-) was added to make a 1000 μg/ml solution or a homogeneous suspension, and then diluted with DMSO-containing PBS (-).

2. Cell lines

A549 (human non-small cell lung cancer cells).

3. Other materials and main instruments

Culture medium: RPMI1640 + 15% NBS + double antibody; MTT: [thiazolyl blue] was purchased from Sigma Company (St.Louis, MO, USA); other reagents were domestic analytical grade. Fully automatic microplate reader WellscanMK-2 (Labsystems Company), CO ₂ constant temperature incubator (Japan Sanyo Company), imported 96-well culture plate, etc.

4. Experimental method

MTT (tetrazolium salt) method: 100 μl of cell suspension with a concentration of 4-6×10 ⁴ cells/ml was added to each well of a 96-well plate, and placed in a 37° C., 5% CO ₂ incubator. After 24 hours, add the sample solution, 10 μl/well, set up duplicate wells, and act at 37°C and 5% CO ₂ for 72 hours. Add 20 μl of 5 mg/ml MTT solution to each well, add DMSO solution after 4 hours of action, 100 μl/well, put it in an incubator, measure the 570nm OD value with MK-2 automatic microplate reader after dissolution.

5. Experimental structure

We tested the inhibitory effect of the synthesized target compound on the cell line in vitro, using doxorubicin as a control, and calculated the concentration of the inhibitor that caused half of the cells to die, that is, the _IC50 value (μg/ml). The specific experimental data are shown in Table 2 .

Table 2 In vitro activity of target compound pairs and human non-small cell lung cancer cells

Compound No. R _IC50 (μg/ml) 1a 4-CH ₃ 46.73 1b 3-CH ₃ 37.90 1c 2-CH ₃ 27.87 1d 4-F 42.75 1e 3-F 121.73 1f 2-F 40.04 1g 4-Cl 21.64 1h 3-Cl 19.06 1i 2-Cl 258.30 1j 4-Br 15.15 1k 3-Br 33.37 1l 4-CN 427.15 1m 3-CN 1340.60

1n 2-CN 485.62 Adriamycin 36.09

The above results show that the compounds provided by the present invention have better tumor cell proliferation inhibitory activity, and the in vitro activity of most compounds, especially compounds 1c, 1g, 1h, 1j and 1k on human non-small cell lung cancer cells (A495) It has a strong inhibitory effect on cell proliferation, and this type of compound can be used as a candidate drug for tumor treatment.

The above is only a preferred embodiment of the present invention, it should be pointed out that for those of ordinary skill in the art, without departing from the method of the present invention, some improvements and supplements can also be made, and these improvements and supplements should also be considered Be the protection scope of the present invention.

Claims (5)

1. A 1,2,3-triazole substituted bisphenylpyrone compound, characterized in that, the 1,2,3-triazole substituted bisphenylpyrone compound structural formula is as follows: Described substituent R is as follows: 2. according to the preparation method of the described 1,2,3-triazole substituted biphenylpyrone compound of claim 1, it is characterized in that, comprises the steps: (a) taking 2-hydroxysalicylic acid and phloroglucinol as raw materials, stirring and reacting in Eaton's reagent to generate 1,3-dihydroxybisphenylpyrone; (b) 1,3-dihydroxybisphenylpyrone, potassium carbonate, and propyne bromide are stirred and reacted in DMF to generate 1-hydroxyl-3-(2-alkynyl oxygen)-bisphenylpyrone; (c) sodium azide, intermediate, 1-hydroxyl-3-(2-alkynyloxy)-diphenylpyrone, copper sulfate, and sodium ascorbate react at room temperature in dimethyl sulfoxide to generate the target compound; Described intermediate structure is as follows: The substituent R is the same as in claim 1. 3. The application of the 1,2,3-triazole-substituted bisphenylpyrone compound in claim 1 in the preparation of antitumor drugs. 4. The use according to claim 3, wherein the tumor is lung cancer. 5. The use according to claim 4, wherein the lung cancer is non-small cell lung cancer.