A nitrogen heterocycle-derived polyarylmethane antitumor compound and its synthesis method

Abstract

The present invention discloses a nitrogen heterocycle-derived polyarylmethane antitumor compound and a synthesis method thereof. The chemical structural formula of the compound is shown in Formula 3; the synthesis method is: 2-pyrrole-derived indole and aromatic aldehyde are added to toluene as reaction raw materials, and the reaction is stirred at 25°C for 6-10 hours under the catalysis of dinaphthylphosphonic acid, and the reaction is followed by TLC to completion, and the product is filtered, concentrated and purified. The nitrogen heterocycle-derived polyarylmethane compound synthesized by the present invention is tested for biological activity, and the results show that the derivatives have high sensitivity and strong cytotoxic activity against human breast cancer cells MCF-7. The reaction conditions of the present invention are conventional, the reaction process is mild, simple, and low-cost, and it is suitable for industrial large-scale production, which broadens the scope of application of the method; the present invention uses a variety of substrates as reactants to obtain products with diverse structures.

Description

Technical Field

[0001] The present invention belongs to the fields of organic chemistry and medicinal chemistry, and particularly relates to a polyarylmethane anti-tumor compound derived from a nitrogen heterocycle and a synthesis method thereof. Background Art

[0002] Polyarylmethane compounds exhibit significant cytotoxic activity against a variety of tumor cells. Nitrogen heterocycles, such as indole and pyrrole, are the core structures of many anti-tumor molecules and hold broad application prospects in the life sciences. Introducing polyarylmethanes and nitrogen heterocycles into a single compound holds promise for yielding compounds with enhanced anti-tumor activity. Nitrogen heterocycle-derived polyarylmethane compounds, which possess multiple nitrogen heterocycles, such as indole and pyrrole, and three polyarylmethane fragments, represent a previously unstudied class of compounds. Their synthesis methods and cytotoxicity against human breast cancer MCF-7 cells have not been investigated. Summary of the Invention

[0003] One of the purposes of the present invention is to provide a nitrogen heterocycle-derived polyarylmethane antitumor compound, which has good sensitivity and cytotoxic activity to human breast cancer cells MCF-7.

[0004] The second object of the present invention is to provide a method for synthesizing the above-mentioned nitrogen heterocycle-derived polyarylmethane anti-tumor compounds, which has the advantages of a mild reaction process, simplicity, safety and easy operation.

[0005] To achieve the above-mentioned purpose, the technical solution adopted by the present invention is: a nitrogen heterocycle-derived polyarylmethane antitumor compound, whose chemical structure is shown in Formula 3:

[0006]

[0007] In formula 3, R is selected from one of hydrogen, methyl, trifluoromethyl, methoxy, and halogen.

[0008] The present invention also provides a method for synthesizing the above-mentioned nitrogen heterocycle-derived polyarylmethane anti-tumor compound, which specifically comprises the following steps: using the 2-pyrrole-derived indole compound of Formula 1 and the aromatic aldehyde compound of Formula 2 as reaction raw materials, adding them to toluene, stirring and reacting at 25° C. for 6-10 hours under the catalysis of binaphthylphosphonic acid, monitoring the reaction by TLC until completion, filtering, concentrating, and purifying to obtain the compound of Formula 3;

[0009] wherein the molar ratio between the 2-pyrrole-derived indole compound of formula 1 and the aromatic aldehyde compound of formula 2 is 2:1;

[0010] The structural formula of the 2-pyrrole-derived indole compound of formula 1 is

[0011] The structural formula of the aromatic aldehyde compound of formula 2 is In formula 2, R is selected from one of hydrogen, methyl, trifluoromethyl, methoxy, and halogen;

[0012] The structural formula of the compound of formula 4, binaphthylphosphonic acid, is

[0013] Preferably, the molar ratio between the aromatic aldehyde of the compound of formula 2 and the binaphthyl phosphonic acid of the compound of formula 4 is 1:0.1.

[0014] Preferably, the ratio of the volume of toluene to the molar amount of the aromatic aldehyde of the compound of formula 2 is 10 mL:1 mmol.

[0015] Preferably, the reaction time is 10 hours.

[0016] Preferably, the purification is performed by silica gel column chromatography, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1.

[0017] Compared with the prior art, the present invention has the following beneficial effects:

[0018] (1) The nitrogen heterocycle-derived polyarylmethane compounds synthesized by the present invention have been shown to have high sensitivity and strong cytotoxic activity against human breast cancer MCF-7 cells through biological activity tests, indicating that the nitrogen heterocycle-derived polyarylmethane anti-tumor compounds designed and synthesized by the present invention are expected to be applied in the medical field;

[0019] (2) The present invention uses relatively conventional reaction conditions for synthesizing nitrogen heterocycle-derived polyarylmethane antitumor compounds. The reaction process is mild, simple, easy to operate, and low-cost, making it suitable for industrial large-scale production, thereby broadening the scope of application of the method. The present invention uses a wider variety of substrates as reactants to obtain products with diverse and complex structures. DETAILED DESCRIPTION

[0020] The present invention will be further described in detail below with reference to the embodiments.

[0021] In the following examples, unless otherwise stated, 2-pyrrole-derived indole, aromatic aldehyde, binaphthyl phosphate and other reagents can be purchased commercially or obtained according to known literature reports; the experimental methods are usually carried out according to conventional conditions or conditions recommended by the manufacturers.

[0022] Example 1

[0023] The synthetic route of the nitrogen heterocycle-derived polyarylmethane compound of formula 3aa is as follows:

[0024]

[0025] 0.2 mmol of 2-pyrrole-derived indole Formula 1 and 0.1 mmol of aromatic aldehyde Formula 2a were added to 1 mL of toluene as reactants. Under the catalysis of 0.01 mmol (10 mol% of aromatic aldehyde) of compound Formula 4, binaphthylphosphonic acid, the reaction was stirred at 25°C for 6 h. The reaction was monitored by TLC until completion. After filtration and concentration, the reaction was purified and separated by silica gel column chromatography (eluent: a mixture of petroleum ether and toluene in a volume ratio of 10:1) to obtain a nitrogen heterocycle-derived polyarylmethane antitumor compound Formula 3a. Its structural characterization data are as follows:

[0026] 82% yield(66.6mg); White solid; mp142.5–143.6℃; 1 H NMR(400MHz, CDCl3)δ7.92(s,2H),7.53(s,1H),7.51(s,1H),7.42–7.34(m,2H),7.25– 7.17(m,15H),7.17–7.04(m,16H),6.24(s,2H),5.80(s,2H),5.12(s,1H),2.03(s,6H); 13 C NMR (100MHz, CDCl3) δ146.49,145.43,145.40,142.88,136.05,131.06,129.44,128.41,128.25,127.98,127.94,126.93,126.90,123.6 6,122.56,121.86,120.53,119.79,111.20,110.90,104.17,56.42,40.15,11.72; IR(KBr):3380,2950,1833,1620,1605,1432,852,763.

[0027] The synthesis methods of Examples 2-10 are the same as the steps for obtaining the product of Formula 3a in Example 1, except that aromatic aldehydes of different structures are used as raw materials.

[0028] The reaction synthesis route is as follows:

[0029]

[0030] The products and yields are shown in Table 1 below:

[0031] Table 1 Reaction materials, products, and yields of Examples 1-10

[0032]

[0033] As can be seen from Table 1, the method of the present invention not only can achieve the synthesis of nitrogen heterocycle-derived polyarylmethane anti-tumor compounds in one step, has high atom economy, is environmentally friendly, and has a wide range of applications, but also has readily available raw materials, simple and safe operation, mild reaction conditions, short reaction time, simple post-processing, and diversified product structures, thus having great implementation value and potential socioeconomic benefits.

[0034] The nitrogen heterocycle-derived polyarylmethane antitumor compounds of the present invention were tested for their cytotoxic activity against human breast cancer cells MCF-7 at different concentrations using the MTT method. The results are shown in Table 2.

[0035] IC 50 Test experimental steps: Human breast cancer cells MCF-7 were cultured in DMEM medium containing 10% fetal bovine serum, and after passaging, they were seeded in 96-well plates at a density of 5000 cells / 100μL culture medium per well. After culturing for 24 hours at 37°C and 5% CO2, the test compound was added to the culture medium at a final concentration of 200, 100, 50, 25, and 12.5μg / mL. The cells were cultured for another 48 hours, and cells without compound addition served as the control group. After the compound effect ended, the culture medium was removed, 30μL of mtt solution was added to each well, and the cells were placed in a 37°C incubator and incubated for another 4 hours. Subsequently, 100μLDMSO was added to each well, and the culture plate was shaken for 30s before the absorbance was read at 490nm. The experiment was repeated three times, and finally the IC of the test compound was calculated using graphpad software. 50 value.

[0036] Table 2 Cytotoxic activity of the compounds of the present invention against human breast cancer cells MCF-7

[0037]

[0038] Note: IC in Table 2 50 Refers to the half-maximal inhibitory concentration.

[0039] As shown in Table 2, the polyarylmethane antitumor compounds derived from nitrogen heterocycles of the present invention have excellent cytotoxic activity against human breast cancer cells MCF-7, IC 50 The lowest is 10.2μM.

Claims

1. A nitrogen heterocycle-derived polyarylmethane antitumor compound, characterized in that: Its chemical structure is shown in Formula 3: In formula 3, R is selected from one of hydrogen, methyl, trifluoromethyl, methoxy, and halogen.

2. A method for synthesizing the nitrogen heterocycle-derived polyarylmethane antitumor compound according to claim 1, characterized in that: The specific steps are as follows: 2-pyrrole-derived indole compound of formula 1 and aromatic aldehyde compound of formula 2 are added to toluene as reaction raw materials, and under the catalysis of binaphthylphosphonic acid compound of formula 4, the reaction is stirred at 25°C for 6-10 hours, and the reaction is monitored by TLC until completion, and the compound of formula 3 is obtained by filtration, concentration and purification. wherein the molar ratio between the 2-pyrrole-derived indole compound of formula 1 and the aromatic aldehyde compound of formula 2 is 2:1; The structural formula of the 2-pyrrole-derived indole compound of formula 1 is The structural formula of the aromatic aldehyde compound of formula 2 is In formula 2, R is selected from one of hydrogen, methyl, trifluoromethyl, methoxy, and halogen; The structural formula of the compound of formula 4, binaphthylphosphonic acid, is 3. The method for synthesizing a nitrogen heterocycle-derived polyarylmethane anti-tumor compound according to claim 2, characterized in that: The molar ratio between the aromatic aldehyde compound of formula 2 and the binaphthyl phosphate compound of formula 4 is 1:0.

1.

4. The method for synthesizing a nitrogen heterocycle-derived polyarylmethane antitumor compound according to claim 2 or 3, characterized in that: The ratio of the volume of the toluene to the molar amount of the aromatic aldehyde of the compound of formula 2 is 10 mL:1 mmol.

5. The method for synthesizing a nitrogen heterocycle-derived polyarylmethane anti-tumor compound according to claim 2 or 3, characterized in that: The reaction time was 6 hours.

6. The method for synthesizing a nitrogen heterocycle-derived polyarylmethane anti-tumor compound according to claim 2 or 3, characterized in that: The purification was performed by silica gel column chromatography, and the eluent was a mixture of petroleum ether and ethyl acetate with a volume ratio of 10:1.

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