Azacyclo-derived polyaryl methane anti-tumor compound and synthesis method thereof

Abstract

The invention discloses an azacyclo-derived polyaryl methane anti-tumor compound and a synthesis method thereof. The chemical structural formula of the compound is shown as a formula 3. The synthesis method comprises the following steps: adding 2-pyrrole derivative indole and aromatic aldehyde as reaction raw materials into toluene, stirring and reacting for 6-10 hours at 25 DEG C under the catalysis of binaphthyl phosphoric acid, tracking the reaction by TLC until the reaction is complete, filtering, concentrating and purifying to obtain the 2-pyrrole derivative indole. According to the azacyclo-derived polyaryl methane compound synthesized by the invention, a biological activity test shows that the derivative has relatively high sensitivity and very strong cytotoxic activity on human breast cancer cells MCF-7. The method is conventional in reaction condition, mild and simple in reaction process, low in cost and suitable for industrial large-scale production, and the application range of the method is widened; according to the method, various substrates are used as reactants, and products with various structures are obtained. # imgabs0 #

Description

Technical Field

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

[0002] Polyarylmethane compounds have good cytotoxic activities against various tumor cells. Azacyclic skeletons such as indole and pyrrole are the core structures of many anti-tumor active molecules, and these structures have broad application prospects in the field of life sciences. Introducing polyarylmethane and azacyclic rings into a compound is expected to obtain a compound with good anti-tumor activity. Azacyclic-derived polyarylmethane compounds have multiple azacyclic rings such as indole and pyrrole, and at the same time have 3 polyarylmethane fragments. They are a class of compounds that have never been studied by anyone, and no one has studied the synthesis methods of these compounds and the cytotoxicity against human breast cancer cell MCF-7. Summary of the Invention

[0003] One of the purposes of the present invention is to provide an azacyclic-derived polyarylmethane anti-tumor compound, which has good sensitivity and cytotoxic activity against human breast cancer cell MCF-7.

[0004] Another purpose of the present invention is to provide a synthesis method of the above-mentioned azacyclic-derived polyarylmethane anti-tumor compound, which has the advantages of mild reaction process, simplicity, safety and easy operation.

[0005] To achieve the above purpose, the technical solution adopted by the present invention is: an azacyclic-derived polyarylmethane anti-tumor compound, the chemical structural formula of which 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 synthesis method of the above-mentioned azacyclic-derived polyarylmethane anti-tumor compound. The specific steps are as follows: Using the compound 2-pyrrole-derived indole of Formula 1 and the compound aromatic aldehyde of Formula 2 as reaction raw materials, adding them to toluene, and under the catalysis of binaphthyl phosphoric acid, stirring and reacting at 25 °C for 6-10 hours. Tracking the reaction by TLC until it is complete, filtering, concentrating, and purifying to obtain the compound of Formula 3;

[0009] Among them, the molar ratio between the compound 2-pyrrole-derived indole of Formula 1 and the compound aromatic aldehyde of Formula 2 is 2:1;

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

[0011] The structural formula of the aromatic aldehyde of the 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 binaphthyl phosphoric acid of the compound of formula 4 is

[0013] Preferably, the molar ratio between the aromatic aldehyde of the compound of formula 2 and the binaphthyl phosphoric 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 by silica gel column chromatography, and the eluent is a mixture of petroleum ether / ethyl acetate with a volume ratio of 10:1.

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

[0018] (1) For the nitrogen heterocycle-derived polyaryl methane compounds synthesized in the present invention, through bioactivity tests, it is shown that these derivatives have high sensitivity and strong cytotoxic activity against human breast cancer cell MCF-7, indicating that the anti-tumor compounds of nitrogen heterocycle-derived polyaryl methane designed and synthesized in the present invention are expected to be applied in the pharmaceutical field;

[0019] (2) The reaction conditions for synthesizing the nitrogen heterocycle-derived polyaryl methane anti-tumor compounds in the present invention are relatively conventional, the reaction process is mild, simple, easy to operate, and low in cost, suitable for large-scale industrial production, and broaden the scope of application of this method; The present invention uses a relatively large variety of substrates as reactants and obtains products with diverse and complex structures. Specific Embodiments

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

[0021] In the following embodiments, unless otherwise specified, 2-pyrrole-derived indole, aromatic aldehyde, binaphthyl phosphoric acid and other reagents can be obtained through commercial purchase or according to the methods reported in known literature; the experimental methods are usually carried out under conventional conditions or the conditions recommended by the manufacturer.

[0022] Example 1

[0023] The synthesis route of the nitrogen heterocycle-derived polyaryl methane compound of formula 3aa is as follows:

[0024]

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

[0026] 82% yield (66.6 mg); White solid; m.p. 142.5–143.6 °C; 1 1H NMR (400 MHz, CDCl3) δ 7.92 (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 13C NMR (100 MHz, CDCl3) δ 146.49, 145.43, 145.40, 142.88, 136.05, 131.06, 129.44, 128.41, 128.25, 127.98, 127.94, 126.93, 126.90, 123.66, 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 were the same as the steps of the product 3a obtained in Example 1, except that aromatic aldehydes with different structures were 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 raw materials, products and yields of Examples 1-10

[0032]

[0033] As can be seen from Table 1, the method of the present invention can not only achieve the synthesis of nitrogen heterocycle-derived multiaryl methane anti-tumor compounds in one step, with high atom economy, environmental friendliness, and wide applicability, but also has easily available raw materials, simple and safe operation, mild reaction conditions, short reaction time, simple post-treatment, and diverse product structures. Therefore, it has great implementation value and potential social and economic benefits.

[0034] For the nitrogen heterocycle-derived multiaryl methane anti-tumor compounds of the present invention, the cytotoxic activities of the compounds synthesized in some examples against human breast cancer cell MCF-7 at different concentrations were tested by the MTT method, and the results are shown in Table 3.

[0035] IC 50 Test experimental procedure: Human breast cancer cell MCF-7 was cultured in DMEM medium containing 10% fetal bovine serum, and after passage, it was inoculated into a 96-well plate at a density of 5000 cells / 100 μL medium per well. Then, after culturing for 24 hours at 37 °C and 5% CO2, the test compounds were added to the medium at final concentrations of 200, 100, 50, 25, and 12.5 μg / mL, and the cells were cultured for another 48 hours. The cells without the added compound were used as the control group. After the action of the compound ended, the culture medium was removed, 30 μL of MTT solution was added to each well, and it was incubated in an incubator at 37 °C for another 4 hours. Subsequently, 100 μL of DMSO was added to each well, and after shaking the culture plate for 30 s, the absorbance was measured at 490 nm. The experiment was repeated three times, and finally, the IC 50 value was calculated using GraphPad software.

[0036] Table 3 Cytotoxic activities of the compounds in the present invention against human breast cancer cell MCF-7

[0037]

[0038] Note: IC 50 in Table 3 refers to the half-maximal inhibitory concentration.

[0039] As can be seen from Table 3, the nitrogen heterocycle-derived multiaryl methane anti-tumor compounds of the present invention have excellent cytotoxic activities against human breast cancer cell MCF-7, and the lowest IC 50 is 10.2 μM.

Claims

1. A nitrogen heterocycle-derived polyaryl methane anti-tumor compound, characterized in that, Its chemical structural formula 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 an antitumor compound of nitrogen heterocycle-derived polyaryl methane according to claim 1, characterized in that, The specific steps are as follows: The compound 2-pyrrole-derived indole of Formula 1 and the aromatic aldehyde of Formula 2 are added as reaction raw materials to toluene, and under the catalysis of the compound of Formula 4, binaphthyl phosphoric acid, the reaction is stirred at 25 °C for 6-10 hours. The reaction is tracked by TLC until it is complete, and then filtered, concentrated, and purified to obtain the compound of Formula 3; Among them, the molar ratio between the compound 2-pyrrole-derived indole of Formula 1 and the aromatic aldehyde of Formula 2 is 2:1; The structural formula of the compound of formula 1, 2-pyrrole-derived indole, is The structural formula of the aromatic aldehyde of the compound of Formula 2 is In Formula 2, R is selected from the group consisting of hydrogen, methyl, trifluoromethyl, methoxy, and halogen; The structural formula of the compound binaphthyl phosphoric acid of Formula 4 is 3. The synthesis method of an antitumor compound of nitrogen heterocycle-derived polyaryl methane according to claim 2, characterized in that, The molar ratio between the aromatic aldehyde of Formula 2 and the binaphthyl phosphoric acid of Formula 4 is 1:0.

1.

4. The synthesis method of an antitumor compound of nitrogen heterocycle-derived polyaryl methane 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 Formula 2 is 10 mL:1 mmol.

5. The synthesis method of an antitumor compound of nitrogen heterocycle-derived polyaryl methane according to claim 2 or 3, characterized in that, The reaction time is 6 hours.

6. The synthesis method of an anti-tumor compound of nitrogen heterocycle-derived polyaryl methane according to claim 2 or 3, characterized in that, The purification is silica gel column chromatography, and the eluent is a mixed solution of petroleum ether / ethyl acetate with a volume ratio of 10:1.

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