An indolodihydrochromene anti-tumor compound based on isoindolinone and its synthesis method

Abstract

An isatin-based indolodihydrochromene anti-tumor compound and its synthesis method. The chemical structural formula of the compound is shown in Formula 3. The synthesis method is as follows: The isatin-derived propargyl alcohol and 2-indolylphenol derivative are added to ethyl acetate as reaction raw materials, and under the catalysis of p-toluenesulfonic acid, the reaction is stirred at 25 °C for 8-12 hours. The reaction is tracked by TLC until it is complete, and then filtered, concentrated, and purified to obtain the product. The isatin-based indolodihydrochromene compounds synthesized in the present invention, through bioactivity tests, show that these derivatives have high sensitivity and strong cytotoxic activity against human nasopharyngeal carcinoma cells HONE-1. The reaction conditions of the present invention are relatively conventional, the reaction process is mild, simple, and low-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, obtaining products with diverse structures and high yields.

Description

Technical Field

[0001] The present invention belongs to the fields of organic chemistry and medicinal chemistry, and particularly relates to an isatin-based indolobenzodihydrochromene anti-tumor compound and a synthesis method thereof. Background Art

[0002] Isatin and indolobenzodihydrochromene compounds are widely present in anti-tumor active compounds and natural products, and have broad application prospects in the field of life sciences. Introducing the isatin and indolobenzodihydrochromene skeletons into one compound is expected to obtain compounds with good anti-tumor activity. Isatin-based indolobenzodihydrochromene compounds are a class of compounds that have never been studied, and no one has studied the synthesis methods of these compounds and the cytotoxicity against human nasopharyngeal carcinoma cells HONE-1. Summary of the Invention

[0003] One object of the present invention is to provide an isatin-based indolobenzodihydrochromene anti-tumor compound, which has good sensitivity and cytotoxic activity against human nasopharyngeal carcinoma cells HONE-1.

[0004] Another object of the present invention is to provide a synthesis method of the above isatin-based indolobenzodihydrochromene anti-tumor compound. The method has a mild reaction process, is simple, safe and easy to operate, and has the advantages of low cost and high yield.

[0005] To achieve the above object, the technical solution adopted by the present invention is: an isatin-based indolobenzodihydrochromene anti-tumor compound, whose chemical structural formula is shown in Formula 3:

[0006]

[0007] In Formula 3, Ar is selected from one of phenyl, halogen-substituted phenyl, C1-C2 alkyl-substituted phenyl, C1-C2 alkoxy-substituted phenyl, naphthyl, and heteroaryl; R and R 1 are both selected from one of hydrogen, C1-C2 alkyl, and halogen.

[0008] The present invention also provides a synthesis method of the above isatin-based indolobenzodihydrochromene anti-tumor compound. The specific steps are as follows: Using the isatin-derived propargyl alcohol of Formula 1 compound and the 2-indolylphenol derivative of Formula 2 compound as reaction raw materials, adding them into ethyl acetate, under the catalysis of p-toluenesulfonic acid, stirring and reacting at 25°C for 10 hours, tracking the reaction by TLC until complete, filtering, concentrating, and purifying to obtain the compound of Formula 3;

[0009] Among them, the molar ratio between the isatin-derived propargyl alcohol of Formula 1 compound and the 2-indolylphenol derivative of Formula 2 compound is 1.2:1;

[0010] The structural formula of the isatin-derived propargyl alcohol of the compound of Formula 1 is In Formula 1, Ar is selected from one of phenyl, halogen-substituted phenyl, C1-C2 alkyl-substituted phenyl, C1-C2 alkoxy-substituted phenyl, naphthyl, and heteroaryl;

[0011] The structural formula of the 2-indolylphenol derivative of the compound of Formula 2 is, in Formula 2 R and R 1 are each independently selected from one of hydrogen, C1-C2 alkyl, and halogen.

[0012] Preferably, the molar ratio between the 2-indolylphenol derivative of Formula 2 and p-toluenesulfonic acid is 1:0.1.

[0013] Preferably, the ratio of the volume of ethyl acetate to the molar amount of the 2-indolylphenol derivative of Formula 2 is 10 mL:1 mmol.

[0014] Preferably, the reaction time is 10 hours.

[0015] 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 3:1.

[0016] Compared with the prior art, the present invention has the following beneficial effects:

[0017] (1) The isatin-based indolo[2,3-b]chromene compounds synthesized in the present invention, through bioactivity tests, show that these derivatives have high sensitivity and strong cytotoxic activity against human nasopharyngeal carcinoma cells HONE-1, indicating that the isatin-based indolo[2,3-b]chromene anti-tumor compounds designed and synthesized in the present invention are expected to be applied in the pharmaceutical field;

[0018] (2) The reaction conditions for synthesizing the isatin-based indolo[2,3-b]chromene 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, obtains products with diverse and complex structures, and has a high yield. Detailed Description of the Invention

[0019] The present invention will be further described in detail below in conjunction with examples.

[0020] In the following examples, unless otherwise specified, the isatin-derived propargyl alcohol, 2-indolylphenol derivative, p-toluenesulfonic acid and other reagents can be obtained by commercial purchase or according to the methods reported in known literature; the experimental methods are generally carried out under conventional conditions or the conditions recommended by the manufacturer.

[0021] Example 1

[0022] The synthetic route of indolo[2,3-c]chromen-6-one compounds of formula 3aa based on isoindolinone is as follows:

[0023]

[0024] Add 0.24 mmol of isoindolinone-derived propargyl alcohol of formula 1a and 0.2 mmol of 2-indolylphenol derivative of formula 2a as reactants into 2 mL of ethyl acetate. Under the catalysis of 0.02 mmol (10 mol% of 2-indolylphenol derivative) of p-toluenesulfonic acid, stir and react at 25 °C for 10 h. Monitor the reaction by TLC until it is completed. After filtration and concentration, purify and separate by silica gel column chromatography (the eluent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 3:1) to obtain the indolo[2,3-c]chromen-6-one anti-tumor compound of formula 3aa based on isoindolinone. The structural characterization data are as follows:

[0025] 90% yield (78.8 mg); Yellow solid; m.p. 151.4–151.8 °C; 1 H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.17 (s, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.69–7.64 (m, 1H), 7.60–7.53 (m, 3H), 7.51–7.41 (m, 2H), 7.41–7.35 (m, 1H), 7.35–7.29 (m, 3H), 7.23–7.12 (m, 3H), 7.09–6.96 (m, 3H), 6.19 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ 168.1, 151.9, 142.9, 137.8, 137.3, 134.7, 132.3, 129.6, 129.5, 128.9, 128.7, 128.6, 127.4, 125.4, 123.6, 123.0, 122.3, 121.1, 120.5, 120.2, 119.3, 117.6, 117.0, 111.7, 111.4, 107.8, 84.3; IR (KBr): 3450, 1698, 1604, 1510, 1455, 1221, 1193, 747; ESI FTMS exact mass calcd for (C 30 H 20 N2O2 + H) + requires m / z 441.1598, found m / z 441.1569.

[0026] The synthesis method of Example 2-14 was the same as the steps for obtaining the product of Formula 3aa in Example 1, except that isatin-derived propargyl alcohols with different structures were used as raw materials.

[0027] The reaction synthesis route is as follows:

[0028]

[0029] The products and yields are shown in Table 1 below:

[0030] Table 1 Reaction raw materials, products, and yields of Examples 1-14

[0031]

[0032] Examples 15-24

[0033] The synthesis method of Examples 15-24 was the same as the steps for obtaining the product of Formula 3aa in Example 1, except that 2-indolylphenol derivatives with different structures were used as raw materials.

[0034] The reaction synthesis route is as follows:

[0035]

[0036] The products and yields are shown in Table 2 below:

[0037] Table 2 Reaction raw materials, products, and yields of Example 1 and Examples 15-24

[0038]

[0039] As can be seen from Table 1 and Table 2, the method of the present invention can not only achieve the synthesis of indolo[2,3-b]chromene-based anti-tumor compounds based on isatin in one step, obtain excellent yields, have high atom economy, be environmentally friendly, and have a wide range of applications, but also the raw materials are easily available, the operation is simple and safe, the reaction conditions are mild, the reaction time is short, the post-treatment is simple, and the product structures are diverse. Therefore, it has great implementation value and potential social and economic benefits.

[0040] For the indolo[2,3-b]chromene-based anti-tumor compounds of the present invention, the cytotoxic activities of the compounds synthesized in some examples against human nasopharyngeal carcinoma cells HONE-1 at different concentrations were tested by the CCK8 method, and the results are shown in Table 3.

[0041] IC 50Test experimental procedure: Human nasopharyngeal carcinoma cells HONE-1 were seeded in a 96-well plate at a density of 5000 cells / 100 μL medium. After culturing the cells to adhere for 24 hours at 37°C under 5% CO2 conditions, the test compound was added to the medium at final concentrations of 200, 100, 50, 25, 12.5, 6.25, and 3.125 μg / mL, and the cells were further cultured for 24 hours. Cells without the compound added were used as the control group, and those with only the medium added were used as the blank group. After the compound stimulation ended, the culture medium was removed, 100 μL of DMEM medium containing 10% CCK8 was added to each well, and the plate was incubated at 37°C for another 1 hour. Then, the culture plate was shaken for 5 s, and the optical density (OD) value was read at 450 nm. The experiment was repeated three times, and finally, the IC 50 value of the test compound was calculated using GraphPad software.

[0042] Table 3 Cytotoxic activity of the compounds in the present invention against human nasopharyngeal carcinoma cells HONE-1

[0043]

[0044]

[0045] Note: IC 50 in Table 3 refers to the half-maximal inhibitory concentration.

[0046] As can be seen from Table 3, the isatin-based indolodihydrochromene anti-tumor compounds of the present invention have excellent cytotoxic activity against human nasopharyngeal carcinoma cells HONE-1, and the lowest IC 50 is 19.2 μM.

Claims

1. An indolo[2,3-c]chromene-based anti-tumor compound based on isoindolinone, characterized in that, Its chemical structural formula is shown in Formula 3: In Formula 3, Ar is selected from one of phenyl, halogen-substituted phenyl, C1-C2 alkyl-substituted phenyl, C1-C2 alkoxy-substituted phenyl, naphthyl, and heteroaryl; R and R 1 are each independently selected from one of hydrogen, C1-C2 alkyl, and halogen.

2. A method for synthesizing an indolodihydrochromene anti-tumor compound based on isoindolinone as described in claim 1, characterized in that, The specific steps are as follows: The isatin-derived propargyl alcohol of Formula 1 and the 2-indolylphenol derivative of Formula 2 are added as reaction raw materials into ethyl acetate, and under the catalysis of p-toluenesulfonic acid, they are stirred and reacted at 25 °C for 8 - 12 hours. The reaction is tracked by TLC until completion, and then filtered, concentrated, and purified to obtain the compound of Formula 3; Among them, the molar ratio between the isatin-derived propargyl alcohol of Formula 1 and the 2-indolylphenol derivative of Formula 2 is 1.2:1; The structural formula of the isatin-derived propargyl alcohol of the compound of Formula 1 is In Formula 1, Ar is selected from the group consisting of phenyl, halogen-substituted phenyl, C1-C2 alkyl-substituted phenyl, C1-C2 alkoxy-substituted phenyl, naphthyl, and heteroaryl; The structural formula of the compound of formula 2, 2-indolylphenol derivative, is In formula 2, R and R 1 are each independently selected from the group consisting of hydrogen, C1-C2 alkyl, and halogen.

3. The synthesis method of an indolodihydrochromene anti-tumor compound based on isoindolinone according to claim 2, characterized in that, The molar ratio between the 2-indolylphenol derivative of Formula 2 and p-toluenesulfonic acid is 1:0.

1.

4. The synthesis method of an indolo[2,3-c]chromene anti-tumor compound based on isoindolinone according to claim 2 or 3, characterized in that, The ratio of the volume of the ethyl acetate to the molar amount of the 2-indolylphenol derivative of Formula 2 is 10 mL:1 mmol.

5. A method for synthesizing an indolo[2,3-c]chromene-based anti-tumor compound based on isoindolinone according to claim 2 or 3, characterized in that, The reaction time is 10 hours.

6. A method for synthesizing an indolodihydrochromene anti-tumor compound based on isoindolinone according to claim 2 or 3, characterized in that, The purification is by silica gel column chromatography, and the eluent is a petroleum ether / ethyl acetate mixed solution with a volume ratio of 3:1.

Images