Indole dihydrochromene antitumor compound based on isoindolone and synthesis method thereof

Abstract

The invention relates to an isoindolone-based indolo dihydrochromene antitumor compound and a synthesis method thereof. The chemical structural formula of the compound is as shown in formula 3. The synthesis method comprises the following steps: adding isoindolone derivative propargyl alcohol and a 2-indol phenol derivative as reaction raw materials into ethyl acetate, stirring and reacting at 25 DEG C under the catalysis of p-toluenesulfonic acid for 8-12 hours, tracking the reaction by TLC until the reaction is complete, filtering, concentrating and purifying to obtain the 2-indol phenol derivative. According to the indolo dihydrochromene compound based on isoindolone synthesized by the invention, a biological activity test shows that the derivative has relatively high sensitivity and very strong cytotoxic activity on human nasopharyngeal carcinoma cells HONE-1. According to the method, reaction conditions are relatively conventional, the reaction process is mild, simple and convenient, the cost is low, the method is 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, products with various structures are obtained, and the yield is high. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of organic chemistry and medicinal chemistry, and specifically relates to an isoindolinone-based indole-dihydrochromene anti-tumor compound and a synthesis method thereof. Background Art

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

[0003] One of the purposes of the present invention is to provide an isoindolinone-based indole dihydrochromene antitumor compound, which has good sensitivity and cytotoxic activity to human nasopharyngeal carcinoma cell HONE-1.

[0004] The second object of the present invention is to provide a method for synthesizing the above-mentioned indole-dihydrochromene antitumor compounds based on isoindolinone, which 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 isoindolinone-based indole dihydrochromene antitumor compound, the chemical structure of which is shown in Formula 3:

[0006]

[0007] In Formula 3, 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; R and R 1 Each of them is selected from hydrogen, C1-C2 alkyl and halogen.

[0008] The present invention also provides a method for synthesizing the above-mentioned indole-dihydrochromene anti-tumor compound based on isoindolinone, which specifically comprises the following steps: using the isoindolinone-derived propargyl alcohol of the compound of formula 1 and the 2-indolinphenol derivative of the compound of formula 2 as reaction raw materials, adding them into ethyl acetate, stirring and reacting at 25° C. for 10 hours under the catalysis of p-toluenesulfonic acid, tracking the reaction by TLC until the reaction is complete, filtering, concentrating and purifying to obtain the compound of formula 3;

[0009] Wherein, the molar ratio between the isoindolinone-derived propargyl alcohol of the compound of formula 1 and the 2-indolephenol derivative of the compound of formula 2 is 1.2:1;

[0010] The structural formula of the isoindolinone-derived propargyl alcohol 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-indolephenol derivative of the compound of formula 2 is: R and R 1 Each of them is selected from hydrogen, C1-C2 alkyl and halogen.

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

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

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

[0015] Preferably, the purification is performed by silica gel column chromatography, and the eluent is a mixture of petroleum ether / ethyl acetate in a volume ratio of 3:1.

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

[0017] (1) The isoindolinone-based indole dihydrochromene compounds synthesized by the present invention have been shown, through biological activity tests, to have high sensitivity and strong cytotoxic activity against human nasopharyngeal carcinoma cell HONE-1, indicating that the isoindolinone-based indole dihydrochromene anti-tumor compounds designed and synthesized by the present invention are expected to be applied in the field of medicine;

[0018] (2) The reaction conditions for synthesizing isoindolinone-based indole-dihydrochromene antitumor compounds in the present invention are relatively conventional, and the reaction process is mild, simple, easy to operate, and low-cost, which is 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 and a high yield. DETAILED DESCRIPTION

[0019] The present invention is further described in detail below in conjunction with embodiments.

[0020] In the following examples, unless otherwise specified, isoindolinone-derived propargyl alcohol, 2-indolephenol derivatives, p-toluenesulfonic acid and other reagents can be purchased from the market or obtained according to known literature reports; the experimental methods are usually carried out under conventional conditions or conditions recommended by the manufacturer.

[0021] Example 1

[0022] The synthetic route of the indole dihydrochromene compound 3aa based on isoindolinone is as follows:

[0023]

[0024] 0.24 mmol of isoindolinone-derived propargyl alcohol formula 1a and 0.2 mmol of 2-indolinol derivative formula 2a were added as reactants in 2 mL of ethyl acetate. The mixture was stirred and reacted at 25° C. for 10 h under the catalysis of 0.02 mmol (10 mol% of the 2-indolinol derivative) of p-toluenesulfonic acid. The reaction was followed by TLC until completion. After filtration and concentration, the mixture was purified and separated by silica gel column chromatography (the eluent was a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 3:1) to obtain an isoindolinone-based indolinone-dihydrochromene antitumor compound formula 3aa, the structural characterization data of which are as follows:

[0025] 90% yield(78.8mg); Yellow solid; mp151.4–151.8℃; 1 H NMR (400MHz, CDCl3) δ8.72(s,1H),8.17(s,1H),7.82(d,J=7.5Hz,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 (100MHz, CDCl3) δ168.1,151.9,142.9,137.8,137.3,134.7,132.3,129.6,129.5,128.9,128.7,128.6,127.4,125.4,123.6,123.0, 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 methods of Examples 2-14 are the same as the steps for obtaining the product 3aa in Example 1, except that isoindolinone-derived propargyl alcohols of different structures are 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 materials, products and yields of Examples 1-14

[0031]

[0032] Examples 15-24

[0033] The synthesis methods of Examples 15-24 are the same as the steps of obtaining the product 3aa in Example 1, except that 2-indolephenol derivatives with different structures are 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 materials, products, and yields of Examples 1 and 15-24

[0038]

[0039] As can be seen from Tables 1 and 2, the method of the present invention can not only realize the synthesis of isoindolinone-based indole-dihydrochromene antitumor compounds in one step, obtain excellent yield, high atom economy, environmental friendliness, and 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, and thus has great implementation value and potential social and economic benefits.

[0040] The isoindolinone-based indole dihydrochromene antitumor compounds of the present invention were tested for their cytotoxic activity against human nasopharyngeal carcinoma cell HONE-1 at different concentrations using the CCK8 method. The results are shown in Table 3.

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

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

[0043]

[0044]

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

[0046] As shown in Table 3, the isoindolinone-based indole dihydrochromene antitumor compounds of the present invention have excellent cytotoxic activity against human nasopharyngeal carcinoma cell HONE-1, IC 50 The lowest was 19.2μM.

Claims

1. An isoindolinone-based indole dihydrochromene antitumor compound, characterized in that: Its chemical structure is shown in Formula 3: In Formula 3, 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; R and R 1 Each of them is selected from hydrogen, C1-C2 alkyl and halogen.

2. A method for synthesizing an isoindolinone-based indole dihydrochromene antitumor compound according to claim 1, characterized in that: The specific steps are: adding the isoindolinone-derived propargyl alcohol of the compound of formula 1 and the 2-indolephenol derivative of the compound of formula 2 as reaction raw materials into ethyl acetate, stirring and reacting at 25° C. for 8-12 hours under the catalysis of p-toluenesulfonic acid, tracking the reaction by TLC until completion, filtering, concentrating and purifying to obtain the compound of formula 3; Wherein, the molar ratio between the isoindolinone-derived propargyl alcohol of the compound of formula 1 and the 2-indolephenol derivative of the compound of formula 2 is 1.2:1; The structural formula of the isoindolinone-derived propargyl alcohol 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 2-indolephenol derivative of the compound of formula 2 is In formula 2, R and R 1 Each of them is selected from hydrogen, C1-C2 alkyl and halogen.

3. The method for synthesizing an isoindolinone-based indole dihydrochromene antitumor compound according to claim 2, characterized in that: The molar ratio between the 2-indolephenol derivative of the compound of formula 2 and p-toluenesulfonic acid is 1:0.

1.

4. A method for synthesizing an isoindolinone-based indole dihydrochromene antitumor compound 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-indolephenol derivative of the compound of formula 2 is 10 mL:1 mmol.

5. The method for synthesizing an isoindolinone-based indole dihydrochromene antitumor compound according to claim 2 or 3, characterized in that: The reaction time is 10 hours.

6. A method for synthesizing an isoindolinone-based indole dihydrochromene antitumor compound according to claim 2 or 3, characterized in that: The purification is performed by silica gel column chromatography, and the eluent is a mixture of petroleum ether / ethyl acetate in a volume ratio of 3:1.

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