An isoindolinone-derived unsaturated imine compound, a synthesis method thereof, and its application in antitumor activity

Abstract

An isoindolinone-derived unsaturated imine compound and its synthesis method and application in anti-tumor activity, the chemical structural formula of the compound is shown in Formula 3; the synthesis method is: using an aniline derivative based on oxidized indole and an isoindolinone-derived propargyl alcohol as reaction raw materials, adding them to 1,2-dichloroethane, adding a dehydrating agent, stirring the reaction at room temperature for 3 hours under the catalysis of binaphthylphosphonic acid, tracking the reaction to completion by TLC, filtering, concentrating and purifying to obtain. The isoindolinone-derived unsaturated imine compound synthesized by the present invention is tested for anti-tumor activity, showing that the compound has high sensitivity and strong cytotoxic activity to human liver cancer cells Hep G2. The reaction conditions of the present invention are relatively conventional, the reaction process is mild, simple, low-cost, suitable for industrial large-scale production, and the scope of application of the method is broadened; a variety of substrates are used as reactants to obtain products with diverse structures and high yields.

Description

Technical Field

[0001] The invention belongs to the field of medicinal chemistry, and specifically relates to an isoindolinone-derived unsaturated imine compound, a synthesis method thereof, and application thereof in anti-tumor activity. Background Art

[0002] Designing and synthesizing a large number of new compounds with potential pharmacological activity, screening these chiral compounds for pharmacological activity, and discovering drug lead compounds are important links in the development of new drugs. Indole, oxidized indole, isoindolinone, imine and other groups are widely present in active drug molecules with anti-tumor activity. It is of great significance to splice these skeletons together, design and synthesize a class of compounds with indole, oxidized indole, isoindolinone, imine and other groups, and screen for anti-tumor activity for the development of new anti-tumor drugs. Isoindolinone-derived unsaturated imine compounds have indole, oxidized indole, isoindolinone, imine and other groups. They are a class of compounds that have never been synthesized and studied, and no one has studied the synthesis methods of these compounds and their cytotoxicity to human liver cancer cells Hep G2. Summary of the invention

[0003] One of the purposes of the present invention is to provide an isoindolinone-derived unsaturated imine compound and its application in anti-tumor activity, wherein the compound has good sensitivity and cytotoxic activity to human liver cancer cell Hep G2.

[0004] The second object of the present invention is to provide a method for synthesizing the above-mentioned isoindolinone-derived unsaturated imine compounds, 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-derived unsaturated imine compound, whose chemical structure is shown in Formula 3:

[0006]

[0007] In Formula 3, R is selected from the group consisting of phenyl, methoxy-substituted phenyl, methyl-substituted phenyl, halogen-substituted phenyl, and naphthyl.

[0008] To achieve the above object, the present invention also provides a method for synthesizing the above-mentioned isoindolinone-derived unsaturated imine compounds, which specifically comprises the following steps: adding the aniline derivative based on indole oxide of the compound of formula 1 and the isoindolinone-derived propargyl alcohol of the compound of formula 2 as reaction raw materials into 1,2-dichloroethane, adding a dehydrating agent, stirring at room temperature under the catalysis of binaphthylphosphonic acid, tracking the reaction until completion by TLC, filtering, concentrating and purifying to obtain the isoindolinone-derived unsaturated imine compounds of formula 3;

[0009] Wherein, the molar ratio between the aniline derivative based on indole oxide of the compound of formula 1 and the isoindolinone-derived propargyl alcohol of the compound of formula 2 is 1:1.2, and the molar ratio between the aniline derivative based on indole oxide of the compound of formula 1 and the binaphthylphosphonic acid of formula 4 is 1:0.2;

[0010] The structural formula of the compound of formula 1 based on the aniline derivative of oxidized indole is

[0011] The structural formula of the isoindolinone-derived propargyl alcohol of the compound of formula 2 is In Formula 2, R is selected from the group consisting of phenyl, methoxy-substituted phenyl, methyl-substituted phenyl, halogen-substituted phenyl, and naphthyl;

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

[0013] Preferably, the volume ratio of the compound of formula 1 based on the molar amount of the aniline derivative of oxidized indole to 1,2-dichloroethane is 1 mmol:10 mL.

[0014] Preferably, the reaction is stirred at room temperature for 3 hours.

[0015] Preferably, the dehydrating agent is Molecular sieve, compound of formula 1 based on oxindole aniline derivative and dehydrating agent The usage ratio of molecular sieve is 1mmol:1g.

[0016] 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.

[0017] To achieve the above object, the present invention also provides the use of the above isoindolinone-derived unsaturated imine compounds in anti-tumor activity.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] (1) The isoindolinone-derived unsaturated imine compounds synthesized by the present invention are a class of compounds that have never been synthesized or studied. The biological activity test shows that the derivatives have high sensitivity and strong cytotoxic activity against human liver cancer cells Hep G2, indicating that the isoindolinone-derived unsaturated imine compounds synthesized by the present invention are expected to be applied in the field of medicine;

[0020] (2) The reaction conditions for synthesizing isoindolinone-derived unsaturated imine compounds of 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 variety of substrates as reactants to obtain products with diverse structures and high yields. DETAILED DESCRIPTION

[0021] The present invention is further described in detail below in conjunction with embodiments.

[0022] In the following examples, unless otherwise stated, oxidized indole-based aniline derivatives, isoindolinone-derived propargyl alcohol, binaphthyl phosphonic 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.

[0023] Example 1

[0024] The synthetic route of the isoindolinone-derived unsaturated imine compound 3a is as follows:

[0025]

[0026] The oxidized indole-based aniline derivative 1 (0.1 mmol), isoindolinone-derived propargyl alcohol 2a (0.12 mmol), 4-binaphthylphosphonic acid (0.02 mmol), Molecular sieves (100 mg) and 1,2-dichloroethane (1 mL) were added to the reaction tube, and the reaction was carried out at room temperature for 3 hours. The reaction was followed by TLC until completion. The product was filtered, the reaction solvent was removed under reduced pressure, and concentrated. The product was purified by flash column chromatography (the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1) to obtain an isoindolinone-derived unsaturated imine compound of formula 3a.

[0027] The structural characterization data of the product formula 3a in Example 1 are as follows:

[0028] 94% yield (63.2mg); yellow solid; mp131.1-131.8℃; 1 H NMR(400MHz, CDCl3)δ14.21(s,1H),9.91(s,1H),7.77–7.69(m,1H),7.58–7.5 1(m,2H),7.50–7.44(m,3H),7.43–7.37(m,3H),7.34–7.11(m,12H),7.10–7.02 (m,1H),6.88(d,J=7.8Hz,1H),6.74(t,J=7.8Hz,1H),6.65(d,J=7.9Hz,1H),6. 30(s,1H),5.95–5.86(m,2H).,5.50(d,J=16.0Hz,1H),5.04(d,J=16.0Hz,1H); 13C NMR (100MHz, CDCl3) δ168.4,166.6,147.4,143.1,142.2,141.6,138.4,138.3,137.5,137 .4,136.4,133.2,132.2,130.5,129.8,129.2,129.1,128.9,128.8,128.4,128.2,127.6,1 27.5,127.4,127.1,125.3,124.7,123.8,123.7,123.5,122.4,122.1,121.5,120.3,120. 1,119.5,114.1,112.7,44.3;IR(KBr):3057,2785,1656,1605,1568,1468,789,745,694cm -1 ;ESI FTMS exact mass calcd for(C 46 H 32 N4O2+Na) + requires m / z 695.2417,found m / z695.2429.

[0029] Embodiment 2-10

[0030] The synthesis method of Example 2-10 is the same as that of Example 1, except that isoindolinone-derived propargyl alcohols of different structures are used as raw materials.

[0031] The reaction synthesis route is as follows:

[0032]

[0033] The products and yields are shown in Table 2 below:

[0034] Table 2 Reaction materials and yields of Examples 1-10

[0035]

[0036] As can be seen from Table 1, the method of the present invention can not only realize the synthesis of isoindolinone-derived unsaturated imine 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-treatment, and diversified product structures, and thus has great implementation value and potential social and economic benefits.

[0037] The cytotoxic activity of the isoindolinone-derived unsaturated imine compound of the present invention on human liver cancer cell Hep G2 at a concentration of 100 μg / mL was tested by CCK8 method. The results are shown in Table 2.

[0038] Experimental steps: Human liver cancer cells Hep G2 were inoculated in a 96-well plate at a density of 5000 cells / 100μL culture medium per well. After culturing the cells for 24 hours at 37°C and 5% CO2, the compound to be tested was added to the culture medium at a concentration of 100μg / 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, 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, and then the culture plate was shaken for 5s, and the optical density (OD) value was read at 450nm, and the survival rate of Hep G2 was calculated using graphpad software.

[0039] Table 2 Cytotoxic activity of isoindolinone-derived unsaturated imine compounds against human liver cancer cells Hep G2

[0040]

[0041] The results showed that the tested compounds all had cytotoxic activity against human liver cancer cells Hep G2, and had excellent inhibitory effect on human liver cancer cells Hep G2 at a concentration of 100 μg / mL. Among them, the compounds prepared in Examples 1-4 and Example 7 respectively had excellent cytotoxic activity against human liver cancer cells Hep G2. Then, the IC values ​​of these compounds against human liver cancer cells Hep G2 were tested in detail through three parallel experiments. 50 (Table 3) The results show that these compounds have very good cytotoxic activity against human liver cancer cells Hep G2.

[0042] IC 50 Test experimental steps: Human liver cancer cells Hep G2 were inoculated 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 compounds were added to the culture medium at final concentrations of 200, 100, 50, 25, 12.5, and 6.25μg / 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 10μL 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.

[0043] Table 3 IC values ​​of the compounds of the present invention against human liver cancer cells Hep G2 50

[0044]

[0045] IC 50 Refers to the half-maximal inhibitory concentration.

[0046] As shown in Table 3, the isoindolinone-derived unsaturated imine compounds of the present invention have excellent cytotoxic activity against human liver cancer cells HepG2, IC 50 The lowest was 7.78μg / mL.

Claims

1. An isoindolinone-derived unsaturated imine compound, characterized in that: Its chemical structure is shown in Formula 3: ； In Formula 3, R is selected from one of phenyl, methoxy-substituted phenyl, methyl-substituted phenyl, halogen-substituted phenyl, and naphthyl.

2. A method for synthesizing an isoindolinone-derived unsaturated imine compound according to claim 1, characterized in that: The specific steps are: adding the aniline derivative based on indole oxide of the compound of formula 1 and the propargyl alcohol derived from isoindolinone of the compound of formula 2 as reaction raw materials into 1,2-dichloroethane, adding a dehydrating agent, stirring at room temperature to react under the catalysis of binaphthylphosphonic acid of formula 4, tracking the reaction until completion by TLC, filtering, concentrating and purifying to obtain the unsaturated imine compound derived from isoindolinone of formula 3; Wherein, the molar ratio between the aniline derivative based on indole oxide of the compound of formula 1 and the isoindolinone-derived propargyl alcohol of the compound of formula 2 is 1:1.2, and the molar ratio between the aniline derivative based on indole oxide of the compound of formula 1 and the binaphthylphosphonic acid of formula 4 is 1:0.2; The structural formula of the compound of formula 1 based on the aniline derivative of oxidized indole is ; The structural formula of the isoindolinone-derived propargyl alcohol of the compound of formula 2 is , in Formula 2, R is selected from one of phenyl, methoxy-substituted phenyl, methyl-substituted phenyl, halogen-substituted phenyl, and naphthyl; The structural formula of the compound of formula 4, binaphthylphosphonic acid, is .

3. The method for synthesizing an isoindolinone-derived unsaturated imine compound according to claim 2, characterized in that: The ratio of the molar amount of the aniline derivative of the compound of Formula 1 based on indole oxide to the volume of 1,2-dichloroethane is 1 mmol:10 mL.

4. The method for synthesizing an isoindolinone-derived unsaturated imine compound according to claim 2 or 3, characterized in that: The reaction was stirred at room temperature for 3 hours.

5. The method for synthesizing an isoindolinone-derived unsaturated imine compound according to claim 2 or 3, characterized in that: The dehydrating agent is a 3Å molecular sieve, and the usage ratio of the aniline derivative based on oxidized indole in the compound of formula 1 to the dehydrating agent 3Å molecular sieve is 1 mmol:1 g.

6. The method for synthesizing an isoindolinone-derived unsaturated imine 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 / ethyl acetate in a volume ratio of 3:

1.

7. Use of an isoindolinone-derived unsaturated imine compound in the preparation of an anti-tumor drug as claimed in claim 1, wherein the tumor is liver cancer.

Images