Matrine amine thiazole derivative, preparation method and application thereof

Abstract

The application discloses a matrine amine thiazole derivative and a preparation method and application thereof, and a structure formula of the matrine amine thiazole derivative is shown in Figure 1, wherein R is any one of 4-chlorophenyl, 4-nitrophenyl, 2,4-difluorophenyl, 4-bromophenyl, 4-methoxyphenyl, 4-phenylphenyl, naphthyl and 4-iodophenyl. First, sophoridine and thiourea are used as starting substrates, N,N-dimethylformamide is used as a solvent, and thiourea matrine is synthesized, then thiourea matrine and alpha-bromo R group ethanone are used as reactants, ethanol is used as a solvent, and a series of matrine derivatives are synthesized. The application not only enhances the antitumor activity of the matrine derivative, but also has simple preparation method and controllable reaction condition.

Description

Technical Field

[0001] This invention belongs to the field of pesticide synthesis technology, specifically involving a matrine thiazole derivative, its preparation method, and its application. Background Technology

[0002] Matrine is an alkaloid extracted from the dried roots of Sophora flavescens, Sophora tonkinensis, etc. Matrine-type alkaloids belong to the quinolone analogues. Matrine-type alkaloids include matrine, allostrine, sophoridine, sophoridine, oxymatrine, sophoridine, sophoridine alcohol, etc. Matrine has effective effects in antibacterial, anti-inflammatory, anti-allergic, antiarrhythmic, immune and biological regulation.

[0003] Matrine has poor chemical stability and is toxic to the central nervous system, resulting in low bioavailability. Therefore, its structure needs to be modified to obtain matrine thiazole derivatives with high bioactivity and safety. Summary of the Invention

[0004] Purpose of the invention: To address the problem of low bioavailability of matrine, this invention provides an antitumor matrine thiazole derivative.

[0005] Technical solution: To achieve the above objectives, the technical solution adopted by this invention is as follows:

[0006] A matrine aminethiazole derivative, the structural formula of which is shown below:

[0007]

[0008] Wherein, R is any one of the groups selected from phenyl, 4-nitrophenyl, naphthyl, 4-iodophenyl, and 4-acrylphenyl.

[0009] Another object of the present invention is to provide a method for preparing matrine thiazole derivatives, comprising the following steps:

[0010] Step 1: Preparation of thiourea matrine intermediate 3. Thiourea matrine intermediate 3 is prepared via the following reaction equation:

[0011]

[0012] Step 2: Prepare matrine aminethiazole derivative 5 using the following reaction equation:

[0013]

[0014] Wherein, R is any one of the groups selected from phenyl, 4-nitrophenyl, naphthyl, 4-iodophenyl, and 4-acrylphenyl.

[0015] Preferred method: First, add NaH, DMF solution and thiourea sequentially to the reaction vessel and stir to mix. Then, add sophoridine to the reaction vessel to react. After the reaction is complete, quench the reaction. Then, extract, concentrate and dry, and separate and purify by column chromatography to obtain the thiourea matrine intermediate.

[0016] Preferred method: First, thiourea matrine intermediate and ethanol are poured into a reactor, then α-bromo-R-methyl ethyl ketone is added to carry out the reaction. After the reaction is completed, a reaction solution is obtained. Finally, the reaction solution is concentrated, dried and separated by column chromatography to obtain matrine aminethiazole derivative 5.

[0017] Preferably, the reaction process is monitored using a TLC plate.

[0018] Preferred: In step 2, the thiourea matrine intermediate 3 is reacted with α-bromoacetophenone, α-bromo-4-nitroacetophenone, α-bromonaphthylacetophenone, α-bromo-4-iodoacetophenone, and α-bromo-4-cyanoacetophenone respectively to obtain matrine-C13-position aminethiazole derivative 5-1, matrine-C13-position aminethiazole derivative 5-4, matrine-C13-position aminethiazole derivative 5-15, matrine-C13-position aminethiazole derivative 5-16, and matrine-C13-position aminethiazole derivative 5-17.

[0019] Another object of the present invention is to provide the application of the matrine thiazole derivative in the preparation of tumor inhibitors.

[0020] Preferably, the tumor inhibitor is a lung cancer cell inhibitor, a cervical cancer cell inhibitor, or a colon cancer cell inhibitor.

[0021] Compared with the prior art, the present invention has the following advantages:

[0022] The matrine aminethiazole derivative of the present invention retains the complete structure of matrine while forming an aminethiazole structure, which enhances the antitumor activity of matrine derivative. Its molecular structure is novel and all are new compounds. It has distinct chemical structural characteristics. The preparation method is not only simple, but the reaction conditions are also easy to control. The product can be obtained by column chromatography. Attached Figure Description

[0023] Figure 1 The diagram below shows the structure of the matrine aminethiazole derivative in an embodiment of the present invention.

[0024] Figure 2 This is the 1H NMR spectrum of compound 5-1 in this embodiment of the invention.

[0025] Figure 3 This is the carbon NMR spectrum of compound 5-1 in this embodiment of the invention.

[0026] Figure 4 The above is the 1H NMR spectrum of compound 5-4 in the embodiments of the present invention.

[0027] Figure 5 This is the carbon NMR spectrum of compound 5-4 in the embodiments of the present invention.

[0028] Figure 6 The above are the proton NMR spectra of compounds 5-15 in the embodiments of the present invention.

[0029] Figure 7 The images show the carbon NMR spectra of compounds 5-15 from embodiments of the present invention.

[0030] Figure 8 The above are the proton NMR spectra of compounds 5-16 in the embodiments of the present invention.

[0031] Figure 9 The images show the carbon NMR spectra of compounds 5-16 from the embodiments of this invention.

[0032] Figure 10 The above are the proton NMR spectra of compounds 5-17 in the embodiments of the present invention.

[0033] Figure 11 The images show the carbon NMR spectra of compounds 5-7 from the embodiments of this invention. Detailed Implementation

[0034] The present invention will be further illustrated below with reference to the accompanying drawings and specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the invention. After reading this invention, any modifications of the invention in various equivalent forms by those skilled in the art will fall within the scope defined by the appended claims.

[0035] Example 1

[0036] A matrine aminethiazole derivative, the structural formula of which is as follows: Figure 1 As shown, Figure 1 In the above, R represents any one of the following groups: phenyl 5-1, 4-nitrophenyl 5-4, naphthyl 5-15, 4-iodophenyl 5-16, and 4-acrylphenyl 5-17.

[0037]

[0038] Example 2

[0039] This embodiment provides a method for preparing matrine aminethiazole derivatives, including the following steps:

[0040] Step 1: Thiourea matrine intermediate 3 is prepared by reacting sophoridine 1 and thiourea 2. The intermediate 3 is synthesized by nucleophilic addition of the lone pair electrons on the nitrogen atom of thiourea to attack the C13 position of matrine.

[0041] First, 60% pure NaH, DMF solution, and thiourea were added sequentially to the reaction vessel and stirred at room temperature for 10 minutes. Next, sophoridine was added to the reaction vessel to initiate the reaction. The reaction process was monitored using a TLC plate. After the reaction was complete, an appropriate amount of acetic acid was added to quench the reaction. Then, extraction, concentration, drying, and column chromatography (dichloromethane:methanol = 10:1-8:1) were performed to purify the product, yielding thiourea matrine intermediate 3.

[0042] The reaction formula for synthesizing thiourea matrine intermediate 3 is as follows:

[0043]

[0044] Step 2: Prepare matrine aminethiazole derivative 5 by using thiourea matrine intermediate 3 and α-bromo-R-ethyl ketone.

[0045] A series of matrine derivatives were synthesized using thiourea matrine and α-bromo-R-ethyl ketone as reactants and ethanol as solvent. Specifically, thiourea matrine intermediate 3 and ethanol were first added to a reactor, and the intermediate 3 was dissolved by ethanol. Then, α-bromo-R-ethyl ketone was added, with a molar ratio of thiourea matrine intermediate 3 to α-bromo-R-ethyl ketone of 0.3:0.36 mmol:mmol. The reaction was carried out at room temperature, and the reaction process was monitored by TLC plate for 1 hour. After the reaction was completed, the reaction solution was obtained, and finally, the reaction solution was concentrated, dried, and separated by column chromatography (dichloromethane:methanol = 30:1 to 20:1) to obtain matrine aminethiazole derivative 5.

[0046] The reaction formula for synthesizing matrine aminethiazole derivative 5 is as follows:

[0047]

[0048] Wherein, R is any one of the following groups: phenyl 5-1, 4-nitrophenyl 5-4, naphthyl 5-15, 4-iodophenyl 5-16, and 4-acrylonitrile 5-17.

[0049] In this embodiment, thiourea matrine intermediates were first synthesized using sophoridine and thiourea as starting substrates and N,N-dimethylformamide as solvent. Then, a series of matrine aminethiazole derivatives were synthesized using the thiourea matrine intermediate and α-bromo-R-ethyl ketone as reactants and ethanol as solvent. While retaining the complete structure of matrine, matrine aminethiazole derivatives with an aminethiazole structure were formed, enhancing the antibacterial activity of the matrine aminethiazole derivatives.

[0050] Example 3

[0051] The difference between this embodiment and Example 2 is that matrine-C13 aminothiazole derivative 5-1 is synthesized by reacting thiourea matrine intermediate 3 with α-bromoacetophenone.

[0052] Thiourea matrine intermediate 3 was added to a round-bottom flask and dissolved in ethanol. Then, α-bromoacetophenone was added, with a molar ratio of thiourea matrine intermediate 3 to α-bromoacetophenone of mmol:mmol:0.3:0.36. The reaction was carried out at room temperature, monitored by TLC plate until completion, for a reaction time of 1 h. The reaction solution was concentrated and dried, and separated by column chromatography (dichloromethane:methanol = 30:1–20:1) to obtain the product matrine-C13 aminothiazole derivative 5-1.

[0053]

[0054] like Figure 2 , 3 As shown, the spectral data analysis of matrine-C13 aminethiazole derivative 5-1 is as follows:

[0055] White solid, R f :0.65 (DCM:MeOH=10:1), 126.6mg (99.5% yield).

[0056] 1 H NMR (400MHz, CDCl3) δ7.81(d,J=7.1Hz,2H),7.37(t,J=7.6Hz,2H),7.27(t,J=7.3Hz,1H),6.68(s, 1H),6.05(d,J=6.8Hz,1H),4.41(dd,J=12.7,4.4Hz,1H),4.26(d,J=6.2Hz,1H),4.16–4.05(m,1H), 3.18(t,J=12.7Hz,1H),2.84(t,J=11.9Hz,2H),2.76(dd,J=17.1,4.9Hz,1H),2.57(dd,J=17.2,6. 0Hz,1H),2.39–2.85(m,1H),2.20(s,1H),2.07–1.90(m,4H),1.82–1.52(m,6H),1.51–1.37(m,3H).

[0057] 13C NMR (101MHz, CDCl3) δ167.4,167.1,151.1,135.0,128.5(2C),127.5,126.0(2C),101.0,63.8, 57.2,57.1,50.4,46.6,42.5,41.8,38.3,35.5,30.6,27.6,26.4,21.0,20.5.HRMS(ESI)Calcd for C 24 H 30 N4OS[M+H] + m / z 423.2213, found 423.2215.

[0058] Example 4

[0059] The difference between this embodiment and Example 2 is that: the matrine-C13 aminothiazole derivative 5-4 is synthesized by reacting thiourea matrine intermediate 3 with α-bromo-4-nitroacetophenone, as shown below:

[0060]

[0061] like Figure 4 , 5 As shown, the spectral data analysis of matrine-C13 aminothiazole derivative 5-4 is as follows:

[0062] Yellow solid, R f :0.65 (DCM:MeOH=10:1), 138.9 mg (99.0% yield).

[0063] 1 H NMR (400MHz, CDCl3) δ8.19(d,J=8.4Hz,2H),7.92(d,J=8.4Hz,2H),6.89(s,1H),6.33(d,J=6.6Hz,1H ),4.40(dd,J=12.8,4.3Hz,1H),4.30(t,J=6.2Hz,1H),4.17–4.04(m,1H),3.19(t,J=12.8Hz,1H),2.9 6–2.80(m,3H),2.73(dd,J=17.1,4.8Hz,1H),2.59(dd,J=17.3,5.3Hz,1H),2.45–2.34(m,1H),2.23(s ,1H),2.08–1.96(m,3H),1.93–1.84(m,1H),1.81–1.73(m,1H),1.71–1.54(m,4H),1.50–1.38(m,3H).

[0064] 13C NMR (101MHz, CDCl3) δ167.5,166.7,149.1,146.8,140.7,126.4(2C),124.0(2C),105.2,63.7, 57.2,50.2,46.9,42.8,41.8,38.2,35.4,30.8,29.7,27.6,26.5,21.1,20.6.HRMS(ESI)Calcd for C 24 H 29 N5O3S[M+H] + m / z 468.2064, found 468.2061.

[0065] Example 5

[0066] The difference between this embodiment and Example 2 is that: matrine-C13 aminothiazole derivative 5-15 is synthesized by reacting thiourea matrine intermediate 3 with α-bromonaphthyl ethyl ketone, as shown below:

[0067]

[0068] like Figure 6 , 7 As shown, the spectral data analysis of matrine-C13 aminothiazole derivative 5-15 is as follows:

[0069] White solid, R f :0.65 (DCM:MeOH=10:1), 124.7 mg (88.0% yield).

[0070] 1 H NMR(400MHz, CDCl3)δ8.35(s,1H),7.93–7.79(m,4H),7.52–7.44(m,2H),6.85(s,1H),5.37(d, J=6.9Hz,1H),4.44(dd,J=12.7,4.4Hz,1H),4.33–4.23(m,1H),4.16–4.08(m,1H),3.19(t,J=1 2.7Hz,1H),2.89–2.78(m,3H),2.61(dd,J=17.0,6.2Hz,1H),2.38–2.29(m,1H),2.20(s,1H),2 .14–1.96(m,4H),1.84–1.72(m,3H),1.71–1.64(m,2H),1.63–1.52(m,2H),1.51–1.42(m,2H).

[0071] 13C NMR (151MHz, CDCl3) δ167.2,166.6,151.4,133.7,133.0,132.2,128.3,128.1,127.7,126.2,125.9,125.0,124 .1,101.8,63.8,57.2,57.2,50.5,47.0,42.6,41.9,38.5,35.6,30.8,27.7,26.6,21.1,20.6.HRMS(ESI)Calcd for C 28 H 32 N4OS[M+H] + m / z473.2370, found 473.2365.

[0072] Example 6

[0073] The difference between this embodiment and Example 2 is that: matrine-C13 aminothiazole derivatives 5-16 are synthesized by reacting thiourea matrine intermediate 3 with α-bromo-4-iodoacetophenone.

[0074]

[0075] like Figure 8 , 9 As shown, the spectral data analysis of matrine-C13 aminothiazole derivatives 5-16 is as follows:

[0076] White solid, R f :0.65 (DCM:MeOH=10:1), 156.3 mg (95.0% yield).

[0077] 1 H NMR (400MHz, CDCl3) δ7.69(d,J=8.1Hz,2H),7.54(d,J=8.1Hz,2H),6.70(s,1H),5.86(s,1H) ,4.44(dd,J=13.0,4.0Hz,1H),4.23(s,1H),4.19–4.08(m,1H),3.21(t,J=12.8Hz,1H),3.00– 2.91(m,2H),2.74(dd,J=17.2,4.7Hz,1H),2.61(dd,J=17.4,5.5Hz,1H),2.37–2.28(m,2H), 2.12–1.92(m,4H),1.87–1.78(m,2H),1.74–1.56(m,4H),1.53–1.40(m,3H).HRMS(ESI)Calcd for C 24 H 29 IN4OS[M+H]+ m / z 549.1180, found 549.1171.

[0078] 13CNMR(101MHz,CDCl3)δ167.4,166.9,150.2,137.5(2C),134.4,127.8(2C),101.9,9 2.9,64.0,57.0(2C),50.2,46.7,42.3,41.5,38.2,35.2,30.8,27.2,26.1,20.6,20.1.

[0079] Example 6

[0080] The difference between this embodiment and Example 2 is that the matrine-C13 aminothiazole derivative 5-17 is synthesized by reacting thiourea matrine intermediate 3 with α-bromo-4-cyanoacetophenone.

[0081]

[0082] like Figure 10 , 11 As shown, the spectral data analysis of matrine-C13 aminothiazole derivatives 5-17 is as follows:

[0083] White solid, R f :0.65 (DCM:MeOH=10:1), 123.5mg (92.0% yield).

[0084] 1 H NMR (400MHz, CDCl3) δ7.91(d,J=8.5Hz,2H),7.66(d,J=8.4Hz,2H),6.87(s,1H),5.73(d,J=6.8Hz,1H), 4.43(dd,J=12.8,4.4Hz,1H),4.33–4.23(m,1H),4.14–4.05(m,1H),3.19(t,J=12.7Hz,1H),2.86(t,J=1 2.5Hz,2H),2.77(dd,J=17.1,4.8Hz,1H),2.66–2.57(m,1H),2.43–2.32(m,1H),2.23(s,1H),2.07–1.99 (m,3H),1.97–1.89(m,1H),1.85–1.75(m,2H),1.74–1.69(m,1H),1.67–1.56(m,3H),1.52–1.41(m,3H).

[0085] 13CNMR(151MHz,CDCl3)δ167.4,166.8,149.4,139.6,132.4(2C),126.4(2C),118.7,110.6,104.4, 63.7,57.2(2C),50.2,46.9,42.8,41.8,38.2,35.4,30.8,27.6,26.4,21.0,20.6.HRMS(ESI)Calcd for C 25 H 29 N5OS[M+H] + m / z 448.2166, found 448.2157.

[0086] The experiment explored aspects such as material ratio, catalyst, temperature, and solvent, and found the optimal scheme for synthesizing thiourea intermediates.

[0087] Example 7

[0088] This embodiment tests the in vitro antitumor activity of matrine derivatives.

[0089] Cell lines: Human lung cancer cells (A549), cervical cancer cells (HeLa), and human colon cancer cells (HCT-116).

[0090] Method: MTT method

[0091] The specific process is as follows:

[0092] (1) Cell culture and drug treatment. Vigorous tumor cells were taken, digested with trypsin, centrifuged, and resuspended in fresh culture medium. The cells were then diluted and counted. Cells were seeded into 96-well plates at a density of 5000 / well and incubated overnight at 37°C in a 5% CO2 incubator. On the second day, the cells were observed to be in an adherent state. The old culture medium was discarded. The experimental group was added with the test sample. Five sample concentration gradients were set up, and the samples were diluted to a final concentration of 200, 100, 50, 25, and 12.5 μmol / L. Five replicates were set for each concentration, with 250 μL in each well. Fresh culture medium was added to the negative control group and the blank group. The plates were incubated for 48 hours. The concentration with an approximate inhibition rate of 50% was screened out. Based on this concentration, 3-4 concentrations above and below the target concentration were tested at intervals of 10 μg / ml, as described above.

[0093] (2) MTT assay: Add 20 μL of pre-prepared MTT solution to each well and incubate in an incubator for 4 h. After incubation, aspirate the liquid from the wells, add 200 μL of dimethyl sulfoxide to each well, shake thoroughly for 10 min, and detect the absorbance at 490 nm using a microplate reader. Record the data, calculate the inhibition rate according to the formula, and obtain the IC50 using Origin software. 50 value

[0094] (3) Calculation: Cell inhibition rate = [(control - background) - (drug administration - background)] / (control - background) * 100%

[0095] The measurement results are shown in the table below:

[0096] Table 1. In vitro antitumor activity (IC50) of matrine-C13 thiazole derivatives 50 (ug / ml)

[0097]

[0098] The in vitro antitumor activity results of the experimental group compounds and the parent compound matrine are shown in Table 1 above. Compounds 5-1, 5-4, 5-15, 5-16, and 5-17 showed significantly enhanced in vitro antitumor activity compared to the parent compound matrine. Among them, compound 5-15 showed good inhibitory effects on human lung cancer cells (A549) and human colon cancer cells (HCT-116) with IC50. 50 The values ​​were 18.1 ug / ml and 16.3 ug / ml, respectively; compound 5-1, which showed the best effect against cervical cancer cells (HeLa), had an IC50 value of 18.1 ug / ml and 16.3 ug / ml, respectively. 50 The value was 23.2 ug / ml, indicating that matrine derivatives have potential antitumor activity and can be developed as antitumor drugs.

[0099] The antitumor matrine derivatives described in this invention exhibit distinct structures and clear chemical characteristics, demonstrating good efficacy in inhibiting tumor cells. They can be used to develop antitumor drugs. The preparation method of these compounds is simple, and the products are stable. The antitumor matrine derivatives synthesized in this invention possess good activity and medicinal value, which provides inspiration for designing novel antitumor agents based on natural products.

[0100] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A matrine thiazole derivative, characterized in that: The structural formula of the matrine aminethiazole derivative is shown below: Wherein, R is any one of the groups selected from phenyl, 4-nitrophenyl, naphthyl, 4-iodophenyl, and 4-acrylphenyl.

2. A method for preparing a matrine-aminethiazole derivative, characterized in that, Includes the following steps: Step 1: Preparation of thiourea matrine intermediate 3. Thiourea matrine intermediate 3 is prepared via the following reaction equation: Step 2: Prepare matrine aminethiazole derivative 5 using the following reaction equation: Wherein, R is any one of the groups selected from phenyl, 4-nitrophenyl, naphthyl, 4-iodophenyl, and 4-acrylphenyl.

3. The method for preparing the matrine thiazole derivative according to claim 2, characterized in that: First, NaH, DMF solution, and thiourea were added sequentially to the reaction vessel and stirred to mix. Then, sophoridine was added to the reaction vessel to carry out the reaction. After the reaction was completed, the reaction was quenched. Then, extraction, concentration and drying, and column chromatography were performed sequentially to separate and purify the intermediate thiourea matrine.

4. The method for preparing the matrine thiazole derivative according to claim 3, characterized in that: First, the thiourea matrine intermediate and ethanol were poured into the reactor, and then α-bromo-R-methyl ethyl ketone was added to carry out the reaction. After the reaction was completed, the reaction solution was obtained. Finally, the reaction solution was concentrated, dried and separated by column chromatography to obtain matrine aminethiazole derivative 5.

5. The method for preparing the matrine thiazole derivative according to claim 4, characterized in that: During the reaction, the reaction process was monitored using a TLC plate.

6. The method for preparing the matrine thiazole derivative according to claim 5, characterized in that: In step 2, the thiourea matrine intermediate 3 is reacted with α-bromoacetophenone, α-bromo-4-nitroacetophenone, α-bromonaphthylacetophenone, α-bromo-4-iodoacetophenone, and α-bromo-4-cyanoacetophenone, respectively, to obtain matrine-C13 aminethiazole derivative 5-1, matrine-C13 aminethiazole derivative 5-4, matrine-C13 aminethiazole derivative 5-15, matrine-C13 aminethiazole derivative 5-16, and matrine-C13 aminethiazole derivative 5-17.

7. The use of the matrine thiazole derivative as described in claim 1 in the preparation of a tumor inhibitor, wherein the tumor inhibitor is a lung cancer cell inhibitor, a cervical cancer cell inhibitor, or a colon cancer cell inhibitor.

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