Anti-tumor matrine hydrazine thiazole derivative as well as preparation method and application thereof

Abstract

The invention discloses an anti-tumor matrine hydrazine thiazole derivative and a preparation method and application thereof.The preparation method comprises the steps that NaH is added into a first reaction container, then a DMF solution is added, thiosemicarbazide is added into the first reaction container, and the solution is stirred; adding sophocarpidine into the stirred solution to perform reflux reaction, performing quenching reaction after the reaction is finished, and performing extraction, concentration drying and column chromatography separation to obtain a thiosemicarbazide sophocarpidine intermediate; adding the obtained thiosemicarbazide matrine intermediate into a reaction container II, and adding a dissolving solvent ethanol for dissolving; adding alpha-bromo-R-ethyl ketone into the dissolved solution for reaction, concentrating and drying after the reaction is finished, and performing column chromatography separation to obtain the anti-tumor matrine hydrazine thiazole derivative. The anti-tumor matrine hydrazine thiazole derivative is high in anti-tumor activity, the preparation method is simple and convenient, and reaction conditions are easy to control.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and specifically relates to an anti-tumor matrine hydrazine thiazole derivative and a preparation method and application thereof. Background Art

[0002] Matrine alkaloids are extracted from the traditional Chinese medicine Sophora flavescens and have been receiving attention for the past few decades. Matrine-type alkaloids belong to quinolizidine analogs and are composed of matrine, allomatrine, sophorocarpine, sophoridine, oxymatrine, sophoramine, sophorol, etc. Matrine-type alkaloids have many biological activities and therapeutic properties. For example, matrine exhibits a variety of effective effects, including anti-inflammatory, antiviral, antitumor, antiparasitic, antimicrobial, immunosuppressive, neuroprotective and cardioprotective effects; on the other hand, matrine is also used to prepare surface imprinting materials for selective molecular recognition. Sophoridine, as another chemical component of the traditional Chinese medicine compound Sophora flavescens injection, also exhibits similar biological activities to matrine. Matrine, oxymatrine and sophoridine, as the main active ingredients, have been widely used in my country to treat acute and chronic liver diseases, vaginitis, chronic cervicitis and arrhythmias. Summary of the invention

[0003] Purpose of the invention: To address the problems existing in the prior art of matrine, the present invention provides an anti-tumor matrine hydrazine thiazole derivative.

[0004] Technical solution: To achieve the above purpose, the technical solution adopted by the present invention is:

[0005] An anti-tumor matrine hydrazine thiazole derivative, the structural formula of which is:

[0006]

[0007] Wherein, R is one of the following groups:

[0008]

[0009] Another object of the present invention is to provide a method for preparing an antitumor matrine hydrazine thiazole derivative, wherein the method comprises the following steps:

[0010] Step S1, adding NaH into a reaction container 1, then adding a DMF solution, and then adding thiosemicarbazide into the reaction container 1 to stir the solution.

[0011] Step S2, adding sophocarpine to the solution of step S1 for reflux reaction, quenching the reaction after the reaction is completed, and then extracting, concentrating and drying, and separating by column chromatography to obtain the semicarbazide matrine intermediate.

[0012] Step S3, adding the semicarbazide matrine intermediate obtained in step S2 into the reaction container 2, adding the dissolving solvent ethanol to dissolve, adding α-bromo R-ethyl ketone to the dissolved solution to react, concentrating and drying after the reaction, and separating by column chromatography to obtain the antitumor matrine hydrazine thiazole derivative 5.

[0013] Preferably: after the reaction is quenched in step S2, the aqueous phase is extracted with ethyl acetate, the organic phases are combined, and then concentrated and dried.

[0014] Preferably, acetic acid is used to quench the reaction in step S2.

[0015] Preferably, during the reaction, the reaction process is monitored by TLC plate.

[0016] Preferably, the molar ratio of sophocarpine to thiosemicarbazide is 1:1-1.2 in mmol:mmol.

[0017] Preferably, the molar ratio of thioureamatrine to α-bromoacetophenone is 1:1.1-1.3 in mmol:mmol.

[0018] Preferably, the solution dissolved in step S3 is added with α-bromo-R-ethyl ketone to react to obtain the anti-tumor matrine hydrazine thiazole derivative 5, which comprises:

[0019] The antitumor matrine-C13 hydrazine thiazole derivative 5-2 was synthesized by reacting thiourea matrine intermediate 3 with α-bromo-4-phenylacetophenone.

[0020] Antitumor matrine-C13 hydrazine thiazole derivatives 5-7 were synthesized by reacting thiourea matrine intermediate 3 with α-bromo-4-nitroacetophenone.

[0021] Antitumor matrine-C13 hydrazine thiazole derivatives 5-8 were synthesized by reacting thiourea matrine intermediate 3 with α-bromo-4-bromoacetophenone.

[0022] Antitumor matrine-C13 hydrazine thiazole derivatives 5-11 were synthesized by reacting thiourea matrine intermediate 3 with α-bromo-4-fluoroacetophenone.

[0023] Antitumor matrine-C13 hydrazine thiazole derivatives 5-13 were synthesized by reacting thiourea matrine intermediate 3 with α-bromo-4-nitrile acetophenone.

[0024] Antitumor matrine-C13 hydrazine thiazole derivatives 5-15 were synthesized by reacting thiourea matrine intermediate 3 with α-bromo-2,4-dichloroacetophenone.

[0025] Antitumor matrine-C13 hydrazine thiazole derivatives 5-16 were synthesized by reacting thiourea matrine intermediate 3 with α-bromo-2,4-difluoroacetophenone.

[0026] Antitumor matrine-C13 hydrazine thiazole derivatives 5-17 were synthesized by reacting thiourea matrine intermediate 3 with α-bromo-4-trifluoromethoxyacetophenone.

[0027] Antitumor matrine-C13 hydrazine thiazole derivatives 5-18 were synthesized by reacting thiourea matrine intermediate 3 with α-bromo-4-methylsulfonyl acetophenone.

[0028] Another object of the present invention is to provide an application of an anti-tumor matrine hydrazine thiazole derivative in the preparation of a tumor inhibitor.

[0029] Preferably, the tumor inhibitor is a lung cancer cell inhibitor, a cervical cancer cell inhibitor, or a colon cancer cell inhibitor.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] The anti-tumor matrine hydrazine thiazole derivatives of the present invention form matrine derivatives with hydrazine thiazole structure while completely retaining the structure of matrine, thereby enhancing the anti-tumor activity of the matrine derivatives, and the molecular structure is novel and all of them are new compounds. They have distinct chemical structure characteristics, and the preparation method is not only simple, but also the reaction conditions are easy to control, and the product can be obtained by column chromatography. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 Schematic diagram of the preparation method of matrine derivatives in an embodiment of the present invention.

[0033] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of Example Compound 5-2 of the present invention.

[0034] Figure 3 This is the carbon nuclear magnetic resonance spectrum of Example Compound 5-2 of the present invention.

[0035] Figure 4 The hydrogen nuclear magnetic resonance spectrum of Example Compound 5-7 of the present invention.

[0036] Figure 5 The carbon nuclear magnetic resonance spectrum of Example Compound 5-7 of the present invention.

[0037] Figure 6 The hydrogen nuclear magnetic resonance spectrum of Example Compound 5-8 of the present invention.

[0038] Figure 7 The carbon nuclear magnetic resonance spectrum of Example Compound 5-8 of the present invention.

[0039] Figure 8 The hydrogen nuclear magnetic resonance spectrum of Example Compound 5-11 of the present invention.

[0040] Fig. 9 The carbon nuclear magnetic resonance spectrum of Example Compound 5-11 of the present invention.

[0041] Fig.10 The nuclear magnetic resonance fluorine spectrum of Example Compound 5-11 of the present invention.

[0042] Fig.11 This is the hydrogen nuclear magnetic resonance spectrum of Example Compound 5-13 of the present invention.

[0043] Fig.12 The carbon nuclear magnetic resonance spectrum of Example Compound 5-13 of the present invention.

[0044] Fig.13 The hydrogen nuclear magnetic resonance spectrum of Example Compound 5-15 of the present invention.

[0045] Fig.14 The carbon nuclear magnetic resonance spectrum of Example Compound 5-15 of the present invention.

[0046] Fig.15 The hydrogen nuclear magnetic resonance spectrum of Example Compound 5-16 of the present invention.

[0047] Fig.16 The carbon nuclear magnetic resonance spectrum of Example Compound 5-16 of the present invention.

[0048] Fig.17 This is the nuclear magnetic resonance fluorine spectrum of Example Compound 5-16 of the present invention.

[0049] Fig.18 This is the hydrogen nuclear magnetic resonance spectrum of Example Compound 5-17 of the present invention.

[0050] Fig.19 This is the carbon nuclear magnetic resonance spectrum of Example Compound 5-17 of the present invention.

[0051] Fig. 20 This is the nuclear magnetic resonance fluorine spectrum of Example Compound 5-17 of the present invention.

[0052] Fig.21 This is the hydrogen nuclear magnetic resonance spectrum of Example Compound 5-18 of the present invention.

[0053] Fig. 22 This is the carbon nuclear magnetic resonance spectrum of Example Compound 5-18 of the present invention. DETAILED DESCRIPTION

[0054] The present invention is further explained below in conjunction with the accompanying drawings and specific embodiments. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention. After reading the present invention, various equivalent forms of modifications to the present invention by those skilled in the art all fall within the scope defined by the claims attached to this application.

[0055] Example 1

[0056] An anti-tumor matrine hydrazine thiazole derivative, the structural formula of which is:

[0057]

[0058] Wherein, R is one of the following groups:

[0059]

[0060] Example 2

[0061] This embodiment provides a method for preparing an anti-tumor matrine hydrazine thiazole derivative, to prepare the anti-tumor matrine hydrazine thiazole derivative in Example 1, comprising the following steps:

[0062] Step S1, add NaH to a reaction vessel 1, then add DMF solution, and then add thiosemicarbazide to the reaction vessel 1 to stir the solution. Specifically, firstly add 60% pure NaH (300 mg) to a reaction bottle containing 10 mL DMF solution, and then add thiosemicarbazide (1.0 g) to the above system, and stir at 0°C for 10 min.

[0063] Step S2, adding sophoracarpine to the solution of step S1 for reflux reaction, quenching the reaction after the reaction is completed, and then extracting, concentrating and drying, and column chromatography separation to obtain the semicarbazide matrine intermediate. The reaction process is as follows: Figure 1 shown.

[0064] Specifically, sophocarpine (2.5 g) is added to the solution of step S1 for reflux reaction, and the reflux reaction is 12 hours. The molar ratio of sophocarpine to thiosemicarbazide is 1:1.1 in mmol:mmol. In another embodiment, the molar ratio of sophocarpine to thiosemicarbazide is 1:1 in mmol:mmol. In another embodiment, the molar ratio of sophocarpine to thiosemicarbazide is 1:1.2 in mmol:mmol. The reaction is detected by TLC plate until the reaction is completed, and then an appropriate amount of acetic acid is added to quench the reaction. Post-reaction treatment: The aqueous phase is extracted three times with ethyl acetate, the organic phases are combined, concentrated and dried, and the crude product is purified by column chromatography (dichloromethane: methanol = 10:1-8:1) to obtain 1.3 g of thiosemicarbazide matrine, with a yield of 40%.

[0065] Step S3, adding the semicarbazide matrine intermediate obtained in step S2 into the reaction vessel 2, and adding ethanol as a dissolving solvent to dissolve; adding α-bromo R-ethyl ketone to the dissolved solution to react, concentrating and drying after the reaction, and separating by column chromatography to obtain the antitumor matrine hydrazine thiazole derivative 5, the reaction process is as follows: Figure 1 shown.

[0066] Specifically, firstly, thiosemicarbazide matrine is dissolved in ethanol, and then α-bromoacetophenone is added to react, and the reaction is completed to obtain a reaction solution, and finally the reaction solution is concentrated and dried in turn, and separated by column chromatography (dichloromethane: methanol = 30: 1 to 10: 1) to obtain matrine derivative 5. Wherein, the molar ratio of thiosemicarbazide matrine and α-bromoacetophenone is 1: 1.2 in mmol: mmol. In another embodiment, the molar ratio of thiosemicarbazide matrine and α-bromoacetophenone is 1: 1.1 in mmol: mmol. In another embodiment, the molar ratio of thiosemicarbazide matrine and α-bromoacetophenone is 1: 1.3 in mmol: mmol.

[0067] In this embodiment, thiosemicarbazide matrine was first synthesized using sophoracarbine and thiosemicarbazide as starting substrates and N,N-dimethylformamide as solvent, and then a series of antifungal matrine derivatives were synthesized using thiosemicarbazide matrine and α-bromo-R-ethyl ketone as reactants and ethanol as solvent. While the structure of matrine was completely retained, antifungal matrine derivatives with hydrazine thiazole structure were formed, which enhanced the antibacterial activity of antifungal matrine derivatives.

[0068] Example 3

[0069] The difference between this embodiment and embodiment 2 is that the anti-tumor matrine-C13 hydrazine thiazole derivative 5-2 is synthesized by reacting the thiourea matrine intermediate 3 with α-bromo-4-phenylacetophenone.

[0070] Add the semicarbazide matrine intermediate 3 to a round-bottom flask, add the solvent ethanol to dissolve, and then add α-bromo-4-phenylacetophenone. The molar ratio of semicarbazide matrine intermediate 3 to α-bromo-4-phenylacetophenone is mmol:mmol:0.3:0.36; react at room temperature, monitor the reaction with a TLC plate until the reaction is completed, and the reaction time is 1h. The reaction solution is concentrated and dried, and separated by column chromatography (dichloromethane:methanol=30:1~10:1) to obtain the product anti-tumor matrine-C13 hydrazine thiazole derivative 5-2:

[0071]

[0072] like Figure 2 , 3 As shown, the spectrum data analysis of the anti-tumor matrine-C13 hydrazine thiazole derivative 5-2:

[0073] White solid, R f :0.60(DCM:MeOH=10:1),114.9mg(74.6%yield)

[0074] 1 H NMR (400MHz, CDCl3) δ7.82 (dd, J=8.3, 2.1Hz, 2H), 7.62 (dd, J=6.4, 4.0Hz, 4H), 7.48- 7.42(m,2H),7.39-7.33(m,1H),6.81(d,J=2.1Hz,1H),4.47-4.19(m,2H),4.11-3.98( m,1H),3.30-3.22(m,1H),3.13(t,J=12.7Hz,1H),2.87(s,2H),2.54-2.36(m,2H),2. 18(s,1H),2.05-1.89(m,3H),1.8-1.61(m,5H),1.55-1.40(m,4H),1.38-1.28(m,3H).

[0075] 13 C NMR (101MHz, CDCl3) δ174.9,167.2,150.8,140.5,140.2,134.1,128.8(2C),127.4,127.2(2C),126.9(2 C),126.3(2C),103.3,63.8,57.1(2C),51.4,50.1,42.5,41.6,36.1,35.4,29.2,27.5,26.2,20.9,20.4.

[0076] Example 4

[0077] The difference between this embodiment and embodiment 2 is that the anti-tumor matrine-C13 hydrazine thiazole derivative 5-7 is synthesized by reacting the thiourea matrine intermediate 3 with α-bromo-4-nitroacetophenone.

[0078]

[0079] like Figure 4 , 5 As shown, the spectrum data analysis of anti-tumor matrine-C13 hydrazine thiazole derivatives 5-7:

[0080] Yellow solid, R f :0.60(DCM:MeOH=10:1),115.7mg(80%yield)

[0081] 1H NMR(400MHz,Chloroform-d)δ8.24(d,J=8.8Hz,2H),7.91(d,J=8.8Hz,2H),7.04(s,1H),6.93(s,1 H),4.42(dd,J=12.9,4.3Hz,1H),4.34(s,1H),4.18-4.05(m,1H),3.47(s,1H),3.18(t,J=12.7Hz, 1 H),2.92-2.78(m,2H),2.62-2.48(m,2H),2.20-2.09(m,2H),2.04-1.95(m,2H),1.88(d,J=13.1Hz,1H),1.80-1.67(m,4H),1.59-1.41(m,6H).

[0082] 13 C NMR (151MHz, CDCl3) δ174.2,166.7,149.6,147.8,139.6,126.3(2C),124.1(2C),108.2, 63.7,57.2(2C),51.8,50.2,43.0,41.4,36.1,35.3,29.5,27.7,26.7,25.1,22.1,20.7.

[0083] Example 5

[0084] The difference between this embodiment and embodiment 2 is that the anti-tumor matrine-C13 hydrazine thiazole derivative 5-8 is synthesized by reacting the thiourea matrine intermediate 3 with α-bromo-4-bromoacetophenone.

[0085]

[0086] like Figure 6 , 7 As shown, the spectrum data analysis of anti-tumor matrine-C13 hydrazine thiazole derivatives 5-8:

[0087] White solid, R f :0.60(DCM:MeOH=10:1),120.5mg(78%yield)

[0088] 1H NMR (400MHz, CDCl3) δ7.63(d,J=8.3Hz,2H),7.49(d,J=8.2Hz,2H),6.79(s, 1H),4.45(dd,J=13.0,4.5Hz,2H),4.20-4.10(m,1H),3.38(d,J=6.1Hz,1H), 3.18(t,J=12.9Hz,1H),3.10-2.97(m,2H),2.56-2.43(m,2H),2.39(s,1H), 2.20-2.02(m,3H),1.92-1.77(m,3H),1.76-1.63(m,3H),1.60-1.41(m,5H).

[0089] 13 C NMR (101MHz, CDCl3) δ174.5,167.3,150.1,133.9,132.0,131.7,127.8,127.5,121.4,1 03.9,64.1,56.9(2C),51.2,49.8,42.3,41.2,36.1,35.0,29.3,26.9,25.9,20.4,19.9.

[0090] Example 6

[0091] The difference between this embodiment and embodiment 2 is that the anti-tumor matrine-C13 hydrazine thiazole derivative 5-11 is synthesized by reacting the thiourea matrine intermediate 3 with α-bromo-4-fluoroacetophenone.

[0092]

[0093] like Figure 8-10 As shown, the spectrum data analysis of matrine-C13 hydrazine thiazole derivatives 5-11:

[0094] White solid, R f :0.60(DCM:MeOH=10:1),107.9mg(79%yield)

[0095] 1H NMR (400MHz, CDCl3) δ7.76-7.68(m,2H),7.06(t,J=8.7Hz,2H),6.70(s,1H),4.52-4.25(m,2H),4.12(s,1H),3.37-3.29(m,1H),3. 18(t,J=12.8Hz,1H),2.97(s,2H),2.56-2.40(m,2H),2.38-2.20(m,1H),2.14-1.95(m,3H),1.92-1.62(m,6H),1.59-1.39(m,5H).

[0096] 13 C NMR (151MHz, CDCl3) δ174.6,167.2,163.2,161.6,150.2,131.3,131.3,127.6,127.6,115.5 ,115.4,102.8,64.0,57.1,51.4,50.0,42.5,41.4,36.1,35.3,29.3,27.3,26.1,20.8,20.4.

[0097] 19 F NMR (377MHz, CDCl3) δ-114.3.

[0098] Example 7

[0099] The difference between this embodiment and embodiment 2 is that the anti-tumor matrine-C13 hydrazine thiazole derivative 5-13 is synthesized by reacting the thiourea matrine intermediate 3 with α-bromo-4-nitrile acetophenone;

[0100] like Fig.11 , 12 As shown, the spectrum data analysis of anti-tumor matrine-C13 hydrazine thiazole derivative 5-13:

[0101] White solid, R f :0.60(DCM:MeOH=10:1),108.9mg(78.5%yield)

[0102] 1H NMR (400MHz, CDCl3) δ7.84(d,J=8.1Hz,2H),7.64(d,J=8.2Hz,2H),6.95(s, 1H),4.40(dd,J=12.8,4.5Hz,2H),4.16-4.04(m,1H),3.51-3.37(m,1H),3.1 5(t,J=12.7Hz,1H),2.91-2.80(m,2H),2.59-2.45(m,2H),2.18(s,1H),2.13 -1.93(m,4H),1.86(d,J=13.1Hz,1H),1.79-1.65(m,4H),1.58-1.40(m,5H).

[0103] 13 C NMR (101MHz, CDCl3) δ174.6,167.1,149.5,139.0,132.4(2C),126.2(2C),119.1,110.6, 106.5,63.7,57.1(2C),51.5,50.0,42.8,41.6,36.0,35.4,29.4,27.6,26.4,21.0,20.5.

[0104] Example 8

[0105] The difference between this embodiment and embodiment 2 is that the anti-tumor matrine-C13 hydrazine thiazole derivative 5-15 is synthesized by reacting the thiourea matrine intermediate 3 with α-bromo-2,4-dichloroacetophenone.

[0106]

[0107] like Fig.13 , 14 As shown, the spectrum data analysis of matrine-C13 hydrazine thiazole derivatives 5-15:

[0108] White solid, R f :0.60(DCM:MeOH=10:1),129.7mg(85.6%yield)

[0109] 1H NMR (400MHz, CDCl3) δ7.71(d,J=8.4Hz,1H),7.45(d,J=2.2Hz,1H),7.27(d,J=2.1Hz,1H),7.02(s,1H),4.52-4.22(m,2H),4.12(d,J=11.7Hz,1H),3. 26-3.12(m,2H),3.03-2.80(m,2H),2.51-2.36(m,2H),2.26(s,1H),2.13- 1.89(m,4H),1.88-1.60(m,6H),1.56(d,J=13.7Hz,1H),1.51-1.37(m,4H).

[0110] 13 C NMR (151MHz, CDCl3) δ174.0,167.2,146.2,133.5,132.5,132.3,131.8,130.1,127.1,1 08.7,63.9,57.1(2C),51.4,50.1,42.5,41.5,36.0,35.3,29.3,27.4,26.2,20.8,19.4.

[0111] Example 9

[0112] The difference between this embodiment and embodiment 2 is that the anti-tumor matrine-C13 hydrazine thiazole derivative 5-16 is synthesized by reacting the thiourea matrine intermediate 3 with α-bromo-2,4-difluoroacetophenone.

[0113]

[0114] like Figure 15-17 As shown, the spectrum data analysis of matrine-C13 hydrazine thiazole derivatives 5-16:

[0115] White solid, R f :0.60(DCM:MeOH=10:1),110.6mg(77.9%yield)

[0116] 1H NMR (400MHz, CDCl3) δ7.96 (q, J = 8.1Hz, 1H), 7.01 (s, 1H), 6.966.82 (m, 2H), 4.39 (d d,J=12.7,4.6Hz,1H),4.28(s,1H),4.14-4.02(m,1H),3.38(s,1H),3.14(t,J=12. 8Hz,1H),2.81(t,J=9.8Hz,2H),2.60-2.40(m,2H),2.11(s,1H),2.07-1.93(m,3H) ,1.82(d,J=13.5Hz,1H),1.77-1.64(m,4H),1.59-1.48(m,2H),1.50-1.36(m,5H).

[0117] 13 C NMR (151MHz, CDCl3) δ172.8,166.9,161.1,161.0,151.4,144.1,130.4,119.7,119.3,111.4,111.3,107.9 ,107.8,104.4,104.2,104.1,63.7,57.2,51.6,50.2,42.8,41.7,36.3,35.5,29.3,27.7,26.5,21.1,20.7.

[0118] 19 F NMR (377MHz, CDCl3) δ-110.1,-110.1,-111.2,-111.2.

[0119] Example 10

[0120] The difference between this embodiment and embodiment 2 is that the anti-tumor matrine-C13 hydrazine thiazole derivative 5-17 is synthesized by reacting the thiourea matrine intermediate 3 with α-bromo-4-trifluoromethoxyacetophenone.

[0121]

[0122] like Figure 18-20 As shown, the spectrum data analysis of matrine-C13 hydrazine thiazole derivatives 5-17:

[0123] White solid, R f :0.60(DCM:MeOH=10:1),135.6mg(86.7%yield)

[0124] 1H NMR (600MHz, CDCl3) δ7.78(d,J=8.4Hz,2H),7.43(s,1H),7.22(d,J=8.3Hz,2H),6.79(s, 1H),4.38(dd,J=12.7,4.3Hz,1H),4.25(d,J=3.3Hz,1H),4.13-3.99(m,1H),3.34(s,1H) ,3.14(t,J=12.6Hz,1H),2.88-2.74(m,2H),2.56-2.41(m,2H),2.10(s,1H),2.02-1.92( m,3H),1.81(d,J=13.6Hz,1H),1.77-1.63(m,4H),1.58-1.49(m,2H),1.48-1.34(m,4H).

[0125] 13 C NMR (151MHz, CDCl3) δ174.4,166.9,150.0,148.6,133.9,127.2(2C),121.0(2C),103 .9,63.7,57.2(2C),51.6,50.1,42.8,41.7,36.1,35.5,29.3,27.7,26.5,21.2,20.7.

[0126] 19 F NMR (377 MHz, CDCl3) δ -57.8.

[0127] Embodiment 11

[0128] The difference between this embodiment and embodiment 2 is that the anti-tumor matrine-C13 hydrazine thiazole derivative 5-18 is synthesized by reacting the thiourea matrine intermediate 3 with α-bromo-4-methylsulfonyl acetophenone.

[0129]

[0130] like Fig.21 , 22 As shown, the spectrum data analysis of anti-tumor matrine-C13 hydrazine thiazole derivatives 5-18:

[0131] White solid, R f :0.60(DCM:MeOH=10:1),108.2mg(70%yield)

[0132] 1H NMR (600MHz, CDCl3) δ7.94-7.87(m,4H),6.95(s,1H),4.65-4.34(m,2H),4.11(s,1H),3.45-3.37(m,1H),3.15(t,J=12.7Hz,1H),3.07(s, 3H), 2.89 (s, 2H), 2.56-2.43 (m, 2H), 2.30-2.15 (m, 1H), 2.11-2.00 (m, 3H), 1.86 (d, J = 13.8Hz, 1H), 1.81-1.59 (m, 5H), 1.57-1.39 (m, 5H).

[0133] 13 C NMR (151MHz, CDCl3) δ175.0,167.2,149.3,140.0,138.8,127.7(2C),126.5(2C),106.6, 63.8,57.1(2C),51.5,50.0,44.6,42.7,41.5,36.0,35.3,29.4,27.5,26.1,21.5,20.4.

[0134] Example 12

[0135] This embodiment provides an application of an anti-tumor matrine hydrazine thiazole derivative in the preparation of a tumor inhibitor. The tumor inhibitor is a lung cancer cell inhibitor, a cervical cancer cell inhibitor, and a colon cancer cell inhibitor.

[0136] The in vitro antitumor activity of the antitumor matrine hydrazine thiazole derivatives was tested as follows:

[0137] Cell lines: human lung cancer cells (A549), cervical cancer cells (Hela), human colon cancer cells (HCT-116)

[0138] Method: MTT method

[0139] The specific process is as follows:

[0140] (1) Cell culture and drug treatment. Actively growing tumor cells were obtained, digested with trypsin, centrifuged, and fresh culture medium was added. The cells were resuspended, diluted, and counted. The cells were inoculated into a 96-well plate at a density of 5000 / well and placed in a 37°C, 5% CO2 incubator for overnight culture. On the second day, the cell morphology was observed to be adherent. The old culture medium was discarded, and the test sample was added to the experimental group. Five sample concentration gradients were set, and the samples were diluted to a final concentration of 200, 100, 50, 25, and 12.5 μmol / L. Five replicate wells were set for each concentration, with 250 μL per well. New culture medium was added to the negative control group and the blank group, and the plates were placed in an incubator for 48 h. The approximate concentration of 50% inhibition rate was screened out. Based on this concentration, 3-4 concentrations were tested at intervals of 10 ug / mL, as described above.

[0141] (2) MTT assay: 20 μL of pre-prepared MTT solution was added to each well and incubated in an incubator for 4 h. After incubation, the liquid in the well was aspirated and 200 μL of dimethyl sulfoxide was added to each well. The well was fully shaken for 10 min. The absorbance was detected at 490 nm using an ELISA reader. The data were recorded and the inhibition rate was calculated according to the formula. The IC was obtained by fitting with the Origin software. 50 value.

[0142] (3) Calculation: Cell inhibition rate = [(control - background) - (drug administration - background)] / (control - background) * 100%

[0143] The measurement results are shown in the table:

[0144] Table 1 In vitro antitumor activity IC of matrine-C13 hydrazine thiazole derivatives 50 (ug / mL)

[0145]

[0146]

[0147] The in vitro antitumor activity results of the experimental group compounds and the parent matrine are shown in Table 1 above. The in vitro antitumor activity of compounds 5-2, 5-7, 5-8, 5-11, and 5-16 are significantly improved relative to the parent matrine. Among them, compound 5-8 has a good inhibitory effect on human lung cancer cells (A549) and human colon cancer cells (HCT-116). 50 The values ​​were 21.9ug / mL and 85.9ug / mL respectively; the compound 5-16 with the best effect on cervical cancer cells (Hela) had an IC 50 The value was 39.6ug / mL. The results showed that matrine derivatives have potential anti-tumor activity and can be developed as anti-tumor drugs.

[0148] The anti-tumor matrine derivatives of the present invention have excellent inhibitory effects on the growth of tumor cells and have great potential for development into anti-tumor drugs. The preparation process is simple and convenient, and the obtained product has good stability. The matrine derivatives synthesized by the present invention have excellent activity and high medicinal value, and have opened up new ideas for designing new anti-tumor agents based on natural products, providing valuable reference and guidance.

[0149] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. An anti-tumor matrine hydrazine thiazole derivative, characterized in that: Its structural formula is: Wherein, R is one of the following groups:

2. A method for preparing the antitumor matrine hydrazine thiazole derivative as claimed in claim 1, characterized in that: The following steps are involved: Step S1, adding NaH into a reaction container 1, then adding a DMF solution, and then adding thiosemicarbazide into the reaction container 1 to stir the solution; Step S2, adding sophoracarpine to the solution of step S1 for reflux reaction, quenching the reaction after the reaction is completed, and then extracting, concentrating and drying, and separating by column chromatography to obtain a semicarbazide matrine intermediate; Step S3, adding the semicarbazide thiourea matrine intermediate obtained in step S2 into the reaction container 2, and adding the dissolving solvent ethanol to dissolve it; adding α-bromo R-ethyl ketone to the dissolved solution to react, concentrating and drying after the reaction is completed, and separating by column chromatography to obtain the antitumor matrine hydrazine thiazole derivative 5.

3. The preparation method according to claim 2, characterized in that: After the reaction is quenched in step S2, the aqueous phase is extracted with ethyl acetate, and the organic phases are combined and then concentrated and dried.

4. The preparation method according to claim 3, characterized in that: In step S2, acetic acid is used to quench the reaction.

5. The preparation method according to claim 4, characterized in that: During the reaction, the reaction progress was monitored by TLC plate.

6. The preparation method according to claim 5, characterized in that: The molar ratio of sophocarpine to thiosemicarbazide is 1:1-1.2 in mmol:mmol.

7. The preparation method according to claim 6, characterized in that: The molar ratio of thioureamatrine to α-bromoacetophenone is 1:1.1-1.3 in mmol:mmol.

8. The preparation method according to claim 7, characterized in that: The solution dissolved in step S3 is added with α-bromo-R-ethyl ketone to react to obtain the anti-tumor matrine hydrazine thiazole derivative 5, which includes: The antitumor matrine-C13 hydrazine thiazole derivative 5-2 was synthesized by reacting thiourea matrine intermediate 3 with α-bromo-4-phenylacetophenone; Antitumor matrine-C13 hydrazine thiazole derivatives 5-7 were synthesized by reacting thiourea matrine intermediate 3 with α-bromo-4-nitroacetophenone; Antitumor matrine-C13 hydrazine thiazole derivatives 5-8 were synthesized by reacting thiourea matrine intermediate 3 with α-bromo-4-bromoacetophenone; Antitumor matrine-C13 hydrazine thiazole derivatives 5-11 were synthesized by reacting thiourea matrine intermediate 3 with α-bromo-4-fluoroacetophenone; Antitumor matrine-C13 hydrazine thiazole derivatives 5-13 were synthesized by reacting thiourea matrine intermediate 3 with α-bromo-4-nitrile acetophenone; Antitumor matrine-C13 hydrazine thiazole derivatives 5-15 were synthesized by reacting thiourea matrine intermediate 3 with α-bromo-2,4-dichloroacetophenone; Antitumor matrine-C13 hydrazine thiazole derivatives 5-16 were synthesized by reacting thiourea matrine intermediate 3 with α-bromo-2,4-difluoroacetophenone; Antitumor matrine-C13 hydrazine thiazole derivatives 5-17 were synthesized by reacting thiourea matrine intermediate 3 with α-bromo-4-trifluoromethoxyacetophenone; Antitumor matrine-C13 hydrathiazole derivatives 5-18 were synthesized by reacting thiourea matrine intermediate 3 with α-bromo-4-methylsulfonyl acetophenone.

9. Use of the anti-tumor matrine hydrazine thiazole derivative as claimed in claim 1 in the preparation of tumor inhibitors.

10. The use according to claim 9, characterized in that: The tumor inhibitors are lung cancer cell inhibitors, cervical cancer cell inhibitors, and colon cancer cell inhibitors.

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