Thiazole derivatives of dioscorea indica and their preparation method and application

Abstract

The present invention belongs to the technical fields of medicinal chemistry and pharmacology, and discloses a thiazole derivative of schizoferrin, its preparation method, and application. The structure of the thiazole derivative of schizoferrin is shown in the following formula: wherein R represents one of methyl, amino, anilino, tert-butyl, ethyl, isopropyl, ethoxycarbonyl, cyclopropyl, methylamino, butylamino, acetamide, and hydrazine. The preparation method comprises: reacting schizoferrin with trifluoromethanesulfonic anhydride and triethylamine to obtain schizoferrin trifluoromethanesulfonate; performing a Stille coupling reaction of schizoferrin trifluoromethanesulfonate with tributyl(1-ethoxyethylene)tin and 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride to obtain a ketone derivative of schizoferrin; brominating the ketone derivative of schizoferrin with PyHBr3 to obtain a brominated derivative; and reacting the brominated derivative with a thioacetamide derivative to obtain a thiazole derivative of schizoferrin. The thiazole derivative of schizoferrin has strong tumor cell proliferation inhibitory activity and good metabolic stability.

Description

Technical Field

[0001] The invention belongs to the technical field of medicinal chemistry and pharmacology, and particularly relates to a thiazole derivative of dioscorea quinata and a preparation method and application thereof. Background Art

[0002] With advances in medicine, common infectious diseases have been gradually brought under control, while malignant tumors—cancer—have become a common and serious threat to human life and quality of life. Plant-derived anti-tumor drugs play an important role in clinical treatment. Recent studies have revealed that various glycoside derivatives of the natural lignan schizofiarin, such as Cleistanthin-A, possess potent anti-tumor activity. However, the chemical synthesis of these glycoside derivatives is complex, and the glycosidic bond is metabolically unstable, making them susceptible to hydrolysis and inactivation by endogenous glycosidases. To address the metabolic stability of schizofiarin glycoside derivatives, hydrocarbon derivatives of schizofiarin were designed and synthesized. While these compounds also exhibit potent anti-tumor activity, they also suffer from the metabolic stability of the olefinic bond.

[0003] Summary of the Invention

[0004] In view of this, the object of the present invention is to provide a thiazole derivative of schizoferrin, a preparation method and application thereof. The thiazole derivative of schizoferrin is a non-glycoside thiazole derivative of schizoferrin, which does not contain glycosidic bonds, double bonds and other structures that are easily hydrolyzed in the body. It has better metabolic stability than glycoside compounds and has strong tumor cell proliferation inhibitory activity.

[0005] The first aspect of the present invention provides a thiazole derivative of dioscorea quinoline, wherein the thiazole derivative of dioscorea quinoline has a structure shown in formula (I):

[0006]

[0007] Wherein, R represents one of methyl, amino, anilino, tert-butyl, ethyl, isopropyl, ethoxycarbonyl, cyclopropyl, methylamino, butylamino, acetamido and hydrazine.

[0008] Furthermore, the thiazole derivative of dioscorea quinata has a structure as shown in any one of Formulas 5a to 51:

[0009]

[0010] in,

[0011] When R is a methyl group, the thiazole derivative of schizoflavin is a compound with a structure shown in Formula 5a; Compound 5a: 4-[2'-methylthiazolyl]-schizoflavin.

[0012] When R is an amino group, the thiazole derivative of schizofiarin is a compound with a structure shown in Formula 5b; Compound 5b: 4-[2'-aminothiazolyl]-schizofiarin.

[0013] When R is an aniline group, the thiazole derivative of dioscorea indica is a compound with a structure shown in Formula 5c; Compound 5c: 4-[2'-anilinothiazole]-dioscorea indica.

[0014] When R is tert-butyl, the thiazole derivative of dioscorea indica is a compound with a structure shown in Formula 5d; Compound 5d: 4-[2'-tert-butylthiazolyl]-dioscorea indica.

[0015] When R is an ethyl group, the thiazole derivative of dioscorea indica is a compound with a structure shown in Formula 5e; Compound 5e: 4-[2'-ethylthiazolyl]-dioscorea indica.

[0016] When R is an isopropyl group, the thiazole derivative of dioscorea indica is a compound having a structure shown in Formula 5f; Compound 5f: 4-[2'-isopropylthiazolyl]-dioscorea indica.

[0017] When R is an ethoxycarbonyl group, the thiazole derivative of dioscorea indica is a compound having a structure shown in Formula 5g; Compound 5g: 4-[2'-ethoxycarbonylthiazolyl]-dioscorea indica.

[0018] When R is a cyclopropyl group, the thiazole derivative of dioscorea salviae nitrile is a compound having a structure shown in Formula 5h; Compound 5h: 4-[2'-cyclopropylthiazolyl]-dioscorea salviae nitrile.

[0019] When R is a methylamino group, the thiazole derivative of schizoflavin is a compound with a structure shown in Formula 5i; Compound 5i: 4-[2'-methylaminothiazolyl]-schizoflavin.

[0020] When R is a butylamino group, the thiazole derivative of dioscorea indica is a compound with a structure shown in Formula 5j; Compound 5j: 4-[2'-butylaminothiazolyl]-dioscorea indica.

[0021] When R is an acetamido group, the thiazole derivative of dioscorea salviae nitrile is a compound having a structure shown in Formula 5k; Compound 5k: 4-[2'-acetamidothiazolyl]-dioscorea salviae nitrile.

[0022] When R is a hydrazine group, the thiazole derivative of dioscorea quinata is a compound with a structure shown in Formula 51; Compound 51: 4-[2'-hydrazinothiazolyl]-dioscorea quinata.

[0023] The second aspect of the present invention provides a method for preparing a thiazole derivative of dioscorea quinata, comprising the following steps:

[0024] S1. Dichroin trifluoromethanesulfonate 2 was obtained by reacting dichroin with trifluoromethanesulfonic anhydride and triethylamine in dichloromethane;

[0025] S2. Stille coupling reaction of schizoferrin trifluoromethanesulfonate 2 with tributyl(1-ethoxyethylene)tin and 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride in N,N-dimethylformamide afforded schizoferrin ketone derivative 3.

[0026] S3. Bromination reaction of the bistort-1 derivative 3 with PyHBr3 in tetrahydrofuran yielded the brominated derivative 4;

[0027] S4. The bromo derivative 4 reacts with a thioacetamide derivative in methanol to obtain the thiazole derivative of Dioscorea serrata;

[0028] Wherein, the reaction formula of the above preparation method is:

[0029]

[0030] Wherein, R represents one of methyl, amino, anilino, tert-butyl, ethyl, isopropyl, ethoxycarbonyl, cyclopropyl, methylamino, butylamino, acetamido and hydrazine.

[0031] Specifically, the preparation method comprises the following steps:

[0032] (1) Dissolve schizoferrin in dichloromethane and stir at -10°C for 5 minutes. Slowly add trifluoromethanesulfonic anhydride (Tf2O) and triethylamine (Et3N) to the mixed solution to obtain a first reaction solution. Add deionized water to the first reaction solution to quench the reaction, extract with dichloromethane (DCM), collect the organic phase and sequentially wash with water, wash with saturated salt water, dry with anhydrous MgSO4, concentrate under reduced pressure, and then flash column chromatography to obtain a light yellow solid, i.e., schizoferrin trifluoromethanesulfonate 2, wherein the molar ratio of schizoferrin, trifluoromethanesulfonic anhydride, and triethylamine is 1:1.3:7;

[0033] (2) Dissolve schizoferrin trifluoromethanesulfonate 2 and [1,1-bis(diphenylphosphino)ferrocene] palladium dichloride (DPPF) in anhydrous N,N-dimethylformamide (DMF), add tributyl(1-ethoxyvinyl)tin under nitrogen protection, and heat to react to obtain a second reaction solution. After the second reaction solution is cooled, HCl solution is added and stirred, and then the reaction is quenched with NaOH solution. Deionized water is added to the reaction solution, and extracted with dichloromethane. The organic phase is collected and washed with water, saturated brine, dried over anhydrous MgSO4, concentrated under reduced pressure, and then flash column chromatography to obtain a light yellow solid, i.e., schizoferrin ketone derivative 3, wherein the molar ratio of schizoferrin trifluoromethanesulfonate 2, [1,1-bis(diphenylphosphino)ferrocene] palladium dichloride and tributyl(1-ethoxyvinyl)tin is 1:0.1:1.5;

[0034] (3) Dissolve the schizoferin derivative 3 in tetrahydrofuran (THF), slowly add pyridinium tribromide (PyHBr3) to the mixed solution under ice bath, and after addition, return to room temperature for reaction to obtain a third reaction solution. The third reaction solution is diluted with ethyl acetate, washed with water and saturated brine in sequence, dried over anhydrous MgSO4, concentrated under reduced pressure, and then flash column chromatography to obtain a yellow solid, i.e., the bromo derivative 4, wherein the molar ratio of the schizoferin derivative 3 to PyHBr3 is 1:1;

[0035] (4) The bromo derivative 4 is dissolved in methanol, and the thioacetamide derivative is added, and the mixture is heated to react to obtain a fourth reaction solution. The fourth reaction solution is concentrated under reduced pressure and then flash column chromatography to obtain a yellow solid, i.e., a thiazole derivative of salvia miltiorrhiza, wherein the molar ratio of the bromo derivative 4 to the thioacetamide derivative is 1:1.2.

[0036] Furthermore, in step S1, the molar ratio of schizofiarin, trifluoromethanesulfonic anhydride and triethylamine is 1:1.3:7; the reaction temperature is -20-0°C, and the reaction time is 30-60 minutes.

[0037] Furthermore, in step S2, the molar ratio of schizoferin trifluoromethanesulfonate 2, [1,1-bis(diphenylphosphino)ferrocene] palladium dichloride and tributyl(1-ethoxyvinyl)tin is 1:0.1:1.5; the reaction temperature is 120-150° C., and the reaction time is 12-24 h.

[0038] Furthermore, in step S3, the molar ratio of the dioscorea ketone derivative 3 to PyHBr3 is 1:1; the reaction temperature is room temperature, and the reaction time is 20-40 minutes.

[0039] Furthermore, in step S4, the molar ratio of the bromo derivative 4 to the thioacetamide derivative is 1:1.2; the reaction temperature is 40-80° C., and the reaction time is 1-6 hours.

[0040] The third aspect of the present invention provides a use of the above-mentioned thiazole derivative of dioscorea in the preparation of a drug for treating cancer, wherein the cancer is one of liver cancer, colorectal cancer and lung cancer.

[0041] Compared to existing technologies, the non-glycosidic thiazole derivatives of schizofiarin provided in this invention lack glycosidic bonds that are easily hydrolyzed in vivo and exhibit superior metabolic stability to glycoside compounds. Furthermore, in vitro tumor cell proliferation inhibition experiments revealed that these compounds exhibited potent tumor cell proliferation inhibition activity, comparable to or superior to that of the positive control drug, paclitaxel. These compounds are potentially useful in the preparation of drugs for the prevention and treatment of liver, colorectal, and lung cancers. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for describing the embodiments or the prior art.

[0043] Figure 1 The nuclear magnetic resonance of 4-[2'-methylthiazolyl]-shanyam leaf extract (5a) provided in Example 4 of the present invention 1 H spectrum;

[0044] Figure 2 The nuclear magnetic resonance of 4-[2'-methylthiazolyl]-shanyam leaf extract (5a) provided in Example 4 of the present invention 13 C spectrum;

[0045] Figure 3 The nuclear magnetic resonance of 4-[2'-aminothiazolyl]-dimethoxycinnamate (5b) provided in Example 5 of the present invention 1 H spectrum;

[0046] Figure 4 The nuclear magnetic resonance of 4-[2'-aminothiazolyl]-dimethoxycinnamate (5b) provided in Example 5 of the present invention 13 C spectrum;

[0047] Figure 5 The nuclear magnetic resonance of 4-[2'-anilinothiazolyl]-shanylin (5c) provided in Example 6 of the present invention 1 H spectrum;

[0048] Figure 6 The nuclear magnetic resonance of 4-[2'-anilinothiazolyl]-shanylin (5c) provided in Example 6 of the present invention 13 C spectrum;

[0049] Figure 7 The nuclear magnetic resonance of 4-[2'-tert-butylthiazolyl]-shanyam leaf extract (5d) provided in Example 7 of the present invention 1 H spectrum;

[0050] Figure 8 The nuclear magnetic resonance of 4-[2'-tert-butylthiazolyl]-shanyam leaf extract (5d) provided in Example 7 of the present invention 13 C spectrum. DETAILED DESCRIPTION

[0051] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0052] Example 1

[0053] In a 50 mL round-bottom flask, 380 mg (1 mmol) of schizoferin was dissolved in 10 mL of anhydrous DCM and stirred at -10°C for 5 minutes. To the mixed solution, 366 mg (1.3 mmol) of trifluoromethanesulfonic anhydride and 1 mL (7 mmol) of triethylamine were slowly added, and the mixture was allowed to react at -10°C for 30 minutes. TLC confirmed the completion of the reaction. 40 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was collected, dried over MgSO4, and concentrated under reduced pressure by column chromatography (petroleum ether:EtOAc = 8:1) to yield 340 mg of compound 2 (schizoferin trifluoromethanesulfonate 2) in a 66% yield.

[0054] 1 H NMR (400MHz, CDCl3) δ7.43(s,1H),7.15(s,1H),6.99(d,J=7.9Hz,1H),6.85(d,J=1.3Hz,1H) ,6.82(dd,J=7.9,1.6Hz,1H),6.10(d,J=17.7Hz,1H),5.48(s,2H),4.09(s,3H),3.84(s,3H); 13 C NMR(100MHz, CDCl3)δ:168.2,153.4,151.0,148.1,147.8,140.4,135.7,131.3,131 .1,127.0,126.3,123.5,119.5,110.4,108.4,106.5,101.5,99.4,65.7,56.2,56.0.

[0055] Example 2

[0056] To a 100ml three-necked flask, add 600mg (1.17mmol) of compound 2 and 85mg (0.12mmol) of [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride. The reaction vessel is then evacuated and filled with nitrogen. Under a nitrogen atmosphere, 15mL of anhydrous DMF is added to the three-necked flask, and 845mg (2.34mmol) of tributyl(1-ethoxyvinyl)tin is slowly added dropwise. The mixed solution is heated to 130°C and stirred under a nitrogen atmosphere for 12 hours. The reaction is complete by TLC. After the reaction solution cools to room temperature, 3mL of 3M HCl solution is added to the mixed solution and stirred at room temperature for 20 minutes. The reaction was completed by TLC, and 2 M NaOH was added to quench the reaction. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was collected, dried over MgSO4, and concentrated under reduced pressure by column chromatography (DCM:EtOAc=30:1) to obtain 375 mg of compound 3 (dioscorea ketone derivative 3) in a yield of 78%.

[0057] 1 H NMR (400MHz, CDCl3) δ7.53(s,1H,ArH),7.16(s,1H,ArH),6.98(d,J=7.8Hz,1H,ArH),6.86-6.79(m,2H,ArH),6.12(d,J=1.3Hz,1 H,OCH2O),6.07(d,J=1.4Hz,1H,OCH2O),5.48(d,J=1.1Hz,2H,COOCH2),4.07(s,3H,OCH3),3.82(s,3H,OCH3),2.79(s,3H,CH3); 13 CNMR (100MHz, CDCl3) δ201.5,169.2,152.7,149.9,147.9,147.7,143.0,139.6,130.1,129.6,129.4,1 27.8,123.3,118.4,110.3,108.3,106.7,103.8,101.4,77.4,77.3,77.1,76.7,68.8,56.1,55.8,31.9.

[0058] Example 3

[0059] In a 50 mL round-bottom flask, 100 mg (0.24 mmol) of bistortin derivative 3 was dissolved in 2 mL of THF. 18.15 mg (0.24 mmol) of PyHBr3 was slowly added to the mixture in an ice bath. After the reaction mixture returned to room temperature, it was stirred for 20 minutes. The reaction was complete by TLC. The reaction mixture was diluted with 15 mL of ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure by column chromatography (petroleum ether:EtOAc = 8:1) to afford 67 mg of compound 4 (bromo derivative 4), with a yield of 56%.

[0060] 1 H NMR (400MHz, CDCl3) δ7.39(s,1H,ArH),7.19(s,1H,ArH),6.99(d,J=7.8Hz,1H,ArH),6.86-6.77(m,2H,ArH),6.10 (dd,J=18.3,1.4Hz,2H,OCH2O),5.46(s,2H,CCH2Br),4.46(s,2H,COOCH2),4.10(s,3H,OCH3),3.83(s,3H,OCH3).

[0061] Example 4

[0062] In a 50 mL round-bottom flask, 80 mg (0.16 mmol) of the bromo derivative 4 was dissolved in 2 mL of MeOH, followed by the addition of 14.86 mg (0.19 mmol) of thioacetamide. The mixture was stirred at 60°C for 1 h. TLC confirmed the reaction was complete. The mixture was concentrated under reduced pressure and the concentrate was subjected to column chromatography (petroleum ether:EtOAc = 5:1) to afford 44 mg of a yellow solid (dioscorein thiazole derivative 5a), in a 58% yield.

[0063] NMR of thiazole derivative 5a of dioscorea indole 1 H spectrum and NMR 13 C spectrum as Figure 1 、 Figure 2 shown.

[0064] 1H NMR (400MHz, CDCl3) δ7.52(s,1H,ArH),7.39(s,1H,ArH),7.14(s,1H,ArH),6.98(d,J=7.8Hz,1H,ArH),6.92-6.79(m,2H, ArH),6.08(dd,J=19.7,1.4Hz,2H,OCH2O),5.37(s,2H,COOCH2),3.94(s,3H,OCH3),3.82(s,3H,OCH3),2.86(s,3H,CH3); 13 C NMR (100MHz, CDCl3) δ170.1,166.6,151.9,150.2,149.8,147.6,147.5,139.6,139.3,131.2,129.7,128. 5,124.6,123.5,118.5,117.8,110.6,108.2,106.3,104.1,101.3,68.6,55.9,55.8,19.4; HRMS(ESI):m / z calcd for C 25 H 20 NO6S:462.1011; found:462.1010[M+H] + .

[0065] Examples 5-15

[0066] According to the method of Example 4 above, thioacetamide was replaced by thiourea, phenylthiourea, 2,2-dimethylthiopropionamide, thiopropionamide, 2-methylthiopropionamide, ethyl thiooxamate, cyclopropanethiocarboxamide, N-methylthiourea, 1-butylthiourea, 1-methyl-2-acylthiourea, and thiosemicarbazide to prepare the following examples of thiazole derivatives 5b-5l.

[0067] NMR of thiazole derivative of dioscorein 5b 1 H spectrum and NMR 13 C spectrum as Figure 3 、 Figure 4 shown.

[0068] NMR of thiazole derivative of dioscorein 5c 1 H spectrum and NMR 13 C spectrum as Figure 5 、 Figure 6 shown.

[0069] NMR of 5d thiazole derivative of dioscorea indica 1 H spectrum and NMR 13 C spectrum as Figure 7 、 Figure 8shown.

[0070] The following are the physicochemical data of compounds 5b-5l:

[0071] 5b: 1 H NMR (400MHz, DMSO-d6) δ7.90(s,1H,ArH),7.22(s,2H,NH2),7.06(dd,J=8.7,6.7Hz,3H,ArH),6.96(d,J=1.6Hz,1 H,ArH),6.82(dd,J=7.9,1.7Hz,1H,ArH),6.14(s,2H,OCH2O),5.48(s,2H,COOCH2),3.89(s,3H,OCH3),3.67(s,3H OCH3); 13 C NMR(100MHz,DMSO-d6)δ169.9,168.8,151.7,149.8,147.4,147.4,145.9,138.8,138.2,130.7,129.2,1 28.9,125.8,123.9,118.5,111.2,108.5,107.5,106.0,105.5,101.6,69.1,55.8,55.6; HRMS(ESI):m / z calcd for C 24 H 19 N2O6S:463.0964; found:463.0965[M+H] + .

[0072] 5c: 1 H NMR(400MHz, CDCl3)δ8.36(s,1H,NH),7.69(s,1H,ArH),7.34-7.27(m,3H,ArH ),7.13(s,1H,ArH),7.10-7.02(m,1H,ArH),6.98(d,J=7.8Hz,1H,ArH),6.83(d ,J=9.8Hz,2H,ArH),6.79(s,1H,ArH),6.11(d,J=1.5Hz,1H,OCH2O),6.03(d,J= 1.3Hz,1H,OCH2O),5.42(s,2H,COOCH2),3.96(s,3H,OCH3),3.82(s,3H,OCH3); 13C NMR(100MHz,CDCl3)δ170.2,165.6,151.9,149.7,147.6,147.5,146.4,139.9,139.5,139.1,131.2,130.0,129.7,129.4,128.5,125.0,124.8,123.5,118.5,118.5,110.6,108.3,106.7,106.2,104.3,101.3,68.8,56.0,55.8;HRMS(ESI):m / z calcd for C 30 H 23 N2O6S:539.1277;found:539.1280[M+H] + .

[0073] 5d: 1 H NMR(400MHz,CDCl3)δ7.68(s,1H,ArH),7.42(s,1H,ArH),7.15(s,1H,ArH),6.99(d,J=7.8Hz,1H,ArH),6.89-6.81(m,2H,ArH),6.09(dd,J=19.4,1.5Hz,2H,OCH2O),5.43(s,2H,COOCH2),3.96(s,3H,OCH3),3.82(s,3H,OCH3),1.55(s,9H,3ⅹCH3); 13 C NMR(100MHz,CDCl3)δ181.7,170.2,151.9,150.1,149.7,147.6,147.5,139.6,139.1,131.0,129.9,128.6,124.8,123.5,118.7,116.9,110.6,108.3,106.3,104.3,101.3,68.9,55.9,55.8,38.0,30.9;HRMS(ESI):m / z calcd for C 28 H 26 NO6S:504.1481;found:504.1477[M+H] + .

[0074] 5e: 1<h2 style=";text-align:left;direction:ltr">H NMR(400 MHz,CDCl3)δ7.57(s,1H,ArH),7.41(s,1H,ArH),7.15(s,1H,ArH),6.99(d,J=7.8 Hz,1H,ArH),6.89-6.81(m,2H,ArH),6.09(dd,J=19.2,1.5 Hz,2H,OCH2O),5.39(s,2H,COOCH2),3.95(s,3H,OCH3),3.82(s,3H,OCH3),3.18(q,J=7.5 Hz,2H,CCH2),1.51(t,J=7.5 Hz,3H,CH3);<h2 style=";text-align:left;direction:ltr"> 13 <h2 style=";text-align:left;direction:ltr"> C NMR(100 MHz,CDCl3)δ173.2,170.1,151.9,150.2,149.8,147.6,147.5,139.6,139.2,131.2,129.8,128.5,124. 7,123.5,118.6,117.2,110.6,108.3,106.3,104.2,101.3,68.7,55.9,55.8,27.0,14.1;HRMS(ESI):m / z calcdforC<h2 style=";text-align:left;direction:ltr"> 26 <h2 style=";text-align:left;direction:ltr"> H<h2 style=";text-align:left;direction:ltr"> 22 <h2 style=";text-align:left;direction:ltr"> NO6S:476.1168;found:476.1165[M+H]<h2 style=";text-align:left;direction:ltr"> + <h2 style=";text-align:left;direction:ltr"> .<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0075] <h2 style=";text-align:left;direction:ltr"> 5f:<h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> H NMR(400 MHz,CDCl3)δ7.62(s,1H,ArH),7.42(s,1H,ArH),7.15(s,1H,ArH),6.98(d,J=7.8 Hz,1H,ArH),6.89-6.74(m,2H,ArH),6.09(dd,J=19.2,1.4 Hz,2H,OCH2O),5.41(s,2H,COOCH2),3.95(s,3H,OCH3),3.82(s,3H,OCH3),3.45(p,J=6.9 Hz,1H,CHCH3CH3),1.53(s,3H,CH3),1.51(s,3H,CH3);<h2 style=";text-align:left;direction:ltr"> 13C NMR(100MHz,CDCl3)δ178.3,170.1,151.9,150.1,149.7,147.6,147.5,139.6,139.2,131.1,129.8,128.6,124.7,123.5,118.6,116.9,110.6,108.2,106.3,104.3,101.3,68.8,55.9,55.8,33.4,23.1;HRMS(ESI):m / z calcd forC 27 H 24 NO6S:490.1324;found:490.1328[M+H] + .

[0076] 5g: 1 H NMR(400 MHz,CDCl3)δ7.77(s,1H,ArH),7.33(s,1H,ArH),7.09(s,1H,ArH),6.92(d,J=7.8 Hz,1H,ArH),6.83-6.74(m,2H,ArH),6.04(d,J=1.4 Hz,1H,OCH2O),6.00(d,J=1.4 Hz,1H,OCH2O),5.29(s,2H,COOCH2),4.47(q,J=7.1 Hz,2H,OCH2CH3),3.85(s,3H,OCH3),3.75(s,3H,OCH3),1.41(t,J=7.1 Hz,3H,OCH2CH3); 13 C NMR(100 MHz,CDCl3)δ168.8,158.7,158.1,151.9,151.2,148.8,146.7,146.6,139.4,138.6,130.2,128.7,127.2,123.1,122.4,122.4,117.5,109.5,107.2,105.4,102.5,100.3,67.3,61.9,54.9,54.8,13.3;HRMS(ESI):m / z calcd for C 27 H 21 NO8SNa 542.0886:;found:542.0884[M+Na] + .

[0077] 5h: 1H NMR(400 MHz,CDCl3)δ7.58(s,1H,ArH),7.30(s,1H,ArH),7.14(s,1H,ArH),6.98(d,J=7.8 Hz,1H,ArH),6.87-6.81(m,2H,ArH),6.11(d,J=1.5 Hz,1H,OCH2O),6.06(d,J=1.4 Hz,1H,OCH2O),5.38(s,2H,COOCH2),3.95(s,3H,OCH3),3.82(s,3H,OCH3),2.42(tt,J=7.9,5.1 Hz,1H,SCCH),1.25(d,J=5.0 Hz,2H,CH2),1.22-1.20(m,2H,CH2); 13 CNMR(100 MHz,CDCl3)δ174.0,170.1,151.9,150.0,149.7,147.6,147.5,139.6,139.2,131.1,129.8,128.5,124.7,123.5,118.6,115.7,110.6,108.3,106.3,104.2,101.3,68.8,55.9,55.8,14.7,11.7;HRMS(ESI):m / z calcd for C 27 H 22 NO6S 488.1168;found:488.1172[M+H] + .

[0078] 5i: 1 H NMR(400 MHz,DMSO-d6)δ7.94(s,1H,ArH),7.75(q,J=4.7 Hz,1H,NH),7.13(s,1H,ArH),7.10-7.03(m,2H,ArH),6.95(d,J=1.6 Hz,1H,ArH),6.83(dd,J=7.8,1.7Hz,1H,ArH),6.15(s,2H,OCH2O),5.50(s,2H,COOCH2),3.89(s,3H,OCH3),3.68(s,3H,OCH3),2.91(d,J=4.6 Hz,3H,NHCH3); 13C NMR(100 MHz,DMSO-d6)δ169.9,169.5,151.7,149.8,147.4,146.1,138.9,138.3,130.7,129.2,128.9,125.8,123.9,118.5,111.1,108.5,107.1,106.0,105.5,101.6,69.2,55.8,55.6,40.5,31.4;HRMS(ESI):m / z calcd forC 25 H 21 N2O6S477.1121;found:477.1120[M+H] + .

[0079] 5j: 1 H NMR(400 MHz,CDCl3)δ7.70(s,1H,ArH),7.12(s,1H,ArH),6.98(d,J=7.8Hz,1H,ArH),6.88-6.79(m,2H,ArH),6.67(s,1H,ArH),6.08(dd,J=19.4,1.5 Hz,2H,OCH2O),5.68(s,1H,NH),5.41(s,2H,COOCH2),3.97(s,3H,OCH3),3.81(s,3H,OCH3),3.27(q,J=6.6 Hz,2H,CH2),1.61(p,J=7.2 Hz,2H,CH2),1.45-1.34(m,2H,CH2),0.93(t,J=7.4Hz,3H,CH3); 13 C NMR(100 MHz,CDCl3)δ170.3,169.9,151.7,149.7,147.5,147.5,146.7,139.2,139.0,131.2,129.7,128.6,125.4,123.5,118.5,110.6,108.2,106.2,105.6,104.5,101.3,68.9,55.9,55.8,45.8,31.4,20.1,13.8;HRMS(ESI):m / z calcd forC 28 H 27 N2O6S 519.1590;found:519.1588[M+H] + .

[0080] 5k: 1H NMR(400 MHz,DMSO-d6)δ12.26(s,1H,CNHCO),7.69(s,1H,ArH),7.63(s,1H,ArH),7.01(d,J=7.8 Hz,2H,ArH),6.91(d,J=1.6 Hz,1H,ArH),6.78(dd,J=7.9,1.7 Hz,1H,ArH),6.08(s,2H,OCH2O),5.41(s,2H,COOCH2),3.81(s,3H,OCH3),3.62(s,3H,OCH3),2.14(s,3H,COCH3); 13 C NMR(100 MHz,DMSO)δ169.8,169.2,158.4,151.9,149.9,147.4,144.7,139.3,138.7,130.7,129.2,128.8,125.1,123.9,118.6,114.0,111.2,108.5,106.1,105.0,101.7,69.0,55.9,55.6,29.5,23.0;HRMS(ESI):m / z calcd for C 26 H 21 N2O7S505.1069;found:505.1068[M+H] + .

[0081] 5l: 1 H NMR(400 MHz,DMSO-d6)δ8.66(s,1H,NH),7.83(s,1H,ArH),7.08(s,1H,ArH),7.04-6.93(m,2H,ArH),6.88(d,J=1.7 Hz,1H,ArH),6.75(dd,J=7.9,1.7 Hz,1H,ArH),6.07(s,2H,OCH2O),5.39(s,2H,COOCH2),4.97(d,J=47.8Hz,2H,NH2),3.81(s,3H,OCH3),3.60(s,3H,OCH3); 13 C NMR(100MHz,DMSO)δ176.4,169.9,151.7,149.8,147.4,147.4,146.6,138.8,138.2,130.7,129.2,128.9,126.1,123.9,118.5,111.2,108.5,108.0,106.0,105.4,101.6,69.1,55.8,55.6;HRMS(ESI):m / z calcd for C 24 H20 N3O6S478.1073; found:478.1068[M+H] + .

[0082] To better understand the essence of this invention, the following pharmacological experimental results demonstrating the inhibitory effects of the thiazole derivatives of schizoflavone on the growth of three tumor cell lines are used to illustrate their novel applications in anti-tumor drug research. The pharmacological examples provide partial activity data for representative compounds. It should be noted that the pharmacological examples are intended to illustrate the invention and are not intended to limit it. Simple modifications to the invention based on its essence fall within the scope of the claimed invention.

[0083] Drug Experiment Example 1: Cytotoxicity Test of Compounds 5a-5l and Paclitaxel on Human Hepatocellular Carcinoma Cells (HepG2)

[0084] Human hepatoma cells (HepG2) were cultured in RPMI1640 medium containing 10% fetal bovine serum, 100 U / mL penicillin, and 100 U / mL streptomycin. 5×10 cells were plated per well. 3 The concentrations were added to 96-well plates and cultured in a 37°C incubator containing 5% CO2 in a humidified air atmosphere for 24 hours.

[0085] Compounds 5a-5l were dissolved in DMSO and prepared into 1×10 -2 mol / L stock solution, the stock solution was diluted to the corresponding concentration with complete medium. Cells in logarithmic growth phase were seeded in 96-well plates. After 24 hours of attachment, different concentrations of compound solutions were added. Four parallel wells were set for each concentration. After 68 hours of culture, tetramethylthiazolium (MTT) solution was added. The culture was continued for 4 hours, the culture medium was discarded, 150 μL of dimethyl sulfoxide was added, and the cells were shaken for 10 minutes. The absorbance (A) value at 570 nm was measured with a microplate reader, and the half-maximal inhibitory concentration (IC) was calculated. 50 ), as shown in Table 1. According to Table 1, the IC 50 The positive control paclitaxel has an IC of 0.8 μM for HepG2 cells. 50 0.4μM.

[0086] Drug Experiment Example 2-3: Cytotoxic activity test of compounds 5a-5l and paclitaxel against human colorectal cancer cells (HCT-15) and human lung cancer cells (A549).

[0087] The pharmacological experiments on the growth inhibition of human colorectal cancer cells (HCT-15) and human lung cancer cells (A549) were carried out using the method shown in Drug Experiment Example 1, and the half-maximal inhibitory concentration (IC 50 ), as shown in Table 1.

[0088] Table 1 Cytotoxic activity test results of compounds 5a-5l and paclitaxel

[0089]

[0090] As shown in Table 1, the thiazole derivatives of schizoferrin provided by the present invention have significant biological activity. In vitro cytotoxic activity tests on three types of tumor cells, namely human hepatocellular carcinoma cells (HepG2), human lung cancer cells (A549), and human colorectal cancer cells (HCT-15), showed that these thiazole derivatives of schizoferrin with the structure represented by formula (1) have an inhibitory effect on tumor cell growth and may be developed into new anti-tumor drugs. From the above pharmacological examples, we can see that these compounds exhibit strong cytotoxic activity against these three types of tumor cells, and the cytotoxic activity of most compounds is close to that of the positive control paclitaxel, indicating that they have the potential to be developed into anti-tumor drugs.

[0091] 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 principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A thiazole derivative of dioscorea quinata, characterized in that The structural formula of the thiazole derivative of dioscorea quinata is shown below: ， Wherein, R represents one of methyl, amino, anilino, tert-butyl, ethyl, isopropyl, ethoxycarbonyl, cyclopropyl, methylamino, butylamino, acetamido and hydrazine.

2. The thiazole derivative of dioscorea quinata according to claim 1, characterized in that The thiazole derivative of dioscorea quinata has a structure as shown in any one of Formulas 5a-51:

3. A method for preparing the thiazole derivative of dioscorea quinata according to claim 1, characterized in that: The following steps are involved: S1. Dichroin trifluoromethanesulfonate 2 was obtained by reacting dichroin with trifluoromethanesulfonic anhydride and triethylamine in dichloromethane; S2. Stille coupling reaction of schizoferrin trifluoromethanesulfonate 2 with tributyl(1-ethoxyethylene)tin and 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride in N,N-dimethylformamide afforded schizoferrin ketone derivative 3; S3. Shan Heyesu ketone derivative 3 was brominated with PyHBr3 in tetrahydrofuran to give a brominated derivative 4; S4. The bromo derivative 4 reacts with a thioacetamide derivative in methanol to obtain the thiazole derivative of Dioscorea serrata; The reaction formula of the preparation method is: ， Here, R represents one of methyl, amino, anilino, tert-butyl, ethyl, isopropyl, ethoxycarbonyl, cyclopropyl, methylamino, butylamino, acetamido and hydrazine.

4. The preparation method according to claim 3, characterized in that In step S1, the molar ratio of schizofiarin, trifluoromethanesulfonic anhydride and triethylamine is 1:1.3:7; the reaction temperature is -20-0°C, and the reaction time is 30-60 minutes.

5. The preparation method according to claim 3, characterized in that In step S2, the molar ratio of schizoferin trifluoromethanesulfonate 2, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium and tributyl(1-ethoxyvinyl)tin is 1:0.1:1.5; the reaction temperature is 120-150°C, and the reaction time is 12-24h.

6. The preparation method according to claim 3, characterized in that In step S3, the molar ratio of the dioscorene derivative 3 to PyHBr3 is 1:1; the reaction temperature is room temperature, and the reaction time is 20-40 minutes.

7. The preparation method according to claim 3, characterized in that In step S4, the molar ratio of the bromo derivative 4 to the thioacetamide derivative is 1:1.2; the reaction temperature is 40-80° C., and the reaction time is 1-6 hours.

8. Use of the thiazole derivative of dioscorea in claim 1 in the preparation of a drug for treating cancer, wherein the cancer is one of liver cancer, colorectal cancer and lung cancer.

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