A glycoside derivative of schizofiarin or its pharmaceutically acceptable derivative or analogue and its preparation method and use

Abstract

The present invention provides a glycoside derivative of schizoflavone or a pharmaceutically acceptable derivative or analog thereof, and a preparation method and use thereof, wherein the structure of the glycoside derivative of schizoflavone is shown in general formula I. The glycoside derivative of schizoflavone or a pharmaceutically acceptable derivative or analog thereof in the present application has better anticancer activity than schizoflavone and the clinically used drug etoposide.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a glycoside derivative of schizofiarin or a pharmaceutically acceptable derivative or analog thereof, and a preparation method and use thereof. Background Art

[0002] Head and neck cancer is a group of malignant tumors that occur in the lips, oral cavity, nasal cavity, pharynx, larynx and other parts of the upper digestive tract. It is one of the cancers with the highest mortality rate in the world. According to research statistics, there are about 890,000 new cases of head and neck cancer and 450,000 new deaths worldwide each year. Due to the special anatomical and physiological structure of the head and neck, most head and neck cancer patients also have physiological dysfunctions such as breathing, speaking, and swallowing before and after treatment, which seriously affects the patients' daily social life. At present, the first-line drugs for the treatment of head and neck cancer are still mainly traditional chemotherapy drugs such as methotrexate, 5-fluorouracil, cisplatin, and paclitaxel. These chemotherapy drugs have no selectivity when exerting anti-cancer activity and are highly toxic to normal cells, resulting in poor treatment effects, many adverse reactions, and the problem of drug resistance is becoming more and more serious after long-term use. At present, the 5-year overall survival rate of patients with head and neck squamous cell carcinoma is still hovering around 50%, and there is an urgent need to develop efficient and low-toxic drugs to improve clinical efficacy.

[0003] Natural products are the main source of lead compounds in new drug development due to their diverse molecular structures and unique modes of action. More than 60% of anticancer drugs are closely related to natural products. Currently, there is a lack of safe, effective, and drug-resistant drugs for the clinical treatment of head and neck cancer. Summary of the invention

[0004] In view of the shortcomings of the prior art described above, the object of the present invention is to provide a glycoside derivative of schizofiarin or a pharmaceutically acceptable derivative or analogue thereof and a preparation method and use thereof, so as to solve the problems in the prior art and provide a chemical drug with significant anti-cancer activity and low toxicity.

[0005] To achieve the above objectives and other related objectives, the present invention is obtained by including the following technical solutions.

[0006] The present invention provides a glycoside derivative of schizofiarin or a pharmaceutically acceptable derivative or analog thereof; the structure of the glycoside derivative of schizofiarin is shown in general formula I:

[0007]

[0008] Wherein, R1 and R2 are each independently selected from hydroxyl, substituted or unsubstituted acyloxy; wherein the substitution is substitution by one or more Ra;

[0009] R3 is independently selected from substituted or unsubstituted C3-C6 heterocyclyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; wherein the substitution is substituted by one or more Ra;

[0010] Ra is selected from the group consisting of halogen, deuterium, hydroxyl, cyano, amino, amide, ether, methylthio, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, C3-C6 heterocyclyl, and heteroaryl.

[0011] Preferably, in the general formula I, R1 and R2 are each independently selected from hydroxyl and acetoxy;

[0012] R3 is independently selected from substituted or unsubstituted C3-C6 heterocyclyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; wherein the substitution is selected from one or more Ra;

[0013] Ra is selected from the group consisting of: halogen, deuterium, hydroxyl, amino, -S-CH3, -CF3, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, aryl, C3-C6 heterocyclyl, and heteroaryl.

[0014] Preferably, the pharmaceutically acceptable derivative or analogue includes one or more of its pharmaceutically acceptable salts, tautomers, stereoisomers, esters, prodrugs or solvates.

[0015] The glycoside derivatives of feroxanthin or pharmaceutically acceptable derivatives or analogs thereof of the present invention include but are not limited to the compounds shown in Table 1:

[0016] Table 1

[0017]

[0018]

[0019]

[0020] The preparation method of the schizofiarin glycoside derivative or its pharmaceutically acceptable derivative or analogue as described above in the present invention is obtained by reaction using the compound of formula II. The synthetic route is as follows:

[0021]

[0022] Preferably, the compound of formula II is reacted with 2-thiophenecarboxaldehyde to obtain the compound of formula I-2. The synthetic route is as follows:

[0023]

[0024] Preferably, the compound of formula II is reacted with 2-furancarboxaldehyde to obtain the compound of formula I-3, and the synthesis route is as follows:

[0025]

[0026] Preferably, the compound of formula II is reacted with 5-methyl-2-thiophenecarboxaldehyde to obtain the compound of formula I-4. The synthetic route is as follows:

[0027]

[0028] Preferably, the compound of formula II is reacted with 4-(methylmercapto)benzaldehyde to obtain the compound of formula I-5. The synthetic route is as follows:

[0029]

[0030] Preferably, the compound of formula II is reacted with 4-(trifluoromethyl)benzaldehyde to obtain the compound of formula I-6. The synthetic route is as follows:

[0031]

[0032] Preferably, the compound of formula II is reacted with 3-thiophenecarboxaldehyde, and then with acetic anhydride and pyridine to obtain the compound of formula I-7. The synthetic route is as follows:

[0033]

[0034] Preferably, the compound of formula II is reacted with 4-tetrahydropyranaldehyde to obtain the compound of formula I-8. The synthetic route is as follows:

[0035]

[0036] Preferably, the compound of formula II is reacted with cyclohexanecarboxaldehyde to obtain the compound of formula I-9, and the synthesis route is as follows:

[0037]

[0038] Preferably, the compound of formula II is reacted with cyclopentanecarboxaldehyde to obtain the compound of formula I-10, and the synthesis route is as follows:

[0039]

[0040] Preferably, the reaction is carried out under oxygen-free and water-free conditions.

[0041] Preferably, the reaction uses zinc chloride as a catalyst.

[0042] Preferably, the reaction temperature is 10-70°C.

[0043] The present application also discloses the use of the above-mentioned schizofiarin glycoside derivatives or their pharmaceutically acceptable derivatives or analogs in the preparation or screening of anticancer drugs, wherein the screening is for non-diagnostic or therapeutic purposes.

[0044] Preferably, the anticancer drug is selected from epithelial cancer drugs. More preferably, the anticancer drug is a head and neck cancer drug.

[0045] The present application also discloses a pharmaceutical composition, which comprises at least one of the above-mentioned schizofiarin glycoside derivatives or its pharmaceutically acceptable derivatives or analogs, and a pharmaceutically acceptable carrier, additive, adjuvant or excipient.

[0046] The inventors of this application previously discovered that schizofol compounds have good cell inhibitory activity against head and neck cancer cells through the method of active screening of natural product libraries. Schizofol is an aromatic naphthol lactone-type lignin compound, which originated from the active compound isolated from the Chinese medicinal material Justicia procumbens linn by Okigawa in 1970, and has good anti-cancer and antiviral activities. Although schizofol has a novel structure and a wide range of activities, it has disadvantages such as poor solubility and relatively weak activity.

[0047] In the present application, the applicant provides a class of schizofiarin glycoside derivatives or pharmaceutically acceptable salts thereof, and conducts biological activity test evaluation. The biological activity results show that the derivatives have significant anti-cancer activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 The compounds of formula I-2, formula I-3 and formula I-4 show inhibitory activity against the head and neck cancer cell line cal27.

[0049] Figure 2 The results show that the compound of formula I-5, diphyllin and etoposide have inhibitory activity against the head and neck cancer cell line cal27.

[0050] Figure 3 The inhibitory activities of Formula I-6, Formula I-7 and Formula I-8 against the head and neck cancer cell line cal27 are shown.

[0051] Figure 4 The inhibitory activity of Formula I-9 and Formula I-10 against the head and neck cancer cell line cal27 was shown. DETAILED DESCRIPTION

[0052] The following is a description of the implementation of the present invention by means of specific embodiments. Those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification.

[0053] Before further describing the specific embodiments of the present invention, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terms used in the examples of the present invention are intended to describe specific embodiments, rather than to limit the scope of protection of the present invention. The test methods in the following examples without specifying specific conditions are generally carried out under conventional conditions or under conditions recommended by the manufacturers.

[0054] When the embodiment gives a numerical range, it should be understood that, unless otherwise specified in the present invention, the two endpoints of each numerical range and any numerical value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those generally understood by those skilled in the art.

[0055] Examples of pharmaceutically acceptable carriers or excipients or additives or adjuvants include conventional diluents (water, etc.), fillers (lactose, etc.), binders (starch, dextrin, etc.), transdermal absorption enhancers, flavoring agents, thickeners, solubilizers (ethanol, etc.) and other excipients.

[0056] The following compounds and intermediates are characterized by liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR), and the starting materials and reagents used in the preparation of the compounds can be purchased from suppliers or prepared by methods known to those skilled in the art. The following general synthetic routes merely illustrate the methods by which the compounds of the present invention can be synthesized, and for those skilled in the art who have referred to the disclosure of the present invention, various modifications of the synthetic routes can be made and are inspired.

[0057] In the following specific embodiments:

[0058] 1H-NMR was measured using an Agilent 400 MHz nuclear magnetic resonance spectrometer.

[0059] The safflower oil was purchased from Baoji Chenguang Biotechnology Co., Ltd., and the other reagents were produced by Shanghai Bid Pharmaceutical Technology Co., Ltd.

[0060] In order to ensure that the reaction was carried out under anhydrous and oxygen-free conditions, all solvents were redistilled before use, and the anhydrous solvents used were obtained by drying according to standard methods; unless otherwise specified, all reactions were carried out under nitrogen protection and tracked by TLC.

[0061] The post-treatment process includes washing with a saturated sodium chloride aqueous solution and drying with anhydrous sodium sulfate.

[0062] The products were purified by silica gel (200-300 mesh) column chromatography unless otherwise specified; the silica gel (200-300 mesh) was produced by Qingdao Ocean Chemical Plant, and the GF-254 thin layer silica gel plate was produced by Yantai Jiangyou Silica Gel Development Co., Ltd.

[0063] The compound of formula II in the technical solution of the present application is an existing product, which can be obtained through commercial purchase. In the specific implementation of the present application, the compound of formula II is prepared using the following specific method.

[0064] Preparation of compounds of formula II

[0065]

[0066] Step 1: Compound 1a (1.95 g, 5 mmol) was dissolved in 25 mL DCM, 12 mL 33% hydrobromic acid solution was added to the solution, and the reaction was carried out at room temperature for 12 h. Then, the reaction solution was neutralized with an appropriate amount of sodium bicarbonate, extracted with DCM, and then separated by column chromatography (PE: EA = 5: 1) to obtain 1.64 g of light yellow intermediate 1b.

[0067]

[0068] Step 2: Compound 1 (1.014 g, 2.67 mmol), compound 1b (1.64 g, 3.99 mmol), and TBAB (0.86 g, 2.67 mmol) were dissolved in 50 mL CHCl3, and NaOH (0.37 g, 9.33 mmol) was dissolved in 50 mL H2O. Then the NaOH aqueous solution was poured into the CHCl3 solution, and then the reaction flask was heated to 40°C to start the reaction. After 12 hours, the reaction solution was neutralized with dilute hydrochloric acid, extracted with DCM, and separated by column chromatography (DCM: MeOH = 200:1) to obtain 1.66 g of intermediate 1c.

[0069]

[0070] Step 3: Add intermediate 1c (1.66 g, 2.34 mmol) to 50 mL MeOH, add K2CO3 (1.29 g, 9.35 mmol), and react at room temperature for 1 h. Then add dilute hydrochloric acid to adjust the pH to neutral, spin dry, dissolve in MeOH, filter to remove salt, and spin dry to obtain 1.42 g of light yellow product. 1H NMR(400MHz, DMSO-d6)δ8.18(d,J=2.8Hz,1H),7.06–7.02(m,1H),6.98(s,1H),6.96–6.90(m,1H),6.80(t,J =9.5Hz,1H),6.13(s,2H),5.95(dd,J=5.3,2.8Hz,1H),5.76(d,J=15.4Hz,1H),5.48(d,J=15.3Hz,1H),5.21( d,J=5.0Hz,1H),5.06(d,J=5.2Hz,1H),4.79–4.72(m,1H),4.67(q,J=5.3Hz,1H),3.95(s,3H),3.77(d,J=7. 6Hz,1H),3.67(s,3H),3.50–3.42(m,2H),3.30–3.26(m,1H),3.26–3.20(m,1H),3.16(dd,J=8.8,5.3Hz,1H).

[0071] Preparation Example of Compound of Formula Ⅰ-2

[0072]

[0073] The compound of formula II (100 mg, 0.18 mmol) and anhydrous zinc chloride (126 mg, 0.92 mmol) were dissolved in 2 mL of 2-thiophenecarboxaldehyde, and the nitrogen was replaced 3 times, and the reaction bottle was placed in an oil bath at 30°C. After reacting for 12 hours, EA was extracted and separated by column chromatography (DCM: MeOH = 100: 1) to obtain 50 mg of a white solid, which was the compound of formula I-2. 1 H NMR (400MHz, DMSO-d6) δ8.14(d,J=2.5Hz,1H),7.54(dd,J=5.0,1.3Hz,1H),7.18(d,J=3.6H z,1H),7.07–6.98(m,3H),6.93(dd,J=8.6,1.6Hz,1H),6.84–6.75(m,1H),6.27(s,1H),6.1 3(s,2H),5.92(s,1H),5.60(d,J=3.6Hz,1H),5.53–5.42(m,2H),5.01(d,J=4.9Hz,1H),4.2 4(dd,J=10.3,4.7Hz,1H),3.95(s,3H),3.84–3.74(m,1H),3.67(s,3H),3.62–3.50(m,4H).

[0074] Preparation Example of Compound of Formula I-3

[0075]

[0076] The compound of formula II (100 mg, 0.18 mmol) and anhydrous zinc chloride (126 mg, 0.92 mmol) were dissolved in 2 mL of 2-furanaldehyde, and the nitrogen was replaced 3 times, and the reaction bottle was placed in an oil bath at 30°C. After reacting for 12 hours, EA was extracted and column chromatography (DCM: MeOH = 100: 1) was used to separate 35.8 mg of a white solid, which was the compound of formula I-3. 1 H NMR (400MHz, DMSO-d6) δ8.15(d,J=2.5Hz,1H),7.65(s,1H),7.05(dd,J=8.0,1.8Hz,1H),7.00(d,J =1.8Hz,1H),6.93(dd,J=8.9,1.6Hz,1H),6.85–6.75(m,1H),6.55–6.41(m,2H),6.29(d,J=4.1Hz, 1H),6.13(s,2H),5.72(s,1H),5.63(d,J=4.0Hz,1H),5.47(d,J=3.1Hz,2H),5.00(q,J=3.4Hz,1H) ,4.23(dd,J=10.2,4.4Hz,1H),3.95(s,3H),3.77(t,J=9.8Hz,1H),3.68(s,3H),3.62–3.47(m,4H).

[0077] Preparation Example of Compound of Formula I-4

[0078]

[0079] The compound of formula II (100 mg, 0.18 mmol) and anhydrous zinc chloride (126 mg, 0.92 mmol) were dissolved in 2 mL of 5-methyl-2-thiophenecarboxaldehyde, and the nitrogen was replaced 3 times, and the reaction bottle was placed in an oil bath at 30°C. After reacting for 12 hours, EA was extracted and separated by column chromatography (DCM: MeOH = 100: 1) to obtain 31.7 mg of a light yellow solid, which was the compound of formula I-4. 1H NMR (400MHz, DMSO-d6) δ8.13(d,J=2.4Hz,1H),7.04(dd,J=8.0,1.9Hz,1H),6.99(d,J=1.4Hz ,1H),6.97–6.88(m,2H),6.84–6.75(m,1H),6.72–6.64(m,1H),6.25(s,1H),6.13(s,2H),5. 81(s,1H),5.58(d,J=3.8Hz,1H),5.53–5.40(m,2H),5.06–4.93(m,1H),4.21(dd,J=10.2,4. 6Hz, 1H), 3.95 (s, 3H), 3.76 (t, J = 10.0Hz, 1H), 3.67 (s, 3H), 3.59–3.47 (m, 4H), 2.41 (s, 3H).

[0080] Preparation Example of Compound of Formula I-5

[0081]

[0082] The compound of formula II (100 mg, 0.18 mmol) and anhydrous zinc chloride (126 mg, 0.92 mmol) were dissolved in 2 mL of 4-(methylmercapto)benzaldehyde, and the nitrogen was replaced 3 times, and the reaction bottle was placed in an oil bath at 30°C. After reacting for 12 hours, EA was extracted and column chromatography (DCM: MeOH = 100: 1) was used to separate 48 mg of a white solid compound of formula I-5. 1 H NMR (400MHz, DMSO-d6) δ8.14(d,J=2.3Hz,1H),7.38(d,J=8.4Hz,2H),7.25(d,J=8.4Hz,2H),7.04(dd ,J=7.9,1.7Hz,1H),6.99(d,J=1.5Hz,1H),6.93(dd,J=7.7,1.7Hz,1H),6.85–6.75(m,1H),6.27(s,1 H),6.13(s,2H),5.60(s,2H),5.53–5.41(m,2H),5.00(q,J=3.3Hz,1H),4.25(dd,J=10.3,4.6Hz,1H) ,3.95(s,3H),3.78(t,J=9.8Hz,1H),3.67(s,3H),3.64–3.58(m,2H),3.56–3.48(m,2H),2.47(s,3H).

[0083] Preparation Example of Compound of Formula I-6

[0084]

[0085] The compound of formula II (100 mg, 0.18 mmol) and anhydrous zinc chloride (126 mg, 0.92 mmol) were dissolved in 2 mL of 4-(trifluoromethyl)benzaldehyde, and the nitrogen was replaced 3 times, and the reaction bottle was placed in an oil bath at 30°C. After reacting for 12 hours, EA was extracted and column chromatography (DCM: MeOH = 100: 1) was used to separate 42 mg of a white solid, which was the compound of formula I-6. 1 H NMR (400MHz, DMSO-d6) δ8.15(d,J=2.4Hz,1H),7.77(d,J=6.7Hz,3H),7.65(t,J=7 .8Hz,1H),7.08–6.89(m,3H),6.80(t,J=6.5Hz,1H),6.28(s,1H),6.13(s,2H),5.7 7(s,1H),5.65(s,1H),5.55–5.43(m,2H),5.07–4.94(m,1H),4.31(dd,J=10.5,4. 6Hz, 1H), 3.96 (s, 3H), 3.82 (t, J = 10.1Hz, 1H), 3.68 (s, 3H), 3.61 (d, J = 8.7Hz, 4H).

[0086] Preparation Example of Compound of Formula I-7

[0087]

[0088] Step 1: Dissolve the compound of formula II (200 mg, 0.37 mmol) and anhydrous zinc chloride (252 mg, 1.85 mmol) in 4 mL of 3-thiophenecarboxaldehyde, replace nitrogen three times, and place the reaction bottle in an oil bath at 30°C. After reacting for 12 h, extract with EA, and separate by column chromatography (DCM: MeOH = 100:1) to obtain 107 mg of intermediate 6a.

[0089]

[0090] Step 2: Dissolve the intermediate 6a (107 mg, 0.17 mmol) in 3 mL DCM, add 127 μL acetic anhydride (1.36 mmol) and 109 μL pyridine (1.36 mmol) and start stirring the reaction at room temperature. After 2 h, add an appropriate amount of water, extract with DCM, and then separate 55.9 mg of white solid by column chromatography (DCM: MeOH = 200: 1), which is the compound of formula I-7. 1H NMR(400MHz,DMSO-d6)δ7.53(d,J=3.2Hz,2H),7.48(d,J=1.7Hz,1H),7.09–7.01(m,2H),6.97 (d,J=2.1Hz,1H),6.91(s,1H),6.82–6.74(m,1H),6.13(s,2H),5.73(d,J=5.8Hz,2H),5.64(d ,J=14.8Hz,1H),5.52–5.46(m,2H),5.35(dd,J=9.5,7.7Hz,1H),4.37(dd,J=10.1,4.6Hz,1H) ,4.03(t,J=9.4Hz,1H),3.96(s,4H),3.82(t,J=10.1Hz,1H),3.67(s,3H),2.09–2.02(m,6H).

[0091] Preparation Example of Compound of Formula I-8

[0092]

[0093] The compound of formula II (100 mg, 0.18 mmol) and anhydrous zinc chloride (126 mg, 0.92 mmol) were dissolved in 1 mL of 4-tetrahydropyranaldehyde, and the nitrogen was replaced 3 times, and the reaction bottle was placed in an oil bath at 30°C. After reacting for 12 hours, EA was extracted and column chromatography (DCM: MeOH = 100: 1) was used to separate 28 mg of a white solid, which was the compound of formula I-8. 1 H NMR (400MHz, DMSO-d6) δ8.12(d,J=2.4Hz,1H),7.04(dd,J=7.8,1.7Hz,1H),6.99(s,1H),6.92(dd,J=7 .8,1.5Hz,1H),6.83–6.75(m,1H),6.22(s,1H),6.13(s,2H),5.46(d,J=14.3Hz,3H),4.95(dd,J=7.1, 3.3Hz,1H),4.39(d,J=5.5Hz,1H),4.12(dd,J=10.2,4.1Hz,1H),3.94(s,3H),3.83(d,J=11.7Hz,2H), 3.67(s,3H),3.52(d,J=8.9Hz,3H),3.24(t,J=11.7Hz,4H),1.77–1.51(m,4H),1.34(d,J=19.9Hz,1H).

[0094] Preparation Example of Compound of Formula I-9

[0095]

[0096] The compound of formula II (100 mg, 0.18 mmol) and anhydrous zinc chloride (126 mg, 0.92 mmol) were dissolved in 2 mL of cyclohexane formaldehyde, and the nitrogen was replaced 3 times, and the reaction bottle was placed in an oil bath at 30°C. After reacting for 12 hours, EA was extracted and column chromatography (DCM: MeOH = 100: 1) was used to separate 23.8 mg of a white solid, which was the compound of formula I-9. 1 H NMR (400MHz, DMSO-d6) δ8.12(d,J=2.6Hz,1H),7.04(d,J=7.8Hz,1H),6.98(s,1H),6.92(d, J=8.9Hz,1H),6.79(t,J=6.8Hz,1H),6.20(d,J=4.1Hz,1H),6.13(s,2H),5.49–5.39(m,3H), 4.98–4.86(m,1H),4.33(d,J=5.2Hz,1H),4.18–4.06(m,1H),3.94(s,3H),3.67(s,3H),3.58 –3.47(m,3H),3.28(d,J=7.3Hz,2H),1.71(dd,J=27.5,12.9Hz,4H),1.08(d,J=36.2Hz,7H).

[0097] Preparation Example of Compound of Formula Ⅰ-10

[0098]

[0099] The compound of formula II (100 mg, 0.18 mmol) and anhydrous zinc chloride (126 mg, 0.92 mmol) were dissolved in 1 mL of cyclopentanecarboxaldehyde, and the nitrogen was replaced 3 times, and the reaction bottle was placed in an oil bath at 30°C. After reacting for 12 hours, EA was extracted and separated by column chromatography (DCM: MeOH = 100: 1) to obtain 28 mg of a white solid, which is the compound of formula I-10. 1H NMR (400MHz, DMSO-d6) δ8.12(d,J=3.1Hz,1H),7.03(dd,J=7.9,1.8Hz,1H),6.98(s,1H),6.92(d,J= 9.7Hz,1H),6.79(t,J=7.1Hz,1H),6.24(s,1H),6.12(d,J=2.2Hz,2H),5.49(s,1H),5.44(s,2H),4. 94(q,J=3.5Hz,1H),4.41(d,J=6.1Hz,1H),4.09(dd,J=9.5,3.5Hz,1H),3.94(s,3H),3.66(s,3H),3 .52(dd,J=10.7,6.2Hz,3H),3.30(d,J=6.2Hz,2H),2.02(q,J=11.4,9.5Hz,1H),1.67–1.48(m,8H).

[0100] Tests for the cellular activity of Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7, Formula I-8, Formula I-9, and Formula I-10

[0101] The test method is: use the MTT method to test the activity of the compound at the cellular level: take the head and neck squamous cell carcinoma cell cal27 in the logarithmic growth phase and digest and count it, and adjust the concentration of the cell suspension to 5000 / mL; take a 96-well plate, set 3 duplicate wells for each compound, add 250μL of cell suspension to each well, fill the empty space on the edge with sterile PBS buffer to eliminate the edge effect, and put the 96-well plate into a 5% CO2, 37°C incubator for routine culture; after 6 hours of cell adhesion, take out the 96-well plate and add compounds with different concentration gradients, incubate for 72 hours and then test: 1. Add 10μL MTT solution (5mg / mL) to each well of the test well, put it in the incubator and continue to culture for 4h, 2. Carefully aspirate the liquid in the well, be careful not to touch or aspirate the crystals, 3. Add 150μL DMSO to each well, shake it slightly for 3min to fully dissolve the crystals, 4. Use an enzyme reader to detect, and use Graphpad Prism 8 software uses absorbance as the vertical axis (inhibition rate = 1-experimental group OD value / control group OD value) and derivative concentration as the horizontal axis to draw the cell inhibition curve and fit the IC value of the compound. 50 .

[0102] Specific results such as Figures 1 to 4 shown.

[0103] Table 2: Inhibitory activity (IC) of compounds in cal27 (head and neck cancer cell line) 50 )

[0104] Compound Cal27(nM) Ⅰ-2 6.2 Ⅰ-3 <1 Ⅰ-4 152.7 Ⅰ-5 19.3 Ⅰ-6 48.5 Ⅰ-7 4.1 Ⅰ-8 27.7 Ⅰ-9 6.3 Ⅰ-10 12.2 Diphyllin 1205 Etoposide 1949

[0105] The compounds listed in this patent have head and neck cancer cell inhibition and anti-cancer activity. Compared with diphyllin and clinically used drug etoposide, compounds Ⅰ-2, Ⅰ-3, Ⅰ-4, Ⅰ-5, Ⅰ-6, Ⅰ-7, Ⅰ-8, Ⅰ-9, Ⅰ-10 all show significantly better positive activity at the cell level. These derivatives can be used as active ingredients to prepare drugs for treating cancer.

[0106] The above embodiments are merely illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Anyone familiar with the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by a person of ordinary skill in the art without departing from the spirit and technical concept disclosed by the present invention shall still be covered by the claims of the present invention.

Claims

1. A glycoside derivative of schizofiarin, characterized in that: The glycoside derivative of schizofiarin is any one of Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7, Formula I-8, Formula I-9 and Formula I-10:

2. Use of the glycoside derivative of feroxetine as claimed in claim 1 in the preparation of anticancer drugs; the anticancer drug is a drug with inhibitory activity against head and neck squamous cell carcinoma cell cal27.

3. A method for preparing the glycoside derivative of schizofiarin as claimed in claim 1, wherein the compound of formula II is reacted with 2-thiophenecarboxaldehyde to obtain the compound of formula I-2, and the synthetic route is as follows: Alternatively, the compound of formula II is reacted with 2-furancarboxaldehyde to obtain the compound of formula I-3. The synthetic route is as follows: Alternatively, the compound of formula II is reacted with 5-methyl-2-thiophenecarboxaldehyde to obtain the compound of formula I-4. The synthetic route is as follows: Alternatively, the compound of formula II is reacted with 4-(methylmercapto)benzaldehyde to obtain the compound of formula I-5. The synthetic route is as follows: Alternatively, the compound of formula II is reacted with 4-(trifluoromethyl)benzaldehyde to obtain the compound of formula I-6. The synthetic route is as follows: Alternatively, the compound of formula II is reacted with 3-thiophenecarboxaldehyde, and then with acetic anhydride and pyridine to obtain the compound of formula I-7. The synthetic route is as follows: Alternatively, the compound of formula II is reacted with 4-tetrahydropyranaldehyde to obtain the compound of formula I-8. The synthetic route is as follows: Alternatively, the compound of formula II is reacted with cyclohexanecarboxaldehyde to obtain the compound of formula I-9. The synthetic route is as follows: Alternatively, the compound of formula II is reacted with cyclopentanecarboxaldehyde to obtain the compound of formula I-10. The synthetic route is as follows:

4. The preparation method according to claim 3, characterized in that: The reaction is carried out under oxygen-free and water-free conditions.

5. The preparation method according to claim 3, characterized in that: The reaction uses zinc chloride as a catalyst; and / or the reaction temperature is 10-70°C.

6. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises at least one glycoside derivative of schizofiarin as claimed in claim 1, and a pharmaceutically acceptable additive.

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