Lycorine derivatives and preparation methods thereof and applications in the preparation of anti-tumor drugs

Abstract

The present invention provides lycorine derivatives and preparation methods thereof and applications thereof in the preparation of anti-tumor drugs. The structure of the lycorine derivatives is shown in Formula I. The lycorine derivatives have good anti-tumor activity against lung cancer, liver cancer, glioma, gastric cancer, colon cancer and esophageal cancer, and have good medicinal prospects.

Description

Technical Field

[0001] The invention relates to the field of biomedicine, and in particular to lycorine derivatives and preparation methods thereof and applications thereof in the preparation of anti-tumor drugs. Background Art

[0002] Any discussion of the prior art throughout the specification should not be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field.

[0003] Tumor is the most common and most serious disease that directly threatens human life in the world today. According to statistics, more than 14 million people suffer from tumors every year in the world. Currently, tumors are ranked second among the causes of death in the world. At present, the main treatments are surgery, chemotherapy, radiotherapy, biological therapy and other comprehensive measures, but their efficacy is not satisfactory. Therefore, scientific researchers have been committed to finding new tumor treatment targets and developing new tumor treatment drugs, especially small molecule targeted drugs. Traditional Chinese medicine has mild effects, good therapeutic effects, and few adverse reactions. It has obvious advantages in the treatment of malignant tumors. In recent years, extracting effective anti-tumor compounds from natural medicines has been an important research direction for the development of new anti-tumor drugs.

[0004] Lycorine is an isoquinoline alkaloid with a molecular formula of C 16 H 17 NO4, widely present in Amaryllis plants, has good antiviral, anti-inflammatory and anti-tumor activities and diverse mechanisms of action.

[0005]

[0006] The anti-tumor activity of lycorine was first discovered by Jimenez et al. in 1976. So far, lycorine has shown different degrees of in vitro inhibitory effects on leukemia, glioblastoma, bladder cancer, prostate cancer, etc. A large number of studies have shown that the anti-tumor activity of lycorine is not achieved through a single pathway or channel. Lycorine can regulate most tumor molecular targets and signal pathways to induce tumor cell apoptosis, regulate tumor cell cycle, affect tumor cell autophagy, and inhibit tumor cell invasion and metastasis. Therefore, it can be used as a lead compound for the development of new anti-tumor drugs.

[0007] The purpose of the present invention is to overcome or improve at least one disadvantage of the prior art, or to provide a useful alternative. Unless the context clearly requires otherwise, throughout the specification and claims, the words "include", "comprises", etc. should be interpreted from an inclusive perspective rather than an exclusive or exhaustive perspective; that is, from the perspective of "including, but not limited to". Summary of the invention

[0008] The inventors have conducted systematic and continuous research on lycorine. During the research process, the inventors obtained a series of compounds by reacting the 1-hydroxyl group with β-aryl acrylic acid. The research results confirmed that when the 1-hydroxyl position of lycorine has a β-aryl acrylic acid ester structure, it is an essential group for the compound to have anti-tumor activity, and it can show good inhibitory activity against lung cancer, liver cancer, glioma, gastric cancer and colon cancer.

[0009] In the present invention, the inventor provides a new lycorine derivative and its preparation method and application. The lycorine derivative of the present invention is based on lycorine, and its 2-hydroxyl group is modified. When the 2-hydroxyl group is esterified with p-fluorophenylthioacetic acid, it exhibits excellent anti-tumor activity, and its activity against various tumor cells is generally better than 5-fluorouracil (5-FU) and the starting compound lycorine. Compared with a series of compounds modified with a β-aryl acrylate structure at the 1-hydroxyl position, the compound of the present invention has a better and further improvement in the inhibitory activity against glioma and gastric cancer cells, and also has a significant inhibitory activity against esophageal cancer cells.

[0010] Specifically, the technical solution of the present invention is as follows:

[0011] In the first aspect of the present invention, the present invention provides a compound, whose Chinese name is: 2-p-fluorophenylthioacetyl-lycorine (abbreviated as TC), and whose structure is shown in Formula I:

[0012]

[0013] At the same time, the present invention also provides a pharmaceutically acceptable salt or solvate of the compound represented by formula I.

[0014] In an embodiment of the present invention, the pharmaceutically acceptable salt of the present invention refers to the compound shown in formula I or its stereoisomer, and the acidic and / or basic salt formed with inorganic and / or organic acid and base, also including zwitterionic salt (inner salt), and also including quaternary ammonium salt, such as alkylammonium salt. In some embodiments of the present invention, the pharmaceutically acceptable salt of the present invention can be the hydrochloride, hydrobromide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, format, acetate, propionate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, succinate, gluconate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate of the compound described above.

[0015] In an embodiment of the present invention, the solvate of the present invention refers to the form of a complex formed by the coordination of a compound with a solvent molecule, which can be solid or liquid. For example, a hydrate is a specific form of a solvate in which a compound coordinates with water. Therefore, the solvate of the present invention includes a hydrate. In some embodiments of the present invention, the solvate includes a solvate formed by a compound with any one of water, ethanol, isopropanol, and acetone.

[0016] In the embodiments of the present invention, it has been verified that the compound represented by formula I of the present invention exhibits inhibitory activity against a variety of tumor cells, especially, in in vitro experiments, it exhibits relatively excellent anti-tumor activity against human tumor cell lines A549, HepG2, Hs683, HGC27, HCT116, KYSE450 and KYSE30, and the anti-tumor activity is significantly better than 5-fluorouracil (5-FU).

[0017] In the second aspect of the present invention, the present invention provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt or a solvate thereof, comprising:

[0018] Using lycorine as the starting compound, tert-butyldimethylsilyl chloride (TBSCl) was used to selectively protect the 2-hydroxyl group to obtain the intermediate INA.

[0019] The intermediate INA undergoes an esterification reaction with levulinic acid, and then the silane protecting group at the 2nd position is removed to obtain the intermediate INB.

[0020] The intermediate INB undergoes esterification reaction with p-fluorophenylthioacetic acid to obtain the intermediate INC

[0021] The intermediate INC is subjected to the removal of the 1-position levulinyl group in the presence of hydrazine acetate to obtain the lycorine derivative TC shown in formula I.

[0022] The pharmaceutically acceptable salts of the compounds of formula I of the present invention can be prepared in the process of separation and purification after the compound of formula I is prepared; or can be prepared by mixing the compound of formula I or its stereoisomer with a certain amount (such as an equal amount) of acid or base. These salts can be obtained by forming a precipitate in a solution and collecting it by filtering, or by recovering it after evaporating the solvent, or by freeze-drying it after reacting in an aqueous medium.

[0023] In the third aspect of the present invention, the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof.

[0024] Furthermore, the present invention provides a pharmaceutical preparation comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient and / or carrier.

[0025] The compounds of the present invention are usually administered in the form of a pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and may also contain conventional excipients. Pharmaceutically acceptable carriers are those conventionally known carriers with acceptable safety characteristics. Compositions include all common solid and liquid forms, including, for example, capsules, tablets, pills, powders, and liquid suspensions, syrups, elixirs, injections, and solutions. If necessary, other excipients such as flavoring agents, colorants, stabilizers, lubricants, etc. may also be added, or suitable dosage forms may also be coated using methods known in pharmacy.

[0026] The pharmaceutical composition can be prepared using common formulation techniques, such as a method for producing a pharmaceutical composition or a pharmaceutical preparation is provided in some embodiments of the present invention, the method comprising mixing the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutical excipient or a pharmaceutical carrier. For example, in some embodiments, a solid or liquid preparation can be prepared by uniformly mixing the compound of the present invention with a liquid and / or finely ground solid excipient in a desired proportion, and then, if necessary, forming the resulting mixture into a desired shape. The dosage form for parenteral administration is prepared, for example, as follows: the compound of the present application is dissolved in a suitable liquid vehicle (such as water), the solution is filtered and sterilized, and then filled into a suitable vial or ampoule and sealed.

[0027] Of course, in addition to this, those skilled in the art can also use other techniques known in the art to prepare the compounds of the present invention into pharmaceutical compositions or pharmaceutical preparations. For example, pharmaceutical preparations can be prepared according to the modern pharmaceutical preparation series edited by Shenyang Pharmaceutical University. And, in addition to the present invention, suitable pharmaceutical excipients can also be other types known in the art, such as those recorded in the Handbook of Pharmaceutical Excipients compiled by author Paul J Sheskey et al., which has been revised to the eighth edition, the first edition was published in 1986, and the eighth edition was first published in 2017.

[0028] In the fourth aspect of the present invention, the present invention provides the use of the compound of formula I or its pharmaceutically acceptable salt or solvate, or a pharmaceutical composition or pharmaceutical preparation comprising the compound of formula I in the preparation of anti-tumor drugs.

[0029] In the embodiments of the present invention, it has been verified through in vitro experiments that the compound represented by Formula I exhibits excellent anti-tumor effects on lung cancer, liver cancer, glioma, gastric cancer, colon cancer and esophageal cancer, and the effect is significantly better than 5-FU.

[0030] In a fifth aspect of the present invention, the present invention provides a method for treating cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula I. The cancer includes but is not limited to lung cancer, liver cancer, glioma, gastric cancer, colon cancer and esophageal cancer.

[0031] The "patient" of the present invention refers to an animal that has been the subject of treatment, observation or experiment, preferably a mammal, and most preferably a human. The "therapeutically effective amount" refers to the amount of a pharmaceutical agent including a compound of the present invention, which can cause the biological or medical response of a tissue system, animal or human sought by a researcher, veterinarian, doctor or other medical personnel, including alleviating or partially alleviating the symptoms of the disease, syndrome, condition or disorder being treated.

[0032] The compounds of the present invention are usually administered as pharmaceutical compositions, and both solid compositions and liquid compositions are usually formulated in dosage units. Generally, solid compositions preferably provide compositions of about 1 mg to 1000 mg of active ingredients per dose, and the dosage can be 1 mg, 10 mg, 100 mg, 250 mg, 500 mg and 1000 mg; generally, other agents will exist in a unit range similar to that of such agents used clinically, and generally, this range is 0.25-1000 mg / unit. Generally, liquid compositions will be in a unit dosage range of 1-100 mg / mL, and the dosage can be 1 mg / mL, 10 mg / mL, 25 mg / mL, 50 mg / mL and 100 mg / mL; generally, other agents will exist in a unit range similar to that of such agents used clinically, and generally, this range is 1-100 mg / mL.

[0033] The present invention includes all conventional modes of administration; oral and parenteral methods are preferred. Generally, the dosage regimen will be similar to other medicaments used clinically. It should be understood that the optimal dosage can be determined by conventional methods. Although the dosage varies with the symptoms and age of the patient, the nature and severity of the disease or disorder and the route and mode of administration, for oral administration of adult patients, as a reference, the normal administration of the compounds of the present application is a total daily dose of 1 to 1000 mg, preferably 5 to 500 mg, administered in a single dose or divided dose form, for example, twice or three times a day; for intravenous injection, 0.1 to 100 mg, preferably 0.5 to 50 mg, can be administered once or three times a day. Generally, oral administration requires more compounds, while parenteral administration requires less compounds. However, the specific dosage regimen will be determined by the doctor using reasonable medical judgment.

[0034] Compared with the prior art, the advantages of the present invention are as follows: the present invention provides a new lycorine derivative, which is found through preliminary activity screening experiments to show good inhibitory activity against lung cancer cells A549, liver cancer cells HepG2, glioma Hs683, gastric cancer cells HGC27, colon cancer cells HCT116, esophageal cancer cells KYSE450 and esophageal cancer cells KYSE30, and its tumor inhibitory activity is significantly better than that of the positive control drug 5-fluorouracil, and its inhibitory activity against glioma, gastric cancer, liver cancer and esophageal cancer cells is significantly better than that of lycorine, and has good anti-tumor application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] The accompanying drawings constituting a part of the present invention are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. The embodiments of the present invention are described in detail below in conjunction with the accompanying drawings, wherein:

[0036] Figure 1 The H NMR spectrum of the intermediate INA ( 1 H-NMR) spectra;

[0037] Figure 2 The C NMR spectrum of the intermediate INA ( 13 C-NMR) spectra;

[0038] Figure 3 The H NMR spectrum of the intermediate INB is 1 H-NMR) spectra;

[0039] Figure 4 The C NMR spectrum of the intermediate INB is ( 13 C-NMR) spectra;

[0040] Figure 5 The H NMR spectrum of the intermediate INC ( 1 H-NMR) spectra;

[0041] Figure 6 The C NMR spectrum of the intermediate INC ( 13 C-NMR) spectra;

[0042] Figure 7 The H NMR spectrum of the lycorine derivative shown in Formula I ( 1 H-NMR) spectra;

[0043] Figure 8 The carbon NMR spectrum of the lycorine derivative shown in formula I ( 13 C-NMR) chart. DETAILED DESCRIPTION

[0044] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer.

[0045] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. The reagents or raw materials used in the present invention can be purchased through conventional channels. Unless otherwise specified, the reagents or raw materials used in the present invention are used in a conventional manner in the art or in accordance with the product instructions. In addition, any method and material similar to or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials described in the text are for demonstration purposes only.

[0046] Unless otherwise specified, raw materials are generally available from commercial sources. Commercially available solvents or reagents are generally used without further purification. The structure of the compound is determined by nuclear magnetic resonance spectroscopy (NMR). The H-NMR and C-NMR shifts (δ) are given in parts per million (ppm). Deuterated chloroform (CDCl3) is used as solvent for H-NMR and C-NMR, and tetramethylsilane (TMS) is used as internal standard. Column chromatography generally uses 200-300 mesh silica gel as carrier and n-hexane-ethyl acetate as elution solvent.

[0047] The abbreviations involved in the present invention are as follows:

[0048] TBSCl: tert-butyldimethylsilyl chloride; Im: imidazole; DMF: N,N-dimethylformamide; EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; DMAP: 4-dimethylaminopyridine; Con.HCl: concentrated hydrochloric acid; EtOH: ethanol.

[0049] The present invention provides a method for preparing a compound shown in formula I (i.e., a lycorine derivative TC), comprising: in the presence of an acid-binding agent, lycorine is selectively protected by using tert-butyldimethylsilyl chloride to obtain an intermediate INA; the intermediate INA is subjected to an esterification reaction with levulinic acid in the presence of a condensing agent and a catalyst, and then the silane protecting group at the 2nd position is removed by using concentrated hydrochloric acid under heating conditions to obtain an intermediate INB; the intermediate INB is subjected to an esterification reaction with p-fluorophenylthioacetic acid in the presence of a condensing agent and a catalyst to obtain an intermediate INC; the intermediate INC is subjected to a levulinic acyl group at the 1st position to obtain the lycorine derivative TC in the presence of a catalyst, wherein the reaction route involved in the preparation method is as follows:

[0050]

[0051] The preparation of the lycorine derivative TC of the present invention will be illustrated below in conjunction with specific examples, and the activity of the lycorine derivative TC of the present invention will be demonstrated in experimental examples.

[0052] Example 1 :2-tert-Butyldimethylsilyl-lycorine (INA)

[0053] INA structure:

[0054] In a 2000mL round-bottomed reaction bottle, lycorine (100.0mmoL) and Im (150.0mmoL) were dissolved in 300mL DMF, and TBSCl (150.0mmoL) was slowly added under vigorous stirring at room temperature. The temperature was raised to 40°C to completely dissolve the reaction system, and after keeping warm and stirring for 4h, the residual amount of the starting material lycorine was less than 5% after HPLC tracking detection, and then post-processing was performed. 500mL ethyl acetate and 800mL purified water were added to the reaction system in sequence, and after stirring at room temperature for 10 minutes, the liquid was separated, and the organic phase was washed with 500mL 10% sodium chloride solution. After separation, 100.0g of anhydrous sodium sulfate was dried, filtered, concentrated under reduced pressure, and separated and purified by column chromatography to obtain white solid INA. 1 HNMR (500MHz, CDCl3) δ6.80 (s, 1H), 6.56 (s, 1H), 5.89 (d, J = 1.1Hz, 2H), 5.39 (s ,1H),4.38(s,1H),4.25(s,1H),4.10(d,J=14.0Hz,1H),3.45(d,J=14.0Hz,1H), 3.38–3.25(m,1H),2.78(d,J=10.6Hz,1H),2.69(d,J=10.6Hz,1H),2.59(dd,J= 15.9,7.9Hz,2H),2.31(q,J=8.8Hz,1H),0.88(s,9H),0.13(s,3H),0.10(s,3H); 13 C NMR (126MHz, CDCl3) δ146.50,146.15,141.81,130.35,128.02,118.35,107.72,104.53 ,100.95,72.30,60.94,57.15,53.92,40.92,28.59,25.87,25.70,18.14,-4.41,-4.70.

[0055] Example 2 :1-levulinyl-lycorine (INB)

[0056] INB structure:

[0057] a: Dissolve 2-tert-butyldimethylsilyl-lycorine INA (10.0 mmol) and levulinic acid (20.0 mmol) in 100 mL of dichloromethane in a 250 mL round-bottomed reaction bottle, and add EDCI·HCl (18.0 mmol) and DMAP (1.0 mmol) in turn under nitrogen protection at room temperature. After the addition, stir and react at 35°C. After HPLC tracking and detection, the residual amount of INA is less than 8%, and then post-processing can be performed. The reaction solution is washed with 100 mL of purified water and 100 mL of 10% sodium chloride solution in turn, and concentrated under reduced pressure for use.

[0058] b: Dissolve the above product in 50 mL of anhydrous ethanol in a 250 mL round-bottomed reaction bottle, and slowly drop 5.0 mL of concentrated hydrochloric acid under stirring at room temperature. After the addition is completed, stir and react at 80°C for 1.0 h, turn off the heating and cool naturally to 25°C, then slowly drop 5.0 mL of ammonia water. Add 80 mL of ethyl acetate and 80 mL of purified water to the reaction system in sequence, extract and separate, wash the organic phase with saturated sodium bicarbonate solution and saturated sodium chloride solution, dry with anhydrous sodium sulfate, concentrate, and separate by column chromatography to obtain white solid INB. 1 H NMR (500MHz, CDCl3) δ6.62 (s, 1H), 6.56 (s, 1H), 5.91 (d, J = 4.3Hz, 2H), 5.5 6(s,1H),5.51(s,1H),4.18–4.08(m,2H),3.49(d,J=13.9Hz,1H),3.34(dt, J=9.2,4.7Hz,1H),2.84(d,J=10.5Hz,1H),2.77–2.65(m,2H),2.64–2.54( m,3H),2.46(ddd,J=17.1,7.8,5.9Hz,1H),2.42–2.33(m,2H),2.09(s,3H); 13 C NMR (125MHz, CDCl3) δ206.44,172.47,146.45,146.19,143.27,129.20,127.07,117.55,107 .24,104.94,100.91,72.99,69.13,61.56,56.79,53.68,39.14,37.92,29.66,28.52,28.00.

[0059] Example 3 :1-levulinyl-2-(p-fluorophenylthioacetyl)-lycorine (INC)

[0060] INC Structure:

[0061] In a 250mL round-bottomed reaction bottle, 1-levulinyl-lycorine INB (5.0mmoL) and p-fluorophenylthioacetic acid (6.0mmoL) were dissolved in 50mL dichloromethane, and EDCI·HCl (9.0mmoL) and DMAP (0.5mmoL) were added in sequence under nitrogen protection at room temperature. After the addition, the mixture was stirred and kept warm at 35°C for reaction. After HPLC tracking and detection, the residual amount of INB was less than 8%, and then the mixture could be post-processed. The reaction solution was washed with 100mL purified water and 100mL 10% sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain colorless viscous INC. 1 H NMR (500MHz, CDCl3) δ7.46 (dd, J=8.5, 5.3Hz, 2H), 7.01 (t, J=8.6Hz, 2H), 6.60 ( s,1H),6.57(s,1H),5.93(s,2H),5.57(s,1H),5.42(s,1H),5.25(s,1H),4.15(d ,J=14.1Hz,1H),3.56(s,2H),3.52(d,J=14.0Hz,1H),3.39–3.32(m,1H),2.76( q,J=10.6Hz,2H),2.68–2.57(m,4H),2.43(qd,J=17.3,9.4Hz,3H),2.09(s,3H); 13 CNMR (125MHz, CDCl3) δ206.04,171.76,168.38,163.49,161.52,146.69,146.48,146.38,133.91,133.85,129.41,126.27,11 6.38,116.21,113.23,107.34,104.95,101.02,71.73,69.31,61.22,56.88,53.62,40.39,37.92,37.83,29.69,28.72,27.89.

[0062] Example 4 :2-p-Fluorophenylthioacetyl-lycorine (TC)

[0063] TC structure:

[0064] In a 250mL round-bottomed reaction bottle, 1-levulinyl-2-p-fluorophenylthioacetyl-lycorine INC (2.0 mmol) was dissolved in a mixed solvent of 80 mL of dichloromethane and 20 mL of methanol, and hydrazine acetate (8.0 mmol) was added dropwise under stirring at room temperature. After the addition was completed, the reaction was stirred at room temperature, and the residual amount of INC was less than 3% after HPLC tracking detection. The reaction solution was washed with 100 mL of purified water and 100 mL of 10% sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain a white solid TC. 1 H NMR (500MHz, CDCl3) δ7.53–7.37(m,2H),7.10–6.92(m,2H),6.65(s,1H),6.59(s,1 H),5.93(d,J=12.0Hz,2H),5.36(s,1H),5.29(d,J=7.8Hz,1H),4.33(s,1H),4.13( d,J=14.1Hz,1H),3.58(s,2H),3.50(d,J=14.0Hz,1H),3.34(ddd,J=9.1,6.0,3.5H z,1H),2.77(d,J=10.5Hz,1H),2.61(d,J=9.0Hz,3H),2.36(dt,J=19.8,9.9Hz,2H); 13 C NMR (126MHz, CDCl3) δ169.23,163.38,161.41,146.66,146.61,146.41,133.37,133.30,130.01,129.48,129.46,1 26.93,116.39,116.22,113.09,107.70,104.58,101.07,74.68,68.88,60.66,56.97,53.71,41.64,37.67,28.76.

[0065] Experimental example: Antitumor activity test

[0066] 1: Experimental cells: The experiment used 7 different types of human tumor cells, including lung cancer cells A549, liver cancer cells HepG2, glioma Hs683, gastric cancer cells HGC27, colon cancer cells HCT116, esophageal cancer cells KYSE450 and esophageal cancer cells KYSE30.

[0067] 2: Test method:

[0068] IC 50 Determination

[0069] 1) Drug preparation: Dissolve the compound in DMSO to a concentration of 10 mM, and then dilute it 10 times in a gradient to 1 mM, 100 μM, 10 μM, 1 μM, and 0.1 μM. The stock solution concentration and working concentration are shown in the following table:

[0070] Stock solution concentration Working concentration 10mM 100μM 1mM 10μM 100μM 1μM 10μM 100nM 1μM 10nM 0.1μM 1nM

[0071] 2) Cell culture and plating: All seven types were cultured in DMEM medium containing 10% FBS. When the confluence reached 75-85%, they were digested and counted, and evenly plated in 96-well plates. The initial cell number is shown in the following table:

[0072]

[0073]

[0074] 3) Drug addition: Drugs were added 24 hours after cell plating, and a DMSO solvent control well was set up on each plate.

[0075] 4) MTT assay: 48 hours after drug addition, add MTT, incubate for 4 hours, discard the supernatant, add 100 μl DMSO, shake on a shaker for 10 minutes, and then measure the OD on an instrument. 570 With OD 720 The cell survival rate is calculated as follows:

[0076] Cell survival rate = drug-added group OD570 -Dosage group OD720 / DMSO group OD570 -DMSO OD720

[0077] The IC of each compound was calculated using Graphpad software 50 .

[0078] 3: Test results:

[0079] For the seven cell lines tested, Hs683, A549, HGC27, HCT116, HepG2, KYSE450 and KYSE30, their IC 50 The test results are shown in the following table:

[0080] IC 50 Test results (unit: μM)

[0081]

[0082] Note: “-” means not tested.

[0083] Through the data analysis in the above table, it can be seen that the lycorine derivative TC of the present invention shows good inhibitory activity on lung cancer cells A549, liver cancer cells HepG2, glioma Hs683, gastric cancer cells HGC27, colon cancer cells HCT116, esophageal cancer cells KYSE450 and esophageal cancer cells KYSE30, and its tumor inhibitory activity is significantly better than the positive control drug 5-fluorouracil. The inhibitory activity of the lycorine derivative TC of the present invention on the above 7 tumor cells is comparable to that of lycorine, and the inhibitory activity for glioma Hs683, gastric cancer cells HGC27, liver cancer cells HepG2 and esophageal cancer cells KYSE30 is even significantly better than its parent nucleus lycorine. It is worth mentioning that the inhibitory activity on glioma Hs683 is nearly 8 times higher than that of the lycorine parent nucleus, and its inhibitory activity on liver cancer cells HepG2 is nearly 3 times higher than that of the lycorine parent nucleus, showing that this new structure of lycorine derivatives has good anti-tumor application prospects.

[0084] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention is described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A compound, the structure of which is shown in Formula I: or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, characterized in that Its pharmaceutically acceptable salt is selected from: hydrochloride, hydrobromide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, formate, acetate, propionate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, succinate, gluconate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate.

3. A method for preparing the compound of claim 1, comprising: Lycorine is used as a starting compound, and tert-butyldimethylsilyl chloride is used to selectively protect the 2-hydroxyl group thereof to obtain an intermediate INA; the intermediate INA undergoes an esterification reaction with levulinic acid, and then the silane protecting group at the 2-position is removed to obtain an intermediate INB; the intermediate INB undergoes an esterification reaction with p-fluorophenylthioacetic acid to obtain an intermediate INC; the intermediate INC is subjected to an acetyl propionyl group at the 1-position removed in the presence of hydrazine acetate; and a lycorine derivative shown in formula I is obtained; Among them, the structures of INA, INB and INC are as follows: 4 . A pharmaceutical composition comprising the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical preparation comprising the compound according to any one of claims 1 or 2 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient or carrier.

6. The pharmaceutical preparation according to claim 5, characterized in that The pharmaceutical preparation is selected from tablets, capsules, pills and injections.

7. Use of the compound according to any one of claims 1 or 2 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 4, or the pharmaceutical preparation according to claim 5 or 6 in the preparation of an anti-tumor drug.

8. The use according to claim 7, characterized in that: The tumor is selected from the group consisting of lung cancer, liver cancer, glioma, gastric cancer, colon cancer and esophageal cancer.

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