3 '-C modified cordycepin derivative as well as preparation method and application thereof

Abstract

The invention discloses a 3 '-C-site modified cordycepin derivative and a preparation method and application thereof, the 3'-C-site modified cordycepin derivative is shown as a formula I. The compound can be used as a potential chemotherapeutic drug to directly inhibit tumor proliferation. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine and relates to a preparation method and application of cordycepin derivatives modified at the 3'-C position based on epoxy synthesis. Background Art

[0002] With the accumulation of external environmental stimuli and cell damage, the cell adaptability in the body changes. One is the loss of cell adaptability, which ultimately evolves into senescence, and the other is the abnormal enhancement of cell adaptability, which transforms into cancer. Among them, cancer is a common disease that endangers human life and health, and the incidence and mortality rates of cancer have been on the rise worldwide. Currently, the treatment methods for malignant tumors mainly include surgery, radiotherapy, chemotherapy, etc., among which chemotherapy mainly uses synthetic drugs. The inhibitory effect of chemotherapeutic drugs on tumors is worthy of recognition, and it is also one of the more effective and commonly used treatment methods for malignant tumors. However, its toxic and side effects are extensive and serious, and there is a problem of drug resistance. In addition, chemotherapeutic drugs have poor selectivity between tumor cells and normal cells. While killing or inhibiting tumor cells, they can also damage the growth of normal cells and have a direct impact on the functions of the heart, liver, kidneys, and nervous system, causing certain toxicity to the human body. Therefore, it is very necessary to find anti-tumor drugs with low toxicity and high efficiency in tumor treatment.

[0003] Cordycepin (3'-deoxyadenosine) is a natural compound with various biological activities such as anti-inflammatory, anti-cancer, and immunomodulatory effects. However, due to its easy metabolism by adenosine deaminase (ADA) in the body into inactive 3'-deoxyinosine, its bioavailability is relatively low, which limits its clinical application. Therefore, improving bioavailability and efficacy has become the key to current research on cordycepin. Common methods to improve bioavailability include using ADA inhibitors, developing new drug delivery systems, and synthesizing cordycepin derivatives through structural modification. Although the first two strategies have made certain research progress, their potential side effects on the human body are not yet clear. Therefore, developing and synthesizing cordycepin derivatives with high activity through structural modification is one of the important research directions currently.

[0004] By modifying the molecular structure of cordycepin, especially modifying key active sites such as amino and hydroxyl groups in its structure, various cordycepin derivatives with different characteristics are synthesized. These chemically modified derivatives can effectively avoid the degradation by adenosine deaminase, thereby improving the stability and utilization rate of cordycepin in the body, prolonging its half-life, and enhancing the drug effect. In addition, studies have found that introducing a modifying group into the 3'-C position of cordycepin can effectively improve its activity. However, due to the high price of cordycepin and the difficulty of modifying the 3'-C position, the present invention provides a preparation method of cordycepin derivatives modified at the 3'-C position based on epoxy synthesis starting from cheap and easily available adenosine. Summary of the Invention

[0005] Object of the Invention: Aiming at the deficiencies of the prior art, the technical problem to be solved by the present invention is to provide a cordycepin derivative with 3'-C position modification based on epoxy and its preparation method and application.

[0006] To solve the above technical problems, the present invention discloses the following technical solutions:

[0007] First aspect, The present invention discloses a cordycepin derivative with 3'-C position modification shown in Formula I, or a pharmaceutically acceptable salt, co-crystalline complex, stereoisomer, tautomer, solvate, prodrug, or metabolite thereof;

[0008]

[0009] Wherein,

[0010] p is selected from 0, 1;

[0011] m is selected from 1, 2;

[0012] X is selected from C, O, S;

[0013] R is selected from H, C1-C3 alkyl, halogen; preferably H, methyl, F;

[0014] represents the absence or presence of a ring;

[0015] When represents the presence of a ring, is and X is C.

[0016] In some embodiments, the structural formula of the cordycepin derivative with 3'-C position modification is as follows;

[0017]

[0018] Wherein,

[0019] p is selected from 0, 1;

[0020] m is selected from 1, 2;

[0021] X is selected from C, O, S;

[0022] R is selected from H, C1-C3 alkyl, halogen, preferably H, methyl, F.

[0023] In some embodiments, when X is C, m is 2; when X is C or O, m is 1.

[0024] In some embodiments, in Formula I-A, is Among them, R is selected from C1-C3 alkyl, halogen, preferably methyl, F; X is selected from O, S.

[0025] In some embodiments, the cordycepin derivative modified at the 3'-C position has the structure shown in any one of I-1 to I-5.

[0026]

[0027] Second aspect, The present invention discloses a preparation method of the cordycepin derivative modified at the 3'-C position described in the first aspect above.

[0028] In some embodiments, the preparation method includes:

[0029] (1) Synthesize an epoxy intermediate from adenosine according to the prior art; or react adenosine with acyl bromide in an organic solvent and obtain an epoxy intermediate under an alkaline environment;

[0030]

[0031] (2) A nucleophile attacks the epoxy intermediate to react and obtain a cordycepin derivative modified at the 3'-C position.

[0032] In step (1), in a first organic solvent, adenosine is reacted with an excess of acyl bromide. After the reaction is completed, the reaction is quenched; the obtained reaction solution is extracted with a second organic solvent, the obtained organic phase is washed with brine, the obtained aqueous phase is extracted with the second organic solvent, the obtained organic phase is dried to obtain a crude mixture, the obtained mixture is dissolved in alcohol, an alkali is added, and stirring is carried out to precipitate a solid to obtain an epoxy intermediate.

[0033] Among them, the first organic solvent includes but is not limited to acetonitrile.

[0034] Among them, the acyl bromide is 2-acetoxyisobutyryl bromide; in some embodiments, the molar ratio of 2-acetoxyisobutyryl bromide to adenosine is 2-6:1, such as 4:1.

[0035] Among them, the temperature of the reaction is room temperature.

[0036] Among them, the reaction is carried out in a nitrogen atmosphere.

[0037] Among them, the reaction time is 3-5 h, such as 4 h.

[0038] Among them, after the reaction is completed, saturated sodium bicarbonate is added to quench the acyl bromide.

[0039] Among them, the second organic solvent includes ethyl acetate.

[0040] Among them, the base is sodium methoxide or a basic ion exchange resin; in some embodiments, the molar ratio of the base to adenosine is 2-6:1, such as 4:1.

[0041] In step (2), the epoxy intermediate is added to a mixed solution containing a nucleophile, a base, and an alcohol, and reacted to obtain a 3'-C-position modified cordycepin derivative.

[0042] Among them, the nucleophile includes any one or a combination of p-methylthiophenol, p-fluorothiophenol, naphthalenethiol, thiophenethiol, and furfuryl mercaptan.

[0043] Among them, the molar ratio of the nucleophile to the epoxy intermediate is 6-8.5:1, preferably 7-7.5:1.

[0044] Among them, the base includes sodium methoxide.

[0045] Among them, the molar ratio of the base to the epoxy intermediate is 4-6:1, such as 5:1.

[0046] Among them, the alcohol includes methanol.

[0047] Among them, the molar volume ratio of the nucleophile to the alcohol is 0.9-1.5 mmol / mL.

[0048] Among them, the temperature of the reaction is the reflux temperature.

[0049] Among them, after the reaction, it is left standing and slurried with ethanol to obtain a 3'-C-position modified cordycepin derivative.

[0050] Third aspect, The present invention discloses a pharmaceutical composition.

[0051] Among them, the pharmaceutical composition contains the 3'-C-position modified cordycepin derivative described in the first aspect above, or a pharmaceutically acceptable salt, co-crystalline complex, stereoisomer, tautomer, solvate, metabolite, or prodrug molecule thereof.

[0052] Fourth aspect, The present invention discloses the use of the 3'-C-position modified cordycepin derivative described in the first aspect above, or a pharmaceutically acceptable salt, co-crystalline complex, stereoisomer, tautomer, solvate, metabolite, or prodrug molecule thereof, or the composition described in the third aspect in the preparation of an anti-tumor drug.

[0053] In some embodiments, the tumor is colorectal cancer, such as rectal colon cancer.

[0054] Fifth aspect,The present invention discloses an anti-tumor drug, and its active ingredients include the combined compound of the cordycepin derivative modified at the 3'-C position described in the first aspect above, or its pharmaceutically acceptable salt, co-crystalline complex, stereoisomer, tautomer, solvate, metabolite, or its prodrug molecule or the composition described in the third aspect.

[0055] In some embodiments, the tumor is intestinal cancer, such as colorectal cancer.

[0056] In summary, the cordycepin derivatives modified at the 3'-C position based on epoxy synthesis provided by the present invention exhibit certain anti-tumor activities. The cordycepin derivatives modified at the 3'-C position all have the following characteristics: 1. By chemically modifying the 3'-C position, the bioavailability is improved; 2. The cordycepin derivatives modified at the 3'-C position may exhibit stronger activities in aspects such as anti-tumor. For example, certain derivatives enhance the apoptosis induction effect on tumor cells by regulating the NF-κB and MAPK signaling pathways; 3. The modified derivatives can also interfere with the energy metabolism and nucleic acid synthesis of cancer cells by competitively inhibiting the binding of ATP, thereby more effectively inhibiting tumor growth; 4. The derivatives modified at the 3'-C position can also further improve their distribution and efficacy in vivo through a nano-carrier or liposome delivery system.

[0057] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0058] The cordycepin derivatives modified at the 3'-C position based on epoxy synthesis provided by the present invention can inhibit the proliferation of tumor cells, can effectively anti-tumor; compared with the parent drug, it has better lipophilicity, better affinity for cell membranes, stays in the body for a longer time, and has a better anti-tumor effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] The following further specifically describes the present invention in conjunction with the drawings and specific embodiments, and the above and / or other advantages of the present invention will become clearer.

[0060] Figure 1 It is the hydrogen spectrum of the cordycepin derivative I-1 modified at the 3'-C position.

[0061] Figure 2 It is the carbon spectrum of the cordycepin derivative I-1 modified at the 3'-C position.

[0062] Figure 3 It is the hydrogen spectrum of the cordycepin derivative I-2 modified at the 3'-C position.

[0063] Figure 4 It is the carbon spectrum of the cordycepin derivative I-2 modified at the 3'-C position.

[0064] Figure 5 1H NMR spectrum of cordycepin derivative I-3 with 3'-C modification.

[0065] Figure 6 13C NMR spectrum of cordycepin derivative I-3 with 3'-C modification.

[0066] Figure 7 19F NMR spectrum of cordycepin derivative I-3 with 3'-C modification.

[0067] Figure 8 1H NMR spectrum of cordycepin derivative I-4 with 3'-C modification.

[0068] Figure 9 13C NMR spectrum of cordycepin derivative I-4 with 3'-C modification.

[0069] Figure 10 1H NMR spectrum of cordycepin derivative I-5 with 3'-C modification.

[0070] Figure 11 13C NMR spectrum of cordycepin derivative I-5 with 3'-C modification.

[0071] Figure 12 Bioactivity test results of cordycepin derivative I-2 with 3'-C modification. Detailed implementation mode

[0072] According to the following examples, the present invention can be better understood. However, those skilled in the art can easily understand that the content described in the examples is only used to illustrate the present invention and should not and will not limit the present invention described in detail in the claims.

[0073] In the following examples, the experimental methods are conventional methods unless otherwise specified; the reagents and materials can be obtained from commercial channels unless otherwise specified.

[0074] Example 1: Preparation of epoxy

[0075]

[0076] Under a nitrogen atmosphere, adenosine (20 g, 75 mmol), α-AIBBr (42.4 mL, 299.6 mmol) and H2O were added to 400 mL of acetonitrile and stirred to form a suspension, which was then stirred at room temperature for 4 h. Saturated NaHCO3 was added (the color changed from dark orange to clear white), and the mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous Na2SO4, filtered to obtain a white gum. The crude mixture was dissolved in 200 mL of CH3OH, and CH3ONa solution (55.5 mL, 299.6 mmol) was added and stirred overnight at room temperature. A large amount of white solid precipitated in the system. The filtrate was filtered to obtain the target product (14.5 g, yield 74%), which was collected for further use.

[0077] 1 1H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 8.18 (s, 1H), 7.34 (s, 2H), 6.22 (s, 1H), 5.09 (d, J = 4.4 Hz, 1H), 4.47 (d, J = 2.6 Hz, 1H), 4.23 (d, J = 2.7 Hz, 1H), 4.20 (d, J = 5.2 Hz, 1H), 3.61–3.49 (m, 2H). 13 13C NMR (101 MHz, DMSO) δ 156.5, 153.2, 149.6, 140.1, 119.2, 82.5, 81.6, 61.4, 59.2, 58.3.

[0078] Example 2: Preparation of 3'-C-position modified cordycepin derivative I-1 based on epoxidation

[0079]

[0080] Furfuryl mercaptan (9 mL, 90 mmol) and sodium methoxide (11 mL, 60 mmol) were dissolved in 100 mL of MeOH and stirred at room temperature for 20 min. The epoxide (3 g, 12 mmol) was added to this solution, and the mixture was stirred at reflux temperature for about 5 h. After standing, it was triturated with ethanol to obtain the white solid compound I-1 (3 g, yield 70%).

[0081] 11H NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 8.15 (s, 1H), 7.61 (dd, J = 1.9, 0.9 Hz, 1H), 7.41 (s, 2H), 6.41 (dd, J = 3.2, 1.9 Hz, 1H), 6.35 (dd, J = 3.2, 0.9 Hz, 1H), 6.00 (d, J = 5.9 Hz, 1H), 5.76 (d, J = 6.4 Hz, 1H), 5.67 (t, J = 5.7 Hz, 1H), 4.70 (m, 1H), 4.27–4.22 (m, 1H), 3.94 (s, 2H), 3.62 (dd, J = 5.8, 3.1 Hz, 2H), 3.53–3.48 (m, 1H). 13 13C NMR (101 MHz, DMSO) δ 156.7, 152.8, 152.1, 149.4, 143.1, 140.4, 119.8, 111.2, 108.3, 88.6, 81.0, 77.8, 62.3, 50.9, 28.8. HRMS (ESI) m / z: [M+H] + Calcd. for C 15 H 18 N5O4S: 364.1079; found 364.1081.

[0082] Example 3: Preparation of 3'-C-position modified cordycepin derivative I-2 based on epoxide synthesis

[0083] p -Methylthiophenol (18.6 g, 150 mmol) and sodium methoxide (18.5 mL, 100 mmol) were dissolved in 150 mL of MeOH, stirred at room temperature for 20 min, and the epoxide (5 g, 20 mmol) was added to this solution. The mixture was stirred at reflux temperature for about 5 h, and then left to stand. Ethanol was used for pulping to obtain the white solid compound I-2 (3.3 g, yield 45%).

[0084] 1 1H NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 8.16 (s, 1H), 7.43 (s, 2H), 7.38–7.36 (m, 2H), 7.17–7.14 (m, 2H), 6.12 (d, J = 5.9 Hz, 1H), 5.85–5.80 (m, 2H), 4.72 (m, 1H), 4.53 (m, 1H), 3.93 (t, J = 8.3 Hz, 1H), 3.79 (dd, J = 7.8, 3.5 Hz, 1H), 3.75–3.71 (m, 1H), 2.28 (s, 3H). 13CNMR(101MHz, DMSO) δ 156.7, 152.8, 149.4, 140.4, 136.3, 133.4, 130.2, 130.1, 119.8, 88.6, 80.9, 77.5, 62.5, 54.0, 21.0. HRMS(ESI) m / z: [M+H] + Calcd. for C 17 H 20 N5O3S: 374.1287; found 374.1285.

[0085] Example 4: Preparation of 3'-C-position modified cordycepin derivative I-3 based on epoxide synthesis

[0086] Dissolve 4-fluorobenzenethiol (16 mL, 150 mmol) and sodium methoxide (18.5 mL, 100 mmol) in 150 mL of MeOH, stir at room temperature for 20 min, add the epoxide (5 g, 20 mmol) to this solution, stir at reflux temperature for about 5 h, let it stand, and pulp with ethanol to obtain the white solid compound I-3 (4.3 g, yield 58%).

[0087] 1 H NMR(400MHz, DMSO) δ 8.36(s, 1H), 8.16(s, 1H), 7.57–7.53(m, 2H), 7.44(s, 2H), 7.22–7.17(m, 2H), 6.14(s, 1H), 5.91(s, 1H), 5.80(d, J = 6.5Hz, 1H), 4.76(dd, J = 8.9, 6.5Hz, 1H), 4.54(m, 1H), 3.94(t, J = 8.6Hz, 1H), 3.82–3.72(m, 2H). 13 C NMR(101MHz, DMSO) δ 162.8, 160.3, 156.8, 152.8, 149.4, 140.5, 132.6, 132.6, 132.5, 132.4, 119.9, 116.6, 116.4, 88.5, 80.8, 77.5, 62.5, 54.4. 19 F NMR(376MHz, DMSO) δ -115.89– -115.97(m). HRMS(ESI) m / z: [M+H] + Calcd. for C 16 H 17 FN5O3S: 378.1042; found 378.1036.

[0088] Example 5: Preparation of 3'-C-position modified cordycepin derivative I-4 based on epoxide synthesis

[0089] Dissolve 2-naphthalenethiol (22 g, 140 mmol) and sodium methoxide (18.5 mL, 100 mmol) in 150 mL of MeOH, stir at room temperature for 20 min, add the epoxide (5 g, 20 mmol) to this solution, stir at reflux temperature for about 5 h, let it stand and slurry with ethanol to obtain the white solid compound of formula I-4 (5.9 g, yield 72%).

[0090] 1 H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 8.17 (s, 1H), 7.99 (s, 1H), 7.92–7.82 (m, 3H), 7.61–7.42 (m, 5H), 6.19 (s, 1H), 5.88 (d, J = 7.6 Hz, 2H), 4.83 (d, J = 9.0 Hz, 1H), 4.66 (d, J = 8.1 Hz, 1H), 4.20 (t, J = 8.5 Hz, 1H), 3.81 (q, J = 12.6 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 156.8, 152.9, 149.4, 140.5, 134.7, 133.8, 131.7, 128.9, 128.1, 127.6, 127.5, 127.2, 126.7, 126.3, 119.9, 88.6, 80.8, 77.4, 62.5, 53.0. HRMS (ESI) m / z: [M+H] + Calcd. for C 20 H 20 N5O3S: 410.1288; found 410.1287.

[0091] Example 6: Preparation of cordycepin derivative I-5 modified at the 3'-C position based on epoxide synthesis

[0092] Dissolve 2-thiophenethiol (8.4 mL, 90 mmol) and sodium methoxide (11 mL, 60 mmol) in 100 mL of MeOH, stir at room temperature for 20 min, add the epoxide (3 g, 12 mmol) to this solution, stir at reflux temperature for about 5 h, let it stand and slurry with ethanol to obtain the white solid compound of formula I-5 (3.3 g, yield 74%).

[0093] 11H NMR (400 MHz, DMSO) δ 8.34 (s, 1H), 8.16 (s, 1H), 7.62 (dd, J = 5.3, 1.3 Hz, 1H), 7.43 (s, 2H), 7.22 (dd, J = 3.5, 1.3 Hz, 1H), 7.04 (dd, J = 5.4, 3.5 Hz, 1H), 6.09 (d, J = 6.0 Hz, 1H), 5.90 (dd, J = 7.8, 3.7 Hz, 1H), 5.77 (d, J = 6.2 Hz, 1H), 4.75 (m, 1H), 4.48 (m, 1H), 3.91–3.83 (m, 1H), 3.82–3.71 (m, 2H). 13 13C NMR (101 MHz, DMSO) δ 156.7, 152.8, 149.3, 140.3, 134.4, 134.2, 130.7, 128.4, 119.9, 88.6, 80.8, 77.3, 62.4, 58.3. HRMS (ESI) m / z: [M+H] + Calcd. for C 15 H 18 N5O4S: 366.0695; found 366.0699.

[0094] Biological activity test:

[0095] 1. Detection of cell viability by MTT method

[0096] (1) Seeding: Take cells in the logarithmic growth phase for subculture and counting, and seed 5×10 3 cells per well in a 96-well plate.

[0097] (2) Preparation of mother liquor: Weigh a certain amount of drug powder and dissolve it in DMSO solution to make a 100 mM stock solution. Dilute the 100 mM mother liquor according to the gradient dilution principle to prepare 1, 20, 50, 100 mM stock solutions.

[0098] (3) Adding drugs: 24 h after seeding, dilute the stock solutions to 1, 20, 50, 100, 200, 300, 500 μM working solutions with culture medium respectively, and vortex to mix evenly. Discard the old culture medium in the well plate and add the prepared drug-containing culture medium.

[0099] (4) MTT treatment: Prepare a 5 mg / mL MTT solution with 1×PBS, dispense it into 1.5 mL EP tubes and store it at -20 °C for short-term. After 72 h of drug administration, observe the cell state, add 10 μL of MTT solution to each well, and incubate it in the incubator for 1 h. Then take out the plate and discard the culture medium. It can be seen that purple formazan crystals are formed at the bottom of the plate. Then add 150 μL of DMSO to each well to dissolve, and incubate it in a 37 °C constant temperature shaker at 600 rpm for 10 min.

[0100] (5) Detection: Set the wavelength of the full-wavelength microplate reader at 570 nm, and record the absorbance of each well in an Excel table. Denote the average absorbance of the sample group as a, the average absorbance of the blank control group as b, and the absorbance of the DMSO control group as c. The cell inhibition rate = [1 - (a - b) / (c - b)] × 100%, and use Prism software to fit the IC 50 curve for plotting.

[0101] 2.3'-C Modified Cordycepin Derivatives' Inhibitory Effects on Different Tumor Cells

[0102] Test the growth inhibitory activities of 3'-C modified cordycepin derivatives on 3 metastatic CRC cells (SW620 cells, H508 cells, and T84 cells) by the MTT method. At specific concentrations, compounds such as I-1, I-2, and I-5 were selected for comparison of inhibitory activities with DMSO (100%). The experimental results are shown in Table 1. It was found that compound I-2 had good solubility and activity, and the strongest growth inhibitory activity on 3 metastatic CRC cells. Therefore, the IC 50 value of compound I-2 was determined. The results are shown in Table 2. It was found that the IC 50 value of compound I-2 in H508 cells was the lowest at 13.81 μM, and its activity was significantly stronger than that of cordycepin, indicating that the introduction of a modification group at 2'-OH or 3'-C was beneficial to the improvement of activity.

[0103] Table 1: Growth Inhibitory Activities of Cordycepin Derivatives on 3 Metastatic CRC Cells

[0104]

[0105] Table 2: Growth Inhibitory Activities of I-2 on 3 Metastatic CRC Cells

[0106]

[0107] The above-described embodiments merely represent several implementation manners of the present invention. Their descriptions are relatively specific and detailed, but they should not be construed as limitations on the scope of the present invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the present invention patent should be subject to the appended claims.

Claims

1. A 3'-C modified cordycepin derivative as shown in formula I, or a pharmaceutically acceptable salt, co-crystal complex, stereoisomer, tautomer, solvate, prodrug, or metabolite thereof; in, p is selected from 0, 1; m is selected from 1 and 2; X is selected from C, O, S; R is selected from H, C1-C3 alkyl, halogen; Indicates the absence or presence of a ring; when Indicates that there is a ring, for And X is C.

2. The 3'-C modified cordycepin derivative according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, prodrug, or metabolite thereof, characterized in that: The structural formula of the 3'-C modified cordycepin derivative is as follows: in, p is selected from 0, 1; m is selected from 1 and 2; X is selected from C, O, S; R is selected from H, C1-C3 alkyl, halogen, preferably H, methyl, F; Preferably, when X is C, m is 2; and when X is C or O, m is 1.

3. The 3'-C modified cordycepin derivative according to claim 2, or a pharmaceutically acceptable salt, co-crystal complex, stereoisomer, tautomer, solvate, metabolite or prodrug molecule thereof, characterized in that: for in, R is selected from C1-C3 alkyl, halogen, preferably methyl, F; X is selected from O and S.

4. The 3'-C modified cordycepin derivative according to claim 1, or a pharmaceutically acceptable salt, co-crystal complex, stereoisomer, tautomer, solvate, metabolite or prodrug molecule thereof, characterized in that: The structural formula of the 3'-C modified cordycepin derivative is as follows:

5. A method for preparing the 3'-C modified cordycepin derivative according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, co-crystal complex, stereoisomer, tautomer, solvate, metabolite or prodrug molecule thereof, characterized in that: The preparation method of the 3'-C modified cordycepin derivative comprises: reacting adenosine with acyl bromide in an organic solvent to obtain an epoxy intermediate under an alkaline environment, and attacking the epoxy intermediate with a nucleophilic reagent to obtain the 3'-C modified cordycepin derivative.

6. The preparation method according to claim 5, characterized in that: The acyl bromide is 2-acetoxyisobutyryl bromide, and the molar ratio of the 2-acetoxyisobutyryl bromide to adenosine is 2-6:1, preferably 3-5:1; Preferably, the base is sodium methoxide; the molar ratio of sodium methoxide to adenosine is 2-6:1, preferably 3-5:1; Preferably, the nucleophilic agent is any one or a combination of furfurylthiol, thiophenethiol, p-methylthiophenol, 4-fluorothiophenol and 2-naphthol.

7. A pharmaceutical composition, characterized in that A cordycepin derivative containing the 3'-C modified cordycepin derivative according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, co-crystal complex, stereoisomer, tautomer, solvate, metabolite or prodrug molecule thereof.

8. Use of the 3'-C modified cordycepin derivative according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, co-crystal complex, stereoisomer, tautomer, solvate, metabolite or prodrug molecule thereof, or the pharmaceutical composition according to claim 7 in the preparation of an anti-tumor drug.

9. An anti-tumor drug, characterized in that: The active ingredient comprises the 3'-C modified cordycepin derivative according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, co-crystal complex, stereoisomer, tautomer, solvate, metabolite or prodrug molecule thereof or the pharmaceutical composition according to claim 7.

10. The use according to claim 8 or the medicine according to claim 9, characterized in that: The tumor is colon cancer.

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