A fluorinated polypeptide and its preparation method and application
By introducing the aryl fluorosulfonate group into the structure of Dolastatin 10 and its analogs, a fluorine-containing polypeptide compound was designed and prepared, which solved the problem of single structure of anti-tumor drugs in the prior art, achieved effective inhibition of multiple tumor cell lines, and demonstrated good anti-tumor effects and application prospects.
Patent Information
- Application Number
- CN202410209916.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-02-26
- Publication Date
- 2025-03-21
- Estimated Expiration
- 2044-02-26
AI Technical Summary
How to introduce aryl fluorosulfonate groups into the structure of Dolastatin 10 and its analogs, develop a new compound with a completely new structure, and have good anti-tumor effects.
A fluorine-containing polypeptide is designed with a combination of a specific aryl fluorosulfonate group and a polypeptide backbone. A new compound with anti-tumor activity is prepared through specific synthetic routes and reaction conditions.
The fluorine-containing polypeptide has the activity of inhibiting proliferation on multiple tumor cell lines (such as A549, HeLa, PC-3, 22RV1), shows good anti-tumor effects, and has broad application prospects in the diagnosis and treatment of tumors.
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Figure SMS_8 
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Abstract
Description
Technical Field
[0001] The present invention relates to the field of biomedicine technology, and in particular to a fluorine-containing polypeptide and a preparation method and application thereof. Background Art
[0002] Aryl fluorosulfonates are more chemically inert than general acyl halide compounds, and they exhibit good stability to aqueous solutions, strong acids and bases, redox agents, and the biological environment. Therefore, as an emerging molecular building block, aryl fluorosulfonates have important application value in the research of medicinal chemistry and molecular pharmacology.
[0003] Dolastatin 10 is a linear pentapeptide isolated from Aplysia, and it is a very potent cytotoxic antitumor drug. With extensive research on the structure-activity relationship of Dolastatin 10, a series of new Dolastatin 10 analogs auristatins have been developed, such as MMAE, MMAF, etc. These analogs can be used as the cytotoxic part of antibody-drug conjugate (ADC) to exert anti-tumor effects.
[0004] Therefore, based on the above research background, the inventors believe that how to introduce an aromatic fluorosulfonate group into the structure of dolastatin 10 and its analogs to prepare a new compound with a completely new structure and a good anti-tumor effect is a technical problem that needs to be solved urgently by technicians in this field.
[0005] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention and should not be regarded as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art. Summary of the invention
[0006] In view of the above technical problems, the embodiments of the present invention provide a fluorine-containing polypeptide and a preparation method and application thereof to solve the problems raised in the above background technology.
[0007] A fluorine-containing polypeptide, the general structural formula of which is shown in formula (I):
[0008] ;
[0009] in:
[0010] R1 is selected from hydrogen, methoxy, cyano, nitro, C1-C 10 Alkyl, C1-C 10 Alkoxy, halogen, carboxyl, ester, aryl, substituted aryl;
[0011] R2 is selected from hydrogen, methoxy, cyano, nitro, C1-C 10 Alkyl, C1-C 10 Alkoxy, halogen, carboxyl, ester, hydroxyl, aryl, substituted aryl;
[0012] R3 is selected from hydrogen and methyl; R4 is selected from hydrogen and methyl; Ar is selected from aromatic rings.
[0013] Preferably, the structural formula is one of formula (a), (b), (c), and (d):
[0014] .
[0015] A method for preparing the fluorinated polypeptide as described above, the reaction route is as follows:
[0016] .
[0017] Preferably, the method for preparing the fluorinated polypeptide comprises the following steps:
[0018] S1: mixing the compound represented by formula (IV) with an acid, stirring at a certain temperature for a certain period of time, and separating and purifying to obtain the compound represented by formula (II);
[0019] S2: dissolving the compounds represented by formula (II) and formula (III) in an organic solvent, adding a condensing agent, an auxiliary condensing agent and a base, stirring at a certain temperature for a certain time, and separating and purifying to obtain a compound represented by formula (Ia);
[0020] S3: dissolving the compound represented by formula (Ia) in an organic solvent, adding a base, stirring at a certain temperature for a certain time, and separating and purifying to obtain the compound represented by formula (I);
[0021] Wherein, R5 is selected from 9-fluorenylmethoxycarbonyl and methyl; R6 is selected from hydrogen and methyl;
[0022] In step S2, when R5 and R6 are both methyl groups, the compound Ia prepared in step S2 has the same structure as compound I, and the reaction in step S3 is no longer performed;
[0023] In step S2, when R5 is 9-fluorenylmethoxycarbonyl, it is necessary to continue the reaction of step S3 to prepare compound I.
[0024] Preferably, in step S1, the acid is selected from one or a combination of trifluoroacetic acid, hydrogen chloride organic solution, hydrogen bromide organic solution; the reaction temperature is 0-60 degrees, preferably 20-25 degrees; the reaction time is 0.5-20 hours, preferably 1-2 hours; the separation and purification method includes one of column chromatography, recrystallization, and distillation, preferably column chromatography;
[0025] In step S2, the organic solvent is selected from one or a combination of dichloromethane, tetrahydrofuran, acetonitrile, and N,N-dimethylformamide, preferably N,N-dimethylformamide; the condensing agent is selected from one or a combination of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (hereinafter referred to as EDCI), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter referred to as HATU), and 1-propylphosphoric acid cyclic anhydride (hereinafter referred to as HATU), preferably HATU;
[0026] The auxiliary condensation agent is selected from one or a combination of N-hydroxy-7-azabenzotriazole (hereinafter referred to as HOAt) and 1-hydroxybenzotriazole (hereinafter referred to as HOBt), preferably HOAt; the base is selected from one or a combination of triethylamine (hereinafter referred to as TEA), N,N-diisopropylethylamine (hereinafter referred to as DIPEA), sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, preferably DIPEA; the reaction temperature is -20-50 degrees, preferably 0-25 degrees; the reaction time is 1-60 hours, preferably 24-48 hours; the separation and purification method includes one of column chromatography, recrystallization, and distillation, preferably column chromatography;
[0027] In step S3, the organic solvent is selected from one or a combination of dichloromethane, tetrahydrofuran, acetonitrile, and N,N-dimethylformamide, preferably acetonitrile; the base is selected from one or a combination of diethylamine, piperidine, cyclohexylamine, morpholine, concentrated ammonia, sodium carbonate, and sodium hydroxide, preferably diethylamine; the reaction temperature is -20-50 degrees, preferably 0-25 degrees; the reaction time is 0.5-60 hours, preferably 1-2 hours; the separation and purification method includes one of column chromatography, recrystallization, and distillation, preferably column chromatography.
[0028] A use of the fluorinated polypeptide as described above in tumor treatment and / or diagnosis.
[0029] Preferably, the types of tumors include melanoma, breast cancer, lung cancer, bladder cancer, cervical cancer, esophageal cancer, liver cancer, pancreatic cancer, colon cancer, and prostate cancer.
[0030] Preferably, the fluorinated polypeptide is used as the sole active ingredient in the preparation of tumor therapeutic drugs and / or diagnostic drugs; or the combination of the fluorinated polypeptide and other drugs is used as an active ingredient in the preparation of tumor therapeutic drugs and / or diagnostic drugs.
[0031] A pharmaceutical composition for treating and / or diagnosing tumors, comprising the fluorine-containing polypeptide represented by the above formula (I) or a pharmaceutically acceptable salt of the fluorine-containing polypeptide represented by the formula (I).
[0032] Preferably, a pharmaceutical composition for tumor treatment and / or diagnosis further comprises a pharmaceutically acceptable excipient.
[0033] Preferably, the dosage form of the pharmaceutical composition is an oral preparation, a pulmonary inhalation preparation, a mucosal administration preparation or an injection.
[0034] A fluorinated polypeptide and a preparation method and application thereof provided in an embodiment of the present invention have the following beneficial effects: the present invention introduces an aromatic fluorinated sulfonate group into the structure of dolastatin 10 and its analogs, and designs a fluorinated polypeptide compound with a completely new structure. The fluorinated polypeptide has the activity of inhibiting proliferation of multiple tumor cell lines such as A549, HeLa, PC-3, 22RV1, etc., and exhibits a good anti-tumor effect, and has broad application prospects in the diagnosis and treatment of tumors. DETAILED DESCRIPTION
[0035] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.
[0036] In view of the above technical problems, the embodiments of the present invention provide a fluorine-containing polypeptide and a preparation method and application thereof to solve the problems raised in the above background technology.
[0037] 1. Specific Example 1: Preparation of Compound A
[0038] 1. The reaction route is:
[0039] .
[0040] 2. The specific preparation method is as follows: 0.60 mmol of compound a1 is dissolved in 6 ml of anhydrous dichloromethane, 6 ml of trifluoroacetic acid is added, and the mixture is stirred at room temperature for 2 h. The organic solvent is removed by concentration under reduced pressure, 10 ml of dichloromethane is added to dissolve the mixture, and the mixture is concentrated under reduced pressure again. This is repeated 4 times to obtain a2. The mixture is then dissolved in 5 ml of N,N-dimethylformamide.
[0041] Compound TRP (0.50 mmol), HATU (380.2 mg, 1.00 mmol), HOAt (136.1 mg, 1.00 mmol) and DIPEA (262 μL, 1.50 mmol) were dissolved in N,N-dimethylformamide under ice-water bath conditions. Then, the N,N-dimethylformamide solution of a2 was added, and the temperature was naturally raised to room temperature and stirred for 48 h. 30 mL of ethyl acetate was added to dilute, and the mixture was washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution and saturated brine. The organic layer was dried and concentrated, and separated by preparative plate (eluent: dichloromethane: methanol = 20:1, V / V) to obtain compound a3.
[0042] 3. Structural characterization data of compound a3: 1 H NMR (400 MHz, DMSO -d6) δ 8.11 (s, 1H),7.90 (d, J = 7.6 Hz, 3H), 7.63 (d, J = 7.5 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H),7.41 (d, J = 8.3 Hz, 5H), 7.33 (q, J = 8.1, 7.5 Hz, 2H), 4.83 – 4.69 (m, 1H),4.69 – 4.56 (m, 1H), 4.56 – 4.17 (m, 6H), 4.11 (d, J = 10.8 Hz, 1H), 4.07 –3.87 (m, 1H), 3.79 (d, J = 9.1 Hz, 1H), 3.76 – 3.69 (m, 1H), 3.67 – 3.60 (m,1H), 3.60 – 3.53 (m, 1H), 3.53 – 3.44 (m, 1H), 3.44 – 3.38 (m, 1H), 3.29 (s,3H), 3.25 (s, 3H), 3.22 – 3.19 (m, 1H), 3.17 (s, 2H), 3.13 (d, J = 9.0 Hz,3H), 2.99 (s, 2H), 2.87 – 2.75 (m, 6H), 2.69 (s, 1H), 2.49 – 2.37 (m, 2H),2.35 – 2.22 (m, 1H), 2.22 – 2.12 (m, 1H), 2.12 – 1.90 (m, 3H), 1.90 – 1.69(m, 4H), 1.66 – 1.45 (m, 3H), 1.38 – 1.27 (m, 2H), 1.27 – 1.21 (m, 1H), 1.06(d, J = 6.5 Hz, 2H), 1.02 (d, J = 6.6 Hz, 2H), 0.98 – 0.67 (m, 23H). HRMScalcd for C 53 H 74 FN5O 11 S 1007.5089;Found 1008.5153 [M+H] + 。
[0043] 0.20 mmol of a3 was dissolved in 3 ml of anhydrous acetonitrile, 3 ml of diethylamine was added, and the mixture was stirred at room temperature for 2 h. The organic solvent was removed by concentration under reduced pressure, and compound a was obtained by preparative plate separation (eluent: dichloromethane: methanol = 20:1, V / V). The high-resolution mass spectrum data was: HRMS calcd for C 38 H 64 FN5O9S 785.4409; Found 786.4489 [M+H] + .
[0044] 2. Specific Example 2: Preparation of Compound B
[0045] 1. The reaction route is:
[0046] .
[0047] 2. The specific preparation method is as follows: 0.60 mmol of b1 is dissolved in 6 ml of anhydrous dichloromethane, 6 ml of trifluoroacetic acid is added, and the mixture is stirred at room temperature for 2 h. The organic solvent is removed by concentration under reduced pressure, 10 ml of dichloromethane is added to dissolve the mixture, and the mixture is concentrated under reduced pressure again. The mixture is repeated 4 times to obtain compound b2. The mixture is then dissolved in 5 ml of N,N-dimethylformamide.
[0048] Compound TRP (0.50 mmol), HATU (380.2 mg, 1.00 mmol), HOAt (136.1 mg, 1.00 mmol) and DIPEA (262 μL, 1.50 mmol) were dissolved in N, N-dimethylformamide under ice-water bath conditions. Then, the N, N-dimethylformamide solution of b2 was added, and the temperature was naturally raised to room temperature and stirred for 48 h. 30 mL of ethyl acetate was added to dilute, and the mixture was washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution and saturated brine. The organic layer was dried and concentrated, and separated by preparative plate (eluent: dichloromethane: methanol = 20:1, V / V) to obtain compound b3.
[0049] 3. Structural characterization data of compound b3: 1 H NMR (400 MHz, Chloroform- d) δ 7.80 – 7.71 (m, 3H), 7.62 – 7.49 (m, 3H), 7.43 – 7.20 (m, 10H), 5.66 – 5.55 (m, 1H), 4.79 – 4.66 (m, 1H), 4.50 – 4.39 (m, 2H), 4.30 – 4.22 (m, 1H), 4.13 – 4.08 (m, 1H), 3.84 (d, J = 7.5 Hz, 1H), 3.52 – 3.43 (m, 1H), 3.39 – 3.35 (m, 2H), 3.33(s, 3H), 3.29 (s, 3H), 2.99 (s, 3H), 2.93 – 2.88 (m, 2H), 2.80 (s, 4H), 2.48 – 2.29 (m, 3H), 2.15 – 1.92 (m, 5H), 1.44 – 1.31 (m, 1H), 1.10 – 0.95 (m, 4H), 0.95 – 0.80 (m, 13H), 0.75 – 0.64 (m, 2H), 0.56 – 0.50 (m, 1H).HRMScalcd for C 56 H 75 F6O 11 S2 1090.4919; Found 1113.4837 [M+Na] + .
[0050] Dissolve 0.20 mmol of b3 in 3 ml of anhydrous acetonitrile, add 3 ml of diethylamine, and stir at room temperature for 2 h. Concentrate under reduced pressure to remove the organic solvent, and separate on a preparative plate (eluent: dichloromethane: methanol = 20:1, V / V) to obtain compound b. Its high-resolution mass spectrum data is: HRMS calcd for C 41 H 65 FN6O9S2 868.4239; Found 869.4305 [M+H] + .
[0051] 3. Specific Example 3: Preparation of Compound C
[0052] 1. The reaction route is:
[0053] .
[0054] 2. The specific preparation method is as follows: 0.60 mmol of compound c1 is dissolved in 6 ml of anhydrous dichloromethane, 6 ml of trifluoroacetic acid is added, and the mixture is stirred at room temperature for 2 h. The organic solvent is removed by concentration under reduced pressure, 10 ml of dichloromethane is added to dissolve the mixture, and the mixture is concentrated under reduced pressure again. This is repeated 4 times to obtain c2. The mixture is then dissolved in 5 ml of N,N-dimethylformamide.
[0055] Compounds TRP (0.50 mmol), HATU (380.2 mg, 1.00 mmol), HOAt (136.1 mg, 1.00 mmol) and DIPEA (262 μL, 1.50 mmol) were dissolved in 5 ml N, N-dimethylformamide under ice-water bath conditions. Then, the N, N-dimethylformamide solution of c2 was added, and the temperature was naturally raised to room temperature and stirred for 48 h. 100 mL of ethyl acetate was added to dilute, and the mixture was washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution, and saturated brine. The organic layer was dried and concentrated, and separated by preparative plate (eluent was dichloromethane: methanol = 20:1, V / V) to obtain compound c3.
[0056] 3. The structural characterization data of compound C3 are: 1 H NMR (400 MHz, Chloroform- d) δ 8.00 (s, 1H), 7.77 (d, J = 7.8 Hz, 2H), 7.65 – 7.47 (m, 4H), 7.40 (t, J = 7.8 Hz, 2H), 7.31 (d, J = 7.8 Hz, 4H), 6.73 (s, 1H), 6.64 (s, 1H), 5.04 (d, J = 18.7 Hz, 1H), 4.80 – 4.63 (m, 2H), 4.43 (t, J = 9.0 Hz, 2H), 4.34 – 3.96 (m, 5H), 3.82 (d, J = 8.4 Hz, 1H), 3.53 (s, 1H), 3.47 (s, 5H), 3.41 (s, 4H), 3.32 (s, 4H), 3.08 (s, 1H), 3.02 (s, 2H), 2.96 (s, 3H), 2.90 (s, 2H), 2.88 (s, 3H), 2.85 –2.78 (m, 2H), 2.54 – 2.42 (m, 1H), 2.42 – 2.31 (m, 2H), 2.31 – 2.17 (m, 2H), 2.17 – 1.56 (m, 13H), 1.35 (s, 2H), 1.27 (s, 5H), 1.18 – 1.05 (m, 1H), 1.05 – 0.93 (m, 7H), 0.93 – 0.75 (m, 13H), 0.71 (d, J = 6.7 Hz, 1H), 0.66 (s, 1H), 0.53 (s, 1H).HRMS calcd for C 54 H 76 F5O 12 S 1037.5195; Found 1060.5078[M+Na] + .
[0057] 0.20 mmol of compound c3 was dissolved in 3 ml of anhydrous acetonitrile, 3 ml of diethylamine was added, and the mixture was stirred at room temperature for 2 h. The organic solvent was removed by concentration under reduced pressure, and compound c was obtained by preparative plate separation (eluent: dichloromethane: methanol = 20:1, V / V). The high-resolution mass spectrum data is: HRMS calcd for C 39 H 66 F5O 10 S 815.4514; Found 816.4584 [M+H] + .
[0058] IV. Specific Example 4: Preparation of Compound d
[0059] 1. The reaction route is:
[0060] .
[0061] 2. The specific preparation method is as follows: 0.60 mmol of compound d3 is dissolved in 6 ml of anhydrous dichloromethane, 6 ml of trifluoroacetic acid is added, and the mixture is stirred at room temperature for 2 h. The organic solvent is removed by concentration under reduced pressure, 10 ml of dichloromethane is added to dissolve the mixture, and the mixture is concentrated under reduced pressure again. The mixture is repeated 4 times to obtain compound d2. The mixture is then dissolved in 5 ml of N,N-dimethylformamide.
[0062] TRP (0.50 mmol), HATU (380.2 mg, 1.00 mmol), HOAt (136.1 mg, 1.00 mmol) and DIPEA (262 μL, 1.50 mmol) were dissolved in N,N-dimethylformamide under ice-water bath conditions. Then, the N,N-dimethylformamide solution of d2 was added, and the temperature was naturally raised to room temperature and stirred for 48 h. 30 mL of ethyl acetate was added to dilute, and the mixture was washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution, and saturated brine. The organic layer was dried and concentrated, and separated by preparative plate (eluent: dichloromethane: methanol = 20:1, V / V) to obtain compound d3.
[0063] 3. The structural characterization data of compound d3 are: 1 H NMR (400 MHz, DMSO -d6) δ 8.55 (d, J = 8.3Hz, 1H), 7.97 – 7.86 (m, 4H), 7.62 (d, J = 7.5 Hz, 2H), 7.43 (d, J = 16.6 Hz, 7H), 7.31 (t, J = 7.5 Hz, 2H), 4.81 – 4.49 (m, 3H), 4.49 – 4.17 (m, 5H), 4.14 – 3.86 (m, 2H), 3.65 (d, J = 5.7 Hz, 3H), 3.46 – 3.41 (m, 1H), 3.28 – 3.19 (m, 4H), 3.19 – 3.13 (m, 5H), 3.10 – 3.04 (m, 2H), 2.99 – 2.89 (m, 4H), 2.89 (s, 3H), 2.80 (t, J = 6.4 Hz, 4H), 2.75 – 2.66 (m, 11H), 2.40 – 2.32 (m, 1H), 2.07 – 2.02 (m, 1H), 1.80 – 1.76 (m, 1H), 1.35 – 1.20 (m, 4H), 1.10 – 0.99 (m, 4H), 0.90 – 0.84 (m, 7H), 0.84 – 0.76 (m, 9H), 0.76 – 0.69 (m, 5H). HRMScalcd for C 55 H 76 F5O 13 S 1065.5144; Found 1088.5032 [M+Na] + .
[0064] 0.20 mmol of d3 was dissolved in 3 ml of anhydrous acetonitrile, 3 ml of diethylamine was added, and the mixture was stirred at room temperature for 2 h. The organic solvent was removed by concentration under reduced pressure, and compound d was obtained by preparative plate separation (eluent: dichloromethane: methanol = 20:1, V / V). The high-resolution mass spectrum data was: HRMS calcd for C 40 H 66 F5O 11 S 843.4464; Found 844.4531 [M+H] + .
[0065] V. Specific Example 5: Antitumor Activity Test
[0066] All cancer cell lines were purchased from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). Human prostate cancer cell lines PC-3 and 22RV1 were cultured in Ham's F-12 nutrition Mix medium (11765054, Gibco, USA). Human lung cancer cell line A549 was cultured in PRMI 1640 medium (VivaCell, Israel, C3010-0500). Human cervical cancer cell line HeLa was cultured in DMEM medium (VivaCell, Israel, C3110-0500). Cells were placed in the corresponding culture medium containing 10% FBS (fetal bovine serum, BI, Israel, 04-001-1ACS) and cultured in a cell culture incubator at 37°C and 5% CO2. Cells were cultured at 3-5 × 10 3 The cells were inoculated into 96-well plates at a concentration of 100 μg / well. After 12 h of adhesion, they were treated with fresh medium containing a series of gradient concentrations of the compound for 72 h, then treated with 0.05 mg / mL MTT for 4 h, and then dissolved with 150 μL DMSO. The absorbance of the solution was measured spectrophotometrically at 490 and 570 nm. The IC values of the test compounds were calculated using a four-parameter logistic regression model using GraphPad Prism software. 50 The IC values of each compound 50 The values are shown in Table 1.
[0067] Table 1 IC of each compound 50 value
[0068]
[0069] From the data analysis in Table 1, it can be seen that compounds a, b, c, and d have good anti-tumor activity against multiple tumor cell lines such as A549, HeLa, PC-3, and 22RV1. Compared with Dolastatin 10, the IC values of compounds a, b, c, and d are 50 The value was lower, showing better anti-tumor activity than Dolastatin 10.
[0070] The embodiments described above are only descriptions of the preferred implementation modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should fall within the protection scope determined by the claims of the present invention.
Claims
1. A fluorinated polypeptide, characterized in that: The structural formula is shown in one of formulas (a), (b), (c), and (d): 。 2. A method for preparing a fluorinated polypeptide as claimed in claim 1, characterized in that: The reaction route is as follows: ； Wherein, when the structural formula of formula (I) is formula (a), R1 is selected from hydrogen; R2 is selected from hydrogen; R3 is selected from hydrogen; R4 is selected from methyl; R5 is selected from 9-fluorenylmethoxycarbonyl; R6 is selected from hydrogen; When the structural formula of formula (I) is formula (b), R1 is selected from 2-thiazolyl; R2 is selected from hydrogen; R3 is selected from hydrogen; R4 is selected from methyl; R5 is selected from 9-fluorenylmethoxycarbonyl; R6 is selected from hydrogen; When the structural formula of formula (I) is formula (c), R1 is selected from methyl; R2 is selected from hydroxyl; R3 is selected from hydrogen; R4 is selected from methyl; R5 is selected from 9-fluorenylmethoxycarbonyl; R6 is selected from hydrogen; When the structural formula of formula (I) is formula (d), R1 is selected from methyl ester group; R2 is selected from hydrogen; R3 is selected from hydrogen; R4 is selected from methyl group; R5 is selected from 9-fluorenylmethoxycarbonyl group; and R6 is selected from hydrogen.
3. The method for preparing a fluorinated polypeptide according to claim 2, characterized in that: The preparation method of the fluorinated polypeptide comprises the following steps: S1: mixing the compound represented by formula (IV) with an acid, stirring at a certain temperature for a certain period of time, and separating and purifying to obtain the compound represented by formula (II); S2: dissolving the compounds represented by formula (II) and formula (III) in an organic solvent, adding a condensing agent, an auxiliary condensing agent and a base, stirring at a certain temperature for a certain time, and separating and purifying to obtain a compound represented by formula (Ia); S3: dissolving the compound represented by formula (Ia) in an organic solvent, adding a base, stirring at a certain temperature for a certain time, and separating and purifying to obtain the compound represented by formula (I).
4. The method for preparing a fluorinated polypeptide according to claim 3, characterized in that: In step S1, the acid is selected from one or a combination of trifluoroacetic acid, hydrogen chloride organic solution, hydrogen bromide organic solution; the reaction temperature is 0-60 degrees; the reaction time is 0.5-20 hours; the separation and purification method includes one of column chromatography, recrystallization, and distillation; In step S2, the organic solvent is selected from one or more combinations of dichloromethane, tetrahydrofuran, acetonitrile, and N,N-dimethylformamide; the condensing agent is selected from one or more combinations of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and 1-propylphosphoric acid cyclic anhydride; the auxiliary condensing agent is selected from one or more combinations of N-hydroxy-7-azabenzotriazole and 1-hydroxybenzotriazole; the base is selected from one or more combinations of triethylamine, N,N-diisopropylethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate; the reaction temperature is -20-50 degrees; the reaction time is 1-60 hours; the separation and purification method includes one of column chromatography, recrystallization, and distillation; In step S3, the organic solvent is selected from one or a combination of dichloromethane, tetrahydrofuran, acetonitrile, and N,N-dimethylformamide; the base is selected from one or a combination of diethylamine, piperidine, cyclohexylamine, morpholine, concentrated ammonia, sodium carbonate, and sodium hydroxide; the reaction temperature is -20-50 degrees; the reaction time is 0.5-60 hours; and the separation and purification method includes one of column chromatography, recrystallization, and distillation.
5. Use of a fluorinated polypeptide as claimed in any one of claims 1 to 4 in the preparation of a drug for treating and / or diagnosing tumors; characterized in that: The tumor is one of lung cancer, cervical cancer and prostate cancer.
6. Use of the fluorinated polypeptide according to claim 5 in the preparation of tumor treatment and / or diagnosis drugs, characterized in that: The invention relates to the use of fluorinated polypeptides as active ingredients in the preparation of tumor therapeutic drugs and / or diagnostic drugs.
7. A pharmaceutical composition for tumor treatment and / or diagnosis, characterized in that: The pharmaceutical composition comprises the fluorine-containing polypeptide represented by formula (I) as claimed in any one of claims 1 to 4 or a pharmaceutically acceptable salt of the fluorine-containing polypeptide represented by formula (I).
8. The pharmaceutical composition for tumor treatment and / or diagnosis according to claim 7, characterized in that: The dosage form of the pharmaceutical composition is oral preparation, pulmonary inhalation preparation, mucosal administration preparation or injection.