Carborane amino acid / oligopeptide derivative as well as preparation method and application thereof

Abstract

The invention provides a strategy of a carborane electron donor-acceptor (EDA) compound, cross coupling of nested carborane and amino acid or oligopeptide is induced through near-infrared light, then a product is further modified, and a novel boron carrying agent with a fluorescence imaging tracing function is successfully designed and synthesized. The invention not only develops a new method for inducing nested carborane functionalization by near-infrared light and expands the chemical synthesis strategy of boron clusters, but also opens up a new way for developing novel drug molecules and cell dyes based on carborane.

Description

Technical Field

[0001] The present invention belongs to the field of chemical synthesis, and particularly relates to a carborane amino acid / oligopeptide derivative, a preparation method thereof, and an application thereof. Background Art

[0002] Carboranes are a special class of compounds, which have advantages such as chemical stability, thermal stability, and low toxicity, and are widely used in many fields, such as the material field, the energy field, the organic catalysis field, the medical field (boron neutron capture therapy), etc.

[0003] Carboranes are polyhedral boron clusters with three-dimensional aromaticity, and can be regarded as boron-based bioisosteres of benzene rings, thus being widely concerned in medicinal chemistry. Among them, ortho-carborane has been applied to drug development, such as purine inhibitors containing carborane. However, most of the currently reported carborane drug molecules involve substitution reactions at the carbon terminus. Due to the inertness of the B-H bond and the complex chemical environment, directly selectively activating the B-H bond has always been a long-standing challenge. Traditional methods for functionalizing the B-H bond of carboranes usually require the use of metal catalysts, high-temperature conditions, and toxic oxidants. These extreme conditions lead to poor compatibility with bioactive molecules, especially when functionalizing at the B-H site to synthesize carborane-based drug molecules (such as amino acids / oligopeptides). Therefore, it is of great significance to develop a new mild, simple, and effective method and strategy for carborane functionalization.

[0004] Amino acids are crucial for the rapid proliferation of cancer cells, and cancer cells have a much higher demand for specific amino acids than normal cells. The team of Zhibo Liu from the College of Chemistry and Molecular Engineering of Peking University designed and synthesized a brand-new small molecule drug BBPA (Trifluoroborate boronophenylalanine) for positron imaging and BNCT of tumors. BBPA realizes the integration of diagnostic and therapeutic functions through different isotopes of the same element ( 18 F- 19 F and 10 B- 11 B) without changing the chemical structure, ensuring the consistency of the pharmacokinetics of the diagnostic and therapeutic functional drugs, and realizing the organic integration of diagnosis and treatment.

[0005] Charushin et al. disclosed the synthesis of carborane amino acids by pre-functionalizing the carbon terminus of carboranes (Coord. Chem. Rev. 2021, 433, 213753). This literature reported that butyllithium was used to synthesize amino or carboxyl groups at the carbon terminus of carboranes under anhydrous and anaerobic conditions, and then condensed with amino acids. However, it has the following deficiencies: (1) The synthesis steps are lengthy; (2) The operation is complex; (3) The reaction conditions are harsh; (4) The atom economy is low. SUMMARY OF THE INVENTION

[0006] In view of the deficiencies of the prior art, the present invention proposes a strategy using carboranyl electron donor-acceptor (EDA) complexes to achieve near-infrared light-induced cross-coupling of closo-carboranes with amino acids / oligopeptides. By further modifying the products, a new type of boron carrier with imaging and tracing functions was successfully designed and synthesized. The present invention not only develops a new method for near-infrared light-induced functionalization of closo-carboranes, expands the synthetic strategies of boron cluster chemistry, but also opens up a new way for the development of new drug molecules and cell dyes based on carboranes.

[0007] The specific technical solution of the present invention is as follows:

[0008] A carborane amino acid / oligopeptide derivative has the following structure:

[0009]

[0010] Wherein, R represents hydrogen, an alkyl group of C1-C6, a cycloalkyl group of C3-C6, a silicon group substituted by one or more of a kind or several of C1-C5 alkyl groups, or a phenyl group substituted by one or more of hydrogen, an alkyl group of C1-C6, a hydroxyl group, fluorine, chlorine, bromine, and iodine;

[0011] R 1 represents hydrogen, an alkyl group of C1-C6, a cycloalkyl group of C3-C6, an alkylamino group of C1-C6, or a phenyl group substituted by one or more of hydrogen, an alkyl group of C1-C6, a hydroxyl group, fluorine, chlorine, bromine, and iodine;

[0012] R 2 represents hydrogen, an alkyl group of C1-C6, a phenyl group or a benzyl group substituted by one or more of hydrogen, an alkyl group of C1-C6, a hydroxyl group, fluorine, chlorine, bromine, and iodine;

[0013] R 3 represents hydrogen, a hydroxyl group, an alkyl group of C1-C6, a cycloalkyl group of C3-C6, an alkenyl group of C3-C6, an ester group of C3-C6, a phenyl group or an indolyl group substituted by one or more of hydrogen, an alkyl group of C1-C6, a hydroxyl group, fluorine, chlorine, bromine, and iodine.

[0014] Preferably, for the carborane amino acid / oligopeptide derivative, R represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, a silicon group substituted by one or more of a kind or several of methyl, ethyl, n-propyl or isopropyl, or a phenyl group substituted by one or more of hydrogen, methyl, ethyl, tert-butyl, fluorine, chlorine, bromine, and iodine;

[0015] R 1represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropane, cyclopentane, cyclohexane, C3-C6 amino groups such as methylamino, ethylamino, propylamino, butylamino, phenyl substituted by one or more of hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, hydroxyl, fluorine, chlorine, bromine, iodine;

[0016] R 2 represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, phenyl or benzyl substituted by one or more of hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, hydroxyl, fluorine, chlorine, bromine, iodine;

[0017] R 3 represents hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, C3-C6 alkenyl, C3-C6 ester group, phenyl or indolyl substituted by one or more of hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, hydroxyl, fluorine, chlorine, bromine, iodine.

[0018] A specific example of the present invention, the carborane amino acid / oligopeptide derivative has the following structure:

[0019]

[0020] R 2 represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, phenyl or benzyl substituted by one or more of hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, hydroxyl, fluorine, chlorine, bromine, iodine;

[0021] R 3 represents phenyl substituted by one or more of hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, hydroxyl, fluorine, chlorine, bromine, iodine.

[0022] Another object of the present invention is to provide a preparation method of the carborane amino acid / polypeptide derivative.

[0023] In an air atmosphere, under the irradiation of 700-730 nm near-infrared light, a carbon-substituted or unsubstituted closo-carborane, an amino acid or oligopeptide with a protected carboxyl terminus, an additive, a photocatalyst and a polar solvent are added to a reaction vessel to obtain a carborane amino acid derivative, and the carbon-substituted or unsubstituted closo-carborane has the following structure: The carboxyl-terminal protected amino acid or oligopeptide has the following structure:

[0024] R represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, a silicon group substituted by one or more of C1-C5 alkyl, or a phenyl group substituted by one or more of hydrogen, C1-C6 alkyl, hydroxy, fluoro, chloro, bromo, iodo;

[0025] R 1 represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylamino, or a phenyl group substituted by one or more of hydrogen, C1-C6 alkyl, hydroxy, fluoro, chloro, bromo, iodo;

[0026] R 2 represents C1-C6 alkyl, a phenyl group substituted by one or more of hydrogen, C1-C6 alkyl, hydroxy, fluoro, chloro, bromo, iodo, or benzyl;

[0027] R 3 represents hydrogen, hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 ester group, a phenyl group substituted by one or more of hydrogen, C1-C6 alkyl, hydroxy, fluoro, chloro, bromo, iodo, or indolyl.

[0028] Preferably, the additive is selected from one or more of carbonate, fluoride, hexafluorophosphate. For example, sodium bicarbonate, ammonium fluoride, ammonium hexafluorophosphate, etc.

[0029] Preferably, the photocatalyst is selected from one or more of pyridine-based photocatalysts, phenothiazine-based photocatalysts, or acridine-based photocatalysts. For example, N-methyl-4-cyclobutylaminopyridine tetrafluoroborate, N-methyl-4-phenylpyridine tetrafluoroborate, N-methyl-8-phenylacridine tetrafluoroborate, methylene blue, etc.

[0030] Preferably, the solvent is selected from one or more of methanol, ethanol, hexafluoroisopropanol, dimethyl sulfoxide, N,N-dimethylformamide, acetone, acetonitrile, ethyl acetate, diethyl ether, dichloromethane, chloroform.

[0031] In a specific example, the solvent is a mixed solvent of dichloromethane:acetonitrile = 1:1 (V / V).

[0032] In a preferred preparation method of the present invention, the near-infrared light wavelength is 700 - 705 nm, the irradiation power is 1 W - 30 W, the reaction time is 1 - 48 hours, preferably 12 - 24 hours, and the reaction temperature is 0 - 40 °C, more preferably carried out at room temperature and in an air atmosphere.

[0033] The method of the present invention further includes a hydrolysis step to remove the protecting group at the carboxyl terminus to obtain a 2 carbaborane amino acid derivative in which R represents H.

[0034] The reaction general formula is as follows:

[0035]

[0036] Another object of the present invention is to provide the application of the carborane amino acid / oligopeptide derivative in the preparation of a precursor for a tumor fluorescence imaging reagent. Specifically, the carboxyl group in the structure of the carborane amino acid / oligopeptide derivative or the carboxyl group in the hydrolysis product structure thereof is used to react and couple with a fluorescent molecule containing an amino group, so as to obtain a fluorescent molecule modified with the carborane amino acid / oligopeptide derivative of the present invention.

[0037] Advantages of the present invention:

[0038] 1. The present invention realizes the functionalization of the B-H site of carborane using amino acids / oligopeptides by a one-step method for the first time. In the prior art, it is usually necessary to first introduce an amino group or a carboxyl group at the carbon end of carborane, and then carry out a condensation reaction with an amino acid. However, this method has the following disadvantages: complex operation, severe reaction conditions, long reaction steps, harsh reaction conditions, and poor compatibility with bioactive molecules. In view of the deficiencies of the prior art, the present invention proposes a new functionalization method. This method utilizes the direct coupling of carborane and amino acids / oligopeptides induced by near-infrared light, and has the following remarkable advantages: (1) Simple operation: It is not necessary to pre-complex chemically modify carborane, and directly realize the functionalization of the B-H site; (2) Mild reaction conditions: It does not require high temperature, high pressure or strong oxidants, avoiding the destruction of bioactive molecules; (3) High reaction efficiency and yield: Through near-infrared light induction, the reaction rate and product yield are significantly improved; (4) Energy consumption saving: Compared with the traditional method, the present invention does not require high temperature conditions, reducing energy consumption; (5) Wide substrate scope: It is applicable to a variety of amino acids and oligopeptides, and can realize the expansion of a large number of different substrates, and these reactions are difficult to achieve through the reported technologies.

[0039] 2. By utilizing the characteristics of amino acids having both carboxyl and amino amphoteric functional groups, the carboxyl group of the carborane amino acid derivative prepared by the present invention (or the carboxyl group of the hydrolysis product) can be used as an active functional group to couple with an active molecule with an amino group such as a fluorescent dye, and the obtained product has the dual functions of both carborane and the active molecule.

[0040] 3. The research results of the present invention show that the carborane amino acid derivative of the present invention exhibits excellent AIE properties after being coupled with a fluorescent molecule. The fluorescence imaging results in 4T1 cells show that the luminescence intensity of the carborane amino acid derivative 3-41 in cells shows a time-dependent increase, with good cell imaging effects. While the luminescence intensity of compound 6b in cells does not change with time. Since carborane itself does not have the ability to trace, it is difficult to judge its enrichment, distribution, etc. in the organism during the research. The further modification after amino acid functionalization in the present invention helps to realize the tracing situation in cells. Description of the Drawings

[0041] Figure 1 1H NMR (Acetone-d6) spectrum of the carborane amino acid derivative 3-35 of the present invention 1

[0042] Figure 2 13C NMR (Acetone-d6) spectrum of the carborane amino acid derivative 3-35 of the present invention 13

[0043] Figure 3 11B{1H} NMR (Acetone-d6) spectrum of the carborane amino acid derivative 3-35 of the present invention 11

[0044] Figure 4 11B NMR (Acetone-d6) spectrum of the carborane amino acid derivative 3-35 of the present invention 11

[0045] Figure 5 Cytotoxicity test results of the carborane amino acid derivative 3-13 of the present invention

[0046] Figure 6 Cytotoxicity test results of the carborane amino acid derivatives 4-5, 4-11, 3-14 and 3-15 of the present invention

[0047] Figure 7 Cell boron content uptake test results of the carborane amino acid derivatives 4-5, 4-11, 3-14 and 3-15 of the present invention

[0048] Figure 8 Cytotoxicity test results of neutron irradiation on cells at the cell level of the carborane amino acid derivatives 4-5, 4-11, 3-14 and 3-15 of the present invention

[0049] Figure 9 Spectra of the carborane amino acid derivative 3-41 of the present invention. a is the ultraviolet absorption spectrum of compounds 3-41 and 6b in methanol solution, b is the solid fluorescence emission spectrum of compounds 3-41 and 6b, and c is the fluorescence emission spectrum of compound 3-41 in 1-99% methanol-ether solution

[0050] Figure 10 Cell imaging test results of the carborane amino acid derivative 3-41 of the present invention Detailed Description of the Invention

[0051] ​​​​The present invention will be described in detail below in conjunction with specific embodiments and exemplary embodiments. However, these descriptions should not be construed as any limitation to the present invention.

[0052] Those skilled in the art understand that without departing from the spirit and scope of the present invention, various equivalent substitutions, modifications or improvements can be made to the technical solutions and their implementation manners of the present invention, such as adjusting reaction conditions, selecting different substrates or using other similar additives, etc. These all fall within the scope of the present invention.

[0053] Example 1 Preparation of carborane amino acid derivative 3-1

[0054] Referring to the conditions in Table 1, the effects of different conditions on the preparation of carborane amino acid / oligopeptide derivatives were investigated. Under an air atmosphere, irradiated with 12 W near-infrared light, bisphenylnido-carborane (0.1 mmol), alanine methyl ester hydrochloride (0.2 mmol), ammonium hexafluorophosphate (0.1 mmol), methylene blue (PC4-Cl) (5 mol%), and acetonitrile / dichloromethane (1 mL / 1 mL) were successively added to the reaction tube. After stirring at room temperature for 24 hours, the reaction mixture was treated by thin-layer chromatography to obtain compound 3-1.

[0055]

[0056] Referring to the above method, the reaction conditions were changed to investigate the effects of different conditions on the preparation, as shown in Table 1 below.

[0057] Table 1

[0058] Wavelength Additive Catalyst Reaction solvent (V / V, mL) Yield 1 700 - 705 nm Ammonium hexafluorophosphate PC4-Cl Acetonitrile / dichloromethane, 1:1 82％ 2 700 - 705 nm Sodium bicarbonate PC4-Cl Acetonitrile / dichloromethane, 1:1 30％ 3 700 - 705 nm Ammonium fluoride PC4-Cl Acetonitrile / dichloromethane, 1:1 40％ 4 700 - 705 nm Ammonium hexafluorophosphate PC4-Cl Acetonitrile 50％ 5 700 - 705 nm Ammonium hexafluorophosphate PC4-Cl Ethylene glycol dimethyl ether 20％ 6 700 - 705 nm Ammonium hexafluorophosphate PC4-Cl Tetrahydrofuran 10％ 7 700 - 705 nm Ammonium hexafluorophosphate <![CDATA[PC1-BF4]]> Acetonitrile / dichloromethane, 1:1 0％ 8 700 - 705 nm Ammonium hexafluorophosphate <![CDATA[PC2-BF4]]> Acetonitrile / dichloromethane, 1:1 0％ 9 700 - 705 nm Ammonium hexafluorophosphate <![CDATA[PC3-BF4]]> Acetonitrile / dichloromethane, 1:1 0％ 10 710 - 730 nm Ammonium hexafluorophosphate PC4-Cl Acetonitrile / dichloromethane, 1:1 10％

[0059]

[0060] According to the results in Table 1, it can be seen that the effect of using ammonium hexafluorophosphate as an additive is better than that of sodium bicarbonate or ammonium fluoride. When using solvents such as acetonitrile, tetrahydrofuran, and ethylene glycol dimethyl ether, the yield differences are relatively large, and the effect of acetonitrile / dichloromethane, 1:1 (V / V) is the best. The reaction does not occur when using PC1-BF4, PC2-BF4, and PC3-BF4. And when increasing the wavelength of the near-infrared light, the yield will also decrease.

[0061] Referring to Condition 1 in Table 1, different C-position substituted or unsubstituted nido-carboranes and amino acids or oligopeptides with protected carboxyl ends were selected as reaction raw materials to synthesize a series of carborane amino acid / oligopeptide derivatives, as shown below.

[0062]

[0063]

[0064] The structural identification results of the above-mentioned partial compounds (identified by a 400 MHz nuclear magnetic resonance spectrometer) are as follows:

[0065]

[0066] 3-1: Yield 82%. White solid. HRMS m / z calcd for C 18 H 27 B9NO2[M-H] - : 388.2879. Found: 388.2881.

[0067] NMR Data of product 3-1:

[0068] 1 1H NMR (400 MHz, Acetone-d6) Isomer I: Isomer II = 1:1, Isomer I: δ 7.28 - 7.22 (m, 2H), 7.21 - 7.15 (m, 2H), 7.07 - 6.85 (m, 6H), 6.76 (br, 1H, -NH2), 6.17 (br, 1H, -NH2), 4.20 - 4.12 (m, 1H), 3.80 (s, 3H), 1.58 (d, J = 7.2 Hz, 3H), -2.10 (br, 1H, B-H-B). Isomer II: δ 7.28 - 7.22 (m, 2H), 7.21 - 7.15 (m, 2H), 7.07 - 6.85 (m, 6H), 6.76 (br, 1H, -NH2), 6.17 (br, 1H, -NH2), 4.00 - 3.91 (m, 1H), 3.68 (s, 3H), 1.55 (d, J = 7.2 Hz, 3H), -2.10 (br, 1H, B-H-B).

[0069] 13 13C NMR (101 MHz, Acetone-d6) Isomer I: δ 172.37, 139.92, 137.44, 137.34, 133.00, 132.23, 128.60, 127.76, 126.88, 56.97, 53.60, 16.65. Isomer II: δ 172.00, 139.92, 137.44, 137.34, 133.00, 132.23, 128.60, 127.76, 126.88, 56.97, 53.40, 16.98.

[0070] 11 B{ 11H NMR (128 MHz, Acetone-d6) δ 0.2 (1B), -6.5 (1B), -12.9 (1B), -15.4 (2B), -21.6 (1B), -26.1 (1B), -32.1 (1B), -37.0 (1B).

[0071]

[0072] 3-2: Yield 79%. White solid. HRMS m / z calcd for C 19 H 29 B9NO2 [M-H] - : 402.3036, Found: 402.3036.

[0073] NMR Data of product 3-2:

[0074] 1 1H NMR (400 MHz, Acetone-d6) Isomer I:Isomer II = 1:1, Isomer I: δ 7.27 - 7.22 (m, 2H), 7.21 - 7.14 (m, 2H), 7.09 - 6.96 (m, 3H), 6.99 - 6.86 (m, 3H), 6.57 (br, 1H, -NH2), 5.77 (br, 1H, -NH2), 4.09 - 3.98 (m, 1H), 3.83 (s, 3H), 1.98 - 1.86 (m, 1H), 1.84 - 1.74 (m, 1H), 0.91 (t, J = 7.5 Hz, 3H), -2.14 (br, 1H, B-H-B). Isomer II: δ 7.27 - 7.22 (m, 2H), 7.21 - 7.14 (m, 2H), 7.09 - 6.96 (m, 3H), 6.99 - 6.86 (m, 3H), 6.21 (br, 1H, -NH2), 5.77 (br, 1H, -NH2), 3.81 - 3.77 (m, 1H), 3.73 (s, 3H), 1.98 - 1.86 (m, 1H), 1.84 - 1.74 (m, 1H), 0.82 (t, J = 7.5 Hz, 3H), -2.14 (br, 1H, B-H-B).

[0075] 1313C NMR (101 MHz, Acetone-d6) Isomer I: δ 171.60, 139.87, 137.50, 133.01, 132.32, 128.72, 127.85, 127.80, 126.93, 62.53, 53.47, 25.28, 9.63. Isomer II: δ 171.30, 139.87, 137.31, 133.01, 132.32, 128.56, 127.85, 127.77, 126.90, 63.13, 53.29, 25.63, 9.80.

[0076] 11 B{ 1 11B{1H} NMR (101 MHz, Acetone-d6) δ 0.3 (1B), -6.3 (1B), -12.8 (1B), -15.5 (2B), -21.8 (1B), -26.1 (1B), -32.0 (1B), -36.9 (1B).

[0077]

[0078] 3-3: Yield 77%. White solid. HRMS m / z calcd for C 20 H 31 11B9NO2 [M-H] - : 416.3192, Found: 416.3192.

[0079] NMR Data of product 3-3:

[0080] 11H NMR (400 MHz, Acetone-d6) Isomer I:Isomer II = 1:1, Isomer I: δ 7.28 - 7.19 (m, 2H), 7.22 - 7.13 (m, 2H), 7.09 - 6.98 (m, 2H), 7.01 - 6.85 (m, 4H), 6.52 (br, 1H, -NH2), 6.27 (br, 1H, -NH2), 4.12 - 4.04 (m, 1H), 3.82 (s, 3H), 1.98 - 1.82 (m, 2H), 1.47 - 1.27 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H), -2.21 (br, 1H, B-H-B). Isomer II: δ 7.28 - 7.19 (m, 2H), 7.22 - 7.13 (m, 2H), 7.09 - 6.98 (m, 2H), 7.01 - 6.85 (m, 4H), 6.52 (br, 1H, -NH2), 6.27 (br, 1H, -NH2), 3.85 - 3.83 (m, 1H), 3.72 (s, 3H), 1.82 - 1.62 (m, 2H), 1.26 - 1.09 (m, 2H), 0.79 (t, J = 7.3 Hz, 3H), -2.21 (br, 1H, B-H-B).

[0081] 13 13C NMR (101 MHz, Acetone-d6) Isomer I: δ 171.68, 139.89, 137.45, 132.98, 132.30, 128.71, 127.85, 127.78, 126.91, 61.28, 53.48, 33.99, 18.98, 13.69. Isomer II: δ 171.38, 139.82, 137.28, 132.98, 132.30, 128.53, 127.85, 127.74, 126.87, 61.28, 53.29, 34.34, 19.09, 13.77.

[0082] 11 11B{ 1 1H} NMR (128 MHz, Acetone-d6) δ 0.3 (1B), -6.4 (1B), -12.9 (1B), -15.5 (2B), -21.7 (1B), -26.1 (1B), -31.9 (1B), -36.9 (1B).

[0083]

[0084] 3 - 4: Yield 67%. White solid. HRMS m / z calcd for C20 H 31 B9NO2[M-H] - : 416.3192. Found: 416.3193。

[0085] NMR Data of product 3-4:

[0086] 1 1H NMR (400 MHz, Acetone-d6) Isomer I:Isomer II = 1:1, Isomer I: δ 7.32 - 7.23 (m, 2H), 7.23 - 7.16 (m, 2H), 7.13 - 6.97 (m, 3H), 6.96 - 6.86 (m, 3H), 6.42 (br, 1H, -NH2), 6.21 (br, 1H, -NH2), 4.18 - 4.10 (m, 1H), 3.84 (s, 3H), 2.26 - 2.13 (m, 1H), 0.98 (d, J = 6.9 Hz, 3H), 0.78 (d, J = 7.0 Hz, 3H), -2.19 (br, 1H, B-H-B). Isomer II: δ 7.32 - 7.23 (m, 2H), 7.23 - 7.16 (m, 2H), 7.13 - 6.97 (m, 3H), 6.96 - 6.86 (m, 3H), 6.42 (br, 1H, -NH2), 6.21 (br, 1H, -NH2), 3.77 (s, 3H), 3.56 - 3.52 (m, 1H), 2.26 - 2.13 (m, 1H), 0.87 (d, J = 6.9 Hz, 3H), 0.72 (d, J = 6.9 Hz, 3H), -2.19 (br, 1H, B-H-B1。

[0087] 13 13C NMR (101 MHz, Acetone-d6) Isomer I: δ 170.37, 139.89, 137.54, 133.00, 132.44, 128.87, 127.98, 127.82, 126.95, 67.90, 53.35, 31.46, 18.86, 17.22. Isomer II: δ 170.37, 139.80, 137.23, 133.00, 132.44, 128.58, 127.89, 127.76, 126.90, 66.97, 53.29, 31.67, 19.14, 17.50。

[0088] 11 B{ 11H NMR (128 MHz, Acetone-d6) δ -0.6 (1B), -5.4 (1B), -11.5 (1B), -15.8 (2B), -21.0 (1B), -26.1 (1B), -31.3 (1B), -36.6 (1B).

[0089]

[0090] 3 - 5: Yield 75%. White solid. HRMS m / z calcd for C 21 H 33 B9NO2 [M - H] - : 430.3349, Found: 430.3349.

[0091] NMR Data of product 3 - 5:

[0092] 1 1H NMR (400 MHz, Acetone-d6) Isomer I:Isomer II = 1:1, Isomer I: δ 7.28 - 7.21 (m, 2H), 7.21 - 7.13 (m, 2H), 7.09 - 6.98 (m, 3H), 6.99 - 6.86 (m, 3H), 6.51 (br, 1H, -NH2), 6.24 (br, 1H, -NH2), 4.07 (t, J = 6.2 Hz, 1H), 3.82 (s, 3H), 1.90 - 1.76 (m, 2H), 1.33 - 1.22 (m, 2H), 1.22 - 1.15 (m, 2H), 0.85 (t, J = 7.0 Hz, 3H), -2.13 (br, 1H, B - H - B). Isomer II: δ 7.28 - 7.21 (m, 2H), 7.21 - 7.13 (m, 2H), 7.09 - 6.98 (m, 3H), 6.99 - 6.86 (m, 3H), 6.51 (br, 1H, -NH2), 6.24 (br, 1H, -NH2), 4.07 (t, J = 6.2 Hz, 1H), 3.72 (s, 3H), 1.90 - 1.76 (m, 2H), 1.33 - 1.22 (m, 2H), 1.22 - 1.15 (m, 2H), 0.80 (t, J = 7.0 Hz, 3H), -2.13 (br, 1H, B - H - B).

[0093] 1313C NMR (101 MHz, Acetone-d6) Isomer I: δ 171.67, 139.88, 137.45, 132.97, 132.30, 128.72, 127.86, 127.77, 126.91, 62.03, 53.47, 32.09, 27.83, 22.80, 13.92. Isomer II: δ 171.40, 139.82, 137.27, 132.97, 132.30, 128.53, 127.86, 127.74, 126.87, 61.52, 53.29, 31.73, 27.68, 22.71, 13.87.

[0094] 11 B{ 1 1H}NMR (128 MHz, Acetone-d6) δ 0.3 (1B), -6.4 (1B), -12.8 (1B), -15.4 (2B), -21.8 (1B), -26.1 (1B), -32.0 (1B), -36.9 (1B).

[0095]

[0096] 3-6: Yield 66%. White solid. HRMS m / z calcd for C 21 H 33 11B9NO2 [M-H] - : 430.3349. Found: 430.3349.

[0097] NMR Data of product 3-6:

[0098] 11H NMR (400 MHz, Acetone-d6) Isomer I:Isomer II = 1:1, Isomer I: δ 7.31 - 7.23 (m, 2H), 7.23 - 7.16 (m, 2H), 7.12 - 6.97 (m, 3H), 6.99 - 6.86 (m, 3H), 6.38 (br, 1H, -NH2), 5.83 (br, 1H, -NH2), 4.23 (s, 1H), 3.83 (s, 3H), 1.98 - 1.86 (m, 1H), 1.55 - 1.40 (m, 1H), 1.24 - 1.13 (m, 1H), 0.93 (t, J = 7.4 Hz, 3H), 0.72 (t, J = 6.7 Hz, 3H), -2.21 (br, 1H, B-H-B). Isomer II: δ 7.31 - 7.23 (m, 2H), 7.23 - 7.16 (m, 2H), 7.12 - 6.97 (m, 3H), 6.99 - 6.86 (m, 3H), 6.38 (br, 1H, -NH2), 5.83 (br, 1H, -NH2), 3.76 (s, 3H), 3.65 (s, 1H), 1.84 - 1.71 (m, 1H), 1.35 - 1.24 (m, 1H), 1.13 - 1.01 (m, 1H), 0.82 (d, J = 6.8 Hz, 3H), 0.72 (t, J = 6.7 Hz, 3H), -2.21 (br, 1H, B-H-B).

[0099] 13 13C NMR (101 MHz, Acetone-d6) Isomer I: δ 170.33, 139.89, 137.54, 132.99, 132.43, 128.87, 127.97, 127.80, 126.93, 66.62, 53.32, 38.51, 27.03, 14.41, 12.00. IsomerII: δ 170.23, 139.79, 137.26, 132.99, 132.34, 128.55, 127.85, 127.75, 126.88, 65.80, 53.26, 38.29, 26.83, 14.13, 11.77.

[0100] 11 B{ 1 1H}NMR (128 MHz, Acetone-d6) δ -0.5 (1B), -5.4 (1B), -11.4 (1B), -15.7 (2B), -21.0 (1B), -26.1 (1B), -31.3 (1B), -36.7 (1B).

[0101]

[0102] 3-13: Yield 82%. White solid. HRMS m / z calcd for C 24 H 31 B9NO2[M-H] - : 464.3192, Found: 464.3192.

[0103] NMR Data of product 3-13:

[0104] 1 H NMR (400 MHz, Acetone-d6) Isomer I:Isomer II = 1:1, Isomer I: δ 7.38 - 7.27 (m, 2H), 7.26 - 7.20 (m, 3H), 7.19 - 7.15 (m, 1H), 7.13 - 7.05 (m, 2H), 7.03 - 6.95 (m, 4H), 6.94 - 6.84 (m, 3H), 6.31 (br, 1H, -NH2), 6.02 (br, 1H, -NH2), 4.37 - 4.33 (m, 1H), 3.73 (s, 3H), 3.23 - 3.07 (m, 2H), -2.14 (br, 1H, B-H-B). Isomer II: δ 7.38 - 7.27 (m, 2H), 7.26 - 7.20 (m, 3H), 7.19 - 7.15 (m, 1H), 7.13 - 7.05 (m, 2H), 7.03 - 6.95 (m, 4H), 6.94 - 6.84 (m, 3H), 6.31 (br, 1H, -NH2), 6.02 (br, 1H, -NH2), 4.13 - 4.09 (m, 1H), 3.59 (s, 3H), 3.23 - 3.07 (m, 2H), -2.14 (br, 1H, B-H-B).

[0105] 13 C NMR (101 MHz, Acetone-d6) Isomer I: δ 170.67, 139.81, 137.07, 135.27, 132.95, 132.08, 130.08, 129.83, 128.81, 128.48, 127.95, 127.76, 126.90, 62.63, 53.29, 38.43. Isomer II: δ 170.52, 139.81, 137.02, 134.76, 132.93, 132.08, 129.80, 129.76, 128.61, 128.45, 127.85, 127.76, 126.90, 62.41, 53.05, 38.00.

[0106] 11 B{ 1 H} NMR (128 MHz, Acetone-d6) δ -0.0 (1B), -6.4 (1B), -12.7 (1B), -15.4 (2B), -21.6 (1B), -26.1 (1B), -31.9 (1B), -36.9 (1B).

[0107]

[0108] 4-4: Yield 68%. White solid. HRMS m / z calcd for C 12 H 23 B9NO2 [M-H] - : 312.2566, Found: 312.2569.

[0109] NMR Data of product 4-4:

[0110] 1 1H NMR (400 MHz, Acetone-d6) Isomer I:Isomer II = 1:1, Isomer I: δ 7.40 - 7.33 (m, 2H), 7.32 - 7.23 (m, 3H), 7.19 (br, 1H, -NH2), 7.18 (br, 1H, -NH2), 4.40 (s, 1H), 3.68 (s, 3H), 3.61 - 3.53 (m, 1H), 3.34 - 3.25 (m, 1H), 2.61 (s, 1H), 1.84 (s, 1H), -3.31 (br, 1H, B-H-B). Isomer II: δ 7.40 - 7.33 (m, 2H), 7.32 - 7.23 (m, 3H), 7.19 (br, 1H, -NH2), 7.18 (br, 1H, -NH2), 4.40 (s, 1H), 3.64 (s, 3H), 3.61 - 3.53 (m, 1H), 3.34 - 3.25 (m, 1H), 2.53 (s, 1H), 1.84 (s, 1H), -3.31 (br, 1H, B-H-B).

[0111] 13 13C NMR (101 MHz, Acetone-d6) Isomer I: δ 170.83, 135.61, 130.19, 129.63, 128.37, 63.85, 53.02, 38.60. Isomer II: δ 170.74, 135.55, 130.19, 129.63, 128.37, 63.46, 52.93, 38.42.

[0112] 11 B{ 1 H} NMR (128 MHz, Acetone-d6) δ -0.9 (1B), -6.1 (1B), -17.3 (2B), -19.1 (1B), -23.9 (1B), -27.1 (1B), -32.2 (1B), -38.7 (1B).

[0113]

[0114] 4 - 5: Yield 76%. White solid. HRMS m / z calcd for C 12 H 22 B9FNO2 _ [M] - : 330.2472, Found: 330.2473.

[0115] NMR Data of product 4 - 5:

[0116] 1 1H NMR (400 MHz, Acetone-d6) Isomer I:Isomer II = 1:1, Isomer I: δ 7.39 - 7.27 (m, 2H), 7.22 (br, 2H, -NH2), 7.15 - 7.05 (m, 2H), 4.44 - 4.33 (m, 1H), 3.70 (s, 3H), 3.65 - 3.52 (m, 1H), 3.36 - 3.24 (m, 1H), 2.61 (s, 1H), 1.85 (s, 1H), -3.30 (br, 1H, B - H - B). Isomer II: δ 7.39 - 7.27 (m, 2H), 7.22 (br, 2H, -NH2), 7.15 - 7.05 (m, 2H), 4.44 - 4.33 (m, 1H), 3.66 (s, 3H), 3.65 - 3.52 (m, 1H), 3.36 - 3.24 (m, 1H), 2.52 (s, 1H), 1.85 (s, 1H), -3.30 (br, 1H, B - H - B).

[0117] 1313C NMR (101 MHz, Acetone-d6) Isomer I: δ 170.62, 164.19, 132.13, 131.58, 116.33, 63.60, 53.03, 49.70, 37.58, 35.87. Isomer II: δ 170.55, 161.77, 132.05, 131.55, 116.12, 63.25, 52.94, 49.70, 37.41, 35.87.

[0118] 11 B{ 1 1H}NMR (128 MHz, Acetone-d6) δ -0.9 (1H), -6.1 (1H), -17.3 (2H), -19.1 (1H), -23.9 (1H), -27.1 (1H), -32.2 (1H), -38.7 (1H).

[0119] 19 19F NMR (376 MHz, Acetone-d6) δ -116.49, -116.51.

[0120]

[0121] 4-11: Yield 78%. White solid. HRMS m / z calcd for C 14 H 26 B9FNO2 - [M] - : 358.2785, Found: 358.2785.

[0122] NMR Data of product 4-11:

[0123] 11H NMR (400 MHz, Acetone-d6) Isomer I:Isomer II = 1:1, Isomer I: δ 7.43 - 7.32 (m, 2H), 7.19 - 7.09 (m, 2H), 6.94 (br, 2H, -NH2), 4.44 - 4.31 (m, 1H), 3.69 (s, 3H), 3.64 - 3.54 (m, 1H), 3.37 - 3.24 (m, 1H), 1.50 (s, 3H), 1.44 (s, 3H), -3.14 (br, 1H, B-H-B). Isomer II: δ 7.43 - 7.32 (m, 2H), 7.19 - 7.09 (m, 2H), 6.94 (br, 2H, -NH2), 4.44 - 4.31 (m, 1H), 3.65 (s, 3H), 3.64 - 3.54 (m, 1H), 3.37 - 3.24 (m, 1H), 1.44 (s, 3H), 1.44 (s, 3H), -3.14 (br, 1H, B-H-B).

[0124] 13 13C NMR (101 MHz, Acetone-d6) Isomer I: δ 170.99, 164.31, 132.21, 131.86, 116.49, 63.07, 53.11, 37.97, 21.46, 18.11. Isomer II: δ 170.60, 161.88, 132.14, 131.75, 116.27, 62.68, 53.05, 37.52, 21.46, 18.11.

[0125] 11 11B{ 1 1H} NMR (128 MHz, Acetone-d6) δ -0.6 (1B), -8.6 (1B), -11.1 (1B), -13.0 (1B), -16.0 (1B), -19.9 (1B), -27.6 (1B), -33.6 (1B), -38.1 (1B).

[0126] 19 19F NMR (376 MHz, Acetone-d6) δ -116.52, -116.53.

[0127] Example 2 Hydrolysis of the carborane amino acid derivative

[0128] In this invention, under an air atmosphere, 3-13 (0.1 mmol), lithium hydroxide (LiOH, 0.5 mmol) and deionized water (2.0 mL) were successively added into a 10 mL reaction tube equipped with a magnetic stir bar. Subsequently, the reaction mixture was stirred at room temperature for 8 hours. After the reaction was completed, 0.5 mL of 1 M hydrochloric acid solution was added to the reaction solution to terminate the reaction. Then, the mixture was extracted with dichloromethane (DCM), and the aqueous layer was separated. The organic phase was collected and the solvent was removed by rotary evaporation under vacuum to finally obtain the target product 3-35.

[0129]

[0130] 3-35: Yield 95%. HRMS m / z calcd for C 23 H 29 B9NO2 [M-H] - : 450.3036, Found: 450.3036.

[0131] NMR Data of product 3-35:

[0132] 1 1H NMR (400 MHz, Acetone-d6) δ 7.42 - 7.25 (m, 3H), 7.25 - 7.15 (m, 2H), 7.09 (d, J = 6.7 Hz, 2H), 7.01 - 6.84 (m, 8H), 4.01 (s, 1H), 3.32 - 3.28 (m, 1H), 3.00 - 3.24 (m, 1H), -2.15 (br, 1H, B-H-B).

[0133] 13 13C NMR (101 MHz, Acetone-d6) δ 173.87, 140.15, 137.59, 136.95, 133.01, 132.25, 130.85, 129.65, 128.74, 128.04, 127.73, 127.69, 126.76, 36.97.

[0134] 11 11B{ 1 1H}NMR (128 MHz, Acetone-d6) δ 0.8 (1B), -7.2 (1B), -15.1 (3B), -21.3 (1B), -25.9 (1B), -32.3 (1B), -37.0 (1B).

[0135] Referring to the above method, hydrolysis reaction was carried out to obtain 4-13 to 4-15.

[0136]

[0137] 4-13: Yield 94%. HRMS m / z calcd for C 11 H 21 B9NO2[M-H] - : 298.2410, Found: 298.2410.

[0138] NMR Data of product 4-13:

[0139] 1 1H NMR (400 MHz, Acetone-d6) δ 7.42 - 7.31 (m, 4H), 7.34 - 7.23 (m, 1), 6.94 (br, 2H, -NH2), 4.49 - 4.35 (m, 1H), 3.77 - 3.48 (m, 1H), 3.41 - 3.20 (m, 1H), 2.56 (s, 1H), 1.81 (s, 1H), -3.32 (br, 1H, B-H-B).

[0140] 13 13C NMR (101 MHz, Acetone-d6) δ 171.27, 135.85, 130.33, 129.60, 128.30, 63.58, 38.33.

[0141] 11 11B{ 1 1H}NMR (128 MHz, Acetone-d6) δ -0.6 (1B), -6.2 (1B), -17.3 (2B), -19.1 (1B), -23.9 (1B), -27.1 (1B), -32.33 (1B), -38.7 (1B).

[0142]

[0143] 4-14: Yield 90%. White solid. HRMS m / z calcd for C 11 H 20 B9FNO2 - [M] - : 316.2316, Found: 316.2316.

[0144] NMR Data of product 4-14:

[0145] 11H NMR (400 MHz, Acetone-d6) Isomer I:Isomer II = 1:1, Isomer I: δ 7.49 - 7.37 (m, 2H), 7.08 - 6.95 (m, 2H), 6.72 (br, 1H, -NH2), 5.91 (br, 1H, -NH2), 4.08 - 4.00 (m, 1H), 3.58 - 3.49 (m, 1H), 3.35 - 3.23 (m, 1H), 2.43 (s, 1H), 1.71 (s, 1H), -3.34 (br, 1H, B-H-B). Isomer II: δ 7.49 - 7.37 (m, 2H), 7.08 - 6.95 (m, 2H), 6.72 (br, 1H, -NH2), 5.91 (br, 1H, -NH2), 4.08 - 4.00 (m, 1H), 3.48 - 3.38 (m, 1H), 3.35 - 3.23 (m, 1H), 2.19 (s, 1H), 1.60 (s, 1H), -3.34 (s, 1H, B-H-B).

[0146] 13 13C NMR (101 MHz, Acetone-d6) Isomer I: δ 175.26, 163.96, 134.36, 132.34, 116.13, 65.99, 49.40, 37.00. Isomer II: 174.86, 161.55, 133.79, 132.26, 115.93, 65.15, 49.40, 35.71.

[0147] 11 B{ 1 1H} NMR (128 MHz, Acetone-d6) δ -0.00 (1B), -6.61 (1B), -19.00 (3B), -23.84 (1B), -26.93 (1B), -32.76 (1B), -38.76 (1B).

[0148] 19 19F NMR (376 MHz, Acetone-d6) δ -117.48, -117.74.

[0149]

[0150] 4 - 15: Yield 92%. White solid. HRMS m / z calcd for C 13 H 24 B9FNO2 - [M] - : 344.2629, Found: 344.2629.

[0151] NMR Data of product 4-15:

[0152] 1 H NMR(400MHz,Acetone-d6)Isomer I:Isomer II=1:1,Isomer I:δ7.51 - 7.40(m,2H),7.12 - 6.99(m,2H),4.10 - 3.98(m,1H),3.49 - 3.28(m,2H),1.41(s,3H),1.38(s,3H),-3.11(br,1H,B-H-B).Isomer II:δ7.51 - 7.40(m,2H),7.12 - 6.99(m,2H),4.10 - 3.98(m,1H),3.49 - 3.28(m,2H),1.40(s,3H),1.34(s,3H),-3.11(br,1H,B-H-B)。

[0153] 13 C NMR(101MHz,Acetone-d6)Isomer I:δ164.06,133.87,132.65,116.27,116.06,64.73,36.77,21.56,18.47.Isomer II:δ161.65,133.68,132.57,116.16,115.95,64.73,36.29,21.49,18.33。

[0154] 11 B{ 1 H}NMR(128MHz,Acetone-d6)δ0.1(1B),-9.0(1B),-11.0(1B),-14.0(1B),-15.3(1B),-19.9(1B),-27.4(1B),-33.8(1B),-38.1(1B)。

[0155] 19 F NMR(376MHz,Acetone-d6)δ-115.27,-115.46。

[0156] Cytotoxicity Study of Carborane Amino Acid Derivatives in Example 3

[0157] Prepare the 4T1 cell culture medium into 1×10 5A cell suspension of [[ID=]], inoculate the cell suspension into a 96-well cell culture plate (100 μL / well), and culture it in a 37 °C carbon dioxide incubator for 24 h. After the cells adhere to the wall, remove the culture medium. Then, add fresh culture medium with different concentrations of the drug (taking derivative 4-13 as an example, the concentrations are 0, 1, 2, 4, 8, 16, 32, 64, 128 μM), and continue to culture in a 37 °C carbon dioxide incubator. After incubation for 24 h, take it out, add 10 μL of CCK8 solution, and continue to incubate for 1 h. Measure its absorbance value with an enzyme-linked immunosorbent detector at a wavelength of 450 nm, and calculate the cell survival rate according to the absorbance using the formula.

[0158] Cell survival rate = [(As - Ab) / (Ac - Ab))] × 100%

[0159] As: Absorbance of the experimental well (containing cells, culture medium, CCK-8 solution, and drug solution).

[0160] Ac: Absorbance of the control well (containing cells, culture medium, CCK-8 solution, and drug solution).

[0161] Ab: Absorbance of the blank well (containing cells, culture medium, CCK-8 solution, and drug solution).

[0162] The results of the cytotoxicity experiment of the compounds of the present invention are as Figure 5 shown, and the results show that the toxicity of the carborane amino acid / oligopeptide derivatives described in the present invention is very low.

[0163] Example 4 Cytotoxicity and neutron irradiation studies of carborane amino acid derivatives

[0164] Using the above CCK8 method, perform cytotoxicity experiments (concentrations are 0, 30, 60, 90, 120 μM) on 4 compounds (4-5, 4-11, 4-14, 4-15) designed and synthesized in the present invention. The results are as Figure 6 shown, and the results show that the toxicity of compounds 4-5, 4-11, 4-14, 4-15 is very low.

[0165] Referring to the above CCK8 method, perform cell boron content uptake experiments (as Figure 7 shown) and neutron irradiation cytotoxicity experiments at the cell level (as Figure 8As shown). The results of the cell boron content uptake experiment showed that after the cells were added and incubated for 2 hours, the boron content met the dose for the neutron irradiation experiment. The results of the neutron irradiation cytotoxicity experiment showed that under the neutron radiation with a power of 2 Gy, after the irradiated cells were cultured for another 72 hours, compared with the blank control and the control group irradiated only with neutrons, in the experimental group where the cells were irradiated with neutrons after being co-incubated with 60 μM of the compound for 2 hours, the cell viability was significantly reduced, indicating that neutron irradiation had a significant killing effect on cancer cells.

[0166] Example 5 Application of the carborane amino acid derivative

[0167] In the present invention, under an argon protection atmosphere, 3-35 (1 mmol), 6a (2 mmol), EDCI (1.2 mmol), HOBT (1.5 mmol) and dichloromethane (DCM, 10 mL) were successively added to a 10 mL reaction tube equipped with a magnetic stir bar. Subsequently, the reaction mixture was stirred thoroughly at room temperature for 24 hours. After the reaction was completed, the product was purified by silica gel flash column chromatography, using n-hexane and dichloromethane (volume ratio 1:3) as the eluent, and finally the pure product 3-41 was obtained in a yield of 66%.

[0168]

[0169] 3-41: Yield 66%. Red solid. HRMS m / z calcd for C 41 H 52 N4O + [M+H] + : 715.4973, Found: 715.4973.

[0170] NMR Data of 3-41:

[0171] 11H NMR (400 MHz, Methanol-d4) δ 8.48 (d, J = 7.0 Hz, 2H), 8.01 - 7.90 (m, 2H), 7.85 (d, J = 16.1 Hz, 1H), 7.62 (d, J = 9.0 Hz, 2H), 7.32 - 7.26 (m, 3H), 7.23 - 7.18 (m, 2H), 7.18 - 7.14 (m, 2H), 7.09 (d, J = 16.1 Hz, 1H), 7.02 - 6.97 (m, 4H), 6.93 - 6.87 (m, 4H), 6.79 (d, J = 9.2 Hz, 2H), 4.36 - 4.22 (m, 2H), 4.22 - 4.13 (m, 1H), 3.29 - 3.10 (m, 2H), 3.07 (s, 6H), 2.99 - 2.87 (m, 2H), 2.12 - 1.93 (m, 2H), -1.97 (br, 1H, B-H-B).

[0172] 13 13C NMR (101 MHz, Methanol-d4) δ 156.62, 154.07, 144.78, 144.27, 140.23, 137.87, 136.14, 133.30, 132.49, 131.75, 130.85, 130.47, 130.03, 129.85, 128.83, 128.69, 127.97, 127.10, 124.14, 123.80, 117.71, 113.10, 63.07, 58.72, 40.23, 40.07, 37.00, 31.91, 30.75.

[0173] 11 11B{ 1 1H} NMR (128 MHz, Methanol-d4) δ 0.30 (1B), -6.88 (1B), -15.68 (3B), -21.71 (1B), -26.39 (1B), -32.33 (1B), -37.11 (1B).

[0174]

[0175] The spectra of Compound 3 - 41 were tested as Figure 9As shown in the figure, a is the ultraviolet absorption spectrum of compounds 3-41 and 6b in methanol solution, b is the solid fluorescence emission spectrum of compounds 3-41 and 6b, and c is the fluorescence emission spectrum of compound 3-41 in 1-99% methanol-ether solution. The results show that the ultraviolet absorption wavelength of compound 3-41 is 460 nm, the solid fluorescence emission wavelength is 650 nm, and the fluorescence emission wavelength in methanol solution is 575 nm. Compound 6b shows fluorescence quenching in the solid state, while compound 3-41 has good luminescence intensity whether in solution or solid state. In 99% ether, which is a poor solvent, compound 3-41 shows excellent AIE properties.

[0176] In the present invention, 10 μM of compound 3-41 was added to a 4T1 cell culture dish and placed in an incubator at 37 °C and 5% CO2 for 24 hours. Then, it was washed twice with phosphate buffer solution to remove the background. The imaging of the compound in 4T1 cells was detected using a MALDI TOF-TOF 4800plus two-photon laser confocal microscope produced by Leica, Germany, as Figure 10 shown. The luminescence intensity of compound 3-41 in cells shows a time-dependent increase. However, the luminescence intensity of compound 6b in cells does not change. The experimental results show that the present invention successfully functionalizes carborane with amino acid functional groups and further couples a fluorescence imaging group to achieve the tracing of carborane and track the distribution of carborane compounds in cells.

Claims

1. A carborane amino acid / oligopeptide derivative, characterized in that It has the following structure: R represents hydrogen, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a silicon group substituted with one or more of one or more alkyl groups having 1 to 5 carbon atoms, or a phenyl group substituted with one or more of hydrogen, an alkyl group having 1 to 6 carbon atoms, a hydroxyl group, fluorine, chlorine, bromine, or iodine; R 1 represents hydrogen, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an alkylamino group having 1 to 6 carbon atoms, or a phenyl group substituted with one or more of hydrogen, an alkyl group having 1 to 6 carbon atoms, a hydroxyl group, fluorine, chlorine, bromine, and iodine; R 2 represents hydrogen, an alkyl group having 1 to 6 carbon atoms, a phenyl group or a benzyl group substituted by one or more of hydrogen, an alkyl group having 1 to 6 carbon atoms, a hydroxyl group, fluorine, chlorine, bromine, and iodine; R 3 represents hydrogen, a hydroxyl group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 alkenyl group, a C3-C6 ester group, a phenyl group or an indolyl group substituted by one or more of hydrogen, a C1-C6 alkyl group, a hydroxyl group, fluorine, chlorine, bromine, and iodine.

2. The carborane amino acid / oligopeptide derivative according to claim 1, wherein R represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, a silicon group substituted with one or more of one or more of methyl, ethyl, n-propyl, or isopropyl, or a phenyl group substituted with one or more of hydrogen, methyl, ethyl, tert-butyl, fluorine, chlorine, bromine, or iodine; R 1 represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropane, cyclopentane, cyclohexane, C3-C6 amino groups such as methylamino, ethylamino, propylamino, butylamino, phenyl substituted by one or more of hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, hydroxyl, fluorine, chlorine, bromine, iodine; R 2 represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, phenyl or benzyl substituted by one or more of hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, hydroxyl, fluorine, chlorine, bromine, iodine; R 3 represents hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, C3-C6 alkenyl, C3-C6 ester group, phenyl or indolyl substituted by one or more of hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, hydroxyl, fluorine, chlorine, bromine, iodine.

3. The carborane amino acid / oligopeptide derivative according to claim 1, characterized in that It has the following structure: R 2 represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, phenyl or benzyl substituted by one or more of hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, hydroxyl, fluorine, chlorine, bromine, iodine; R 3 represents phenyl substituted by one or more of hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, hydroxyl, fluorine, chlorine, bromine, iodine.

4. A method for preparing a carborane amino acid / oligopeptide derivative, characterized in that, In an air atmosphere, under irradiation with near-infrared light at a wavelength of 700 - 730 nm, a carbon-substituted or unsubstituted closo-carborane, an amino acid or oligopeptide with a protecting group at the carboxyl terminus, an additive, a photocatalyst, and a polar solvent are added to a reaction vessel to obtain a carborane amino acid derivative. The carbon-substituted or unsubstituted closo-carborane has the following structure: The amino acid or oligopeptide with a protecting group at the carboxyl terminus has the following structure: R represents hydrogen, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a silicon group substituted with one or more of one or more alkyl groups having 1 to 5 carbon atoms, or a phenyl group substituted with one or more of hydrogen, an alkyl group having 1 to 6 carbon atoms, a hydroxyl group, fluorine, chlorine, bromine, or iodine; R 1 represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylamino, phenyl substituted by one or more of hydrogen, C1-C6 alkyl, hydroxy, fluorine, chlorine, bromine, iodine; R 2 represents an alkyl group having 1 to 6 carbon atoms, a phenyl group or a benzyl group substituted with one or more of hydrogen, an alkyl group having 1 to 6 carbon atoms, a hydroxyl group, fluorine, chlorine, bromine, and iodine; R 3 represents hydrogen, a hydroxyl group, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an alkenyl group having 3 to 6 carbon atoms, an ester group having 3 to 6 carbon atoms, a phenyl group or an indolyl group substituted by one or more of hydrogen, an alkyl group having 1 to 6 carbon atoms, a hydroxyl group, fluorine, chlorine, bromine, and iodine.

5. The method according to claim 4, wherein The additive is selected from one or more of carbonates, fluorides, and hexafluorophosphates.

6. The method according to claim 4, wherein The photocatalyst is selected from one or more of pyridine-based photocatalysts, phenothiazine-based photocatalysts, or acridine-based photocatalysts.

7. The method according to claim 4, wherein The near-infrared light has a wavelength of 700 - 705 nm, an irradiation power of 1 W - 30 W, a reaction time of 1 - 48 hours, and a reaction temperature of 0 to 40 °C.

8. The method according to any one of claims 4 to 7, characterized in that It further includes a hydrolysis step to remove the protecting group at the carboxyl terminus to obtain R 2 a carborane amino acid derivative representing H.

9. Use of the carborane amino acid / oligopeptide derivative according to any one of claims 1 - 3 in the preparation of a tumor fluorescence imaging reagent precursor.

10. The application according to claim 9, wherein React and couple the carboxyl group in the structure of the carborane amino acid / oligopeptide derivative according to any one of claims 1 - 3 or the carboxyl group in the structure of its hydrolysis product with a fluorescent molecule containing an amino group.

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