2, 2 '-biquinoline-4, 4'-dicarboxylic acid aliphatic amino acid derivative and preparation and application thereof

Abstract

The invention discloses a 2, 2 '-biquinoline-4, 4'-dicarboxylic acid aliphatic amino acid derivative as well as preparation and application thereof, and belongs to the technical field of medicines. The structure of the 2, 2 '-biquinoline-4, 4'-dicarboxylic acid aliphatic amino acid derivative disclosed by the invention is as follows: # imgabs0, RNH is selected from # imgabs1, # imgabs2 and # imgabs3, and the 2, 2 '-biquinoline-4, 4'-dicarboxylic acid aliphatic amino acid derivative is stable in structure and low in toxicity, has anti-tumor activity and can be used as an active ingredient of an anti-tumor drug for anti-tumor treatment. The preparation process of the 2, 2 '-biquinoline-4, 4'-dicarboxylic acid aliphatic amino acid derivative is simple, and industrialization is easy when the 2, 2 '-biquinoline-4, 4'-dicarboxylic acid aliphatic amino acid derivative is used for preparing antitumor drugs.

Description

Technical Field

[0001] The invention belongs to the field of medical technology and relates to a 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative with anti-tumor effect and a preparation method and application thereof. Background Art

[0002] According to the 2020 Global Cancer Statistics Report, there are approximately 19.29 million newly diagnosed cancer cases and approximately 9.96 million cancer deaths worldwide. The treatment of malignant tumors remains a major clinical problem that the global medical field strives to overcome, and the development of safe and effective anti-tumor drugs is particularly urgent. Cottonpol is a yellow polyphenol compound contained in the roots, stems and seeds of cotton, a plant of the Malvaceae family. It is a chiral optical isomer with multiple biological activities such as sperm inhibition, immunomodulation, and anti-cancer. The anti-tumor activity of cottonpol is related to its effect on Bcl family proteins. Cottonpol is a BH3 analog that can bind to the BH3 binding groove of the anti-apoptotic proteins Bcl-2 and Bcl-XL, thereby inducing apoptosis of cancer cells, becoming a hot spot in anti-tumor drug research, but its side effects limit its clinical application. Summary of the invention

[0003] Considering that the formyl group of gossypol is related to its cytotoxicity, the present invention simplifies its structure, removes the formyl group and phenolic hydroxyl group, and only retains the basic skeleton of the binaphthyl structure of gossypol, and then replaces the binaphthyl structure with a binaphthyl core, and considers introducing amino acids at both ends of its structure to reduce toxicity, and designs and synthesizes a series of new 2,2'-binaquinoline-4,4'-dicarboxylic acid derivatives. Disodium 2,2'-binaquinoline-4,4'-dicarboxylate itself has no anti-tumor activity, but after modification with aliphatic amino acids such as L-serine methyl ester and L-isoleucine methyl ester, it is found through anti-tumor activity screening that it has strong tumor cell growth inhibition activity and low toxicity. There is no related research report so far. Based on this discovery, the purpose of the present invention is to provide a 2,2'-binaquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative and its preparation method and application, and the present invention provides a new idea for finding new anti-tumor drugs.

[0004] The purpose of the present invention is achieved through the following technical solutions:

[0005] In the first aspect of the present invention, a 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative is provided, and the structure of the 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative is shown in the following formula I:

[0006]

[0007]

[0008] Among them, RNH is selected from

[0009] One of them.

[0010] When RNH is When RNH is When RNH is When RNH is When RNH is When RNH is When RNH is When the 2,2'-binaphthyl-6,6'-dicarboxylic acid aliphatic amino acid derivative is compound 7.

[0011] The structural formulas of the above-mentioned compound 1, compound 2, compound 3, compound 4, compound 5, compound 6 and compound 7 are shown below respectively:

[0012]

[0013] In a second aspect of the present invention, a pharmaceutical preparation is provided, the pharmaceutical preparation comprising at least one of the above-mentioned 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivatives.

[0014] In one or more embodiments of the present invention, the pharmaceutical preparation is a tablet, a pill, a capsule, an injection, a suspension, an emulsion or an implant.

[0015] In the third aspect of the present invention, there is provided the use of the above-mentioned 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative or the above-mentioned pharmaceutical preparation in the preparation of anti-tumor drugs.

[0016] In one or more embodiments of the present invention, the tumor includes liver cancer, melanoma, lung cancer, pancreatic cancer, breast cancer, etc.

[0017] In a fourth aspect of the present invention, an anti-tumor drug is provided, wherein the anti-tumor drug comprises at least one of the above-mentioned 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivatives, or comprises the above-mentioned pharmaceutical preparation.

[0018] In the fifth aspect of the present invention, a method for preparing the above-mentioned 2,2'-binaphthyl-4,4'-dicarboxylic acid aliphatic amino acid derivative is provided, wherein the 2,2'-binaphthyl-4,4'-dicarboxylic acid aliphatic amino acid derivative is prepared by acylation reaction of 2,2'-binaquinoline-4,4'-dicarboxylic acid or its salt with L-amino acid methyl ester or its hydrochloride, and the salt of 2,2'-binaquinoline-4,4'-dicarboxylic acid includes disodium 2,2'-binaquinoline-4,4'-dicarboxylate. The reaction formula for preparing the 2,2'-binaquinoline-4,4'-dicarboxylic acid aliphatic derivative from 2,2'-binaquinoline-4,4'-dicarboxylic acid or its salt with L-amino acid methyl ester or its hydrochloride is as follows:

[0019]

[0020] In one or more embodiments of the present invention, the preparation method of 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic derivatives comprises the following steps: adding 2,2'-biquinoline-4,4'-dicarboxylic acid or a salt thereof, L-amino acid methyl ester or a hydrochloride thereof, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) into an organic solvent for reaction to obtain 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic derivatives. Furthermore, the preparation method of the aliphatic derivative of 2,2'-biquinoline-4,4'-dicarboxylic acid comprises the following steps: taking disodium 2,2'-biquinoline-4,4'-dicarboxylate and adding it to an organic solvent and stirring and mixing, then adding L-amino acid methyl ester hydrochloride, the solution changes from the original turbid state to slightly clear, reacting under stirring, and then adding 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) to react to obtain the aliphatic derivative of 2,2'-biquinoline-4,4'-dicarboxylic acid.

[0021] In one or more embodiments of the present invention, the organic solvent is selected from any one or more solvents selected from dichloromethane, tetrahydrofuran and dimethylformamide in any proportion.

[0022] In one or more embodiments of the present invention, the molar ratio of the 2,2'-biquinoline-4,4'-dicarboxylic acid or its salt to the L-amino acid methyl ester or its hydrochloride is 1:2-3.

[0023] In one or more embodiments of the present invention, the molar ratio of 2,2'-biquinoline-4,4'-dicarboxylic acid to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate is 1:2-4.

[0024] In one or more embodiments of the present invention, the L-amino acid methyl ester is L-alanine methyl ester, L-valine methyl ester, L-leucine methyl ester, L-isoleucine methyl ester, L-methionine methyl ester, L-threonine methyl ester or L-serine methyl ester.

[0025] The beneficial effects of the present invention are:

[0026] (1) The present invention provides a 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative, which can be used to prepare anti-tumor drugs.

[0027] (2) The 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivatives provided by the present invention have a stable structure, low cytotoxicity, and show strong inhibitory activity against standard tumor cell lines such as HepG2, A375, A549, PANC-1 and MCF-7 in vitro.

[0028] (3) The method for preparing the 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative provided by the present invention has a simple process and is easy to industrialize. DETAILED DESCRIPTION

[0029] The present invention will be further described below in conjunction with specific examples, but the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. In the following examples, if specific conditions are not specified, they are carried out according to normal conditions or conditions recommended by the manufacturer. The methods used are conventional methods known in the art unless otherwise specified, and the consumables and reagents used are commercially available unless otherwise specified. Unless otherwise specified, the professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any method or material similar or equivalent to the recorded content may also be applied to the present invention.

[0030] Example 1 Synthesis of L-alanine methyl ester derivative of 2,2'-biquinoline-4,4'-dicarboxylic acid (Compound 1)

[0031]

[0032] Take 1.00g (2.6mmol) of disodium 2,2'-biquinoline-4,4'-dicarboxylate and place it in a 100mL eggplant-shaped bottle, add 20mL of dry DMF, stir at room temperature for 10min, add 0.86g (6.2mmol) of L-propylamino acid methyl ester hydrochloride, the solution becomes slightly clear from the original turbid state, react for 10min under stirring, add condensing agent HATU 2.35g (6.1mmol), continue to react for 6h, use TLC (developing solvent is petroleum ether / ethyl acetate: 1 / 1, v / v) to monitor the reaction process, after the reaction is completed, add an equal volume of purified water to the reactant to quench the reaction, and let it stand overnight. Filter, wash the solid layer with 5-fold diluted concentrated ammonia water 3 times, then wash with purified water until neutral, and purify by column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) as the mobile phase to obtain a white solid with a yield of 67.7% and a melting point of 257.7-258.5℃. 1 H NMR (600 MHz, DMSO-d 6 )δ9.45(d,J=6.7Hz,2H),8.82(s,2H),8.30(d,J=8.4Hz,2H),8.25(d,J=8.3Hz,2H),7.93(t, J=7.7Hz,2H),7.78(t,J=7.6Hz,2H),4.69–4.62(m,2H),3.78(s,6H),1.48(d,J=7.4Hz,6H); 13 C NMR (151 MHz, DMSO-d 6 )δ173.07,167.05,154.43,147.67,143.55,130.87,129.94,128.50,125.70,124.80,116.25,52.34,48.52,16.75; HRMS(ESI + ): m / z calcd for C 28 H 26 N 4 O 6 [M+H] + 515.19251,found515.19397.

[0033] Example 2 Synthesis of L-valine methyl ester derivative of 2,2'-biquinoline-4,4'-dicarboxylic acid (Compound 2)

[0034]

[0035] The synthesis method is the same as compound 1, except that L-alanine methyl ester hydrochloride is replaced by L-valine methyl ester hydrochloride. Compound 2 is a white solid with a yield of 61.3% and a melting point of 286.8-288.7°C.1 H NMR (600 MHz, DMSO-d 6 )δ9.32(d,J=7.6Hz,2H),8.75(s,2H),8.26(d,J=8.4Hz,2H),8.13(d,J=8.0Hz,2H),7.91-7.85(m,2H),7.74(t ,J=7.5Hz,2H),4.52(t,J=7.0Hz,2H),3.76(s,6H),2.22(q,J=6.7Hz,2H),1.01(s,6H),0.99(s,6H); HRMS(ESI + ): m / z calcd for C 32 H 34 N 4 O 6 [M+H] + 571.25511, found 571.25610.

[0036] Example 3 Synthesis of L-leucine methyl ester derivative of 2,2'-biquinoline-4,4'-dicarboxylic acid (Compound 3)

[0037]

[0038] The synthesis method is the same as compound 1, except that L-alanine methyl ester hydrochloride is replaced by L-leucine methyl ester hydrochloride. Compound 3 is a white solid with a yield of 54.6% and a melting point of 272.8-273.0°C. 1 H NMR (600 MHz, DMSO-d 6 )δ9.41(d,J=7.4Hz,2H),8.80(s,2H),8.29(d,J=8.4Hz,2H),8.20(d,J=8.3Hz,2H),7.92(t,J=7.6Hz,2H),7.79-7.76(m,2H),4. 65(dd,J=11.1,3.9Hz,2H),3.78(s,6H),1.79-1.76(m,4H),1.66(d,J=4.7Hz,2H),1.00(d,J=6.3Hz,6H),0.97(d,J=6.2Hz,6H); 13 C NMR (151 MHz, DMSO-d 6 )δ172.85, 167.23, 154.28, 147.53, 143.47, 130.78, 129.86, 128.45, 125.44, 124.65, 116.15, 52.24, 51.10, 24.64, 22.84, 21.30 (2C); HRMS (ESI +): m / z calcdfor C 34 H 38 N 4 O 6 [M+H] + 599.28641, found 599.28845.

[0039] Example 4 Synthesis of L-isoleucine methyl ester derivative of 2,2'-biquinoline-4,4'-dicarboxylic acid (Compound 4)

[0040]

[0041] The synthesis method is the same as compound 1, except that L-alanine methyl ester hydrochloride is replaced by L-isoleucine methyl ester hydrochloride. Compound 4 is a white solid with a yield of 62.9% and a melting point of 247.1-248.2°C. 1 H NMR (600 MHz, DMSO-d 6 )δ9.37(d,J=7.4Hz,2H),8.78(s,2H),8.33~8.27(m,2H),8.16(dd,J=8.4,1.3Hz,2H),7.92(ddd,J=8.4,6.8,1.4Hz,2H),7.78(ddd,J=8.2,6 .8,1.3Hz,2H),4.59(dd,J=7.5,6.5Hz,2H),3.79(s,6H),2.02–1.98(m,2H),1.55-1.34(m,4H),1.00(d,J=6.9Hz,6H),0.92(t,J=7.4Hz,6H); 13 C NMR (151 MHz, DMSO-d 6 )δ171.91, 167.39, 154.26, 147.46, 143.61, 130.66, 129.82, 128.34, 125 .40, 124.73, 116.19, 57.34, 51.94, 35.94, 25.12, 15.61, 11.21; HRMS (ESI + )m / z calcd for C 34 H 38 N 4 O 6 [M+H] + 599.28641, found 599.28809.

[0042] Example 5 Synthesis of L-methionine methyl ester derivative of 2,2'-biquinoline-4,4'-dicarboxylic acid (Compound 5)

[0043]

[0044] The synthesis method is the same as compound 1, except that L-alanine methyl ester hydrochloride is replaced by L-methionine methyl ester hydrochloride. Compound 5 is a white solid with a yield of 70.2% and a melting point of 261.5-261.6°C. 1 H NMR (600 MHz, DMSO-d 6 )δ9.46(d,J=7.2Hz,2H),8.83(s,2H),8.30(d,J=8.4Hz,2H),8.24(d,J=8.4Hz,2H),7.93(d,J=6.9Hz,2H),7 .79(t,J=7.6Hz,2H),4.78(s,2H),3.80(s,6H),2.67(d,J=4.5Hz,4H),2.15(d,J=12.7Hz,4H),2.12(s,6H); 13 C NMR (151 MHz, DMSO-d 6 )δ172.57,167.69,154.68,147.93,143.80,131.17,130.25,128.83,125.89,125.04,116.57,52.74,52.14,30.42,30.22,15.02; HRMS (ESI + ): m / z calcd for C 32 H 34 N 4 O 6 S 2 [M+H] + 635.19925,found635.20081.

[0045] Example 6 Synthesis of L-threonine methyl ester derivative of 2,2'-biquinoline-4,4'-dicarboxylic acid (Compound 6)

[0046]

[0047]

[0048] The synthesis method is the same as compound 1, except that L-alanine methyl ester hydrochloride is replaced by L-threonine methyl ester hydrochloride. Compound 6 is a white solid with a yield of 65.1% and a melting point of 243.2-244.7°C. 1 H NMR (600 MHz, DMSO-d 6)δ9.16(d,J=8.0Hz,2H),8.83(s,2H),8.29(d,J=8.4Hz,2H),8.24(d,J=8.3Hz,2H),7.92(t,J=7.8Hz,2H),7.77 (t,J=7.6Hz,2H),4.68(dd,J=8.1,3.9Hz,2H),4.28(dt,J=10.6,6.2Hz,2H),3.79(s,6H),1.27(d,J=6.4Hz,6H); 13 C NMR (151 MHz, DMSO-d 6 )δ171.33,167.98,154.71,147.90,143.95,131.03,130.21,128.68,125.96,125.13,116.75,66.64,59.39,52.57,20.75; HRMS (ESI + ): m / z calcd for C 30 H 30 N 4 O 8 [M+H] + 575.21364,found575.21503.

[0049] Example 7 Synthesis of L-serine methyl ester derivative of 2,2'-biquinoline-4,4'-dicarboxylic acid (Compound 7)

[0050]

[0051] The synthesis method is the same as compound 1, except that L-alanine methyl ester hydrochloride is replaced by L-serine methyl ester hydrochloride. Compound 7 is a white solid with a yield of 55.9% and a melting point of 237.8-237.9°C. 1 H NMR (600 MHz, DMSO-d 6 )δ9.34(d,J=7.3Hz,2H),8.81(d,J=4.1Hz,2H),8.27(d,J=8.4Hz,2H),8.23(d,J=8.3Hz,2H),7.90 (t,J=7.6Hz,2H),7.74(t,J=7.6Hz,2H),4.69(q,J=5.9Hz,2H),3.86(t,J=5.6Hz,4H),3.75(s,6H); 13 C NMR (151 MHz, DMSO-d 6)δ171.18,167.65,154.71,147.92,143.87,131.09,130.17,128.72,126.06,125.09,116.67,61.32,56.08,52.62; HRMS(ESI + ): m / z calcd for C 28 H 26 N 4 O 8 [M+H] + 547.18234,found547.18286.

[0052] Example 8 Antitumor Experiment of Aliphatic Amino Acid Derivatives of 2,2'-Binaphthyl-4,4'-Dicarboxylic Acid of the Present Invention

[0053] The cell lines used in this experiment were purchased from the Shanghai Institute of Life Sciences, Chinese Academy of Sciences, including: human hepatoma cell line HepG2, human malignant melanoma cell line A375, human non-small cell lung cancer cell line A549, human pancreatic cancer cell line PANC-1 and human breast cancer cell line MCF-7. Positive control drug: 5-fluorouracil (Fluorouracil, 5-Fu), purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0054] 1. Cell Culture

[0055] (1) Recovery: Take out the frozen cells from the refrigerator, place them in a 37°C water bath to completely thaw, then add 10 times more DMEM high-glucose complete medium, centrifuge, discard the liquid layer, obtain the cell pellet, repeat adding 10 times more DMEM high-glucose complete medium, centrifuge, and obtain the cell pellet again. Add 2 mL of DMEM high-glucose complete medium to blow the cells into single cells, transfer the medium containing single cells to the culture bottle, and add medium to 7 mL or 9 mL. Place the culture bottle in a 37°C, 5% CO 2 Incubate the cells in an incubator for subculture and replace the medium the next day.

[0056] (2) Culture and passaging: Replace the culture medium with fresh one according to the growth status of the cells. When the cell confluence reaches 80%, discard the culture medium, wash twice with PBS, add 1 mL of 0.25% trypsin, immerse the cells at the bottom of the bottle in the solution, and discard the trypsin. Return the culture bottle to the incubator and digest for 1-2 minutes, then terminate the digestion with complete culture medium. After blowing the cells evenly, add them evenly to the culture bottle, and pass them in the ratio of 1:3-1:5. When the cells grow to 85%-90% abundance, they are confluent and passaged. Add the cells to the culture plate, add culture medium to the corresponding volume, and wait until the cells enter the logarithmic growth phase.

[0057] (3) Cryopreservation: Replace the culture medium with fresh one the night before. Blow the cells apart into single cells, centrifuge, discard the supernatant, prepare the cell freezing solution, and adjust the cell density to 1×10 6 The cell solution was placed in a 4°C refrigerator for 30 min, then in a -20°C refrigerator for 30 min, and finally in a -80°C low-temperature refrigerator for long-term freezing.

[0058] 2. MTT assay to detect the inhibitory activity of compounds on tumor cells

[0059] (1) Preparation of compounds: Dissolve the compound in DMSO to prepare a stock solution with a concentration of 25 mg / mL, and dilute it with complete culture medium to a series of concentrations of 50 μmol / L, 15 μmol / L, 5 μmol / L, 1.5 μmol / L, 0.5 μmol / L, 0.15 μmol / L, 0.05 μmol / L, and 0.015 μmol / L.

[0060] (2) Cell inoculation: When the tumor cells grow to 80-90% abundance, the cell suspension is inoculated into a 96-well plate, with approximately 10,000 tumor cells in each well. Incubate at 37°C and 5% CO 2 The cells were cultured in a constant temperature incubator, and after the cells adhered to the wall, complete culture medium containing the compounds to be tested in the above series of concentrations was given and incubated for 72 hours.

[0061] (3) Add 10 μL of MTT solution to each well and incubate in a cell culture incubator in the dark for 4 h. Discard the supernatant, add 100 μL of DMSO to each well, and shake for 10 min. Detect the absorbance of each well at 570 nm using an ELISA reader. Inhibition rate = (OD control group - OD drug group) / OD control group × 100%. The IC of each compound was calculated using graphpad prism9 software. 50 , and the average value was taken after repeating the experiment three times.

[0062] The IC of each compound was calculated using Graphpad prism9 software. 50 The experiment was repeated three times and the average value was taken. HepG2, A375, A549, PANC-1 and MCF-7 cell lines were treated with the test compounds for 72 h, and the IC 50 The results are shown in Table 1.

[0063] Table 1 Antitumor activity of the aliphatic amino acid derivatives of 2,2'-binaphthyl-4,4'-dicarboxylic acid of the present invention

[0064]

[0065]

[0066] As shown in Table 1, except for compound 7, the other new compounds have certain antitumor activity against one or even five of the five cell lines, including A375, A549, PANC-1, MCF-7 and HepG2, which is better than 5-fluorouracil. Among them, compound 4 has strong antitumor activity against five cell lines, including A375, A549, PANC-1, MCF-7 and HepG2, and its antitumor activity against four cell lines, including A375, A549, PANC-1 and MCF-7, is better than 5-fluorouracil. In addition, for the A375 cell line, compound 4 showed the highest inhibitory activity (IC 50 Compound 5 (IC 50 :2.19μmol / L) also has strong inhibitory activity against MCF-7 cell line, which is better than 5-fluorouracil. The above results show that modifying 2,2'-biquinoline-4,4'-dicarboxylic acid with aliphatic amino acids can enhance its anti-tumor activity.

[0067] Example 9 Acute toxicity test of the aliphatic amino acid derivatives of 2,2'-biquinoline-4,4'-dicarboxylic acid of the present invention

[0068] Compound 4 was selected for acute toxicity experiment, and mice weighing 18-22 grams were randomly divided into a normal saline group, a low-dose group of 200 mg / kg, and a high-dose group of 400 mg / kg, with 10 mice in each group. After the mice were given the drug for 7 consecutive days, there was no significant change in body weight and hair, and no death occurred, indicating that the 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivatives of the present invention have low toxicity and can be used for the preparation of anti-tumor drugs.

[0069] The above embodiments are only used to help illustrate the present invention. The implementation methods of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative, characterized in that: The structure of the 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative is shown in the following formula I: Among them, RNH is selected from One of them.

2. A pharmaceutical preparation, characterized in that: The pharmaceutical preparation comprises at least one of the 2,2'-binaphthyl-4,4'-dicarboxylic acid aliphatic amino acid derivatives according to claim 1.

3. The pharmaceutical preparation according to claim 2, characterized in that: The pharmaceutical preparation is a tablet, a pill, a capsule, an injection, a suspension, an emulsion or an implant.

4. Use of the 2,2'-binaphthyl-4,4'-dicarboxylic acid aliphatic amino acid derivative according to claim 1 or the pharmaceutical preparation according to claim 2 or 3 in the preparation of anti-tumor drugs.

5. An anti-tumor drug, characterized in that: The anti-tumor drug comprises at least one of the 2,2'-binaphthyl-4,4'-dicarboxylic acid aliphatic amino acid derivatives according to claim 1, or comprises the pharmaceutical preparation according to claim 2 or 3.

6. The method for preparing the 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative according to claim 1, characterized in that: The 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative is prepared by acylation reaction of 2,2'-biquinoline-4,4'-dicarboxylic acid or its salt and L-amino acid methyl ester or its hydrochloride.

7. The method for preparing the 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative according to claim 6, characterized in that: The method comprises the following steps: adding 2,2'-biquinoline-4,4'-dicarboxylic acid or its salt, L-amino acid methyl ester or its hydrochloride and HATU into an organic solvent for reaction to obtain a 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic derivative.

8. The method for preparing the 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative according to claim 7, characterized in that: The organic solvent is selected from any one or more of dichloromethane, tetrahydrofuran and dimethylformamide in any proportion.

9. The method for preparing the 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative according to claim 6 or 7, characterized in that: The molar ratio of the 2,2'-biquinoline-4,4'-dicarboxylic acid or its salt to the L-amino acid methyl ester or its hydrochloride is 1:2-3; the molar ratio of the 2,2'-biquinoline-4,4'-dicarboxylic acid or its salt to HATU is 1:2-4.

10. The method for preparing the 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative according to claim 6 or 7, characterized in that: The L-amino acid methyl ester is L-alanine methyl ester, L-valine methyl ester, L-leucine methyl ester, L-isoleucine methyl ester, L-methionine methyl ester, L-threonine methyl ester or L-serine methyl ester.

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