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

Abstract

The application discloses a 2,2'-biquinoline-4,4'-dicarboxylic aliphatic amino acid derivative, and a preparation and application thereof, and belongs to the technical field of medicines.The structure of the 2,2'-biquinoline-4,4'-dicarboxylic aliphatic amino acid derivative is shown in the following formula: wherein RNH is selected from the group consisting of structures that are stable, have low toxicity, have antitumor activity, and can be used as effective components of antitumor drugs for antitumor treatment.The preparation process of the 2,2'-biquinoline-4,4'-dicarboxylic aliphatic amino acid derivative is simple, and the 2,2'-biquinoline-4,4'-dicarboxylic aliphatic amino acid derivative is easy to be industrialized when being used for preparing antitumor drugs.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and relates to a 2,2'-biquinoline-4,4'-dicarboxylic aliphatic amino acid derivative with an antitumor effect and a preparation method and application thereof. BACKGROUND

[0002] According to the 2020 global cancer statistics report, about 19.29 million new cases of cancer were diagnosed worldwide, and about 9.96 million people died of cancer. The treatment of malignant tumors is still a major clinical problem that the global medical field is struggling to overcome, and the research and development of safe and effective antitumor drugs are particularly urgent. Gossypol is a yellow polyphenolic compound contained in the roots, stems and seeds of cotton plants in the Malvaceae family. It is a chiral optical isomer with biological activities such as sperm inhibition, immune regulation and anticancer. The antitumor activity of gossypol is related to its effect on Bcl family proteins. Gossypol is a BH3 analog that can bind to the BH3 binding groove of anti-apoptotic proteins Bcl-2 and Bcl-XL, thereby inducing apoptosis of cancer cells, and has become a hot spot for research on antitumor drugs. However, its side effects limit its clinical application. SUMMARY

[0003] Considering that the formyl group of gossypol is related to its cytotoxicity, the present application simplifies the structure by removing the formyl group and the phenolic hydroxyl group and only retaining the basic skeleton of the binaphthalene structure of gossypol. Then, the binaphthalene structure is replaced with a biquinoline parent nucleus, and amino acids are introduced at both ends of the structure to reduce toxicity, thereby designing and synthesizing a series of new 2,2'-biquinoline-4,4'-dicarboxylic acid derivatives. 2,2'-Biquinoline-4,4'-dicarboxylic acid disodium itself has no antitumor activity, but after modification with L-serine methyl ester, L-isoleucine methyl ester and other aliphatic amino acids, it is found through antitumor activity screening that all of them have strong tumor cell growth inhibition activity and low toxicity, and no related research reports have been reported to date. Based on this finding, the purpose of the present application is to provide a 2,2'-biquinoline-4,4'-dicarboxylic aliphatic amino acid derivative and a preparation method and application thereof. The present application provides a new idea for finding new antitumor drugs.

[0004] The purpose of the present application is achieved by the following technical solutions:

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

[0006]

[0007]

[0008] wherein RNH is selected from

[0009] one of the following compounds.

[0010] when RNH is , the 2,2'-binaphthalene-6,6'-dicarboxylic aliphatic amino acid derivative is compound 1. when RNH is , the 2,2'-binaphthalene-6,6'-dicarboxylic aliphatic amino acid derivative is compound 2. when RNH is , the 2,2'-binaphthalene-6,6'-dicarboxylic aliphatic amino acid derivative is compound 3. when RNH is , the 2,2'-binaphthalene-6,6'-dicarboxylic aliphatic amino acid derivative is compound 4. when RNH is , the 2,2'-binaphthalene-6,6'-dicarboxylic aliphatic amino acid derivative is compound 5. when RNH is , the 2,2'-binaphthalene-6,6'-dicarboxylic aliphatic amino acid derivative is compound 6. when RNH is , the 2,2'-binaphthalene-6,6'-dicarboxylic aliphatic amino acid derivative is compound 7.

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

[0012]

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

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

[0015] In a third aspect of the present application, the use of the above-mentioned 2,2'-binaphthalene-4,4'-dicarboxylic aliphatic amino acid derivatives or the above-mentioned pharmaceutical preparation in the preparation of an antitumor drug is provided.

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

[0017] In a fourth aspect of the present application, an antitumor drug is provided, which comprises at least one of the above-mentioned 2,2'-binaphthalene-4,4'-dicarboxylic aliphatic amino acid derivatives or the above-mentioned pharmaceutical preparation.

[0018] In a fifth aspect of the present application, there is provided a method for preparing the above-mentioned 2,2'-binaphthalene-4,4'-dicarboxylic aliphatic amino acid derivative, which is prepared by acylation reaction of 2,2'-binaphthalene-4,4'-dicarboxylic acid or a salt thereof with L-amino acid methyl ester or a hydrochloride salt thereof, and the salt of 2,2'-binaphthalene-4,4'-dicarboxylic acid includes disodium 2,2'-binaphthalene-4,4'-dicarboxylate. The reaction formula for preparing the 2,2'-binaphthalene-4,4'-dicarboxylic aliphatic derivative from 2,2'-binaphthalene-4,4'-dicarboxylic acid or a salt thereof and L-amino acid methyl ester or a hydrochloride salt thereof is shown below:

[0019]

[0020] In one or more embodiments of the present application, the method for preparing the 2,2'-binaphthalene-4,4'-dicarboxylic aliphatic derivative includes the steps of: adding 2,2'-binaphthalene-4,4'-dicarboxylic acid or a salt thereof, L-amino acid methyl ester or a hydrochloride salt thereof, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) into an organic solvent to react, thereby obtaining the 2,2'-binaphthalene-4,4'-dicarboxylic aliphatic derivative. Further, the method for preparing the 2,2'-binaphthalene-4,4'-dicarboxylic aliphatic derivative includes the steps of: adding disodium 2,2'-binaphthalene-4,4'-dicarboxylate into an organic solvent and stirring to mix, then adding L-amino acid methyl ester hydrochloride, and the solution becomes slightly clear from the original turbidity, and then reacting under stirring by adding 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), thereby obtaining the 2,2'-binaphthalene-4,4'-dicarboxylic aliphatic derivative.

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

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

[0023] In one or more embodiments of the present application, the molar ratio of the 2,2'-binaphthalene-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 application, 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 present application has the following advantages:

[0026] (1) The present application provides a 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative, which can be applied to the preparation of an antitumor drug.

[0027] (2) The 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative provided by the present application has stable structure, small cytotoxicity, and shows strong inhibitory activity on standard tumor cell strains such as HepG2, A375, A549, PANC-1 and MCF-7 in vitro.

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

[0029] The present application will be further described below in conjunction with specific examples. However, the following examples are only used to illustrate the present application, and should not be regarded as limiting the scope of the present application. In the following examples, if the specific conditions are not specified, the conventional conditions or the conditions recommended by the manufacturer are used, and the methods used are the conventional methods known in the art, unless otherwise specified. In addition, any method or material similar or equivalent to those described can also be applied to the present application.

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

[0031]

[0032] Take 2,2'-biquinoline-4,4'-dicarboxylic acid disodium 1.00 g (2.6 mmol) in 100 mL of a tomato-shaped bottle, add 20 mL of dry DMF, stir at room temperature for 10 min, add L-alanine methyl ester hydrochloride 0.86 g (6.2 mmol), the solution becomes slightly clear from the original turbidity, stir for 10 min, add the condensing agent HATU 2.35 g (6.1 mmol), continue to react for 6 h, monitor the reaction process by TLC (developing agent is petroleum ether / ethyl acetate: 1 / 1, v / v), after the reaction is completed, add an equal volume of purified water to the reaction to quench the reaction, stand overnight. Filter, wash the solid layer with 5 times diluted concentrated ammonia water 3 times, then wash with purified water until neutral, purify by column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) as the mobile phase, obtain white solid, yield 67.7%, melting point: 257.7-258.5°C. 1 H NMR (600 MHz, DMSO-d6) δ 9.45 (d, J = 6.7 Hz, 2H), 8.82 (s, 2H), 8.30 (d, J = 8.4 Hz, 2H), 8.25 (d, J = 8.3 Hz, 2H), 7.93 (t, J = 7.7 Hz, 2H), 7.78 (t, J = 7.6 Hz, 2H), 4.69-4.62 (m, 2H), 3.78 (s, 6H), 1.48 (d, J = 7.4 Hz, 6H); 13 C NMR (151 MHz, DMSO-d6) δ 173.07, 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 N4O6[M+H] + 515.19251, found 515.19397.

[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 that of compound 1, except that L-alanine methyl ester hydrochloride is replaced by L-valine methyl ester hydrochloride. Compound 2 is a white solid, yield 61.3%, melting point: 286.8-288.7°C. 1H NMR (600 MHz, DMSO-d6) δ 9.32 (d, J = 7.6 Hz, 2H), 8.75 (s, 2H), 8.26 (d, J = 8.4 Hz, 2H), 8.13 (d, J = 8.0 Hz, 2H), 7.91 - 7.85 (m, 2H), 7.74 (t, J = 7.5 Hz, 2H), 4.52 (t, J = 7.0 Hz, 2H), 3.76 (s, 6H), 2.22 (q, J = 6.7 Hz, 2H), 1.01 (s, 6H), 0.99 (s, 6H); HRMS (ESI + ) : m / z calcd for C 32 34 N4O6[M+H] + 571.25511, found 571.25610.

[0036] 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 that of Compound 1, except that L-leucine methyl ester hydrochloride is used instead of L-alanine 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-d6) δ 9.32 (d, J = 7.6 Hz, 2H), 8.75 (s, 2H), 8.26 (d, J = 8.4 Hz, 2H), 8.13 (d, J = 8.0 Hz, 2H), 7.91 - 7.85 (m, 2H), 7.74 (t, J = 7.5 Hz, 2H), 4.52 (t, J = 7.0 Hz, 2H), 3.76 (s, 6H), 2.22 (q, J = 6.7 Hz, 2H), 1.01 (s, 6H), 0.99 (s, 6H); HRMS (ESI 13 C NMR (151 MHz, DMSO-d6) δ 172.85, 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 + 34 38 N4O6[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 that of 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-d6) δ 9.37 (d, J = 7.4 Hz, 2H), 8.78 (s, 2H), 8.33 ~ 8.27 (m, 2H), 8.16 (dd, J = 8.4, 1.3 Hz, 2H), 7.92 (ddd, J = 8.4, 6.8, 1.4 Hz, 2H), 7.78 (ddd, J = 8.2, 6.8, 1.3 Hz, 2H), 4.59 (dd, J = 7.5, 6.5 Hz, 2H), 3.79 (s, 6H), 2.02 ~ 1.98 (m, 2H), 1.55-1.34 (m, 4H), 1.00 (d, J = 6.9 Hz, 6H), 0.92 (t, J = 7.4 Hz, 6H); 13 C NMR (151 MHz, DMSO-d6) δ 171.91, 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 N4O6[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 that of 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. 1H NMR (600 MHz, DMSO-d6) δ 9.46 (d, J = 7.2 Hz, 2H), 8.83 (s, 2H), 8.30 (d, J = 8.4 Hz, 2H), 8.24 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 6.9 Hz, 2H), 7.79 (t, J = 7.6 Hz, 2H), 4.78 (s, 2H), 3.80 (s, 6H), 2.67 (d, J = 4.5 Hz, 4H), 2.15 (d, J = 12.7 Hz, 4H), 2.12 (s, 6H); 13 C NMR (151 MHz, DMSO-d6) δ 172.57, 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 N4O6S2[M+H] + 635.19925, found 635.20081.

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

[0046]

[0047]

[0048] Synthetic 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, yield 65.1%, melting point: 243.2-244.7°C. 1 H NMR (600 MHz, DMSO-d6) δ 9.46 (d, J = 7.2 Hz, 2H), 8.83 (s, 2H), 8.30 (d, J = 8.4 Hz, 2H), 8.24 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 6.9 Hz, 2H), 7.79 (t, J = 7.6 Hz, 2H), 4.78 (s, 2H), 3.80 (s, 6H), 2.67 (d, J = 4.5 Hz, 4H), 2.15 (d, J = 12.7 Hz, 4H), 2.12 (s, 6H); 13C NMR (151 MHz, DMSO-d6) d 171.33, 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 N4O8[M+H] + 575.21364, found 575.21503.

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

[0050]

[0051] The synthesis method is the same as that of Compound 1, except that L-serine methyl ester hydrochloride is used instead of L-alanine 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-d6) d 9.34 (d, J = 7.3 Hz, 2H), 8.81 (d, J = 4.1 Hz, 2H), 8.27 (d, J = 8.4 Hz, 2H), 8.23 (d, J = 8.3 Hz, 2H), 7.90 (t, J = 7.6 Hz, 2H), 7.74 (t, J = 7.6 Hz, 2H), 4.69 (q, J = 5.9 Hz, 2H), 3.86 (t, J = 5.6 Hz, 4H), 3.75 (s, 6H); 13 C NMR (151 MHz, DMSO-d6) d 171.18, 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 N4O8[M+H] + 547.18234, found 547.18286.

[0052] Example 8 Anti-tumor experiment of the aliphatic amino acid derivative of 2,2'-binaphthalene-4,4'-dicarboxylic acid of the present application

[0053] The cell lines used in this experiment were purchased from the Shanghai Institute of Life Sciences of the Chinese Academy of Sciences, including: human hepatocellular carcinoma 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) Resuscitation: Take the frozen cells out of the refrigerator, place them in a 37°C water bath to completely melt, then add 10 times more DMEM high-sugar complete culture medium, centrifuge, discard the liquid layer, and obtain the cell precipitate. Repeat the addition of 10 times more DMEM high-sugar complete culture medium, centrifuge, and obtain the cell precipitate again. Add 2 mL of DMEM high-sugar complete culture medium, blow the cells into single cells, and transfer the medium containing single cells to the culture bottle, add medium to 7 mL or 9 mL. Place the culture bottle in a 37°C, 5% CO2 incubator to allow the cells to be passaged, and perform medium replacement the next day.

[0056] (2) Culture and passage: Replace fresh culture medium according to the growth status of the cells. When the cell confluence reaches 80%, discard the culture medium, wash twice with PBS, and then add 1 mL of 0.25% trypsin to immerse the cells at the bottom of the bottle in the solution. Discard the trypsin. Place the culture bottle back in the incubator for 1-2 min of digestion, then terminate the digestion with complete culture medium. Blow the cells evenly and add them to the culture bottle in equal amounts, with a 1:3-1:5 ratio for subculturing. When the cells grow to 85%-90% abundance, subculture them. Add the cells to the culture plate and add the culture medium to the corresponding volume. When the cells enter the logarithmic growth phase, they can be used.

[0057] (3) Freezing: Replace fresh culture medium the night before. Blow the cells to single cells, centrifuge, discard the supernatant, and prepare the cell freezing solution. Adjust the cell density to 1x10 6 6 / mL. Place the cell solution 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 storage.

[0058] 2. MTT method for detecting the inhibitory activity of compounds on tumor cells

[0059] (1) Preparation of compounds: Dissolve the compounds in DMSO to prepare a 25 mg / mL stock solution. Dilute with complete culture medium to obtain 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, about 10000 tumor cells per well. Incubate in a 37°C, 5% CO2 incubator, after the cells adhere, give the above series of concentrations of complete medium containing the compounds to be tested, incubate for 72 hours.

[0061] (3) Add 10 μL of MTT solution to each well, incubate in the cell culture box for 4h in the dark. Discard the supernatant, add 100 μl of DMSO to each well, shake for 10 min. Detect the absorbance value of each well at 570 nm by microplate reader. Inhibition rate = (OD control group-OD drug group) / OD control group x 100%. The IC 50 of each compound is calculated by graphpad prism9 software.

[0062] The IC 50 of each compound is calculated by graphpad prism9 software. After repeating the experiment three times, take the average value. Treat HepG2, A375, A549, PANC-1 and MCF-7 cell lines with the test compounds for 72h, detect and calculate the IC 50 values, the results are shown in Table 1.

[0063] Table 1 Anti-tumor activity of 2,2'-binaphthalene-4,4'-dicarboxylic aliphatic amino acid derivatives of the application

[0064]

[0065]

[0066] From Table 1, it can be seen that, in addition to compound 7, the other new compounds have certain anti-tumor activity against one or even five of the five cell strains A375, A549, PANC-1, MCF-7 and HepG2, which is better than 5-fluorouracil. Among them, compound 4 has strong anti-tumor activity against the five cell strains A375, A549, PANC-1, MCF-7 and HepG2, and the anti-tumor activity against the four cell strains A375, A549, PANC-1 and MCF-7 is better than 5-fluorouracil. In addition, for the A375 cell strain, compound 4 shows the highest inhibitory activity (IC 50 : 0.93 μmol / L). Compound 5 (IC 50 : 2.19 μmol / L) also has strong inhibitory activity against the MCF-7 cell strain, which is better than 5-fluorouracil. The above results show that the modification of 2,2'-binaphthalene-4,4'-dicarboxylic acid with aliphatic amino acid can enhance its anti-tumor activity.

[0067] Example 9 Acute toxicity experiment of 2,2'-biqunoline-4,4'-dicarboxylic fatty amino acid derivative of the present application

[0068] The compound 4 was selected for the acute toxicity experiment, 18-22 gram mice were randomly divided into normal saline group, low dose group 200 mg / kg, high dose group 400 mg / kg, 10 mice in each group, after the mice were administered continuously for 7 days, there was no significant change in body weight and hair, and no death phenomenon occurred, indicating that the 2,2'-biqunoline-4,4'-dicarboxylic fatty amino acid derivative of the present application has small toxicity and can be used for the preparation of anti-tumor drugs.

[0069] The above examples are only used to help illustrate the present application, and the embodiments of the present application are not limited by the above examples, and any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present application should be equivalent replacement methods, and are all included in the protection scope of the present application.

Claims

1. A 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative, characterized in that: The 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative is selected from compounds 1-6: Compound 1: , Compound 2: , Compound 3: , Compound 4: , Compound 5: , Compound 6: .

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

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

4. The use of the 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative of claim 1 or the pharmaceutical formulation of claim 2 or 3 in the preparation of antitumor drugs, characterized in that: When the 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative is compound 1 in claim 1, or when the pharmaceutical preparation of claim 2 or 3 contains compound 1 in claim 1, the tumor is breast cancer; When the 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative is compound 2 in claim 1, or when the pharmaceutical preparation of claim 2 or 3 contains compound 2 in claim 1, the tumor is malignant melanoma, non-small cell lung cancer, pancreatic cancer or breast cancer. When the 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative is compound 3 in claim 1, or when the pharmaceutical preparation of claim 2 or 3 contains compound 3 in claim 1, the tumor is breast cancer; When the 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative is compound 4 in claim 1, or when the pharmaceutical preparation of claim 2 or 3 contains compound 4 in claim 1, the tumor is liver cancer, malignant melanoma, non-small cell lung cancer, pancreatic cancer, or breast cancer. When the 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative is compound 5 of claim 1, or when the pharmaceutical preparation of claim 2 or 3 contains compound 5 of claim 1, the tumor is non-small cell lung cancer or breast cancer; When the 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivative is compound 6 of claim 1, or when the pharmaceutical preparation of claim 2 or 3 contains compound 6 of claim 1, the tumor is non-small cell lung cancer, pancreatic cancer, or breast cancer.

5. An antitumor drug, characterized in that: The antitumor drug comprises at least one of the 2,2'-biquinoline-4,4'-dicarboxylic acid aliphatic amino acid derivatives of claim 1, or comprises the pharmaceutical formulation of 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 with 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 process includes the following steps: adding 2,2'-biquinoline-4,4'-dicarboxylic acid or its salt, L-amino acid methyl ester or its hydrochloride salt, and HATU to an organic solvent for reaction to obtain an aliphatic amino acid derivative of 2,2'-biquinoline-4,4'-dicarboxylic acid.

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 solvents selected from 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 to 3; the molar ratio of the 2,2'-biquinoline-4,4'-dicarboxylic acid or its salt to HATU is 1:2 to 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, or L-threonine methyl ester.

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