Glycoconjugated Schiff base platinum anticancer complex as well as synthesis method and application thereof

Abstract

The invention discloses a glycoconjugated Schiff base platinum anticancer complex as well as a synthesis method and application thereof. The synthesis method of the sugar-conjugated Schiff base platinum anticancer complex comprises the following steps: (1) synthesizing a sugar-containing ligand L1; (2) synthesizing a Schiff base ligand; (3) synthesizing a platinum complex by using the Schiff base ligand; and (4) modifying the platinum complex by using the sugar ligand so as to synthesize the platinum anticancer complex. The glycoconjugated Schiff base platinum anticancer complex disclosed by the invention has better anticancer activity on gastric cancer and colorectal cancer; by introducing sugar molecules, the complex is safer, and meanwhile, the targeting property of the complex is improved.

Description

Technical Field:

[0001] The present invention belongs to the technical field of biomedicine, and particularly relates to a glycoconjugated Schiff base platinum-based anticancer complex, a synthesis method thereof, and an application thereof. Background Art:

[0002] With the continuous progress of society and the rapid development of technology, humanity has made breakthroughs in the pathogenesis and treatment of diseases. However, cancer remains one of the greatest disease challenges faced by humanity and is also one of the public health problems that countries around the world need to confront currently.

[0003] Facing cancer that invades human health and its increasing incidence rate, it is imperative to synthesize highly effective and low-toxic anticancer drugs. Since cisplatin has been widely used in clinical treatment globally, the research and development of metal anticancer drugs have become a hot topic. Currently, the platinum-based anticancer drugs widely used in clinical practice have good anticancer effects, but there are still some deficiencies, such as toxic side effects, drug resistance, poor selectivity, etc. Therefore, efforts should be made to synthesize new platinum-based anticancer drugs. Summary of the Invention:

[0004] The first object of the present invention is to provide a glycoconjugated Schiff base platinum-based anticancer complex.

[0005] The second object of the present invention is to provide a synthesis method of a glycoconjugated Schiff base platinum-based anticancer complex.

[0006] The third object of the present invention is to further provide a synthesis method of a glycoconjugated Schiff base platinum-based anticancer complex.

[0007] The fourth object of the present invention is to further provide a synthesis method of a glycoconjugated Schiff base platinum-based anticancer complex.

[0008] The fifth object of the present invention is to further provide a synthesis method of a glycoconjugated Schiff base platinum-based anticancer complex.

[0009] The sixth object of the present invention is to provide an application of a glycoconjugated Schiff base platinum-based anticancer complex in the preparation of antitumor drugs.

[0010] The first object of the present invention is implemented by the following technical solution: A glycoconjugated Schiff base platinum-based anticancer complex, characterized in that the complex is any one of complex C1, complex C2, complex C3, and complex C4; the structural formulas of the complex C1, complex C2, complex C3, and complex C4 are respectively shown as Formula I, Formula II, Formula III, and Formula IV:

[0011]

[0012] Formula I, Formula II, Formula III, Formula IV

[0013] Wherein, in Formula I, R is selected from a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group or a nitro group; in Formula III, R is selected from a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group or a nitro group.

[0014] The second object of the present invention is implemented by the following technical solution: a method for synthesizing a sugar-conjugated Schiff base platinum-based anticancer complex, which comprises the following steps:

[0015] (1) Synthesis of the sugar-containing ligand L1: Dissolve 4-hydroxypyridine in an NaOH solution to obtain Solution I, quickly pour Solution I into an AgNO3 solution, stir for 30 min, filter, wash, and dry to obtain a solid; add acetyl bromide-α-D-glucose to the obtained solid and dissolve it in toluene, reflux at 120 °C for 2 h, monitor the reaction by TLC, after the reaction is completed, filter the reaction solution, wash with water, dry, and perform column chromatography separation on the dried solution to obtain the sugar-containing ligand L1;

[0016] (2) Synthesis of the Schiff base ligand: Add salicylaldehyde or a derivative of salicylaldehyde and 2-(phenylthio)aniline to an ethanol solution, heat under reflux for reaction, and obtain the Schiff base ligand after the reaction is completed;

[0017] (3) Synthesis of the platinum-based complex using the Schiff base ligand: Add the Schiff base ligand, sodium acetate, and a pre-prepared K2PtCl4 solution to a methanol solution, carry out the reaction at 60 °C, monitor the completion of the reaction by TLC, filter the obtained solid, wash, and dry to obtain the platinum-based complex;

[0018] (4) Modify the platinum-based complex with the sugar ligand to further synthesize the platinum-based anticancer complex: Dissolve the platinum-based complex obtained in step (3) in dichloromethane and ethanol solvents, add silver tetrafluoroborate, reflux the reaction at 60 °C overnight, monitor the reaction by TLC, after the reaction is completed, wait for the reaction to cool, add dichloromethane solvent, filter with diatomaceous earth, wash with dichloromethane, add the sugar-containing ligand L1, react overnight, monitor the reaction by TLC, after the reaction is completed, spin-dry the reaction solution, add a small amount of ethanol, adjust the water bath to the temperature for recrystallization with ethanol, continue to add ethanol until it just dissolves, put it in the refrigerator to cool and crystallize to obtain the complex C3 solid.

[0019] The third object of the present invention is implemented by the following technical solution: a method for synthesizing a sugar-conjugated Schiff base platinum-based anticancer complex, which comprises the following steps:

[0020] (1) Synthesis of sugar-containing ligand L1: Dissolve 4-hydroxypyridine in NaOH solution to obtain solution I. Pour solution I quickly into AgNO₃ solution, stir for 30 min, filter, wash, and dry to obtain a solid. Add acetyl bromo-α-D-glucose to the obtained solid and dissolve it in toluene. Reflux at 120 °C for 2 h. Monitor the reaction by TLC. After the reaction is completed, filter the reaction solution, wash it with water, dry it, and perform column chromatography separation on the dried solution to obtain sugar-containing ligand L1;

[0021] (2) Synthesis of Schiff base ligand: Add salicylaldehyde or its derivative and 2-(methylthio)aniline to an ethanol solution, heat under reflux, and monitor the completion of the reaction by TLC to obtain the Schiff base ligand;

[0022] (3) Synthesis of platinum complex using Schiff base ligand: Add the Schiff base ligand, sodium acetate, and the pre-prepared K₂PtCl₄ solution to a methanol solution, and carry out the reaction at 60 °C. Monitor the completion of the reaction by TLC. Filter the obtained solid, wash it, and dry it to obtain the platinum complex.

[0023] (4) Modify the platinum complex with sugar ligand to synthesize platinum-based anticancer complex: Dissolve the platinum complex obtained in step (3) in dichloromethane and ethanol solvents, add silver tetrafluoroborate, and reflux the reaction overnight at 60 °C. Monitor the reaction by TLC. After the reaction is completed, wait for the reaction to cool, add dichloromethane solvent, filter with diatomaceous earth, wash with dichloromethane, add sugar-containing ligand L1, and react overnight. Monitor the reaction by TLC. After the reaction is completed, spin-dry the reaction solution, add a small amount of ethanol, adjust the water bath to the temperature for recrystallization with ethanol, continue to add ethanol until it just dissolves, put it in the refrigerator to cool and crystallize to obtain the solid of complex C1.

[0024] Further, the derivative of salicylaldehyde is any one of 5-fluorosalicylaldehyde, 5-chlorosalicylaldehyde, 5-bromosalicylaldehyde, 5-methylsalicylaldehyde, 5-methoxysalicylaldehyde, and 5-nitrosalicylaldehyde.

[0025] The fourth object of the present invention is implemented by the following technical solution: A method for synthesizing a sugar-conjugated Schiff base platinum-based anticancer complex, which comprises the following steps:

[0026] (1) Synthesis of sugar-containing ligand L1: Dissolve 4-hydroxypyridine in NaOH solution to obtain solution I. Pour solution I quickly into AgNO₃ solution, stir for 30 min, filter, wash, and dry to obtain a solid. Add acetyl bromo-α-D-glucose to the obtained solid and dissolve it in toluene. Reflux at 120 °C for 2 h. Monitor the reaction by TLC. After the reaction is completed, filter the reaction solution, wash it with water, dry it, and perform column chromatography separation on the dried solution to obtain sugar-containing ligand L1;

[0027] (2) Synthesis of Schiff base ligand: Add 2-hydroxy-1-naphthaldehyde and 2-(methylthio)aniline into an ethanol solution, heat under reflux, monitor the completion of the reaction by TLC, and obtain the Schiff base ligand;

[0028] (3) Synthesis of platinum complexes using the Schiff base ligand: Add the Schiff base ligand, sodium acetate, and the pre-prepared K2PtCl4 solution into a methanol solution, carry out the reaction at 60 °C, monitor the completion of the reaction by TLC, filter, wash, and dry the obtained solid to obtain the platinum complexes.

[0029] (4) Modify the platinum complexes with sugar ligands to synthesize platinum-based anticancer complexes: Dissolve the platinum complexes obtained in step (3) in dichloromethane and ethanol solvents, add silver tetrafluoroborate, reflux the reaction overnight at 60 °C, monitor the reaction by TLC, after the reaction is completed, wait for the reaction to cool, add dichloromethane solvent, filter with diatomaceous earth, wash with dichloromethane, add the sugar ligand L1, react overnight, monitor the reaction by TLC, after the reaction ends, spin-dry the reaction solution, add a small amount of ethanol, adjust the water bath to the temperature for recrystallization with ethanol, continue to add ethanol until it just dissolves, put it in the refrigerator to cool and crystallize to obtain the solid of complex C2.

[0030] The fifth object of the present invention is implemented by the following technical solution: A method for synthesizing a sugar-conjugated Schiff base platinum-based anticancer complex, which comprises the following steps:

[0031] (1) Synthesis of sugar ligand L1: Dissolve 4-hydroxypyridine in an NaOH solution to obtain solution I, quickly pour solution I into an AgNO3 solution, stir for 30 min, filter, wash, and dry to obtain a solid; Add acetyl bromide-α-D-glucose to the obtained solid and dissolve it in toluene, reflux at 120 °C for 2 h, monitor the reaction by TLC, after the reaction ends, filter, wash with water, and dry the reaction solution, and carry out column chromatography separation on the dried solution to obtain the sugar ligand L1;

[0032] (2) Synthesis of Schiff base ligand: Add 2-hydroxy-1-naphthaldehyde and 2-(phenylthio)aniline into an ethanol solution, heat under reflux, monitor the completion of the reaction by TLC, and obtain the Schiff base ligand;

[0033] (3) Synthesis of platinum complexes using the Schiff base ligand: Add the Schiff base ligand, sodium acetate, and the pre-prepared K2PtCl4 solution into a methanol solution, carry out the reaction at 60 °C, monitor the completion of the reaction by TLC, filter, wash, and dry the obtained solid to obtain the platinum complexes.

[0034] (4) Synthesize platinum-based anticancer complexes by modifying platinum-based complexes with sugar ligands: Dissolve the platinum-based complexes obtained in step (3) in dichloromethane and ethanol solvents, add silver tetrafluoroborate, and reflux the reaction overnight at 60 °C. Monitor the reaction by TLC. After the reaction is complete, let the reaction cool, add dichloromethane solvent, filter with diatomaceous earth, wash with dichloromethane, add sugar ligand L1, and react overnight. Monitor the reaction by TLC. After the reaction ends, spin-dry the reaction solution, add a small amount of ethanol, adjust the water bath to the temperature for recrystallization with ethanol, continue to add ethanol until it just dissolves, put it in the refrigerator to cool and crystallize to obtain solid complex C4.

[0035] The sixth object of the present invention is implemented by the following technical solution: The application of sugar-conjugated Schiff base platinum-based anticancer complexes in the preparation of anti-tumor drugs.

[0036] Further, the tumor is gastric cancer or colorectal cancer.

[0037] The specific synthesis strategy is shown in the following reaction formula:

[0038]

[0039] The present invention conducts research from two aspects. On the one hand, by changing the leaving group, based on the fact that Schiff base ligands have certain biological activities, different Schiff base ligands are synthesized and the corresponding platinum-based complexes are synthesized, aiming to synthesize anti-cancer drugs with better biological activities. On the other hand, some sugar molecules are introduced. Since platinum-based anti-cancer drugs have certain toxicities, sugar molecules are introduced with the goal of further modifying these ligands with sugar molecules to make these complexes safer. More importantly, the advantage of glycosylation modification is that it can improve the controllability of targeted delivery of anti-tumor drugs. This modification will help these complexes be better taken up by cancer cells and improve the targeting of the complexes. Based on the above, the present invention is committed to synthesizing sugar-conjugated Schiff base platinum-based complexes, and the synthesis of the novel platinum-based anti-cancer drugs of the present invention will play an important role in promoting the entire anti-tumor drug field.

[0040] Advantages of the present invention: The sugar-conjugated Schiff base platinum-based anti-cancer complexes of the present invention have better anti-cancer activities; by introducing sugar molecules, while making the complex safer, the targeting of the complex is improved. Description of the drawings:

[0041] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0042] Figure 1 : Bioactivity graphs of glycoconjugated Schiff base platinum anticancer complexes C1-C12 against human gastric cancer MKN45 cell line at different drug dosages under dark conditions.

[0043] Figure 2 : Bioactivity graphs of glycoconjugated Schiff base platinum anticancer complexes C1-C12 against human colorectal cancer RPMI4788 cell line at different drug dosages under dark conditions.

[0044] Figure 3 : Hoechst33342 staining graphs of glycoconjugated Schiff base platinum anticancer complex C12 against human colorectal cancer RPMI4788 cell line at different drug dosages under dark conditions.

[0045] Figure 4 : Hoechst33342 staining graphs of glycoconjugated Schiff base platinum anticancer complex C9 against human gastric cancer MKN45 cell line at different drug dosages under dark conditions.

[0046] Figure 5 : Bioactivity graphs of glycoconjugated Schiff base platinum anticancer complex C9 against GLUT inhibitor of human gastric cancer MKN45 cell line at different drug dosages under dark conditions.

[0047] Figure 6 : Bioactivity graphs of glycoconjugated Schiff base platinum anticancer complex C12 against GLUT inhibitor of human gastric cancer MKN45 cell line at different drug dosages under dark conditions.

[0048] Figure 7 : Bioactivity graphs of glycoconjugated Schiff base platinum anticancer complex C12 against GLUT inhibitor of human colorectal cancer RPMI4788 cell line at different drug dosages under dark conditions.

[0049] Figure 8 : Bioactivity graphs of glycoconjugated Schiff base platinum anticancer complex C9 against GLUT inhibitor of human colorectal cancer RPMI4788 cell line at different drug dosages under dark conditions.

[0050] Figure 9 : Bioactivity graphs of cisplatin against human colorectal cancer RPMI4788 cell line.

[0051] Figure 10 : Bioactivity graphs of cisplatin against human gastric cancer MKN45 cell line.

[0052] Figure 11 : Bioactivity graphs of oxaliplatin against human gastric cancer MKN45 cell line.

[0053] Figure 12 :Bioactivity diagram of oxaliplatin against human colorectal cancer RPMI4788 cell line. Specific implementation mode:

[0054] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0055] Example 1: Synthesis method of complex 1 (C1).

[0056] The structural formula of complex 1 (C1) is:

[0057]

[0058] Synthesis of sugar ligand L1: Weigh 10 mmol of AgNO3 and add it to a reaction flask, dissolve it with deionized water to obtain an AgNO3 solution; dissolve 10 mmol of NaOH in deionized water to prepare a NaOH solution, and then dissolve 10 mmol of 4-hydroxypyridine in the prepared NaOH solution to obtain solution I; quickly pour the prepared solution I into the AgNO3 solution, stir for 30 min, filter, and then wash with water and methanol solution in sequence to obtain a solid. Vacuum dry the solid and continue the next reaction. Weigh 3 mmol of this solid and weigh 1 mmol of acetyl bromide-α-D-glucose, dissolve them in toluene, reflux at 120 °C for 2 h, monitor the reaction by TLC. After the reaction is completed, filter with diatomaceous earth, wash the filtrate obtained by filtration 3 times with water, dry it with anhydrous MgSO4, spin-dry the water in the filtered solution, and then perform column chromatography separation (the eluent is EA) to obtain sugar ligand L1, with a yield of 67%.

[0059] Synthesis of Schiff base ligand L2: Dissolve 1 mmol of 2-(methylthio)aniline in 20 mL of ethanol in a reaction flask, add 2 mmol of salicylaldehyde, heat under reflux, and stir until the reaction is complete (monitored by TLC). After completion, cool the reaction solution in the refrigerator to crystallize out a solid, filter the solid and wash it with cold ethanol to obtain the solid, namely Schiff base ligand L2.

[0060] Synthesis of platinum complexes using Schiff base ligands: Add 0.1 mmol of K2PtCl4 (potassium tetrachloroplatinate) to a reaction flask, add 1 mL - 2 mL of DMSO (dimethyl sulfoxide), stir and dissolve it at 50 °C until all the red solid dissolves to form a yellow solution. Weigh 0.1 mmol of Schiff base ligand L2 and 0.2 mmol of NaOAc (sodium acetate) and add them to the reaction flask. Then add 25 mL of MeOH (methanol) and carry out the reaction at 60 °C overnight. After monitoring the reaction by TLC and completion of the reaction, distill the reaction solution under reduced pressure, add water, wash it by ultrasonic treatment, filter to obtain a solid, and dry the solid to obtain the platinum complex.

[0061] Modifying the platinum complex with a sugar ligand and then synthesizing the platinum anticancer complex C1: Add the platinum complex obtained in the previous step to a reaction flask, add 15 mL of DCM (dichloromethane) and 15 mL of EtOH (ethanol) to dissolve it, add 0.2 mmol of AgBF4 (silver tetrafluoroborate), and reflux the reaction at 60 °C overnight. Monitor the reaction by TLC. After the reaction is completed and cooled, add 15 mL of DCM, filter with diatomaceous earth, wash with DCM, add 0.12 mmol of sugar ligand L1, and react overnight. Monitor the reaction by TLC (the developing agent is DCM:MeOH = 100:7). After the reaction is completed, distill the reaction solution under reduced pressure, add a small amount of ethanol, adjust the water bath to 80 °C, continue to add ethanol until it just dissolves, then put it in the refrigerator to cool and crystallize to obtain a solid, which is the target product complex C1, a yellow solid. R f = 0.42 (DCM:MeOH = 100:7), and the yield is 50.5%. 11H NMR (600 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.93 (d, J = 6.5 Hz, 2H), 8.54 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 7.7 Hz, 1H), 8.00 (d, J = 8.9 Hz, 1H), 7.72 - 7.68 (m, 1H), 7.68 - 7.64 (m, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.41 (d, J = 6.2 Hz, 2H), 7.02 (d, J = 8.5 Hz, 1H), 6.91 (t, J = 7.0 Hz, 1H), 5.98 (d, J = 8.0 Hz, 1H), 5.45 (t, J = 9.5 Hz, 1H), 5.22 - 5.18 (m, 1H), 5.11 - 5.07 (m, 1H), 4.40 - 4.36 (m, 1H), 4.26 - 4.20 (m, 1H), 4.13 (t, J = 10.8 Hz, 1H), 2.88 (s, 3H), 2.05 (s, 2H), 2.05 (s, 3H), 2.03 (s, 3H), 2.02 (s, 1H), 2.00 (s, 3H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 170.47, 170.11, 169.77, 169.56, 164.80, 162.75, 156.30, 154.40, 152.88, 138.12, 136.97, 132.61, 132.38, 130.34, 127.38, 121.35, 120.57, 119.41, 118.31, 115.00, 96.39, 72.19, 71.89, 70.69, 68.10, 61.86, 28.82, 20.96, 20.85, 20.80, 20.74 ppm. HRMS (ESI): Calcd for C 33 H 35 N2O 11 SPt: 862.1609. Found: 862.1608, [M - BF4] + . FT-IR (KBr Pellet) cm -1 : 3439, 2931, 1745, 1611, 1514, 1392, 1234, 1059, 755.

[0062] Example 2: Synthesis method of complex 2 (C2).

[0063] The structural formula of complex 2 (C2) is:

[0064]

[0065] Replace salicylaldehyde with 5-fluorosalicylaldehyde, and the other required reagents and preparation method are the same as in Example 1 to obtain ligand L3. Replace ligand L2 with L3, and the other required reagents and preparation method are the same as in Example 1 to obtain the target product C2, a yellow solid. R f = 0.38 (DCM:MeOH = 100:7), and the yield is 70.0%. 1 1H NMR (600 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.92 (d, J = 7.0 Hz, 2H), 8.47 (d, J = 8.6 Hz, 1H), 8.20 (d, J = 7.9 Hz, 1H), 7.81 (dd, J = 9.2, 2.7 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.60 (t, J = 7.7 Hz, 2H), 7.40 (d, J = 6.1 Hz, 2H), 7.05 (d, J = 9.3 Hz, 1H), 5.98 (d, J = 7.8 Hz, 1H), 5.45 (t, J = 9.8 Hz, 1H), 5.22 - 5.17 (m, 1H), 5.09 (td, J = 9.8, 2.3 Hz, 1H), 4.40 - 4.36 (m, 1H), 4.23 (td, J = 13.3, 5.4 Hz, 1H), 4.13 (t, J = 11.1 Hz, 1H), 2.88 (s, 3H), 2.05 (s, 2H), 2.04 (s, 3H), 2.03 (s, 3H), 2.02 (s, 1H), 2.00 (s, 3H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 170.47, 170.11, 169.77, 169.56, 164.86, 159.60, 155.69, 154.79, 154.34, 153.24, 152.65, 132.66, 132.44, 130.59, 127.58, 126.67, 126.51, 122.32, 122.24, 120.29, 120.23, 119.36, 119.04, 118.89, 115.01, 96.39, 72.19, 71.90, 70.69, 68.11, 61.86, 28.78, 20.97, 20.85, 20.80, 20.74 ppm. HRMS (ESI): Calcd for C 33 H 34 N2O 11 SPtF: 880.1515. Found: 880.1513, [M - BF4] + .FT-IR (KBr Pellet) cm -1:3423,2932,1746,1616,1522,1388,1226,1059,835,758.

[0066] Example 3: Synthesis method of complex 3 (C3).

[0067] The structural formula of complex 3 (C3) is as follows:

[0068]

[0069] Replace salicylaldehyde with 5-chlorosalicylaldehyde, and the other required reagents and preparation methods are the same as those in Example 1 to obtain ligand L4. Replace ligand L2 with L4, and the other required reagents and preparation methods are the same as those in Example 1 to obtain the target product C3, a brown-yellow solid. R f = 0.58 (DCM:MeOH = 100:7), and the yield is 70.8%. 1 1H NMR (600 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.91 (d, J = 6.3 Hz, 2H), 8.48 (d, J = 8.5 Hz, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.10 (s, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 9.5 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.40 (d, J = 6.4 Hz, 2H), 7.05 (d, J = 8.3 Hz, 1H), 5.97 (d, J = 7.8 Hz, 1H), 5.45 (t, J = 9.5 Hz, 1H), 5.22 - 5.17 (m, 1H), 5.09 (t, J = 8.6 Hz, 1H), 4.40 - 4.35 (m, 1H), 4.25 - 4.19 (m, 1H), 4.13 (t, J = 11.2 Hz, 1H), 2.88 (s, 3H), 2.05 (s, 2H), 2.04 (s, 3H), 2.03 (s, 3H), 2.02 (s, 1H), 2.00 (s, 3H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 170.47, 170.11, 169.77, 169.55, 164.89, 161.32, 155.90, 154.36, 152.59, 137.36, 134.62, 132.69, 132.41, 130.69, 127.65, 122.70, 122.11, 121.18, 119.41, 115.03, 96.39, 72.19, 71.89, 70.69, 68.10, 61.86, 28.79, 20.97, 20.85, 20.80, 20.74 ppm. HRMS (ESI): Calcd for C33 H 34 N2O 11 SPtCl: 896.1220. Found: 896.1216, [M - BF4] + .FT - IR(KBr Pellet) cm -1 : 3452, 2935, 1752, 1609, 1511, 1388, 1231, 1057, 837, 748.

[0070] Example 4: Synthesis method of complex 4 (C4).

[0071] The structural formula of complex 4 (C4) is:

[0072]

[0073] Replace salicylaldehyde with 5 - bromosalicylaldehyde, and the other required reagents and preparation methods are the same as in Example 1 to obtain ligand L5. Replace ligand L2 with L5, and the other required reagents and preparation methods are the same as in Example 1 to obtain the target product C4, a green solid. R f = 0.31 (DCM:MeOH = 100:7), and the yield is 56.0%. 1 H NMR(600 MHz, DMSO - d6) δ 9.57(s, 1H), 8.91(d, J = 6.5 Hz, 2H), 8.48(d, J = 8.7 Hz, 1H), 8.24(s, 1H), 8.20(d, J = 7.9 Hz, 1H), 7.73(dd, J = 21.6, 8.7 Hz, 2H), 7.60(t, J = 7.6 Hz, 1H), 7.40(d, J = 6.4 Hz, 2H), 6.99(d, J = 9.0 Hz, 1H), 5.98(d, J = 7.8 Hz, 1H), 5.45(t, J = 9.5 Hz, 1H), 5.22 - 5.18(m, 1H), 5.10(t, J = 9.6 Hz, 1H), 4.39(dd, J = 6.5, 3.0 Hz, 1H), 4.25 - 4.20(m, 1H), 4.13(t, J = 10.8 Hz, 1H), 2.88(s, 3H), 2.05(s, 2H), 2.04(s, 3H), 2.03(s, 3H), 2.02(s, 1H), 2.00(s, 3H) ppm. 1313C NMR(150 MHz, DMSO-d6) δ 170.45, 170.11, 169.77, 169.56, 164.86, 161.58, 155.74, 154.35, 152.57, 139.88, 137.78, 132.69, 132.39, 130.68, 127.64, 123.03, 122.93, 119.44, 115.02, 108.37, 96.38, 72.19, 71.89, 70.68, 68.09, 61.86, 28.80, 20.98, 20.86, 20.80, 20.74 ppm. HRMS(ESI): Calcd for C 33 H 34 N2O 11 SPtBr: 940.0714. Found: 940.0710, [M - BF4] + . FT-IR(KBr Pellet) cm -1 : 3456, 2935, 1748, 1608, 1511, 1388, 1231, 1049, 833, 744, 633.

[0074] Example 5: Synthesis method of complex 5 (C5).

[0075] The structural formula of complex 5 (C5) is:

[0076]

[0077] Replace salicylaldehyde with 5-methylsalicylaldehyde, and the other required reagents and preparation methods are the same as in Example 1 to obtain ligand L6. Replace ligand L2 with L6, and the other required reagents and preparation methods are the same as in Example 1 to obtain the target product C5, a yellow solid. R f = 0.35 (DCM:MeOH = 10:1), and the yield is 53.9%. 11H NMR (600 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.92 (d, J = 6.4 Hz, 2H), 8.52 (d, J = 8.6 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.77 (s, 1H), 7.69 (t, J = 8.1 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 6.2 Hz, 2H), 6.95 (d, J = 8.9 Hz, 1H), 5.98 (d, J = 9.0 Hz, 1H), 5.47 - 5.43 (m, 1H), 5.22 - 5.18 (m, 1H), 5.10 (t, J = 9.6 Hz, 1H), 4.40 - 4.36 (m, 1H), 4.25 - 4.20 (m, 1H), 4.13 (t, J = 11.9 Hz, 1H), 2.87 (s, 3H), 2.31 (s, 3H), 2.05 (s, 1H), 2.04 (s, 3H), 2.03 (s, 3H), 2.02 (s, 2H), 2.00 (s, 3H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 170.44, 170.11, 169.77, 169.56, 164.77, 161.28, 155.82, 154.37, 152.92, 139.86, 135.42, 132.61, 132.38, 130.18, 127.33, 126.68, 120.89, 120.38, 119.27, 114.97, 96.38, 72.19, 71.88, 70.68, 68.10, 61.86, 28.76, 20.96, 20.86, 20.80, 20.74, 20.09 ppm. HRMS (ESI): Calcd for C 34 H 37 N2O 11 SPt: 876.1766. Found: 876.1766 [M - BF4] + . FT-IR (KBr Pellet) cm -1 : 3443, 2935, 1749, 1616, 1519, 1388, 1231, 1062, 833, 748, 668.

[0078] Example 6: Synthesis method of complex 6 (C6).

[0079] The structural formula of complex 6 (C6) is:

[0080]

[0081] Replace salicylaldehyde with 5-methoxysalicylaldehyde, and the rest of the required reagents and preparation methods are the same as those in Example 1 to obtain ligand L7. Replace ligand L2 with L7, and the rest of the required reagents and preparation methods are the same as those in Example 1 to obtain the target product C6, a red solid. R f = 0.37 (DCM:MeOH = 10:1), and the yield is 58.8%. 1 1H NMR (600 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.92 (d, J = 6.5 Hz, 2H), 8.50 (d, J = 8.7 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.70 (t, J = 5.9 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.52 - 7.49 (m, 1H), 7.40 (d, J = 6.4 Hz, 2H), 7.36 (d, J = 7.9 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H), 5.98 (d, J = 8.0 Hz, 1H), 5.45 (t, J = 9.5 Hz, 1H), 5.22 - 5.17 (m, 1H), 5.10 (t, J = 9.7 Hz, 1H), 4.40 - 4.36 (m, 1H), 4.23 (td, J = 13.9, 13.4, 5.2 Hz, 1H), 4.13 (d, J = 23.4 Hz, 1H), 3.79 (s, 3H), 2.87 (s, 3H), 2.05 (s, 2H), 2.04 (s, 3H), 2.03 (s, 3H), 2.00 (s, 3H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 170.47, 170.11, 169.77, 169.56, 164.76, 158.61, 155.30, 154.33, 152.94, 150.96, 132.57, 132.42, 130.11, 129.04, 127.28, 121.63, 120.15, 119.11, 114.96, 114.76, 96.43, 72.20, 71.90, 70.69, 68.12, 61.86, 56.01, 28.75, 20.97, 20.85, 20.80, 20.74 ppm. HRMS (ESI): Calcd for C 34 H 37 N2O 12 SPt: 892.1715. Found: 892.1704, [M - BF4] + . FT-IR (KBr Pellet) cm -1 : 3452, 2939, 1753, 1613, 1524, 1388, 1231, 1058, 833, 752.

[0082] Example 7: Synthesis method of complex 7 (C7).

[0083] The structural formula of complex 7 (C7) is:

[0084]

[0085] Replace salicylaldehyde with 5-nitrosalicylaldehyde, and the other required reagents and preparation methods are the same as in Example 1 to obtain ligand L8. Replace ligand L2 with L8, and the other required reagents and preparation methods are the same as in Example 1 to obtain the target product C7, a yellow solid. R f = 0.36 (DCM:MeOH = 10:1), and the yield is 50.9%. 1 1H NMR (600 MHz, DMSO-d6) δ 9.83 (s, 1H), 9.17 (d, J = 3.0 Hz, 1H), 8.93 (d, J = 6.2 Hz, 2H), 8.56 (d, J = 8.6 Hz, 1H), 8.42 (d, J = 9.4 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.42 (d, J = 6.3 Hz, 2H), 7.14 (d, J = 9.4 Hz, 1H), 5.98 (d, J = 7.9 Hz, 1H), 5.45 (t, J = 9.6 Hz, 1H), 5.20 (t, J = 8.8 Hz, 1H), 5.10 (t, J = 9.9 Hz, 1H), 4.40 - 4.37 (m, 1H), 4.23 (d, J = 4.9 Hz, 1H), 4.13 (t, J = 11.9 Hz, 1H), 2.90 (s, 3H), 2.05 (s, 4H), 2.03 (s, 3H), 2.02 (s, 2H), 2.00 (s, 3H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 170.49, 170.13, 169.78, 169.57, 166.13, 164.97, 157.25, 154.37, 152.16, 138.60, 134.74, 132.80, 132.37, 131.26, 130.92, 127.88, 122.05, 120.89, 119.82, 115.12, 96.40, 72.17, 71.88, 70.66, 68.07, 61.84, 28.88, 20.99, 20.86, 20.81, 20.75 ppm. HRMS (ESI): Calcd for C 33 H 34 N3O 13SPt: 907.1460. Found: 907.1459, [M-BF4] + .FT-IR (KBr Pellet) cm -1 : 3451, 2934, 1752, 1612, 1523, 1484, 1324, 1234, 1057, 824, 739, 667.

[0086] Example 8: Synthesis method of complex 8 (C8).

[0087] The structural formula of complex 8 (C8) is:

[0088]

[0089] Replace salicylaldehyde with 2-hydroxy-1-naphthaldehyde, and the other required reagents and preparation methods are the same as in Example 1 to obtain ligand L9. Replace ligand L2 with L9, and the other required reagents and preparation methods are the same as in Example 1 to obtain the target product C8, a yellow solid. Rf = 0.35 (DCM:MeOH = 100:7), and the yield is 50.1%. 1 H NMR (600 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.97 (d, J = 6.3 Hz, 2H), 8.63 (dd, J = 28.0, 8.5 Hz, 2H), 8.16 (dd, J = 15.9, 8.5 Hz, 2H), 7.92 (d, J = 7.8 Hz, 1H), 7.69 (dt, J = 14.4, 7.8 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.42 (d, J = 6.3 Hz, 2H), 7.20 (d, J = 9.2 Hz, 1H), 5.99 (d, J = 7.9 Hz, 1H), 5.46 (t, J = 9.6 Hz, 1H), 5.21 (t, J = 8.9 Hz, 1H), 5.10 (q, J = 6.5 Hz, 1H), 4.42 - 4.36 (m, 1H), 4.24 (ddd, J = 17.4, 12.6, 5.2 Hz, 1H), 4.14 (t, J = 12.5 Hz, 1H), 2.91 (s, 3H), 2.05 (s, 4H), 2.04 (s, 3H), 2.03 (s, 2H), 2.00 (s, 3H) ppm. 1313C NMR (150 MHz, DMSO-d6) δ 170.48, 170.12, 169.77, 169.57, 164.80, 164.31, 154.45, 153.65, 148.94, 139.01, 133.87, 132.63, 132.24, 129.68, 129.61, 129.05, 128.13, 126.82, 124.74, 123.11, 122.27, 119.83, 115.03, 112.33, 96.40, 72.20, 71.90, 70.70, 68.10, 61.86, 28.90, 20.97, 20.86, 20.82, 20.75 ppm. HRMS (ESI): Calcd for C 37 H 37 N2O 11 SPt: 912.1766. Found: 912.1759, [M - BF4] + . FT-IR (KBr Pellet) cm -1 : 3443, 2930, 1748, 1621, 1388, 1231, 1062, 841, 748, 668.

[0090] Example 9: Synthesis method of complex 9 (C9).

[0091] The structural formula of complex 9 (C9) is:

[0092]

[0093] Replace 2-(methylthio)aniline with 2-(phenylthio)aniline, and use the same other required reagents and preparation method as in Example 1 to obtain ligand L10. Replace ligand L2 with L10, and use the same other required reagents and preparation method as in Example 1 to obtain the target product C9, a yellow solid. R f = 0.40 (DCM:MeOH = 100:7), and the yield is 47.7%, 11H NMR (600 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.75 (dd, J = 16.7, 6.3 Hz, 2H), 8.62 (d, J = 8.7 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.81 - 7.74 (m, 2H), 7.74 - 7.66 (m, 2H), 7.53 (dt, J = 14.9, 7.6 Hz, 2H), 7.47 (q, J = 7.4 Hz, 2H), 7.35 - 7.29 (m, 2H), 7.04 (d, J = 8.7 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 5.93 (dd, J = 7.9, 5.1 Hz, 1H), 5.40 (td, J = 9.6, 4.8 Hz, 1H), 5.19 - 5.13 (m, 1H), 5.07 (td, J = 9.8, 6.0 Hz, 1H), 4.33 (t, J = 8.2 Hz, 1H), 4.20 (ddd, J = 20.0, 12.4, 5.5 Hz, 1H), 4.11 (dd, J = 17.4, 12.5 Hz, 1H), 2.03 (s, 4H), 2.02 (s, 3H), 1.99 (s, 3H), 1.96 (s, 2H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 170.41, 170.09, 169.76, 169.53, 164.77, 162.80, 156.85, 154.02, 152.90, 138.34, 137.11, 133.07, 132.89, 132.55, 131.81, 131.03, 130.90, 130.82, 127.34, 121.35, 120.45, 119.71, 118.53, 115.01, 96.35, 72.15, 71.88, 70.61, 68.04, 61.80, 20.94, 20.85, 20.78, 20.73 ppm. HRMS (ESI): Calcd for C 38 H 37 N2O 11 SPt: 924.1766. Found: 924.1765 [M - BF4] + . FT-IR (KBr Pellet) cm -1 : 3448, 2930, 1752, 1612, 1519, 1388, 1231, 1066, 841, 757, 659.

[0094] Example 10: Synthesis method of complex 10 (C10).

[0095] The structural formula of complex 10 (C10) is as follows:

[0096]

[0097] Replace salicylaldehyde with 5-methylsalicylaldehyde and 2-(methylthio)aniline with 2-(phenylthio)aniline. The rest of the required reagents and the preparation method are the same as in Example 1 to obtain ligand L11. Replace ligand L2 with L11, and the rest of the required reagents and the preparation method are the same as in Example 1 to obtain the target product C10, a yellow solid. R f = 0.35 (DCM:MeOH = 10:1), and the yield is 48.6%. 1 1H NMR (600 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.75 (dd, J = 16.3, 6.3 Hz, 2H), 8.61 (d, J = 8.7 Hz, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.82 (s, 1H), 7.77 (t, J = 6.5 Hz, 2H), 7.71 (t, J = 7.9 Hz, 1H), 7.52 (dt, J = 19.1, 7.4 Hz, 3H), 7.46 (q, J = 7.4 Hz, 2H), 7.31 (d, J = 6.3 Hz, 2H), 6.97 (d, J = 8.7 Hz, 1H), 5.92 (dd, J = 7.7, 5.4 Hz, 1H), 5.40 (td, J = 9.7, 5.0 Hz, 1H), 5.16 (t, J = 8.7 Hz, 1H), 5.07 (td, J = 9.7, 5.9 Hz, 1H), 4.32 (t, J = 7.9 Hz, 1H), 4.20 (dt, J = 19.9, 6.4 Hz, 1H), 4.13 - 4.07 (m, 1H), 2.34 (s, 3H), 2.03 (s, 7H), 1.99 (s, 3H), 1.96 (s, 2H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 170.40, 170.10, 169.78, 169.53, 164.74, 161.32, 156.38, 154.00, 152.99, 140.07, 135.55, 133.09, 132.89, 132.53, 131.80, 131.02, 130.66, 127.27, 126.94, 120.87, 120.26, 119.56, 114.97, 96.38, 72.14, 71.88, 70.60, 68.03, 61.80, 20.94, 20.85, 20.78, 20.73, 20.11 ppm HRMS (ESI): Calcd for C 39 H 39 N2O 11SPt: 938.1922. Found: 938.1924 [M-BF4] + .FT-IR (KBr Pellet) cm -1 : 3435, 2926, 1752, 1609, 1519, 1456, 1383, 1231, 1057, 837, 752.

[0098] Example 11: Synthesis method of complex 11 (C11).

[0099] The structural formula of complex 11 (C11) is:

[0100]

[0101] Replace salicylaldehyde with 5-nitrosalicylaldehyde and 2-(methylthio)aniline with 2-(phenylthio)aniline. The other required reagents and preparation methods are the same as in Example 1 to obtain ligand L12. Replace ligand L2 with L12, and the other required reagents and preparation methods are the same as in Example 1 to obtain the target product C11, a yellow solid. R f = 0.36 (DCM:MeOH = 10:1), the yield is 47.1%, 1 1H NMR (600 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.21 (d, J = 3.0 Hz, 1H), 8.75 (dd, J = 16.1, 6.3 Hz, 2H), 8.65 (d, J = 8.7 Hz, 1H), 8.47 - 8.40 (m, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.86 - 7.79 (m, 2H), 7.78 (t, J = 7.9 Hz, 1H), 7.57 (dt, J = 16.8, 7.9 Hz, 2H), 7.48 (q, J = 7.5 Hz, 2H), 7.34 (dd, J = 7.1, 3.1 Hz, 2H), 7.16 (d, J = 9.4 Hz, 1H), 5.93 (dd, J = 7.9, 5.0 Hz, 1H), 5.40 (td, J = 9.6, 5.8 Hz, 1H), 5.17 (t, J = 8.8 Hz, 1H), 5.11 - 5.03 (m, 1H), 4.36 - 4.30 (m, 1H), 4.20 (ddd, J = 21.9, 12.4, 5.5 Hz, 1H), 4.11 (dd, J = 17.8, 12.1 Hz, 1H), 2.03 (s, 4H), 2.03 (s, 3H), 1.99 (s, 3H), 1.96 (s, 2H) ppm. 1313C NMR(150 MHz, DMSO-d6) δ 170.37, 170.08, 169.76, 169.51, 166.26, 164.93, 157.94, 154.03, 152.20, 138.79, 134.81, 133.28, 132.88, 132.72, 132.01, 131.95, 131.74, 131.09, 130.38, 127.88, 121.94, 120.99, 120.12, 115.13, 96.37, 72.15, 71.90, 70.61, 68.04, 61.81, 20.94, 20.85, 20.78, 20.73 ppm. HRMS(ESI): Calcd for C 38 H 36 N3O 13 SPt: 969.1617. Found: 969.1614 [M - BF4] + . FT-IR(KBr-Pellet) cm -1 : 3447, 2934, 1752, 1612, 1527, 1480, 1319, 1227, 1061, 837, 743, 671.

[0102] Example 12: Synthesis method of complex 12 (C12).

[0103] The structural formula of complex 12 (C12) is:

[0104]

[0105] Replace salicylaldehyde with 2-hydroxy-1-naphthaldehyde, 2-(methylthio)aniline with 2-(phenylthio)aniline, and the other required reagents and preparation method are the same as in Example 1 to obtain ligand L13. Replace ligand L2 with L13, and the other required reagents and preparation method are the same as in Example 1 to obtain the target product C12, a yellow solid. R f = 0.40 (DCM:MeOH = 100:7), and the yield is 56.5%, 11H NMR (600 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.84 - 8.78 (m, 2H), 8.72 (d, J = 8.7 Hz, 1H), 8.64 (d, J = 8.6 Hz, 1H), 8.17 (dd, J = 9.2, 2.9 Hz, 1H), 7.95 - 7.90 (m, 2H), 7.80 (d, J = 5.9 Hz, 2H), 7.71 (dt, J = 21.5, 7.6 Hz, 2H), 7.55 (q, J = 7.4 Hz, 1H), 7.51 - 7.44 (m, 4H), 7.34 (d, J = 5.3 Hz, 2H), 7.21 (d, J = 9.2 Hz, 1H), 5.94 (dd, J = 7.1, 5.0 Hz, 1H), 5.45 - 5.38 (m, 1H), 5.20 - 5.15 (m, 1H), 5.09 (td, J = 9.8, 7.0 Hz, 1H), 4.38 - 4.31 (m, 1H), 4.22 (ddd, J = 21.9, 12.4, 5.2 Hz, 1H), 4.16 - 4.08 (m, 1H), 2.03 (s, 7H), 2.00 (s, 3H), 1.97 (s, 2H). 13 13C NMR (150 MHz, DMSO-d6) δ 170.41, 170.09, 169.77, 169.53, 164.76, 164.52, 154.08, 153.79, 149.62, 139.25, 133.90, 133.16, 132.80, 132.48, 131.80, 131.75, 131.04, 130.17, 129.65, 129.12, 128.20, 126.74, 124.86, 122.93, 122.42, 120.20, 115.04, 112.38, 96.36, 72.16, 71.90, 70.64, 68.06, 61.88, 20.94, 20.85, 20.78, 20.73. HRMS (ESI): Calcd for C 42 H 39 N2O 11 SPt: 974.1922. Found: 974.1916 [M - BF4] + . FT-IR (KBr-Pellet) cm -1 -1: 3456, 2935, 1752, 1621, 1519, 1388, 1227, 1062, 837, 748, 667.

[0106] The activity of the glycoconjugated Schiff base platinum anticancer complex of the present invention will be further elaborated below in conjunction with specific examples. In the following examples, the test materials used and their sources include:

[0107] The human gastric cancer cell line MKN45 and the colorectal cancer cell line RPMI4788 are cells preserved in the laboratory. Reagents for the MTT assay: 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) was purchased from Beijing Myriad Technology Co., Ltd.; dimethyl sulfoxide (DMSO) was purchased from Biosharp; Hoechst 33342 live cell staining solution (100X) was purchased from Shanghai Beyotime Biotechnology Co., Ltd.; quercetin (Quer for short hereinafter) was purchased from Shanghai Macklin Biochemical Co., Ltd.; other chemical reagents involved were purchased from chemical reagent companies.

[0108] Example 13: Determination of the antitumor activity of glycoconjugated Schiff base platinum anticancer complexes

[0109] (1) Tumor cell seeding method: Two types of tumor cells, the human gastric cancer cell line MKN45 and the colorectal cancer cell line RPMI4788, were respectively seeded in RPMI 1640 medium containing serum and antibiotics.

[0110] (2) Determination of the MTT method and IC 50 value: The human gastric cancer cell line MKN45 and the colorectal cancer cell line RPMI4788 were respectively placed in 96-well cell culture plates. The cells were counted under a microscope using a hemocytometer to ensure that each well had 3000 cells and cultured for 24 hours. Then, each complex (C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12), cisplatin, and oxaliplatin at different concentrations (DMSO, 2 μM, 4 μM, 8 μM, 16 μM, 32 μM) and (DMSO, 10 μM, 20 μM, 40 μM, 80 μM) were used to treat the cells for 48 hours. Then, after treating with MTT reagent for 4 hours, DMSO was added, and the mixture was shaken evenly in the dark. The absorbance of the above 96-well cell culture plates was measured at 490 nm using an enzyme-linked immunosorbent assay (ELISA) instrument. At the same time, the half-maximal inhibitory concentration IC 50 (the concentration required to inhibit cell growth by 50%) can be calculated. (The calculation method for the half-maximal inhibitory concentration IC 50 is as follows: Taking log 10 (drug concentration) as x, the inhibition rate as y, plotting log 10 (drug concentration) against the inhibition rate to obtain their linear relationship. Assuming y = 50, the value of x is calculated, and the value of x is the IC50)

[0111] The glycoconjugated Schiff base platinum anticancer complexes of the present invention have a significant inhibitory effect on the growth of human gastric cancer cell line MKN45 and colorectal cancer cell line RPMI4788 in vitro, and their IC 50The value is 1.17 - 20.30 μM, and the IC of cisplatin and oxaliplatin 50 values are all greater than 10, as shown in Table 1 and Figure 1-2 , Figures 9-12 shown.

[0112] Table 1: In vitro antitumor activities of complexes C1 - C12, cisplatin, and oxaliplatin in various cancer cells: IC 50 (μM)

[0113]

[0114]

[0115] The sugar - conjugated Schiff - base platinum anticancer complexes of the present invention show more effective inhibitory effects on the proliferation of human gastric cancer cell line MKN45 and human colorectal cancer cell line RPMI4788 in vitro compared with cisplatin and oxaliplatin.

[0116] (3) Hoechst33342 staining experiment: Human gastric cancer cell line MKN45 and human colorectal cancer cell line RPMI4788 were respectively placed in six - well cell culture plates. Using the hemocytometer method, the cells were counted under a microscope to make each well contain 5×10 5 cells and cultured for 24 hours. Gastric cancer cell line MKN45 was treated with different concentrations (DMSO, 0 μM, 1.25 μM, 2.5 μM, 5 μM, 10 μM) of C12 for 48 hours, and human colorectal cancer cell line RPMI4788 was treated with different concentrations (DMSO, 0 μM, 1.25 μM, 2.5 μM, 5 μM, 10 μM) of C9 for 48 hours. 2 μL of Hoechst staining solution was added to each well in the six - well cell culture plate and incubated for 10 min. The culture medium was aspirated, and the cells were washed 2 - 3 times with PBS and photographed under a fluorescence microscope.

[0117] The sugar - conjugated Schiff - base platinum anticancer complexes C9 and C12 of the present invention were used for Hoechst33342 staining of gastric and colorectal cancer cells without light. The experiments showed that the cancer cells were in the process of apoptosis. When 10 μM of C9 and C12 were added, the number of cancer cells decreased significantly, and the brightness of the cell nuclei increased. As the concentration of the added complexes increased, the fluorescence intensity of the cells increased, indicating that the apoptosis of the cancer cells was more obvious. These two drugs could induce apoptosis in the two types of tumor cells as Figures 3-4 shown.

[0118] (4) GLUT Inhibitor Experiment: The GLUT inhibitor used in this example is quercetin. Human gastric cancer cell line MKN45 and human colorectal cancer cell line RPMI4788 were respectively placed in 96-well cell culture plates. Using the hemocytometer method, the cells were counted under a microscope to ensure that each well had 3000 cells, and then cultured for 24 hours. The culture medium was aspirated, and the cells were starved for 2 hours in serum-free RPMI 1640 medium, washed 1 - 2 times with PBS, and then experiments were conducted on the colorectal cancer cell line RPMI4788 and human gastric cancer cell line MKN45 with different concentrations of the compound. The set concentrations of C9 for the colorectal cancer cell line RPMI4788 were: Control, (Quer)(20 μM), Oxa (oxaliplatin)(100 μM), Oxa(100 μM)+Quer(20 μM), C9(3 μM), C9(3 μM)+Quer(20 μM); and for the human gastric cancer cell line MKN45, the set concentrations were: Control, Quer(20 μM), Oxa(100 μM), Oxa(100 μM)+Quer(20 μM), C9(2.5 μM), C9(2.5 μM)+Quer(20 μM); The set concentrations of C12 for the colorectal cancer cell line RPMI4788 were Control, Quer(20 μM), Oxa(100 μM), Oxa(100 μM)+Quer(20 μM), C12(1.5 μM), C12(1.5 μM)+Quer(20 μM); and for the human gastric cancer cell line MKN45, the set concentrations were: Control, Quer(20 μM), Oxa(100 μM), Oxa(100 μM)+Quer(20 μM), C12(2.5 μM), C12(2.5 μM)+Quer(20 μM). After incubation for 48 hours, the culture medium in the 96-well cell culture plates was aspirated, MTT reagent was added, incubated for 4 hours, and then lysis solution DMSO was added. The mixture was shaken evenly in the dark, and the absorbance at 490 nm of the above 96-well cell culture plates was measured using an enzyme-linked immunosorbent assay (ELISA) instrument. It was found that under the action of quercetin, the inhibition of cancer cells by the Schiff base platinum-based anticancer complexes C9 and C12 conjugated with sugars in the present invention was reduced. The GLUT inhibitor can inhibit the absorption of the Schiff base platinum-based anticancer complexes C9 and C12 by tumor cells, thereby reducing their anticancer effects.

[0119] The cytotoxicity experiment of the present invention relying on the GLUT1 inhibitor (quercetin) shows that the Schiff base platinum-based anticancer complexes conjugated with sugars in the present invention are dependent on the GLUT1 inhibitor, are transported to cancer cells through GLUT1, and achieve good drug targeting effects.

[0120] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A sugar-conjugated Schiff base platinum-based anticancer complex, characterized in that, The complex is any one of complex C1, complex C2, complex C3 and complex C4; the structural formulas of the complex C1, complex C2, complex C3 and complex C4 are shown in Formula I, Formula II, Formula III and Formula IV respectively: Among them, in Formula I, R is selected from a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group or a nitro group; in Formula III, R is selected from a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group or a nitro group.

2. The synthesis method of the glycoconjugated Schiff base platinum anticancer complex according to claim 1, characterized in that, It includes the following steps: (1) Synthesis of the sugar ligand L1: Dissolve 4-hydroxypyridine in an NaOH solution to obtain Solution I, quickly pour Solution I into an AgNO3 solution, stir for 30 min, filter, wash and dry to obtain a solid; add acetyl bromide-α-D-glucose to the obtained solid and dissolve it in toluene, reflux at 120 °C for 2 h, monitor the reaction by TLC. After the reaction is completed, filter, wash with water and dry the reaction solution, and perform column chromatography separation on the dried solution to obtain the sugar ligand L1; (2) Synthesis of the Schiff base ligand: Add salicylaldehyde or a derivative of salicylaldehyde and 2-(phenylthio)aniline to an ethanol solution, heat and reflux the reaction, and obtain the Schiff base ligand after the reaction is completed; (3) Synthesis of the platinum complex using the Schiff base ligand: Add the Schiff base ligand, sodium acetate, and the pre-prepared K2PtCl4 solution to a methanol solution, and carry out the reaction at 60 °C. Monitor the completion of the reaction by TLC, filter the obtained solid, wash and dry to obtain the platinum complex; (4) Modify the platinum complex with the sugar ligand to further synthesize the platinum anticancer complex: Dissolve the platinum complex obtained in step (3) in dichloromethane and ethanol solvents, add silver tetrafluoroborate, and reflux the reaction overnight at 60 °C. Monitor the reaction by TLC. After the reaction is completed, wait for the reaction to cool, add dichloromethane solvent, filter with diatomaceous earth, wash with dichloromethane, add the sugar ligand L1, react overnight, monitor the reaction by TLC. After the reaction is completed, spin-dry the reaction solution, add a small amount of ethanol, adjust the water bath to the recrystallization temperature of ethanol, continue to add ethanol until it just dissolves, put it in the refrigerator to cool and crystallize to obtain the solid of complex C3.

3. The synthesis method of the glycoconjugated Schiff base platinum anticancer complex according to claim 1, characterized in that, It includes the following steps: (1) Synthesis of the sugar ligand L1: Dissolve 4-hydroxypyridine in an NaOH solution to obtain Solution I, quickly pour Solution I into an AgNO3 solution, stir for 30 min, filter, wash and dry to obtain a solid; add acetyl bromide-α-D-glucose to the obtained solid and dissolve it in toluene, reflux at 120 °C for 2 h, monitor the reaction by TLC. After the reaction is completed, filter, wash with water and dry the reaction solution, and perform column chromatography separation on the dried solution to obtain the sugar ligand L1; (2) Synthesis of the Schiff base ligand: Add salicylaldehyde or a derivative of salicylaldehyde and 2-(methylthio)aniline to an ethanol solution, heat and reflux, monitor the completion of the reaction by TLC, and obtain the Schiff base ligand; (3) Synthesis of platinum complexes using Schiff base ligands: Add Schiff base ligands, sodium acetate, and the pre-prepared K2PtCl4 solution into a methanol solution, and carry out the reaction at 60 °C. Monitor the completion of the reaction by TLC. Filter, wash, and dry the obtained solid to get platinum complexes; (4) Modify the platinum complexes with sugar ligands to synthesize platinum anticancer complexes: Dissolve the platinum complexes obtained in step (3) in dichloromethane and ethanol solvents, add silver tetrafluoroborate, and reflux the reaction overnight at 60 °C. Monitor the reaction by TLC. After the reaction is completed and cooled, add dichloromethane solvent, filter with diatomaceous earth, wash with dichloromethane, add sugar ligand L1, and react overnight. Monitor the reaction by TLC. After the reaction ends, spin-dry the reaction solution, add a small amount of ethanol, adjust the water bath to the recrystallization temperature of ethanol, continue to add ethanol until it just dissolves, and then put it in the refrigerator to cool and crystallize to obtain solid complex C1.

4. The method for synthesizing the glycoconjugated Schiff base platinum anticancer complex according to claim 2 or 3, characterized in that, The derivatives of salicylaldehyde are any one of 5-fluorosalicylaldehyde, 5-chlorosalicylaldehyde, 5-bromosalicylaldehyde, 5-methylsalicylaldehyde, 5-methoxysalicylaldehyde, and 5-nitrosalicylaldehyde.

5. The synthesis method of the glycoconjugated Schiff base platinum anticancer complex according to claim 1, characterized in that, It includes the following steps: (1) Synthesis of sugar ligand L1: Dissolve 4-hydroxypyridine in NaOH solution to obtain solution I. Quickly pour solution I into AgNO3 solution, stir for 30 min, filter, wash, and dry to obtain a solid. Add acetyl bromide-α-D-glucose to the obtained solid and dissolve it in toluene. Reflux at 120 °C for 2 h. Monitor the reaction by TLC. After the reaction ends, filter, wash with water, and dry the reaction solution. Perform column chromatography separation on the dried solution to obtain sugar ligand L1; (2) Synthesis of Schiff base ligand: Add 2-hydroxy-1-naphthaldehyde and 2-(methylthio)aniline into an ethanol solution, heat and reflux, and monitor the completion of the reaction by TLC to obtain Schiff base ligand; (3) Synthesis of platinum complexes using Schiff base ligands: Add Schiff base ligands, sodium acetate, and the pre-prepared K2PtCl4 solution into a methanol solution, and carry out the reaction at 60 °C. Monitor the completion of the reaction by TLC. Filter, wash, and dry the obtained solid to get platinum complexes; (4) Modify the platinum complexes with sugar ligands to synthesize platinum anticancer complexes: Dissolve the platinum complexes obtained in step (3) in dichloromethane and ethanol solvents, add silver tetrafluoroborate, and reflux the reaction overnight at 60 °C. Monitor the reaction by TLC. After the reaction is completed and cooled, add dichloromethane solvent, filter with diatomaceous earth, wash with dichloromethane, add sugar ligand L1, and react overnight. Monitor the reaction by TLC. After the reaction ends, spin-dry the reaction solution, add a small amount of ethanol, adjust the water bath to the recrystallization temperature of ethanol, continue to add ethanol until it just dissolves, and then put it in the refrigerator to cool and crystallize to obtain solid complex C2.

6. The synthesis method of the glycoconjugated Schiff base platinum anticancer complex according to claim 1, characterized in that, It includes the following steps: (1) Synthesis of sugar ligand L1: Dissolve 4-hydroxypyridine in NaOH solution to obtain solution I. Quickly pour solution I into AgNO₃ solution, stir for 30 min, filter, wash, and dry to obtain a solid. Add acetyl bromide-α-D-glucose to the obtained solid and dissolve it in toluene. Reflux at 120 °C for 2 h. Monitor the reaction by TLC. After the reaction is completed, filter, wash with water, and dry the reaction solution. Perform column chromatography separation on the dried solution to obtain sugar ligand L1; (2) Synthesis of Schiff base ligand: Add 2-hydroxy-1-naphthaldehyde and 2-(phenylthio)aniline to an ethanol solution, heat under reflux, and monitor the completion of the reaction by TLC to obtain the Schiff base ligand; (3) Synthesis of platinum complex using Schiff base ligand: Add the Schiff base ligand, sodium acetate, and the pre-prepared K₂PtCl₄ solution to a methanol solution, and carry out the reaction at 60 °C. Monitor the completion of the reaction by TLC. Filter, wash, and dry the obtained solid to obtain the platinum complex; (4) Synthesis of platinum-based anticancer complex by modifying the platinum complex with sugar ligand: Dissolve the platinum complex obtained in step (3) in dichloromethane and ethanol solvents. Add silver tetrafluoroborate, and reflux the reaction overnight at 60 °C. Monitor the reaction by TLC. After the reaction is completed, wait for the reaction to cool, add dichloromethane solvent, filter with diatomaceous earth, wash with dichloromethane, add sugar ligand L1, and react overnight. Monitor the reaction by TLC. After the reaction is completed, evaporate the reaction solution to dryness, add a small amount of ethanol, adjust the water bath to the temperature for recrystallization with ethanol, continue to add ethanol until it just dissolves, put it in the refrigerator to cool and crystallize to obtain the solid of complex C4.

7. Use of the sugar-conjugated Schiff base platinum-based anticancer complex according to claim 1 in the preparation of an antitumor drug.

8. Use of the glycoconjugated Schiff base platinum anticancer complex according to claim 7 in the preparation of an antitumor drug, characterized in that, The tumor is gastric cancer or colorectal cancer.

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