A divalent palladium complex containing 2, 2'-dihydroxydiphenyl anti-pancreatic cancer drug

Abstract

The application discloses a bivalent palladium complex containing 2,2'-dihydroxydiphenyl and a preparation method and application thereof. The compound of the application is a bivalent palladium complex containing 2,2'-dihydroxydiphenyl with a structural general formula as shown in formula 1. The bivalent palladium complex containing 2,2'-dihydroxydiphenyl has a simple synthesis route, raw materials are easy to obtain, the synthesis method is easy to realize, and the cost is low. The bivalent palladium complex containing 2,2'-dihydroxydiphenyl has a relatively obvious proliferation inhibition effect on pancreatic cancer PANC-1 / GEM, the anti-tumor activity of part of the complex is obviously better than that of cisplatin, and the complex has the advantages of low toxicity and high activity.

Description

Technical Field

[0001] This invention relates to a pharmaceutical compound and its preparation and use. More specifically, this invention relates to a divalent palladium complex containing 2,2′-dihydroxybiphenyl, its preparation method, and its antitumor application. Background Technology

[0002] The high incidence and mortality rates of malignant tumors bring profound suffering and enormous economic burdens to families. Traditional anti-tumor treatments have limited effectiveness in inhibiting tumor progression; even after surgical removal of the tumor, many patients experience local recurrence or distant metastasis. Treatment for solid tumors primarily involves surgery, but surgery easily leads to micrometastasis, increasing the risk of metastasis. Chemotherapy can kill cancer cells that have metastasized through various pathways, thus preventing metastasis. Platinum-based anti-tumor drugs are widely used clinically for the treatment of malignant tumors. The US FDA has approved three platinum-based drugs for marketing, including cisplatin, carboplatin, and oxaliplatin. Platinum-based anti-tumor drugs are the most widely used chemotherapy drugs for cancer patients in my country, but long-term use easily leads to drug resistance and has side effects such as nephrotoxicity, gastrointestinal adverse reactions, and hematologic toxicity. Oxidizing divalent platinum-based drugs to tetravalent platinum and further introducing other anti-tumor pharmacodynamic groups into the structure is a hot research area for novel platinum-based anti-tumor drugs in recent years. To design anti-tumor drugs with pharmacological indicators exceeding those of cisplatin, it is necessary to overcome the limitations of cisplatin-based drugs and find a new class of anti-tumor drugs. Summary of the Invention

[0003] This invention provides a compound that can overcome the problems of large side effects and low activity of divalent platinum-based antitumor drugs in antitumor treatment.

[0004] The compound of the present invention is a divalent palladium complex containing 2,2′-dihydroxybiphenyl as shown in Formula 1, wherein R1 to R8 are H,

[0005] Halogen, nitro, carboxyl, ester, amino, C1-C 20 Straight-chain or branched alkyl groups, or C3-C4 alkyl groups. 20 cycloalkyl groups, or C6-C6 groups 20 Any of the aryl groups, and R1 to R8 may be the same or different.

[0006] Preferably, the substituents R1 to R8 of the divalent palladium complex containing 2,2′-dihydroxybiphenyl of the present invention are H, halogen, nitrosyl, carboxyl, ester, amino, C1 to C8, respectively. 10 Straight-chain or branched alkyl groups, or C3-C4 alkyl groups. 10 cycloalkyl groups, or C6-C6 groups 10Any of the aryl groups.

[0007] Preferably, the divalent palladium complex of the present invention containing 2,2′-dihydroxybiphenyl is characterized in that the complex...

[0008] The compound is a divalent palladium complex of 2,2′-dihydroxybiphenyl as shown in Formula 2, wherein the substituents R1 to R8 are all H.

[0009] Preferably, the present invention comprises a divalent palladium complex containing 2,2′-dihydroxybiphenyl, said complex being as follows:

[0010] 3 shows 5-methyl ester-2,2′-dihydroxybiphenyl palladium, where R3 is a methyl ester group and all other substituents are H.

[0011] Preferably, the divalent palladium complex containing 2,2′-dihydroxybiphenyl of the present invention is a 6-aminobenzene as shown in Formula 4.

[0012] R4 is an amino group, and all other substituents are H.

[0013] Preferably, the divalent palladium complex of the present invention containing 2,2′-dihydroxybiphenyl

[0014] It is 3-methyl-3′-chloro-2,2′-dihydroxybiphenylpalladium as shown in Formula 5, wherein R1 is methyl, R8 is chlorine, and all other substituents are H.

[0015] Preferably, the divalent palladium complex of the present invention containing 2,2′-dihydroxybiphenyl

[0016] It is 4-ethyl-5′-nitro-2,2′-dihydroxybiphenyl palladium as shown in Formula 6, wherein R2 is ethyl, R6 is nitro, and all other substituents are H.

[0017] Preferably, the divalent palladium complex of the present invention containing 2,2′-dihydroxybiphenyl

[0018] It is 4-ethyl ester-4′-bromo-2,2′-dihydroxybiphenyl palladium as shown in Formula 7, wherein R2 is ethyl ester, R7 is bromine, and all other substituents are H.

[0019] Preferably, the divalent palladium complex of the present invention containing 2,2′-dihydroxybiphenyl

[0020] It is 3-chloro-6′-amino-2,2′-dihydroxybiphenyl palladium as shown in Formula 8, wherein R1 is chlorine, R5 is amino, and all other substituents are H.

[0021] Preferably, the divalent palladium complex of the present invention containing 2,2′-dihydroxybiphenyl

[0022] It is 5-ethyl-5′-methyl-2,2′-dihydroxybiphenyl as shown in Formula 9, wherein R3 is ethyl, R6 is methyl, and all other substituents are H.

[0023] Preferably, the divalent palladium complex of the present invention containing 2,2′-dihydroxybiphenyl

[0024] It is 3-ethyl-6′-ethyl ester-2,2′-dihydroxybiphenyl palladium as shown in Formula 13, wherein R1 is ethyl, R5 is ethyl ester, and all other substituents are H.

[0025] The method for preparing the divalent palladium complex containing 2,2′-dihydroxybiphenyl of the present invention is as shown in Formula 11.

[0026] Show, that is: (1) Add 10-100 molar equivalents of organic alcohol to 1 molar equivalent of 2,2′-dihydroxybiphenyl (II), and heat and stir at 50-80 °C for 1-6 h to obtain a dissolved 2,2′-dihydroxybiphenyl organic alcohol solution.

[0027] (2) Add 2 molar equivalents of NaOH to the above 2,2′-dihydroxybiphenyl organic alcohol solution and stir at room temperature for 1 to 12 h to obtain an organic alcohol solution of compound III.

[0028] (3) Add 1 molar equivalent of PdCl2 to 5-20 molar equivalents of organic alcohol, and heat and stir at 50-80 °C for 1-6 h to obtain a dissolved PdCl2 organic alcohol solution.

[0029] (4) The above PdCl2 organic alcohol solution was slowly added to the organic alcohol solution of compound III. After the addition was completed, the mixture was stirred at room temperature for 1 to 6 h to obtain a solid precipitate of product compound 1. The product compound 1 was then filtered and dried to obtain compound 1.

[0030] The organic alcohol is any one of methanol, ethanol, propanol, butanol, cyclohexanol, benzyl alcohol, ethylene glycol, and glycerol, with cyclohexanol and benzyl alcohol being preferred.

[0031] Any of the complexes described in this invention can be used in anticancer drugs.

[0032] 2,2′-Dihydroxybiphenyl has a large rigid aromatic ring, and its derivative complexes have become an important class of complexes for designing nucleic acid-targeted anticancer drugs due to their unique stability, redox properties, and excellent interaction with DNA.

[0033] The present invention has the following advantages and beneficial effects: To address the problems of significant side effects and low activity of current divalent platinum-based antitumor drugs in antitumor treatment, this invention provides a class of divalent palladium complexes containing 2,2′-dihydroxybiphenyl. These complexes utilize the unique stability, redox properties, and excellent DNA-reactive properties of 2,2′-dihydroxybiphenyl derivatives, along with the highly efficient antitumor activity of divalent palladium, to overcome drug resistance in divalent platinum-based drugs and achieve excellent synergistic antitumor effects.

[0034] This invention provides a class of divalent palladium complexes containing 2,2′-dihydroxybiphenyl, which exhibit significant inhibitory effects on the proliferation of pancreatic cancer PANC-1 / GEM. Some complexes show significantly superior antitumor activity compared to cisplatin and can be considered as candidate antitumor drugs for further investigation. For example, complex 5 exhibits the best antitumor activity, with an IC50 (half-maximal inhibitory concentration) against pancreatic cancer PANC-1 / GEM. 50 The minimum molecular weight is 1.06 µM. The complex provided by this invention has a novel skeletal structure and exhibits excellent antitumor activity, making it suitable for the development of pancreatic cancer drugs.

[0035] The synthetic route for the divalent palladium complex of 2,2′-dihydroxybiphenyl provided by this invention is simple, the raw materials are readily available, the synthetic method is easy to implement, and the cost is low. Detailed Implementation

[0036] To more clearly illustrate the present invention, the following description, in conjunction with preferred embodiments, further clarifies the invention. Those skilled in the art should understand that the specific descriptions below are illustrative rather than restrictive, and should not be construed as limiting the scope of protection of the present invention.

[0037] Example 1: Synthesis of Complex 1 See Formula 11 for the specific preparation method:

[0038] (1) Take 3.72 g (0.02 mol) of 2,2′-dihydroxybiphenyl (II) and add 50 mL of cyclohexanol. Stir at 60 °C for 2 h until a clear solution is completely dissolved. Add 1.6 g (0.04 mol) of sodium hydroxide (NaOH) to the above solution and stir at 50 °C for 1 h until the reaction is complete. Distill at atmospheric pressure to obtain solid compound III, dry and weigh. The yield is 96%. The NMR and high-resolution mass spectrometry data of compound III are as follows. 1 ¹H NMR (DMSO-d6): 6.79 (2H), 6.88 (2H), 7.05 (2H), 7.31 (2H). HRMS: m / z molecular ion peak: 230.03.

[0039] (2) 2.30 g (0.01 mol) of compound III was dissolved in 50 mL of cyclohexanol, and 1.78 g (0.01 mol) of palladium chloride (PdCl2) was dissolved in 30 mL of cyclohexanol. The above PdCl2 cyclohexanol solution was slowly added to the cyclohexanol solution of compound III. After the addition was complete, the mixture was stirred at room temperature for 3 h to obtain a solid precipitate of product complex 1. The precipitate was filtered and dried to obtain complex 1 with a yield of 95%. The NMR and high-resolution mass spectrometry data of complex 1 are as follows. 1 ¹H NMR (DMSO-d6): 6.79 (2H), 6.88 (2H), 7.05 (2H), 7.31 (2H). HRMS: m / z molecular ion peak: 289.96. Example

[0040] Synthesis of Complex 2

[0041] (1) Take 4.88 g (0.02 mol) of 5-methyl ester-2,2′-dihydroxybiphenyl (IV) and add 50 mL of cyclohexanol. Stir at 60 °C for 2 h until a clear solution is completely dissolved. Add 1.6 g (0.04 mol) of sodium hydroxide (NaOH) to the above solution and stir at 50 °C for 1 h until the reaction is complete. Distill at atmospheric pressure to obtain solid compound V, dry and weigh. The yield is 98%. The NMR and high-resolution mass spectrometry data of compound V are as follows. 1 ¹H NMR (DMSO-d6): 3.88 (3H), 6.79 (1H), 6.88 (1H), 6.90 (1H), 7.05 (1H), 7.31 (2H), 7.76 (1H), 8.02 (1H). HRMS: m / z molecular ion peak: 288.04.

[0042] (2) 2.88 g (0.01 mol) of compound V was dissolved in 50 mL of cyclohexanol, and 1.78 g (0.01 mol) of palladium chloride (PdCl2) was dissolved in 30 mL of cyclohexanol. The above PdCl2 cyclohexanol solution was slowly added to the cyclohexanol solution of compound V. After the addition was complete, the mixture was stirred at room temperature for 3 h to obtain a solid precipitate of product complex 2. The precipitate was filtered and dried to obtain complex 2 with a yield of 96%. The NMR and high-resolution mass spectrometry data of complex 2 are as follows. 1 ¹H NMR (DMSO-d6): 73.88 (3H), 6.79 (1H), 6.88 (1H), 6.90 (1H), 7.05 (1H), 7.31 (2H), 7.76 (1H), 8.02 (1H). HRMS: m / z molecular ion peak: 347.96. Example

[0043] Synthesis of Complex 3

[0044] (1) 4.02 g (0.02 mol) of 6-amino-2,2′-dihydroxybiphenyl (VI) was added to 60 mL of cyclohexanol and stirred at 60 °C for 2 h until a clear solution was completely dissolved. 1.6 g (0.04 mol) of sodium hydroxide (NaOH) was added to the above solution, and the mixture was stirred at 50 °C for 1 h until the reaction was complete. The mixture was distilled at atmospheric pressure to obtain solid compound VII, dried, and weighed. The yield was 98%. The NMR and high-resolution mass spectrometry data of compound VII are as follows. 1 ¹H NMR (DMSO-d6): 4.00 (2H), 6.08 (1H), 6.15 (1H), 6.79 (1H), 6.80 (1H), 6.88 (1H), 7.05 (1H), 7.31 (1H). HRMS: m / z molecular ion peak: 245.04.

[0045] (2) 2.45 g (0.01 mol) of compound VII was dissolved in 50 mL of cyclohexanol, and 1.78 g (0.01 mol) of palladium chloride (PdCl2) was dissolved in 30 mL of cyclohexanol. The above PdCl2 cyclohexanol solution was slowly added to the cyclohexanol solution of compound VII. After the addition was complete, the mixture was stirred at room temperature for 3 h to obtain a solid precipitate of product complex 3. The precipitate was filtered and dried to obtain complex 3 with a yield of 97%. The NMR and high-resolution mass spectrometry data of complex 3 are as follows. 1¹H NMR (DMSO-d6): 4.00 (2H), 6.08 (1H), 6.15 (1H), 6.79 (1H), 6.80 (1H), 6.88 (1H), 7.05 (1H), 7.31 (1H). HRMS: m / z molecular ion peak: 304.97. Example

[0046] Synthesis of Complex 4

[0047] (1) 4.68 g (0.02 mol) of 3-methyl-3′-chloro-2,2′-dihydroxybiphenyl (VIII) was added to 60 mL of cyclohexanol and stirred at 60 °C for 2 h until a clear solution was completely dissolved. 1.6 g (0.04 mol) of sodium hydroxide (NaOH) was added to the above solution, and the mixture was stirred at 50 °C for 1 h until the reaction was complete. The mixture was distilled at atmospheric pressure to obtain solid compound IX, dried, and weighed. The yield was 97%. The NMR and high-resolution mass spectrometry data of compound IX are as follows. 1 ¹H NMR (DMSO-d6): 2.35 (3H), 6.76 (1H), 6.82 (1H), 6.85 (1H), 7.06 (1H), 7.12 (1H), 7.19 (1H). HRMS: m / z molecular ion peak: 278.01.

[0048] (2) 2.78 g (0.01 mol) of compound IX was dissolved in 50 mL of cyclohexanol, and 1.78 g (0.01 mol) of palladium chloride (PdCl2) was dissolved in 30 mL of cyclohexanol. The above PdCl2 cyclohexanol solution was slowly added to the cyclohexanol solution of compound IX. After the addition was complete, the mixture was stirred at room temperature for 3 h to obtain a solid precipitate of product complex 4. The precipitate was filtered and dried to obtain complex 4, with a yield of 96%. The NMR and high-resolution mass spectrometry data of complex 4 are as follows. 1 ¹H NMR (DMSO-d6): 2.35 (3H), 6.76 (1H), 6.82 (1H), 6.85 (1H), 7.06 (1H), 7.12 (1H), 7.19 (1H). HRMS: m / z molecular ion peak: 339.93. Example

[0049] Synthesis of Complex 5

[0050] (1) Take 5.20 g (0.02 mol) of 4-ethyl-5′-nitro-2,2′-dihydroxybiphenyl (X) and add 60 mL of cyclohexanol. Stir at 60 °C for 2 h until a clear solution is completely dissolved. Add 1.6 g (0.04 mol) of sodium hydroxide (NaOH) to the above solution and stir at 50 °C for 1 h until the reaction is complete. Distill at atmospheric pressure to obtain solid compound XI, dry and weigh. The yield is 96%. The NMR and high-resolution mass spectrometry data of compound XI are as follows. 1 ¹H NMR (DMSO-d6): 1.24 (3H), 2.59 (2H), 6.65 (1H), 6.74 (1H), 7.05 (1H), 7.26 (1H), 7.98 (1H), 8.24 (1H). HRMS: m / z molecular ion peak: 303.05.

[0051] (2) 3.13 g (0.01 mol) of compound XI was dissolved in 50 mL of cyclohexanol, and 1.78 g (0.01 mol) of palladium chloride (PdCl2) was dissolved in 30 mL of cyclohexanol. The PdCl2 cyclohexanol solution was slowly added to the cyclohexanol solution of compound XI. After the addition was complete, the mixture was stirred at room temperature for 3 h to obtain a solid precipitate of product complex 5. The precipitate was filtered and dried to obtain complex 5 with a yield of 95%. The NMR and high-resolution mass spectrometry data of complex 5 are as follows. 1 ¹H NMR (DMSO-d6): 1.24 (3H), 2.59 (2H), 6.65 (1H), 6.74 (1H), 7.05 (1H), 7.26 (1H), 7.98 (1H), 8.24 (1H). HRMS: m / z molecular ion peak: 362.97. Example

[0052] Synthesis of Complex 6

[0053] (1) Take 6.74 g (0.02 mol) of 4-ethyl ester-4′-bromo-2,2′-dihydroxybiphenyl (XII) and add 60 mL of cyclohexanol. Stir at 60 °C for 2 h until a clear solution is completely dissolved. Add 1.6 g (0.04 mol) of sodium hydroxide (NaOH) to the above solution and stir at 50 °C for 1 h until the reaction is complete. Distill at atmospheric pressure to obtain solid compound XIII, dry and weigh. The yield is 96%. The NMR and high-resolution mass spectrometry data of compound XIII are as follows. 1¹H NMR (DMSO-d6): 1.30 (3H), 4.29 (2H), 6.96 (1H), 7.05 (1H), 7.20 (1H), 7.42 (1H), 7.50 (1H), 7.59 (1H). HRMS: m / z molecular ion peak: 379.96.

[0054] (2) 3.79 g (0.01 mol) of compound XIII was dissolved in 50 mL of cyclohexanol, and 1.78 g (0.01 mol) of palladium chloride (PdCl2) was dissolved in 30 mL of cyclohexanol. The above PdCl2 cyclohexanol solution was slowly added to the cyclohexanol solution of compound XIII. After the addition was complete, the mixture was stirred at room temperature for 3 h to obtain a solid precipitate of product complex 6. The precipitate was filtered and dried to obtain complex 6 with a yield of 95%. The NMR and high-resolution mass spectrometry data of complex 6 are as follows. 1 ¹H NMR (DMSO-d6): 1.30 (3H), 4.29 (2H), 6.96 (1H), 7.05 (1H), 7.20 (1H), 7.42 (1H), 7.50 (1H), 7.59 (1H). HRMS: m / z molecular ion peak: 441.89. Example

[0055] Synthesis of Complex 7

[0056] (1) 4.71 g (0.02 mol) of 3-chloro-6′-amino-2,2′-dihydroxybiphenyl (XIV) was added to 60 mL of cyclohexanol and stirred at 60 °C for 2 h until a clear solution was completely dissolved. 1.6 g (0.04 mol) of sodium hydroxide (NaOH) was added to the above solution, and the mixture was stirred at 50 °C for 1 h until the reaction was complete. The mixture was distilled at atmospheric pressure to obtain solid compound XV, dried, and weighed. The yield was 97%. The NMR and high-resolution mass spectrometry data of compound XV are as follows. 1 ¹H NMR (DMSO-d6): 4.00 (2H), 6.08 (1H), 6.15 (1H), 6.80 (1H), 6.82 (1H), 7.06 (1H), 7.19 (1H). HRMS: m / z molecular ion peak: 279.00.

[0057] (2) 2.79 g (0.01 mol) of compound XV was dissolved in 50 mL of cyclohexanol, and 1.78 g (0.01 mol) of palladium chloride (PdCl2) was dissolved in 30 mL of cyclohexanol. The above PdCl2 cyclohexanol solution was slowly added to the cyclohexanol solution of compound XV. After the addition was complete, the mixture was stirred at room temperature for 3 h to obtain a solid precipitate of product complex 7. The precipitate was filtered and dried to obtain complex 7 with a yield of 96%. The NMR and high-resolution mass spectrometry data of complex 7 are as follows. 1 ¹H NMR (DMSO-d6): 4.00 (2H), 6.08 (1H), 6.15 (1H), 6.80 (1H), 6.82 (1H), 7.06 (1H), 7.19 (1H). HRMS: m / z molecular ion peak: 338.93. Example

[0058] Synthesis of Complex 8

[0059] (1) 4.56 g (0.02 mol) of 5-ethyl-5′-methyl-2,2′-dihydroxybiphenyl (XVI) was added to 60 mL of cyclohexanol and stirred at 60 °C for 2 h until a clear solution was completely dissolved. 1.6 g (0.04 mol) of sodium hydroxide (NaOH) was added to the above solution, and the mixture was stirred at 50 °C for 1 h until the reaction was complete. The mixture was distilled at atmospheric pressure to obtain solid compound XVII, dried, and weighed. The yield was 95%. The NMR and high-resolution mass spectrometry data of compound XVII are as follows. 1 ¹H NMR (DMSO-d6): 1.23 (3H), 2.35 (3H), 2.59 (2H), 6.67 (1H), 6.74 (1H), 6.85 (1H), 6.91 (1H), 7.11 (1H), 7.17 (1H). HRMS: m / z molecular ion peak: 272.08.

[0060] (2) 2.76 g (0.01 mol) of compound XVII was dissolved in 50 mL of cyclohexanol, and 1.78 g (0.01 mol) of palladium chloride (PdCl2) was dissolved in 30 mL of cyclohexanol. The above PdCl2 cyclohexanol solution was slowly added to the cyclohexanol solution of compound XVII. After the addition was complete, the mixture was stirred at room temperature for 3 h to obtain a solid precipitate of product complex 8. The precipitate was filtered and dried to obtain complex 8 with a yield of 95%. The NMR and high-resolution mass spectrometry data of complex 8 are as follows. 1¹H NMR (DMSO-d6): 1.23 (3H), 2.35 (3H), 2.59 (2H), 6.67 (1H), 6.74 (1H), 6.85 (1H), 6.91 (1H), 7.11 (1H), 7.17 (1H). HRMS: m / z molecular ion peak: 332.00. Example

[0061] Synthesis of Complex 9

[0062] (1) Take 5.72 g (0.02 mol) of 3-ethyl-6′-ethyl ester-2,2′-dihydroxybiphenyl (XVIII) and add 60 mL of cyclohexanol. Stir at 60 °C for 2 h until a clear solution is completely dissolved. Add 1.6 g (0.04 mol) of sodium hydroxide (NaOH) to the above solution and stir at 30 °C for 1 h until the reaction is complete. Distill at atmospheric pressure to obtain solid compound XIX, dry and weigh. The yield is 97%. The NMR and high-resolution mass spectrometry data of compound XIX are as follows. 1 1H NMR (DMSO-d6): . HRMS: m / z molecular ion peak: 330.08.

[0063] (2) 2.67 g (0.01 mol) of compound XIX was dissolved in 50 mL of cyclohexanol, and 1.78 g (0.01 mol) of palladium chloride (PdCl2) was dissolved in 30 mL of cyclohexanol. The above PdCl2 cyclohexanol solution was slowly added to the cyclohexanol solution of compound XIX. After the addition was complete, the mixture was stirred at room temperature for 3 h to obtain a solid precipitate of product complex 9. The precipitate was filtered and dried to obtain complex 9 with a yield of 95%. The NMR and high-resolution mass spectrometry data of complex 9 are as follows. 1 ¹H NMR (DMSO-d6): 1.24 (3H), 1.30 (3H), 2.59 (2H), 4.29 (2H), 6.83 (1H), 6.91 (1H), 7.00 (1H), 7.13 (1H), 7.16 (1H), 7.58 (1H). HRMS: m / z molecular ion peak: 390.01.

[0064] Antitumor activity test of the complexes of the present invention The tumor cell proliferation inhibition assay was performed on the complex of the present invention using the conventional CKK-8 assay. The cell line used was pancreatic cancer PANC-1 / GEM. The culture medium was DMEM + 10% NBS + penicillin antibiotics.

[0065] Sample solution preparation: The test complexes were dissolved in DMSO to prepare stock solutions with a concentration of 10 mM. The stock solutions were diluted with culture medium to prepare final drug concentrations of 50 µM, 25 µM, 10 µM, 5 µM, 1 µM, 0.5 µM, 0.25 µM and 0.125 µM.

[0066] The concentration added to each well of the 96-well plate is 6 × 10⁻⁶. 4 100 μL of cell suspension (60,000 cells / well) was added to each well and incubated at 37 °C in a 5% CO2 incubator. After 24 hours, the supernatant was aspirated, and 100 μL of culture medium containing the sample and control solution was added to each well. The well was incubated at 37 °C for 72 hours. 10 μL of CKK-8 was added to each well and the well was incubated for 1 hour. The OD value at 570 nm was measured using an MK-2 automated microplate reader, and the half-maximal inhibitory concentration (IC50) was calculated. 50 The antitumor activity of the complexes is detailed in Table 1. Cisplatin was used as a control sample in the antitumor activity test.

[0067]

[0068] The results in Table 1 show that the complexes of this application generally exhibit excellent pancreatic cancer activity, such as the half-maximal inhibitory concentration (IC50) of complex 5 against pancreatic cancer PANC-1 / GEM. 50 The IC50 value is close to 1 µM, significantly higher than that of the control sample cisplatin. 50 =19.95µM. Therefore, the complex provided by this invention has a novel skeletal structure and excellent antitumor activity, and can be used for the development of antitumor drugs.

[0069] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make modifications or alterations to the above-described technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A divalent palladium complex containing 2,2′-dihydroxybiphenyl, as shown in Formula 1, wherein R1 to R8 are H0, halogen, nitro, carboxyl, ester, amino, C1 to C8, respectively. 20 Straight-chain or branched alkyl groups, or C3-C4 alkyl groups. 20 cycloalkyl groups, or C6-C6 groups 20 Any of the aryl groups, and R1 to R8 are the same or different. 。 2. The divalent palladium complex containing 2,2′-dihydroxybiphenyl according to claim 1, characterized in that... The substituents R1 to R8 of the divalent palladium complex of 2,2′-dihydroxybiphenyl are H, halogen, nitrosyl, carboxyl, ester, amino, C1-C8, respectively. 10 Straight-chain or branched alkyl groups, or C3-C4 alkyl groups. 10 cycloalkyl groups, or C6-C6 groups 10 Any of the aryl groups.

3. The divalent palladium complex containing 2,2′-dihydroxybiphenyl according to claim 1, characterized in that... The complex is a divalent palladium complex of 2,2′-dihydroxybiphenyl as shown in Formula 2, wherein the substituents R1 to R8 are all H. 。 4. The divalent palladium complex containing 2,2′-dihydroxybiphenyl according to claim 1, characterized in that... The complex is 5-methyl ester-2,2′-dihydroxybiphenyl palladium as shown in Formula 3, wherein R3 is a methyl ester group and the other substituents are all H. 。 5. The divalent palladium complex containing 2,2′-dihydroxybiphenyl according to claim 1, characterized in that... The complex is 6-amino-2,2′-dihydroxybiphenylpalladium as shown in Formula 4, wherein R4 is an amino group and the other substituents are all H. 。 6. The divalent palladium complex containing 2,2′-dihydroxybiphenyl according to claim 1, characterized in that... The complex is 3-methyl-3′-chloro-2,2′-dihydroxybiphenylpalladium as shown in Formula 5, wherein R1 is methyl, R8 is chlorine, and the other substituents are all H. 。 7. The divalent palladium complex containing 2,2′-dihydroxybiphenyl according to claim 1, characterized in that... The complex is 4-ethyl-5′-nitro-2,2′-dihydroxybiphenylpalladium as shown in Formula 6, wherein R2 is ethyl, R6 is nitro, and the other substituents are all H. 。 8. The divalent palladium complex containing 2,2′-dihydroxybiphenyl according to claim 1, characterized in that... The complex is 4-ethyl ester-4′-bromo-2,2′-dihydroxybiphenyl palladium as shown in Formula 7, wherein R2 is ethyl ester, R7 is bromine, and the other substituents are all H. 。 9. The divalent palladium complex containing 2,2′-dihydroxybiphenyl according to claim 1, characterized in that... The complex is 3-chloro-6′-amino-2,2′-dihydroxybiphenylpalladium as shown in Formula 8, wherein R1 is chlorine, R5 is amino, and the other substituents are all H. 。 10. The divalent palladium complex containing 2,2′-dihydroxybiphenyl according to claim 1, characterized in that... The complex is 5-ethyl-5′-methyl-2,2′-dihydroxybiphenyl as shown in Formula 9, wherein R3 is ethyl, R6 is methyl, and the other substituents are all H. 。 11. The divalent palladium complex containing 2,2′-dihydroxybiphenyl according to claim 1, characterized in that... The complex is 3-ethyl-6′-ethyl ester-2,2′-dihydroxybiphenyl palladium as shown in Formula 13, wherein R1 is ethyl, R5 is ethyl ester, and the other substituents are all H. 。 12. The method for preparing the divalent palladium complex containing 2,2′-dihydroxybiphenyl as described in claim 1, characterized in that... As shown in Formula 11, that is: (1) 10-100 molar equivalents of organic alcohol are added to 1 molar equivalent of 2,2′-dihydroxybiphenyl (II), and the mixture is heated and stirred at 50-80 °C for 1-6 h to obtain a dissolved 2,2′-dihydroxybiphenyl organic alcohol solution; (2) Add 2 molar equivalents of NaOH to the above 2,2′-dihydroxybiphenyl organic alcohol solution and stir at room temperature for 1 to 12 h to obtain an organic alcohol solution of compound III; (3) Add 1 molar equivalent of PdCl2 to 5-20 molar equivalents of organic alcohol, and heat and stir at 50-80 °C for 1-6 h to obtain a dissolved PdCl2 organic alcohol solution. (4) The above PdCl2 organic alcohol solution was slowly added to the organic alcohol solution of compound III. After the addition was completed, the mixture was stirred at room temperature for 1-6 h to obtain a solid precipitate of product compound 1. The precipitate was filtered and dried to obtain compound 1. The organic alcohol is any one of methanol, ethanol, propanol, butanol, cyclohexanol, benzyl alcohol, ethylene glycol, and glycerol, preferably cyclohexanol and benzyl alcohol. 。 13. The use of any of the complexes described in claims 1 to 10 in an anticancer drug.

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