A new type of terpyridine-platinum (II) complex containing guanine derivative ligands and its preparation method and application

Abstract

The invention discloses a novel terpyridine-platinum (II) complex containing a guanine derivative ligand, and a preparation method and application thereof. Specifically, the terpyridine-platinum (II) complex containing a guanine derivative ligand as shown in formula I has dual inhibitory activity against tumor cells and tumor stem cells, can overcome the drug resistance caused by tumor stem cells, and can be used to prepare drugs for treating various malignant tumors, especially drugs for treating malignant tumors resistant to existing chemotherapy drugs; the preparation method is simple and easy to operate.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a novel terpyridine-platinum (II) complex containing a guanine derivative ligand, and a preparation method and application thereof. Background Art

[0002] At present, the main treatments for malignant tumors include surgery, chemotherapy, radiotherapy, molecular targeted therapy and immunotherapy. Chemotherapy is still one of the main means of clinical tumor treatment. Platinum drugs are one of the most commonly used chemotherapy drugs in clinical practice and have been widely used in the treatment of common malignant tumors such as lung cancer, bladder cancer, ovarian cancer, cervical cancer, gastric cancer and colorectal cancer. At present, the main platinum drugs used in clinical practice are first-generation cisplatin, second-generation carboplatin and third-generation oxaliplatin. Although platinum has become the first-line chemotherapy drug for the clinical treatment of tumors, there is a serious problem of drug resistance, which greatly limits its clinical application.

[0003] Tumor stem cells are a type of cancer cell with stem cell characteristics, with self-renewal and differentiation potential. They play an important role in the occurrence and development of tumors and are closely related to tumor invasion, metastasis, and drug resistance. Traditional cancer treatments can only kill common cancer cells with limited proliferation potential, resulting in the shrinkage of tumor masses, but tumor stem cells still survive and, after a period of proliferation and differentiation, form new tumors, leading to tumor recurrence. The existence of tumor stem cells is one of the key factors leading to the failure of platinum-based anti-tumor drug treatment. Summary of the invention

[0004] Purpose of the invention: In order to solve the problem of platinum drug resistance caused by tumor stem cells, the present invention aims to provide a type of terpyridine-platinum (II) complex containing guanine NHC derivative ligands with excellent inhibitory activity on the proliferation of malignant tumor cells and tumor stem cells. This type of complex improves the problem of poor solubility of guanine and shows strong inhibitory activity on tumor cells, especially triple-negative breast cancer cells and their stem cells, which are currently difficult to treat, without obvious toxicity to normal cells.

[0005] The invention also provides a preparation method and application of a novel terpyridine-platinum (II) complex containing a guanine derivative ligand.

[0006] Technical solution: In order to achieve the above-mentioned purpose, the complex of general formula (I) or a pharmaceutically acceptable salt thereof of the present invention is:

[0007]

[0008] in:

[0009] R 1 , R 2 , R3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 are each independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl, hydroxyl, amino, carboxyl, C1-C10 straight-chain alkyl, C1-C10 straight-chain heteroalkyl, C3-C12 branched or cyclic alkyl, C3-C12 branched or cyclic heteroalkyl, C2-C12 alkenyl or alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C10 alkoxy, substituted or unsubstituted phenoxy, substituted or unsubstituted aromatic hydrocarbonoxy, C1-C10 alkylthio, substituted or unsubstituted phenylthio, substituted or unsubstituted aromatic thio, C1-C10 alkanoyl, C1-C10 substituted alkylamino or C1-C10 substituted alkanoylamino;

[0010] X is O or S;

[0011] A is the anion of the complex;

[0012] b is the charge number of the anion;

[0013] y is the absolute value of 2 / b.

[0014] Preferably, the R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 Each is independently selected from hydrogen, halogen, cyano, trifluoromethyl, carboxyl, hydroxyl, methoxy, amino, methylamino, dimethylamino, acetamido;

[0015] X is O;

[0016] A is the anion of the complex;

[0017] b is the charge number of the anion;

[0018] y is the absolute value of 2 / b.

[0019] Preferably, the complex is selected from any one of the following:

[0020]

[0021]

[0022]

[0023] Wherein, the pharmaceutically acceptable salt is a salt formed by the above-mentioned complex and hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid or ferulic acid.

[0024] The method for preparing the complex or a pharmaceutically acceptable salt thereof of the present invention comprises the following steps:

[0025] Compounds II and III were mixed with AgSO 3 CF 3 After the reaction, an acid-binding agent is added to carry out coordination reaction to obtain; the reaction solvent is acetonitrile, methanol, tetrahydrofuran, 1,4-dioxane, or N,N-dimethylformamide, preferably acetonitrile; the acid-binding agent is potassium tert-butoxide, sodium tert-butoxide, potassium carbonate or sodium hydroxide, preferably potassium tert-butoxide;

[0026] The chemical reaction route is as follows:

[0027]

[0028] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , X, y, A and b are as defined above.

[0029] The invention relates to the use of the complex or a pharmaceutically acceptable salt thereof in the preparation of anti-tumor drugs.

[0030] Furthermore, the complex or a pharmaceutically acceptable salt thereof is used in the preparation of an anti-tumor drug having a dual inhibitory effect on tumor cells and tumor stem cells.

[0031] Wherein, the tumor is a malignant tumor such as breast cancer, pancreatic cancer, etc.

[0032] The anti-tumor drug composition of the present invention comprises the complex or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0033] Wherein, the pharmaceutical composition is a capsule, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment, suppository or patch.

[0034] Preferably, the above complex and a pharmaceutically acceptable carrier form a pharmaceutical composition. Specifically, the pharmaceutical composition is in the form of a pharmaceutical preparation such as tablets, capsules, syrups, and suspensions, and can be added with common pharmaceutical excipients such as flavors, sweeteners, liquid or solid fillers or diluents.

[0035] The present invention designs a series of complexes, which have the dual activity of inhibiting tumor cells and tumor stem cells at the same time, overcome the drug resistance problem caused by tumor stem cells, and improve the anti-tumor efficacy.

[0036] Guanine has important physiological functions. However, guanine has poor water solubility. Through appropriate structural modification, guanine derivatives with good solubility and important biological activities such as anti-tumor and anti-viral can be obtained. The present invention introduces guanine in the form of N-heterocyclic carbene (NHC) into a terpyridine-platinum fragment with anti-tumor activity. On the one hand, the NHC ligand can form a stable platinum-carbon bond with the platinum ion center to improve the stability of the complex; on the other hand, the solubility of the formed ionic complex can be adjusted by changing the substituents on the ligand, thereby improving the bioavailability and overcoming the problem of poor water solubility of guanine.

[0037] The present invention obtains a novel structural complex with good solubility by introducing biologically active guanine into a terpyridine-platinum fragment with anti-tumor activity. The obtained complex not only has a strong inhibitory activity on the proliferation of human triple-negative breast cancer cells MD-MBA-231 and human pancreatic cancer cells SW1990, which is significantly better than the existing platinum drug cisplatin, but also has a good proliferation inhibitory activity on human triple-negative breast cancer cells MD-MBA-231 stem cells. In addition, the obtained complex has no obvious inhibitory activity on the proliferation of normal cell rat kidney cells NRK. At present, there are few reports on compounds with dual inhibitory activity on tumor cells and tumor stem cells, but weak toxicity to normal cells. In addition, breast cancer is currently the cancer with the highest incidence rate in the world, and the number of breast cancer cases in China ranks first in the world. Triple-negative breast cancer is a type of breast cancer with negative expression of estrogen receptors, progesterone receptors and human epidermal growth factor 2 receptors, accounting for about 15% of the total breast cancer, is insensitive to conventional breast cancer treatment, is the breast cancer subtype with the highest recurrence rate and mortality rate, and the presence of triple-negative breast cancer stem cells is also one of the key factors leading to treatment failure. Therefore, it is of great significance to develop new drugs that can effectively treat triple-negative breast cancer. The complex of the present invention has strong inhibitory activity on triple-negative breast cancer cells and their stem cells, and is expected to become a new generation of anti-triple-negative breast cancer drugs.

[0038] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0039] (1) The terpyridine-platinum (II) complex containing a guanine derivative ligand and the pharmaceutical composition thereof disclosed in the present invention have inhibitory activity against both tumor cells and tumor stem cells, but have no obvious toxicity to normal cells, and can be used to prepare drugs for treating various types of malignant tumors, especially for preparing drugs for malignant tumors resistant to existing chemotherapy drugs.

[0040] (2) The platinum (II) complex of the present invention has the dual anti-tumor effect of inhibiting both tumor cells and tumor stem cells, overcoming the drug resistance caused by tumor stem cells, and avoiding the toxic side effects caused by multi-drug combination, thereby improving the anti-tumor efficacy.

[0041] (3) The terpyridine-platinum (II) complex containing a guanine derivative ligand of the present invention has a simple structure, an ingeniously designed synthesis route, cheap and readily available raw materials, a safe and environmentally friendly synthesis process, and is easy to mass produce. DETAILED DESCRIPTION

[0042] The present invention will be further described below in conjunction with the embodiments.

[0043] Unless otherwise specified, the materials and reagents used in the examples can be obtained from commercial sources.

[0044] Example 1

[0045] Preparation of complex 1

[0046] In a 50 mL three-necked flask, add chloro(2,2':6',2"-terpyridine)platinum(II) chloride (cas60819-00-3

[0047] )(80 mg, 0.16 mmol) and CH 3 CN (10 mL), add AgCF under reflux 3 SO 3 (82 mg, 0.32 mmol), react in the dark for 2 h, and then filter to remove the insoluble matter. In another 50 mL three-necked flask, add compound 7,9-dimethylguanine bromide (cas1240956-83-5) (62 mg, 0.24 mmol) and CH 3 CN (5 mL), AgCF was added at room temperature 3 SO 3 (61 mg, 0.24 mmol), react at room temperature in the dark for 30 min, then filter to remove insoluble matter. Combine the two filtrates, add t-BuOK (30 mg, 0.27 mmol), react at room temperature for 24 h under nitrogen protection, filter to obtain a yellow clear filtrate, evaporate the solvent under reduced pressure, and add 2 mL CH 3 CN was dissolved, 6 mL of ether was added to form a precipitate, and the mixture was allowed to stand for 1 h. The supernatant was removed and 2 mL of CH 3 CN dissolved, and 6 mL of saturated NH 4 PF 6 Aqueous solution, solid precipitated, washed with water and dried, 2 mL of CH 3 CN was dissolved, and 10 mL of ether was diffused and crystallized to obtain 15 mg of yellow powdery solid complex 1 with a yield of 10.4%.

[0048] 1 H-NMR (300 MHz, Acetonitrile-d 3 ): δ (ppm) 8.55 (dd, J=8.8, 7.6Hz, 1H, Ar H ),8.45-8.35(m,7H,Ar H ,N H ),8.30-8.19(m,2H,Ar H ),7.75(ddd,J=7.4,5.6,1.8Hz,2H,Ar H ),6.13(s,2H,N H 2 ),4.09(s,3H,NC H 3),3.81(s,3H,NC H 3 ).

[0049] 13 C-NMR (151 MHz, Acetonitrile-d 3 ): δ(ppm)160.86,160.16,158.31,155.17,152.21,150.54,143.08,142.84,136.16,129.19,125.79,124.23,109.13,35.20,30.79.

[0050] HR-MS(ESI)m / z[M] 2+ Calcd for C 22 H 20 N 8 OPt,303.5704; Found:303.57011.

[0051] Anal.Calcd for C 22 H 20 F 12 N 8 OP 2 Pt:C 29.44,H 2.25,N 12.49.Found:C 30.47,H2.22,N13.19.

[0052] Example 2

[0053] Preparation of complex 2

[0054] Synthesis of 7-Methyl-9-n-Butylguanine Iodide

[0055] 9-n-butylguanine (cas93905-75-0) (1.0 g, 4.83 mmol), iodomethane (3.4 g, 23.95 mmol), N,N-dimethylformamide (7.5 mL) were added to a 45 mL sealed tube and reacted at 65 ° C for 16 h. Ammonia water was added to adjust the pH to 9, and a yellow solid was precipitated. The solid was collected and recrystallized from methanol and water to obtain a white solid. Hydrochloric acid and ethyl acetate solution was added to the white solid to adjust the pH to 5, and dried to obtain 0.9 g of a light yellow solid product with a yield of 53.4%.

[0056] 1 H-NMR (300 MHz, DMSO-d 6 ):δ(ppm)11.91(s,1H,N H ),9.29(s,1H,NC H N),7.44(s,2H,NH 2 ),4.10(t,J=7.2Hz,2H,NC H 2 ),3.99(s,3H,NC H 3 ),1.83-1.73(m,2H,NCH 2 C H 2 ),1.37-1.25(m,2H,C H 2 CH 3 ),0.91(t,J=7.3Hz,3H,CH 2 C H 3 ).

[0057] Synthesis of complex 2

[0058] The reaction mixture was prepared with chloro(2,2':6',2"-terpyridine)platinum(II) chloride (80 mg, 0.16 mmol), 7-methyl-9-n-butylguanine iodide (83 mg, 0.24 mmol), AgCF 3 SO 3 (144 mg, 0.56 mmol) and t-BuOK (30 mg, 0.27 mmol) were used as raw materials, and the operation was the same as the synthesis of complex 1 to obtain 15 mg of yellow powdery solid complex 2, with a yield of 10.0%

[0059] 1 H-NMR (500 MHz, DMSO-d 6 ):δ(ppm)9.17(s,1H,N H ),8.74-8.72(m,5H,Ar H ),8.55(td,J=8.0,1.6Hz,2H,Ar H ),8.31(d,J=5.6Hz,2H,Ar H ),7.86(t,J=6.9Hz,2H,ArH),7.35(s,2H,NH 2 ),4.18(t,J=7.4Hz,2H,NCH 2 CH 2 ),4.06(s,3H,NCH 3 ),1.90-1.84(m,2H,NCH 2 CH 2 CH 2 ),1.45-1.37(m,2H,CH 2 CH 2 CH 3),0.98(t,J=7.4Hz,3H,CH 2 CH 3 ).

[0060] 13 C-NMR (126 MHz, DMSO-d 6 ): δ(ppm)161.19,160.28,158.47,155.07,152.56,150.34,143.45,143.22, 136.72,129.78,126.34,124.83,108.61,44.64,35.72,31.06,19.57,13.90.

[0061] HR-MS(ESI)m / z[M] 2+ Calcd for C 25 H 26 N 8 OPt,324.5939; Found:324.59301.

[0062] Example 3

[0063] Preparation of complex 3

[0064] Synthesis of 7-Methyl-9-n-hexylguanine iodide

[0065] Using 9-n-hexylguanine (cas108776-70-1) (0.9 g, 3.83 mmol) and iodomethane (2.8 g, 19.73 mmol) as raw materials, the operation was the same as the synthesis of 7-methyl-9-n-butylguanine iodide to obtain 0.9 g of light yellow solid product with a yield of 62.3%.

[0066] 1 H-NMR (300 MHz, DMSO-d 6 ): δ(ppm)11.85(s,1H,NH),9.27(s,1H,NCHN),7.38(s,2H,NH 2 ),4.09(t,J=7.2Hz,2H,NCH 2 ),3.99(s,3H,NCH 3 ),1.81-1.74(m,2H,NCH 2 CH 2 ),1.29-1.27(m,6H,CH 2 CH 2 CH 2 CH 3 ),0.87(m,3H,CH 2 CH 3 ).

[0067] Synthesis of complex 3

[0068] The reaction mixture was prepared with chloro(2,2':6',2"-terpyridine)platinum(II) chloride (80 mg, 0.16 mmol), 7-methyl-9-n-hexylguanine iodide (90 mg, 0.24 mmol), AgCF 3 SO 3 (144 mg, 0.56 mmol) and t-BuOK (30 mg, 0.27 mmol) were used as raw materials, and the operation was the same as that of the synthesis of complex 1 to obtain 35 mg of yellow powdery solid complex 3 with a yield of 22.6%.

[0069] 1 H-NMR (400 MHz, DMSO-d 6 ): δ (ppm) 9.17 (s, 1H, NH), 8.74-8.71 (m, 5H, ArH), 8.55 (td, J = 7.8, 1.5Hz, 2H, ArH), 8 .30(dd,J=5.6,1.5Hz,2H,ArH),7.86(ddd,J=7.4,5.6,1.4Hz,2H,ArH),7.35(s,2H,NH 2 ),4.17(t,J=7.3Hz,2H,NCH 2 CH 2 ),4.06(s,3H,NCH 3 ),1.92-1.85(m,2H,NCH 2 CH 2 CH 2 ),1.41-1.33(m,6H,CH 2 CH 2 CH 2 CH 2 CH 3 ),0.92(t,J=6.8Hz,3H,CH 2 CH 3 ).

[0070] 13 C-NMR (126 MHz, DMSO-d 6 ): δ(ppm)161.19,160.28,158.47,155.07,152.55,150.33,143.45,143.22,136.70 ,129.77,126.34,124.83,108.61,44.91,35.72,31.17,29.04,25.95,22.43,14.38.

[0071] HR-MS(ESI)m / z[M] 2+ Calcd for C 27 H 30 N 8 OPt,338.6095; Found:338.60874.

[0072] Example 4

[0073] Preparation of complex 4

[0074] Synthesis of 7-Methyl-9-octylguanine iodide

[0075] Using 9-octylguanine (cas108870-41-3) (1.0 g, 3.80 mmol) and iodomethane (2.7 g, 19.02 mmol) as raw materials, the operation was the same as the synthesis of 7-methyl-9-n-butylguanine iodide to obtain 0.7 g of light yellow solid product with a yield of 45.5%.

[0076] 1 H-NMR (300 MHz, DMSO-d 6 ): δ(ppm)11.87(s,1H,NH),9.27(s,1H,NCHN),7.39(s,2H,NH 2 ),4.14-4.03(t,J=7.2Hz,2H,NCH 2 CH 2 ),3.99(s,3H,NCH 3 ),1.79(t,J=7.4Hz,2H,NCH 2 CH 2 ),1.30-1.23(m,10H,CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ),0.86(t,J=6.5Hz,3H,CH 2 CH 3 ).

[0077] Synthesis of complex 4

[0078] The reaction mixture was prepared with chloro(2,2':6',2"-terpyridine)platinum(II) chloride (80 mg, 0.16 mmol), 7-methyl-9-octylguanine iodide (97 mg, 0.24 mmol), AgCF 3 SO 3(144 mg, 0.56 mmol) and t-BuOK (30 mg, 0.27 mmol) were used as raw materials, and the operation was the same as that of the synthesis of complex 1 to obtain 32 mg of yellow powdery solid complex 4 with a yield of 20.0%.

[0079] 1 H-NMR (400 MHz, DMSO-d 6 ): δ (ppm) 9.16 (s, 1H, NH), 8.74-8.71 (m, 5H, ArH), 8.55 (td, J = 7.9, 1.5Hz, 2H, ArH), 8 .30(dd,J=5.6,1.5Hz,2H,ArH),7.86(ddd,J=7.4,5.6,1.4Hz,2H,ArH),7.34(s,2H,NH 2 ),4.17(t,J=7.3Hz,2H,NCH 2 CH 2 ),4.06(s,3H,NCH 3 ),1.92-1.85(m,2H,NCH 2 CH 2 CH 2 ),1.37-1.28(m,10H,CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ),0.88(t,J=6.5Hz,3H,CH 2 CH 3 ).

[0080] 13 C-NMR (126 MHz, DMSO-d 6 ): δ(ppm)161.19,160.28,158.47,155.06,152.54,150.32,143.44,143.22,136.71,129.7 7,126.34,124.83,108.61,44.92,35.72,31.69,29.08,29.04,28.98,26.31,22.57,14.44.

[0081] HR-MS(ESI)m / z[M] 2+ Calcd for C 29 H 34 N 8 OPt,352.6252; Found:352.62424.

[0082] Example 5

[0083] Preparation of complex 5

[0084] Synthesis of 9-cyclopropylmethylguanine

[0085] 2-Amino-6-chloro-9-cyclopropylpurine (cas151370-27-3) (2.0 g, 8.94 mmol) and 0.5 M hydrochloric acid aqueous solution (98 mL) were added to a 250 mL three-necked flask and refluxed for 16 h. A 10% aqueous solution of sodium hydroxide was added to the reaction solution to adjust the pH to 8, and a white solid precipitated. The solid was collected by filtration, washed with water, and dried to obtain 1.7 g of a white solid product with a yield of 92.7%. ESI-MS [M+H] + 206.1.

[0086] Synthesis of 7-Methyl-9-cyclopropylmethylguanine iodide

[0087] Using 9-cyclopropylmethylguanine (1.0 g, 4.87 mmol) and iodomethane (3.5 g, 24.66 mmol) as raw materials, the operation was the same as the synthesis of 7-methyl-9-n-butylguanine iodide to obtain 0.8 g of light yellow solid product with a yield of 47.3%.

[0088] 1 H-NMR (400 MHz, DMSO-d 6 ): δ(ppm)11.81(s,1H,NH),9.32-9.31(m,1H,NCHN),7.31(s,2H,NH 2 ), 4.02(s,3H,NCH 3 ),3.97(d,J=7.3Hz,2H,NCH 2 ),1.33-1.25(m,1H,NCH 2 CH), 0.64-0.60(m,2H,CHCH 2 CH 2 ),0.51-0.47(m,2H,CHCH 2 CH 2 ).

[0089] Synthesis of complex 5

[0090] The reaction mixture was prepared with chloro(2,2':6',2"-terpyridine)platinum(II) chloride (80 mg, 0.16 mmol), 7-methyl-9-cyclopropylmethylguanine iodide (83 mg, 0.24 mmol), AgCF 3 SO 3(144 mg, 0.56 mmol) and t-BuOK (30 mg, 0.27 mmol) were used as raw materials, and the operation was the same as that of the synthesis of complex 1 to obtain 30 mg of yellow powdery solid complex 5 with a yield of 20.0%.

[0091] 1 H-NMR (300 MHz, Acetonitrile-d 3 ): δ(ppm)8.58-8.52(m,2H,ArH),8.45-8.35(m,6H,ArH,NH),8.32-8.20(m,2H,ArH),7.75(ddd,J=7.4,5.6,1.8Hz,2H,ArH),6.12(s,2H,NH 2 ),4.10(s,3H,NCH 3 ),4.05(d,J=7.4Hz,2H,NCH 2 CH)1.46-1.33(m,1H,NCH 2 CH), 0.79-0.73 (m, 2H, CHCH 2 CH 2 ),0.61-0.56(m,2H,CHCH 2 CH 2 ).

[0092] Example 6

[0093] Preparation of complex 6

[0094] Synthesis of 7-methyl-9-benzylguanine iodide

[0095] Using 9-benzylguanine (cas14937-72-5) (1.0 g, 4.15 mmol) and iodomethane (2.9 g, 20.43 mmol) as raw materials, the operation was the same as the synthesis of 7-methyl-9-n-butylguanine iodide to obtain 0.8 g of light yellow solid product with a yield of 50.3%.

[0096] 1 H-NMR (400 MHz, DMSO-d 6 ): δ(ppm)11.91(m,1H,NH),9.32(s,1H,NCHN),7.44-7.35(m,7H,ArH,NH 2 ),5.37(s,2H,NCH 2 ),4.01(s,3H,NCH 3 ).

[0097] Synthesis of complex 6

[0098] The reaction mixture was prepared with chloro(2,2':6',2"-terpyridine)platinum(II) chloride (80 mg, 0.16 mmol), 7-methyl-9-benzylguanine iodide (92 mg, 0.24 mmol), AgCF 3 SO 3 (144 mg, 0.56 mmol) and t-BuOK (30 mg, 0.27 mmol) were used as raw materials, and the operation was the same as that of the synthesis of complex 1 to obtain 32 mg of yellow powdery solid complex 6 with a yield of 20.4%.

[0099] 1 H-NMR (300 MHz, Acetonitrile-d 3 ): δ (ppm) 8.55 (dd, J = 8.8, 7.6Hz, 1H, ArH), 8.45-8.35 (m, 7H, ArH, NH), 8.32-8.20 (m, 2 H,ArH),7.75(ddd,J=7.5,5.7,1.8Hz,2H,ArH),7.54-7.44(m,5H,ArH),6.17(s,2H,NH 2 ),5.40(s,2H,NCH 2 ),4.07(s,3H,NCH 3 ).

[0100] HR-MS(ESI)m / z[M] 2+ Calcd for C 28 H 24 N 8 OPt,341.5860; Found:341.58365.

[0101] Example 7

[0102] Preparation of complex 7

[0103] Synthesis of 7-methyl-9-(4-methylbenzyl)guanine iodide

[0104] Using 9-(4-methylbenzyl)guanine (cas101134-15-0) (1.0 g, 3.92 mmol) and iodomethane (2.8 g, 19.72 mmol) as raw materials, the operation was the same as the synthesis of 7-methyl-9-n-butylguanine iodide to obtain 0.9 g of light yellow solid product with a yield of 57.8%.

[0105] 1 H-NMR (400 MHz, DMSO-d 6): δ(ppm)11.92(d,J=8.1Hz,1H,NH),9.29(d,J=4.6Hz,1H,NCHN),7.41(s,2H,NH 2 ),7.30(d,J=8.1Hz,2H,ArH),7.22(d,J=7.9Hz,2H,ArH),5.30(s,2H,NCH 2 ),3.99(s,3H,NCH 3 ),2.30(s,3H,CCH 3 ).

[0106] Synthesis of complex 7

[0107] Chloro(2,2':6',2"-terpyridine)platinum(II) chloride (80 mg, 0.16 mmol), 7-methyl-9-(4-methylbenzyl)guanine iodide (95 mg, 0.24 mmol), AgCF 3 SO 3 (144 mg, 0.56 mmol) and t-BuOK (30 mg, 0.27 mmol) were used as raw materials, and the operation was the same as that of the synthesis of complex 1 to obtain 20 mg of yellow powdery solid complex 7 with a yield of 12.7%.

[0108] 1 H-NMR (300 MHz, Acetonitrile-d 3 ): δ(ppm)8.55(dd,J=8.8,7.6Hz,1H,ArH),8.43-8.42(m,2H,ArH),8.40-8.39(m,1H,ArH),8.38-8.37(m,2H,ArH,NH),8.36-8.35(m,2H,A rH),8.31-8.20(m,2H,ArH),7.75(ddd,J=7.4,5.6,1.8Hz,2H,ArH),7.41(d,J=8.1Hz,2H,ArH),7.31(d,J=7.8Hz,2H,ArH),6.16(s,2H,NH 2 ),5.35(s,2H,NCH 2 ),4.07(s,3H,NCH 3 ),2.39(s,3H,CCH 3 ).

[0109] Example 8

[0110] Pharmacological experiments

[0111] In this experiment, the CCK8 method was used to test the in vitro tumor cell proliferation inhibition activity of the complex of the present invention and the commonly used platinum anti-tumor drugs in clinical practice.

[0112] (1) Experimental methods

[0113] The cells were plated at 4 × 10 3 The density of cells / well (100μL) was inoculated into a 96-well plate, and the 96-well plate was placed in an incubator at 37°C and 5% CO2 overnight. On the second day, 100μL of fresh culture medium containing 200μM of each compound complex was added to the first column of wells, mixed evenly, and then applied by half dilution. After a certain period of incubation for 96h, 20μL of CCK8 reagent was added to each well. After incubation for another 2h, OD 450nm was measured with an enzyme reader. A freshly prepared 10mM solution of the compound complex in N,N-dimethylformamide (DMF) was used as a stock solution, stored at -20°C for future use, and diluted to 200μM with complete culture medium when used; cisplatin was prepared with culture medium before each use.

[0114] (2) Test results

[0115] The anti-proliferative activity data of the complex of the present invention on human triple-negative breast cancer cells MDA-MB-231, human triple-negative breast cancer stem cells MDA-MB-231CSCs, human pancreatic cancer cells SW1990 and normal rat kidney cells NRK are shown in Table 1, and cisplatin is used as the positive control drug 1;

[0116] Compound 14 As a positive control drug 2.

[0117] Table 1 Antiproliferative activity data of the complexes on MDA-MB-231, MDA-MB-231CSCs, SW1990 and NRK, the action time is 96 hours

[0118]

[0119]

[0120] As can be seen from Table 1, the complex has selective inhibitory activity against malignant tumor cells: the complex has better proliferation inhibitory activity against human triple-negative breast cancer cells MDA-MB-231, human breast cancer stem cells MDA-MB-231 and human pancreatic cancer cells SW1990 than the positive drug cisplatin; the complex has no obvious proliferation inhibitory activity against normal rat kidney cells NRK, and its inhibitory activity is significantly weaker than the positive drug cisplatin, while the inhibitory activity of the complex of the present invention against tumor stem cells is significantly better than the positive control drug 2 (Compound 14). The above description shows that the complex of the present invention shows strong inhibitory activity against tumor cells, especially triple-negative breast cancer cells and their stem cells, which are currently difficult to treat, and has no obvious toxicity to normal cells, and has very good selectivity.

Claims

1. A complex or a pharmaceutically acceptable salt thereof, It is characterized in that The complex is selected from any one of the following:

2. The complex according to claim 1 or a pharmaceutically acceptable salt thereof, It is characterized in that The pharmaceutically acceptable salt is a salt formed by the above-mentioned complex and hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid or ferulic acid.

3. Use of the complex according to claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of an anti-tumor drug, wherein the tumor is breast cancer or pancreatic cancer.

4. The use according to claim 3, It is characterized in that The complex or a pharmaceutically acceptable salt thereof is used in the preparation of an anti-tumor drug having a dual inhibitory effect on tumor cells and tumor stem cells.

5. An anti-tumor drug composition, It is characterized in that It comprises the complex according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and the tumor is breast cancer or pancreatic cancer.

6. The pharmaceutical composition according to claim 5, It is characterized in that The pharmaceutical composition is a capsule, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment, suppository or patch.

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