Pt complex with beta-carboline derivative as ligand, synthesis method and application thereof

Abstract

This invention discloses a series of platinum complexes using β-carboline derivatives as ligands, their synthesis methods, and applications, belonging to the field of pharmaceutical technology. The synthesis method of the platinum complexes of this invention involves a coordination reaction between β-carboline derivatives as ligands and dichlorobis(dimethyl sulfoxide) platinum in a mixed solvent composed of ethanol and acetonitrile or chloroform, wherein the proportion of ethanol in the mixed solvent is ≥30 v / v%. The platinum complexes of this invention exhibit good inhibitory effects on Mcl-1-dependent tumor cell lines and demonstrate tumor growth inhibition in a nude mouse xenograft model of human non-small cell lung cancer (NCl-H23). They show lower toxicity to normal cells than cisplatin and are expected to be used as anti-tumor therapeutic drugs.

Description

Technical Field

[0001] This invention relates to platinum complexes with β-carboline derivatives as ligands, their synthesis methods and applications, belonging to the field of pharmaceutical technology. Background Technology

[0002] Mcl-1 (myeloid leukemia-1 protein), an anti-apoptotic protein, is an important member of the B-cell lymphoma-2 (Bcl-2) protein family. It plays a central role in regulating programmed cell death (apoptosis) and is crucial for maintaining cell survival. Mcl-1 combats apoptosis by neutralizing BH3 proteins (such as tBID, BIM, PUMA, and NOXA) and effectors Bax and Bak. When cells suffer irreparable damage, the apoptotic program is initiated, increasing the expression of pro-apoptotic BH3 proteins such as BIM, PUMA, and NOXA. Bax and Bak then form pores outside the mitochondrial membrane, allowing cytochrome c and other apoptotic proteins to infiltrate the cytoplasm, promoting the formation of apoptotic microbodies, activating caspase, and leading to cell lysis and death. In tumor cells, aberrant expression of Mcl-1 disrupts the dynamic balance between anti-apoptotic and pro-apoptotic proteins, significantly inhibiting the apoptotic process in tumor cells, ultimately leading to malignant proliferation and invasion of tumor cells. Therefore, Mcl-1 has become a highly promising and effective target in the field of cancer therapy.

[0003] Researchers have developed various small molecule inhibitors targeting Mcl-1 for tumor treatment. Mcl-1 inhibitors with β-carboline derivatives as their structural backbone, such as AZD5991, not only exhibit good anti-tumor activity but also potent Mcl-1 inhibitory activity, providing an important research direction for Mcl-1 targeted therapy. Currently, there are no reports of Mcl-1 targeted anti-tumor drugs that use β-carboline derivatives as ligands to coordinate with platinum to obtain excellent anti-tumor activity and targeting. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a series of platinum complexes with novel structures, good antitumor activity and strong affinity for Mcl-1 using β-carboline derivatives as ligands, as well as their synthesis methods and applications.

[0005] In a first aspect, the present invention provides platinum complexes with β-carbaline derivatives as ligands having the structure shown in formula (I) below, or pharmaceutically acceptable salts thereof:

[0006] (I);

[0007] Wherein, R represents a C1~C6 alkyl group, or a group represented by the following formula (II);

[0008] (II), in formula (II), n = 0~4, R1 represents hydrogen, trifluoroalkyl, trifluoroalkoxy or C1~C6 alkyl, and R1 is monosubstituted.

[0009] Furthermore, in formula (II), n = 0~4, and R1 represents hydrogen, trifluoroalkyl, trifluoromethoxy or C1~C4 alkyl; even further, R1 represents hydrogen, trifluoroalkyl, trifluoromethoxy, methyl or tert-butyl.

[0010] In some specific embodiments, R represents -CH3, , , , or .

[0011] In a second aspect, the present invention provides a method for synthesizing the above-mentioned platinum complex with β-carboline derivative as ligand, comprising: taking a β-carboline derivative with the structure shown in the following formula (L) and dichlorobis(dimethyl sulfoxide) platinum in a reaction vessel, adding a mixed solvent, and reacting under heating conditions to obtain the target complex;

[0012] (L);

[0013] Wherein, R represents a C1~C6 alkyl group, or a group represented by the following formula (II);

[0014] (II), in formula (II), n = 0~4, R1 represents hydrogen, trifluoroalkyl, trifluoroalkoxy or C1~C6 alkyl;

[0015] The mixed solvent is a combination of ethanol and acetonitrile or chloroform, wherein the proportion of ethanol in the mixed solvent is greater than or equal to 30 v / v%.

[0016] Furthermore, in the composition of the mixed solvent, the proportion of ethanol in the mixed solvent is greater than or equal to 50 v / v.

[0017] In some specific examples of synthesis, when R represents When the mixed solvent is a combination of ethanol and chloroform, and when R represents -CH3, , , or In this case, the mixed solvent is a combination of ethanol and acetonitrile.

[0018] Furthermore, when the mixed solvent is a combination of ethanol and acetonitrile, the volume ratio of ethanol to acetonitrile is 2:1 to 1:1; when the mixed solvent is a combination of ethanol and chloroform, the volume ratio of ethanol to chloroform is 1:2 to 1:1.

[0019] Furthermore, the reaction is carried out at a temperature greater than or equal to 50°C, more preferably at a temperature of 60-70°C, and the reaction time is preferably controlled at 24-72 hours.

[0020] In the above synthesis method, the ratio of the β-carboline derivative with the structure shown in formula (L) to dichlorobis(dimethyl sulfoxide) platinum is a stoichiometric ratio. In actual operation, the amount of the β-carboline derivative with the structure shown in formula (L) is relatively excessive.

[0021] In the above synthetic method, the β-carbaline derivative with the structure shown in the starting material formula (L) can be prepared with reference to existing literature (J.Org. Chem. 2022, 87, 18, 12287-12296; Eur. J. Med. Chem. 2014, 87, 63-70; Bioorg. Med. Chem. Lett. 2012, 22, 17, 5707-5713; Mol. Catal. 2019, 468, 86-93), preferably prepared by the following method:

[0022] 1) Compound i and compound j are placed in an organic solvent and subjected to a substitution reaction in the presence of a base and under a protective atmosphere (such as nitrogen or argon) to obtain compound k;

[0023] 2) Compound k was placed in a solvent consisting of water and 1,4-dioxane and hydrolyzed in the presence of acetic acid to obtain compound m;

[0024] 3) Compound m and an aqueous solution of methylamine (monomethylamine aqueous solution) were reacted in an organic solvent to carry out a Schiff base reaction, thereby obtaining a β-carboline derivative with the structure shown in formula (L);

[0025] , , , ;

[0026] Wherein, R represents a C1~C6 alkyl group, or a group represented by the following formula (II);

[0027] (II), in formula (II), n = 0~4, R1 represents hydrogen, trifluoroalkyl, trifluoroalkoxy or C1~C6 alkyl;

[0028] X represents halogen.

[0029] In the preparation method of the β-carbaline derivative with the structure shown in formula (L) above, X preferably represents bromine or iodine. Compound i in step 1) can be prepared by reacting tryptamine, 2,2-dimethoxyacetaldehyde and trifluoroacetic acid in dichloromethane, followed by oxidation with potassium permanganate.

[0030] In the preparation method of the β-carbaline derivative with the structure shown in formula (L) above, the organic solvent can be N,N-dimethylformamide, tetrahydrofuran, or dichloromethane. The base can be an organic base (such as potassium tert-butoxide, 1,8-diazabicyclo[5.4.0]-7-undecene, or diisopropylethylamine, etc.) or an inorganic base (such as potassium carbonate, sodium hydroxide, or sodium hydride, etc.), preferably sodium hydride. The substitution reaction can be carried out at room temperature; the hydrolysis reaction and Schiff base reaction are preferably carried out under heating conditions, and further reflux reaction is adopted.

[0031] In the preparation method of the β-carbaline derivative with the structure shown in formula (L) above, the products obtained in steps 1), 2), and 3) are crude products of the corresponding compounds, which can be purified according to conventional purification methods. For example, the crude product obtained in step 1) can be separated and purified by silica gel column chromatography (the eluent is a combination of ethyl acetate and petroleum ether), and the crude products obtained in steps 2) and 3) can be separated and purified by recrystallization. The solvent for recrystallization can be a combination of ethanol and petroleum ether, or a combination of ethyl acetate and petroleum ether.

[0032] Thirdly, the present invention provides a crystal form of a platinum complex IE, which belongs to the monoclinic crystal system, space group P21 / c, with cell parameters of: a=8.9396(10) Å, b=11.4562(10) Å, c=21.3714(2) Å, α=90 o , β=98.6670(10) o γ=90 o The single-crystal structure shows that the platinum complex has a mononuclear IE crystal form. The central metal ion Pt coordinates with two chlorine atoms and the ligands N1 and N2, respectively, forming a four-coordinate planar tetragonal geometry.

[0033] Fourthly, the present invention provides a method for synthesizing the above-mentioned platinum complex Pt-IE crystal form, comprising: taking a β-carbamoline derivative with the structure shown in the following formula (L) and dichlorobis(dimethyl sulfoxide) platinum in a reaction vessel, adding a mixed solvent, reacting under heating conditions, cooling the reactants, precipitating crystals, collecting the crystals, which are the target products;

[0034] (L);

[0035] Where R represents ;

[0036] The mixed solvent is a composition of ethanol and acetonitrile in a volume ratio of 2:1 to 1:1.

[0037] The preparation of the β-carboline derivative with the structure shown in formula (L) and the selection of temperature and time for the reaction of the β-carboline derivative with the structure shown in formula (L) and dichlorobis(dimethyl sulfoxide) platinum are the same as those in the aforementioned platinum complex synthesis method.

[0038] Fifthly, this invention provides the application of the above-mentioned platinum complexes or crystalline forms of platinum complexes IE with β-carboline derivatives as ligands in the preparation of antitumor drugs or Mcl-1 inhibitors. The applicant discovered through in vitro antitumor activity assays that the platinum complexes or crystalline forms of platinum complexes IE described in this invention exhibit high selectivity for Mcl-1-dependent sensitive cells (MV-4-11, A2780, and NCI-H23) and broad-spectrum tumor cells, and all platinum complexes show lower toxicity to normal cells than cisplatin, while exhibiting higher inhibitory activity against tumor cells than cisplatin.

[0039] In a sixth aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned platinum complex with β-carboline derivative as a ligand or the crystal form of the above-mentioned platinum complex IE.

[0040] Compared with the prior art, the present invention provides a series of novel platinum complexes with β-carboline derivatives as ligands and their synthesis methods. The applicant's experimental results show that the complexes of the present invention have significant anti-proliferative effects on Mcl-1 dependent tumor cells. The activity of most of the complexes is significantly improved compared with that of the single ligand, and is comparable to the anti-tumor activity of cisplatin. More importantly, their toxicity to normal cells is lower than that of cisplatin, and they are expected to be developed into anti-tumor drugs. Attached Figure Description

[0041] Figure 1 This is the crystal structure diagram of the platinum complex IE.

[0042] Figure 2 The curve shows the effect of the platinum complex IC on the tumor volume of the NCl-H23 nude mouse xenograft model.

[0043] Figure 3 The curve shows the effect of platinum complex IC on tumor weight in (NCl-H23) nude mouse xenograft model mice.

[0044] Figure 4 Histological morphology images of heart, liver, spleen, lung, and kidney sections from NCl-H23 nude mouse xenograft model mice using platinum complex IC. Detailed Implementation

[0045] To better explain the technical solution of the present invention, the present invention will be further described in detail below with reference to the embodiments, but the implementation of the present invention is not limited thereto.

[0046] Example 1: Synthesizing β-carboline derivatives (hereinafter referred to as ligands L1~L6) with the structure shown in formula (L) according to the following synthetic route

[0047]

[0048] a: dichloromethane; b: N,N-dimethylformamide, sodium hydride; c: 1,4-dioxane / water = 1:1 (volume ratio), acetic acid; d: aqueous methylamine solution.

[0049] The following example illustrates the synthesis of ligand L1 ((E)-N-methyl-1-(9-(4-methylbenzyl)-9H-pyrido[3,4-b]indol-1-yl)methylimine):

[0050] 1) Synthesis of 1-(dimethoxymethyl)-9H-pyrido[3,4-b]indole (i)

[0051] To a 250 mL round-bottom flask, add tryptophan (6 g), dichloromethane (60 mL), and 2,2-dimethoxyacetaldehyde (60% aqueous solution, 6 mL). Dissolve 3 mL of trifluoroacetic acid in 24 mL of dichloromethane and add it to the flask in three portions. Stir at room temperature for 12 h. Stop the reaction by adding 10% sodium bicarbonate solution. Adjust the pH of the solution to between 7 and 8. Extract with dichloromethane and collect the organic phase. Dry with anhydrous sodium sulfate, filter, and rotary evaporate at 50 °C to obtain a black oil. Dissolve the black oil in tetrahydrofuran (10 mL), add potassium permanganate (6 g), and stir at room temperature for 24 h. Confirm the reaction is complete by thin-layer chromatography. Filter with diatomaceous earth, wash with dichloromethane, dry the filtrate with anhydrous sodium sulfate, filter, and rotary evaporate to obtain 3.75 g of a yellow oil, which is compound i, with a yield of 62.5%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm)11.10 (s, 1H), 8.31 – 8.27 (m, 1H), 8.22 (d, J = 7.9 Hz, 1H), 8.12 (d, J =5.2 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.57–7.51 (m, 1H), 7.26 – 7.23 (m,1H), 5.62 (s, 1H), 3.42 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ (ppm) 141.27,141.25, 137.29, 133.06, 129.39, 128.62, 121.91, 120.64, 119.68, 115.44,112.93, 106.44, 67.49, 54.44, 25.59. 13 C NMR (101 MHz, DMSO-d6) δ (ppm)141.26, 137.29, 133.06, 129.39, 128.62, 121.91, 120.64, 119.68, 115.44,112.93, 106.44, 67.49, 54.44, 25.59.

[0052] 2) Synthesis of 1-(dimethoxymethyl)-9-(4-methylbenzyl)-9H-pyrido[3,4-b]indole (k1)

[0053] N,N-dimethylformamide (20 mL) and sodium hydride (1.5 mmol) were added to a double-necked round-bottom flask. Then, under nitrogen protection, a solution of compound i (1 mmol) in N,N-dimethylformamide was added, and the reaction was allowed to proceed at room temperature for 1 h. 4-Methylbenzyl bromide (1.5 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 h. Thin-layer chromatography confirmed the completion of the reaction. The pH of the solution was adjusted to between 7 and 8 with acetic acid. The reactants were poured into a beaker containing a large amount of ice water and stirred. The mixture was extracted with ethyl acetate, and the organic phase was repeatedly washed with saturated sodium chloride solution. Anhydrous sodium sulfate was added to the organic phase, and the mixture was dried overnight. The mixture was filtered and rotary evaporated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1, v / v) to give compound k1. 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.35(d, J = 5.1 Hz, 1H), 8.31 (d, J = 7.8 Hz, 1H), 8.28 (d, J = 5.1 Hz, 1H), 7.53– 7.46 (m, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 7.02 (d,J = 7.9 Hz, 2H), 6.82 (d, J = 7.8 Hz, 2H), 6.00 (s, 2H), 5.54 (s, 1H), 3.27(s, 6H), 2.20 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ (ppm) 141.89, 141.38,137.09, 136.01, 135.98, 134.44, 130.58, 129.22 (2C), 128.99, 126.31 (2C),121.89, 121.33, 120.44, 116.14, 111.76, 109.82, 55.54 (2C), 49.00, 21.06.ESI-MS: m / z 347.1751[M+H] + .

[0054] 3) Synthesis of 9-(4-methylbenzyl)-9H-pyrido[3,4-b]indole-1-carboxaldehyde (m1)

[0055] Compound k1 (1 g) was dissolved in 20 mL of acetic acid, and 20 mL of a mixed solvent consisting of 1,4-dioxane and water (1:1, volume ratio) was added. The mixture was refluxed at 100 °C for 6 h. After confirming the complete reaction of the starting material by thin-layer chromatography, the solvent was removed by vacuum distillation. The crude product was recrystallized from ethanol to obtain compound m1, with a yield of 69%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm)10.16 (s, 1H), 8.68 (d, J = 4.8 Hz, 1H), 8.58 (d, J = 4.9 Hz, 1H), 8.41 (d, J= 7.8 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.65 (t, J = 8.2 Hz, 1H), 7.39 (t, J= 7.4 Hz, 1H), 7.00 (d, J = 7.8 Hz, 2H), 6.81 (d, J = 8.0 Hz, 2H), 6.13 (s,2H), 2.17 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 194.24, 142.80, 139.15,137.97, 136.74, 135.38, 135.25, 132.56, 130.09, 129.57 (2C), 126.62 (2C),122.41, 121.57, 121.01, 120.01, 111.98, 49.50, 21.02. ESI-MS: m / z 301.1329[M+H] + .

[0056] 4) Synthesis of (E)-N-methyl-1-(9-(4-methylbenzyl)-9H-pyrido[3,4-b]indol-1-yl)methylimine (ligand L1)

[0057] Compound m1 (1 mmol) was dissolved in 20 mL of dichloromethane, and anhydrous magnesium sulfate (3 mmol) was added. The mixture was stirred at room temperature for 20 min, and then an aqueous solution of methylamine (40 wt%, 1 mL) was added. The mixture was refluxed under nitrogen protection for 24 h. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was dried over anhydrous sodium sulfate. The filtrate was then filtered and rotary evaporated to obtain ligand L1, with a yield of 53%. 1 HNMR (400 MHz, DMSO-d6)δ (ppm) 8.55 (q, J = 1.7 Hz, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.35 (d, J = 7.7Hz, 1H), 8.31 (d, J = 5.0 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.66 – 7.59 (m,1H), 7.34 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 7.9 Hz, 2H), 6.65 (d, J = 8.1 Hz,2H), 6.12 (s, 2H), 3.55 (d, J = 1.7 Hz, 3H), 2.14 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 163.50, 142.91, 139.88, 138.46, 136.51, 135.56, 134.38,131.48, 129.51 (2C), 129.46, 126.24 (2C), 122.18, 121.17, 120.85, 116.36,111.60, 48.42, 48.31, 21.00. ESI-MS: m / z 314.1646 [M+H] +

[0058] Following the same method used to synthesize ligand L1, ligands L2 through L6 were synthesized. The compounds involved in the synthesis and their characterization data are as follows:

[0059] Compound K2: 11H NMR (600 MHz, DMSO-d6) δ (ppm) 8.35 (d, J = 5.1 Hz, 1H), 8.32 (d, J = 7.7 Hz, 1H), 8.28 (d, J = 5.1 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.28 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.00 (s, 2H), 5.52 (s, 1H), 3.25 (s, 6H), 1.20 (s, 9H). 13 13C NMR (151 MHz, DMSO-d6) δ (ppm) 149.26, 141.98, 141.37, 137.11, 136.03, 134.38, 130.59, 129.07, 126.05 (2C), 125.35 (2C), 121.90, 121.28, 120.45, 116.13, 111.73, 109.60, 55.45 (2C), 48.81, 34.55, 31.58 (3C). ESI-MS: m / z 389.2234 [M+H] + .

[0060] Compound k3: 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.37 (d, J = 5.1 Hz, 1H), 8.34 (d, J = 7.8 Hz, 1H), 8.31 (d, J = 5.1 Hz, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.56 – 7.49 (m, 1H), 7.38 (d, J = 8.3 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.09 (d, J = 8.1 Hz, 2H), 6.17 (s, 2H), 5.50 (s, 1H), 3.23 (s, 6H). 19 19F NMR (376MHz, DMSO-d6) δ (ppm) -60.79. 13¹³C NMR (101 MHz, DMSO-d₆) δ (ppm) 144.20, 141.77, 141.57, 137.33, 134.21, 130.79, 129.28, 127.59 (q, 2 J_C-F = 31.8 Hz, 1C), 126.97 (2C), 125.52 (q, 3 J_C-F = 3.8 Hz, 2C), 124.78 (q, 1 J_C-F = 272.8 Hz, 1C), 122.05, 121.36, 120.74, 116.29, 111.43, 110.36, 55.66 (2C), 48.92. ESI-MS: m / z 401.1470 [M+H] + .

[0061] Compound k4: 1 ¹H NMR (600 MHz, DMSO-d₆) δ (ppm) 8.37 (d, J = 5.1 Hz, 1H), 8.34 (d, J = 7.7 Hz, 1H), 8.31 (d, J = 5.1 Hz, 1H), 7.55 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.45 – 7.41 (m, 1H), 7.31 (ddd, J = 7.9, 7.0, 0.9 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H), 6.10 (s, 2H), 5.50 (s, 1H), 3.24 (s, 6H). 19 ¹⁹F NMR (376 MHz, DMSO-d₆) δ (ppm) -56.94. 13 ¹³C NMR (101 MHz, DMSO-d₆) δ (ppm) 147.29 (q, 3 J_C-F = 1.7 Hz, 1C), 141.79, 141.53, 138.69, 137.28, 134.19, 130.75, 129.23, 128.00 (2C), 122.01, 121.34, 121.27 (2C), 120.67, 120.52 (q, 1J_C-F= 257.1 Hz, 1C), 116.23, 111.49, 110.25, 55.60 (2C), 48.52. ESI-MS: m / z 417.1428[M+H] + .

[0062] Compound K5: 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.28 (s, 1H), 8.27 (d, J =2.2 Hz, 1H), 8.21 (d, J = 5.1 Hz, 1H), 7.65 – 7.59 (m, 2H), 7.31 – 7.27 (m,1H), 7.25 (d, J = 7.4 Hz, 2H), 7.20 – 7.14 (m, 3H), 5.53 (s, 1H), 4.73 (t, J= 7.1 Hz, 2H), 3.37 (s, 6H), 2.66 – 2.62 (m, 2H), 1.70 (dd, J = 7.1, 3.6 Hz, 4H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 142.51, 141.56, 141.26, 136.64,133.40, 130.44, 128.97, 128.81 (2C), 128.71 (2C), 126.16, 121.87, 121.09,120.14, 116.03, 111.19, 110.76, 55.84 (2C), 45.47, 35.46, 28.82, 28.51. ESI-MS: m / z 375.2076[M+H] + .

[0063] Compound K6: 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.31 (d, J = 5.1 Hz, 1H), 8.30 – 8.27 (m, 1H), 8.22 (d, J = 5.1 Hz, 1H), 7.71 – 7.67 (m, 1H), 7.65 (dd,J = 6.9, 1.3 Hz, 1H), 7.32 – 7.28 (m, 1H), 5.63 (s, 1H), 4.13 (s, 3H), 3.46(s, 6H). 13C NMR (101 MHz, DMSO-d6) δ (ppm) 142.43, 141.50, 136.71, 134.23,130.28, 129.00, 121.79, 120.73, 120.13, 115.93, 110.80, 110.13, 55.75 (2C),33.53. ESI-MS: m / z 357.1951[M+DMSO+Na] + .

[0064] Compound m2: 1 H NMR (400 MHz, DMSO-d6) 10.18 (s, 1H), 8.70 (d, J = 4.9 Hz,1H), 8.60 (d, J = 4.8 Hz, 1H), 8.42 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 8.4 Hz,1H), 7.69 – 7.63 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 7.40 (t, J = 7.1 Hz, 1H), 7.24 – 7.19 (m, 2H), 6.89 – 6.83 (m, 2H), 6.16 (s, 2H), 1.17 (s, 9H). 13 C NMR(101 MHz, DMSO-d6) δ (ppm) 194.35, 149.92, 142.77, 139.17, 137.93, 135.43,135.33, 132.56, 130.13, 126.36 (2C), 125.80 (2C), 122.41, 121.59, 121.01,120.06, 112.00, 49.36, 34.58, 31.47 (3C). ESI-MS: m / z 343.1798 [M+H] + .

[0065] Compound m3: 11H NMR (400 MHz, DMSO-d6) δ (ppm) 10.13 (s, 1H), 8.72 (d, J = 4.8 Hz, 1H), 8.62 (d, J = 4.8 Hz, 1H), 8.44 (d, J = 7.9, 1H), 7.69 – 7.66 (m, 2H), 7.61 (d, J = 8.2 Hz, 2H), 7.45 – 7.40 (m, 1H), 7.17 (d, J = 8.1 Hz, 2H), 6.29 (s, 2H). 19 19F NMR (376 MHz, DMSO-d6) δ (ppm) -60.79. 13 13C NMR (101 MHz, DMSO-d6) δ (ppm) 194.47, 143.44, 142.57, 139.38, 137.99, 135.45, 132.57, 130.25, 128.16 (q, 2 J_C-F = 31.9 Hz, 1C), 127.25 (2C), 125.97 (q, 3J_C-F = 3.8 Hz, 2C), 124.80 (q, 1 J_C-F = 266.8 Hz, 1C), 122.50, 121.79, 121.03, 120.12, 111.72, 49.72. ESI-MS: m / z 387.1310 [M+H+CH3OH] + .

[0066] Compound m4: 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.14 (s, 1H), 8.71 (d, J = 4.9 Hz, 1H), 8.61 (d, J = 4.9 Hz, 1H), 8.43 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.68 – 7.44 (m, 1H), 7.43 – 7.38 (m, 1H), 7.23 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 8.7 Hz, 2H), 6.21 (s, 2H). 19 19F NMR (376 MHz, DMSO-d6) δ (ppm) -56.90. 13C NMR (101 MHz, DMSO-d6) δ (ppm) 194.47, 147.73 (q, ³J_C-F =1.6 Hz, 1C), 142.58, 139.32, 137.96, 135.38, 132.57, 130.22, 128.49 (2C),122.48, 121.73, 121.66 (2C), 121.04, 120.50 (q, 1 J_C-F = 266.6 Hz, 1C),120.09, 111.80, 49.28. ESI-MS: m / z 371.1012 [M+H] + .

[0067] Compound m5: 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 10.20 (s, 1H), 8.65 (d, J= 4.8 Hz, 1H), 8.53 (d, J = 4.8 Hz, 1H), 8.37 (d, J = 7.8 Hz, 1H), 7.79 (d, J= 8.4 Hz, 1H), 7.71 – 7.66 (m, 1H), 7.38 (t, J = 7.4 Hz, 1H), 7.24 – 7.18 (m,2H), 7.15 – 7.10 (m, 1H), 7.10 – 7.05 (m, 2H), 4.86 (t, J = 7.4 Hz, 2H), 2.53(t, J = 7.5 Hz, 2H), 1.71 – 1.66 (m, 2H), 1.56 – 1.46 (m, 2H). 13 C NMR (101MHz, DMSO-d6) δ (ppm) 194.19, 142.53, 142.27, 138.71, 137.87, 134.55, 132.31,129.92, 128.67 (2C), 128.61 (2C), 126.15, 122.32, 121.24, 120.70, 119.84,111.54, 46.13, 35.15, 29.01, 28.33.ESI-MS: m / z 329.1653[M+H] + .

[0068] Compound m6: 11H NMR (600 MHz, DMSO-d6) δ (ppm) 10.23 (s, 1H), 8.62 (d, J = 4.8 Hz, 1H), 8.49 (d, J = 4.8 Hz, 1H), 8.36 (d, J = 7.7, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.72 – 7.69 (m, 1H), 7.40 – 7.37 (m, 1H), 4.14 (s, 3H). 13 13C NMR(151 MHz, DMSO-d6) δ (ppm) 192.51, 142.16, 137.53, 137.09, 134.56, 130.92, 128.83, 121.16, 120.09, 119.47, 118.48, 110.20, 33.45. ESI-MS: m / z 211.0873 [M+H] + .

[0069] Ligand L2: 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.26 (d, J = 6.2 Hz, 1H), 8.83 (d, J = 6.2 Hz, 1H), 8.51 (d, J = 7.9 Hz, 1H), 7.82 – 7.74 (m, 2H), 7.51 – 7.45 (m, 1H), 7.26 – 7.21 (m, 3H), 6.99 (d, J = 8.4 Hz, 2H), 6.53 (s, 2H), 3.07 (s, 3H), 1.19 (s, 9H). 13 13C NMR (101 MHz, DMSO-d6) δ (ppm) 163.69, 149.75, 142.86, 139.83, 138.46, 135.65, 134.44, 131.50, 129.46, 126.12 (2C), 125.72 (2C), 122.17, 121.21, 120.85, 116.40, 111.68, 48.44, 48.09, 34.54, 31.46 (3C). ESI-MS: m / z 356.2129 [M+H] + .

[0070] Ligand L3: 11H NMR (400 MHz, DMSO-d6) δ (ppm) 8.55 (d, J = 1.7 Hz, 1H), 8.52 (d, J = 5.0 Hz, 1H), 8.40 (d, J = 7.8 Hz, 1H), 8.36 (d, J = 5.0 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.67 – 7.61 (m, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.38 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.34 (s, 2H), 3.51 (d, J = 1.6 Hz, 3H). 19 19F NMR (376 MHz, DMSO-d6) δ (ppm) -60.94. 13 13C NMR (101 MHz, DMSO-d6) δ (ppm) 163.68, 143.65, 142.68, 139.81, 138.72, 134.42, 131.57, 129.64, 128.02 (q, 2 J_C-F = 33.0 Hz, 1C), 126.95 (2C), 125.91 (q, 3 J_C-F = 3.8 Hz, 2C), 124.11 (q, 1 J_C-F = 261.3 Hz, 1C), 122.28, 121.21, 121.11, 116.51, 111.43, 48.66, 48.33. ESI-MS: m / z 368.1363 [M+H] + .

[0071] Ligand L4: 11H NMR (400 MHz, DMSO-d6) δ (ppm) 8.57 (d, J = 1.8 Hz, 1H), 8.51 (d, J = 5.0 Hz, 1H), 8.38 (d, J = 7.6 Hz, 1H), 8.35 (d, J = 5.0 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.67 – 7.61 (m, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 6.25 (s, 2H), 3.53 (d, J = 1.7 Hz, 3H). 19 19F NMR (376 MHz, DMSO-d6) δ (ppm) -56.92. 13 13C NMR (101 MHz, DMSO-d6) δ (ppm) 163.65, 147.60 (q, 3J_C-F = 1.6 Hz, 1C), 142.69, 139.81, 138.66, 138.18, 134.35, 131.56, 129.61, 128.13 (2C), 122.26, 121.61 (2C), 121.21, 121.05, 120.44 (q, 1 J_C-F = 257.0 Hz, 1C), 116.48, 111.49, 48.35, 48.14. ESI-MS: m / z 384.1328 [M+H] + .

[0072] Ligand L5: 11H NMR (400 MHz, DMSO-d6) δ (ppm) 8.69 (q, J = 1.6 Hz, 1H), 8.46 (d, J = 5.0 Hz, 1H), 8.31 (d, J = 7.8, 1H), 8.27 (d, J = 5.0 Hz, 1H), 7.76 (d, J = 8.4, 1H), 7.66 – 7.61 (m, 1H), 7.34 – 7.29 (m, 1H), 7.24 – 7.19 (m, 2H), 7.16 – 7.12 (m, 1H), 7.09 – 7.05 (m, 2H), 4.81 (t, J = 7.4 Hz, 2H), 3.58 (d, J = 1.7 Hz, 3H), 2.53 – 2.51 (m, 2H), 1.57 – 1.49 (m, 2H), 1.48 – 1.41 (m, 2H). 13 13C NMR (101 MHz, DMSO-d6) δ (ppm) 163.45, 142.43, 142.28, 139.71, 138.03, 133.82, 131.16, 129.25, 128.68 (2C), 128.64 (2C), 126.16, 122.09, 120.90, 120.48, 116.25, 111.27, 48.42, 44.95, 35.17, 28.47, 28.36. ESI-MS: m / z 342.1972 [M+H] + .

[0073] Ligand L6: 1 1H NMR (600 MHz, DMSO-d6) δ (ppm) 8.75 (q, J = 1.7 Hz, 1H), 8.45 (d, J = 4.9 Hz, 1H), 8.31 (d, J = 7.7 Hz, 1H), 8.26 (d, J = 5.0 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.67 – 7.64 (m, 1H), 7.32 (t, J = 7.4 Hz, 1H), 4.02 (s, 3H), 3.62 (d, J = 1.7 Hz, 3H). ESI-MS: m / z 183.0920 [M-(CH=N-CH3)+H] + .

[0074] Example 2: Synthesis of platinum complex IA

[0075] Ligand L1 (1 mmol) and dichlorobis(dimethyl sulfoxide)platinum (0.8 mmol) were added to a 5 mL transparent sample vial. 2 mL of a mixed solvent of ethanol and chloroform in a 1:2 (v / v) ratio was added. The vial was sealed and sonicated to ensure homogeneity. The vial was then wrapped in aluminum foil and placed in a 60 °C oven for 48 h. After the reaction, the temperature was slowly lowered to room temperature. Orange-red strip-shaped crystals were observed forming in the sample vial. The crystals were collected and dried. The yield was 68% (calculated as (actual product mass / theoretical product mass) × 100%), the same below.

[0076] Single crystals of suitable size and shape were selected for characterization. The specific characterization data are as follows: 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 9.36 (d, J = 1.6 Hz, 1H), 9.33 (d, J = 6.0 Hz, 1H), 8.72 (d,J = 6.0 Hz, 1H), 8.48 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.87 –7.81 (m, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.11 (d, J = 7.9 Hz, 2H), 6.96 (d, J= 7.9 Hz, 2H), 5.97 (s, 2H), 3.78 (d, J = 1.4 Hz, 3H), 2.23 (s, 3H). 13 C NMR(101 MHz, DMSO-d6) δ (ppm) 167.89, 144.71, 140.21, 139.54, 137.60, 136.61,134.25, 132.86, 132.28, 130.13 (2C), 126.39 (2C), 123.67, 122.60, 120.13,119.98, 111.62, 48.89, 48.16, 21.11. ESI-MS: m / z 622.1052 [M-Cl+DMSO+H] + .

[0077]

[0078] Example 3: Synthesis of platinum complexes IB, IC and ID

[0079] Ligand L2 (1 mmol) and dichlorobis(dimethyl sulfoxide)platinum (0.8 mmol) were added to a 5 mL transparent sample vial. 2 mL of a mixed solvent of ethanol and acetonitrile in a 2:1 (v / v) ratio was added. The vial was sealed and sonicated to ensure homogeneity. The vial was then wrapped in aluminum foil and placed in a 60 °C oven for 48 h. After the reaction, the temperature was slowly lowered to room temperature. Orange-red strip-shaped crystals were observed forming in the sample vial. The crystals were collected and dried. The yield was 69%.

[0080] Single crystals of suitable size and shape were selected for characterization. The specific characterization data are as follows: 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 9.41 (d, J = 1.7 Hz, 1H), 9.34 (d, J = 6.1 Hz, 1H), 8.73 (d,J = 6.0 Hz, 1H), 8.47 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.83 (t,J = 7.3 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.01 (d,J = 8.4 Hz, 2H), 5.97 (s, 2H), 3.79 (d, J = 1.4 Hz, 3H), 1.20 (s, 9H). ESI-MS: m / z 664.1520 [M-Cl+DMSO+H] + .

[0081]

[0082] Platinum complexes IC and ID were synthesized according to the method described in this embodiment, and their characterization data are as follows:

[0083] Platinum complex IC: Orange-red strip-shaped crystals, yield 46%. 1H NMR (600 MHz, DMSO-d6) δ (ppm)9.40 – 9.33 (m, 2H), 8.76 (d, J = 6.0 Hz, 1H), 8.50 (d, J = 7.9 Hz, 1H), 7.86– 7.82 (m, 2H), 7.69 (d, J = 8.2 Hz, 2H), 7.52 – 7.49 (m, 1H), 7.31 (d, J =8.1 Hz, 2H), 6.13 (s, 2H), 3.80 (d, J = 1.4 Hz, 3H). ESI-MS: m / z 676.0781[M-Cl+DMSO+H] + .

[0084]

[0085] Platinum complex ID: Orange-red strip-shaped crystals, yield 72%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm)9.38 (d, J = 1.7 Hz, 1H), 9.36 (d, J = 6.0 Hz, 1H), 8.74 (d, J = 6.0 Hz, 1H), 8.49 (d, J = 7.9 Hz, 1H), 7.90 – 7.81 (m, 2H), 7.52 – 7.42 (m, 1H), 7.32 (d,J = 8.3 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 6.06 (s, 2H), 3.80 (d, J = 1.4 Hz,3H). 19 F NMR (376 MHz, DMSO-d6) δ (ppm) –56.85. 13 C NMR (101 MHz, DMSO-d6) δ(ppm) 167.63, 148.24 (q, ³J_C-F = 1.6 Hz, 1C), 144.38, 140.26, 139.64,136.69, 135.55, 134.24, 132.27, 128.60 (2C), 124.28, 123.64, 122.67, 122.12(2C), 120.46 (q, 1J_C-F = 257.2 Hz, 1C), 120.09, 111.60, 48.90, 47.92. ESI-MS: m / z 692.0718 [M-Cl+DMSO+H] + .

[0086]

[0087] Example 4: Synthesis of platinum complex IE

[0088] Ligand L5 (1 mmol) and dichlorobis(dimethyl sulfoxide)platinum (0.8 mmol) were added to a 5 mL transparent sample vial. 2 mL of a mixed solvent of ethanol and acetonitrile in a 1:1 (v / v) ratio was added. The vial was sealed and sonicated to ensure homogeneity. The vial was then wrapped in aluminum foil and placed in a 60 °C oven for 48 h. After the reaction, the temperature was slowly lowered to room temperature. Orange-red strip-shaped crystals were observed forming in the sample vial. The crystals were collected and dried. The yield was 71%.

[0089] Single crystals of suitable size and shape were selected for characterization. Their structures were determined using methods such as single-crystal X-ray diffraction analysis. The specific characterization data are as follows:

[0090] 1H NMR spectrum: 1 H NMR (600 MHz, DMSO-d6) δ (ppm) 9.42 (d, J = 1.7 Hz, 1H),9.33 (d, J = 6.0 Hz, 1H), 8.66 (d, J = 6.0 Hz, 1H), 8.41 (d, J = 7.8 Hz, 1H),7.91 (d, J = 8.4 Hz, 1H), 7.83 (t, J = 8.2 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.23 (t, J = 7.5 Hz, 2H), 7.16 – 7.13 (m, 1H), 7.11 (d, J = 7.1 Hz, 2H), 4.71(t, J = 7.2 Hz, 2H), 3.95 (d, J = 1.4 Hz, 3H), 2.57 (t, J = 7.7 Hz, 2H), 1.86– 1.79 (m, 2H), 1.63 – 1.56 (m, 2H).

[0091] Electrospray ionization mass spectrometry: ESI-MS: m / z 650.1374 [M-Cl+DMSO+H] + .

[0092] Single-crystal X-ray diffraction analysis:

[0093] Selected orange-red strip-shaped crystals of suitable size were placed on an Agilent SuperNova X-ray single-crystal diffractometer, and monochromated using a Mo-K monochromator. α Single-crystal structure determination was performed using (λ = 0.71073 Å) X-rays as the light source. The initial crystal structures of the products obtained in this embodiment were all solved using the SHELXS-97 direct method. Diffraction data were corrected for LP factor and empirical absorption. The coordinates of all non-hydrogen atoms and their anisotropic thermal parameters were refined using the full-matrix least squares method. The coordinates of all hydrogen atoms were determined by theoretical calculations. The obtained crystallographic data are shown in Table 1 below, and some bond length and bond angle data are shown in Table 2 below. The crystal structure is as follows: Figure 1 As shown, the planar structure is as follows.

[0094]

[0095] Table 1. Crystallographic parameters of platinum complexes for IE

[0096]

[0097] Table 2. Partial bond lengths [Å] and bond angles of platinum complexes IE

[0098]

[0099] Example 5: Synthesis of platinum complex IF

[0100] Ligand L6 (1 mmol) and dichlorobis(dimethyl sulfoxide)platinum (0.8 mmol) were added to a 5 mL transparent sample vial. 2 mL of a mixed solvent of ethanol and acetonitrile in a 1.5:1 (v / v) ratio was added. The vial was sealed and sonicated to ensure homogeneity. The vial was then wrapped in aluminum foil and placed in a 70 °C oven for 48 h. After the reaction, the temperature was slowly lowered to room temperature. Orange-red strip-shaped crystals were observed forming in the sample vial. The crystals were collected and dried. The yield was 74%.

[0101] Single crystals of suitable size and shape were selected for characterization. The specific characterization data are as follows: 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.65 (q, J = 1.5 Hz, 1H), 9.27 (d, J = 6.0 Hz, 1H), 8.62 (d,J = 6.0 Hz, 1H), 8.40 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.86 –7.80 (m, 1H), 7.46 – 7.40 (m, 1H), 4.18 (s, 3H), 3.92 (d, J = 1.5 Hz, 3H).ESI-MS: m / z 531.0598[M-Cl+DMSO] + .

[0102]

[0103] Example 6: In vitro antitumor activity experiment

[0104] 1) Cell Culture

[0105] Human myeloid monocytic leukemia cells MV-4-11 were cultured in prepared IMDM medium; A549, human cervical cells HeLa, and human non-small cell lung cancer NCl-H23 cells were cultured in prepared 1640 medium; and human ovarian cancer cells A2780 and human normal liver cells HL-7702 were cultured in prepared DMEM medium. Cells were cultured at 37 °C in a 5% CO2 incubator until a cell density of 90% was reached, at which point they were passaged. For adherent cells, trypsin was used to digest the cells before passage; for suspension cells, only a portion of the original cell culture solution needed to be aspirated and fresh medium added. All operations were performed in a sterile environment.

[0106] 2) Experimental Procedure

[0107] The compounds to be tested are platinum complexes IA to IF synthesized according to the method described in the embodiments of the present invention, and their ligands L1 to L6. The positive control is cisplatin (CDDP).

[0108] CCK-8 assay: Cells were seeded into 96-well plates, and after gently tapping the edges of the plates, they were incubated for 2 hours. 20 μL of diluted drug was added to each well, and the plates were incubated for 48 hours. Subsequently, 10 μL of CCK-8 reagent was added to each well, and the plates were incubated for 24 hours. The absorbance at 450 nm was then measured using an ELISA reader. The IC50 of the compound was calculated using SPSS software. 50(During the experiment, a blank control should be set up for each compound, that is, add 180 μL of IMDM medium, 20 μL of diluted drug, and 10 μL of CCK-8 reagent to each well and incubate with the experimental group, and measure its absorbance value at 450 nm using an enzyme-linked immunosorbent assay (ELISA) instrument.)

[0109] MTT assay: Due to edge effects (such as water evaporation), cell growth may be affected around the perimeter of a 96-well plate. Therefore, 200 μL of PBS solution was added to each well perimeter, and 180 μL of cell suspension was added to the other wells. After gently tapping the perimeter of the plate, it was placed in an incubator. Once the cells were fully adhered and the cell density reached 60% / 70%, the stock solution of the compound was diluted in the 96-well plate with PBS to a final concentration of 20, 10, 5, 2.5, 1.25, 0.625 μM or a final concentration of 1, 0.5, 0.25, 0.125, 0.0625 μM. 20 μL of the diluted drug was added to each well. After culturing for 48 h, 10 μL of MTT solution was added to each well, and the plate was incubated in the dark for 46 h. Discard the liquid in the plate, add 150 μL of dimethyl sulfoxide solution to each well, and wait until the formazan is completely dissolved to form a purple solution. Measure the absorbance at 490 nm using an ELISA reader. Calculate the IC50 value of the compound using SPSS software.

[0110] The experimental results are shown in Table 3. As can be seen from Table 3, except for platinum complex IF, the activities of the other platinum complexes were superior to those of their ligands, indicating a synergistic effect after the ligands coordinate with platinum to form complexes. Furthermore, the platinum complexes described in this invention exhibit higher selectivity for Mcl-1-dependent sensitive cells (MV-4-11, A2780, and NCI-H23) and broad-spectrum tumor cells. All platinum complexes showed lower toxicity to normal cells than cisplatin, while exhibiting higher inhibitory activity against tumor cells than cisplatin. Among them, platinum complexes I-C and I-D showed the best antitumor activity.

[0111] Table 3 IC50 values ​​(μM) of ligands and complexes for different cell lines.

[0112]

[0113] Example 7: Study on the affinity and selectivity of the complex to Mcl-1 (ELISA experiment)

[0114] Experimental Procedure: Streptavidin was dissolved in carbonate buffer to a final concentration of 4 μg / mL. 100 μL was added to each well of a high-binding ELISA plate and incubated overnight at 4 °C to obtain a streptavidin-pre-coated ELISA plate. After washing the plate with PBST buffer (0.05% Tween), 300 μL of BSA was added to each well, and the plate was blocked at room temperature for 2 h. The plate was then washed with PBST and set aside. Bim peptide was diluted to 0.09 μg / mL, and 100 μL was added to each well. The plate was incubated at room temperature for 1.5 h, washed with PBST, and set aside. A mixture of the drug and his-Mcl-1 (90 nM) was added to each well and incubated at room temperature for 1 h. The mixture was then added to the cleaned plate and incubated for 2 h, followed by washing with PBST. Horseradish peroxidase-containing his antibody was added and incubated for 1 h. The plate was then washed with PBST and patted dry. Add 100 μL of TMB chromogenic solution to each well and incubate for 20-30 min. Then add 100 μL of TMB stop solution. Measure the absorbance at 450 nm using a multi-mode microplate reader and calculate the IC50. 50 Value. IC 50 The value reflects the concentration of small molecules required to halve the functional inhibition of Bim protein binding to Mcl-1.

[0115] The experimental results are shown in Table 4. The platinum (II) complex and gold (III) complex have a much higher affinity for Mcl-1 than their metal salts. The affinity of the complexes for Mcl-1 is similar to the structure-activity relationship of their cell activity, with platinum complexes I-C and I-D showing the strongest affinity for Mcl-1.

[0116] Table 4. IC50 of compounds inhibiting Mcl-1 protein function 50 Value (μM)

[0117]

[0118] Example 8: In vivo antitumor activity experiment

[0119] 1) Establishment of a human non-small cell lung cancer (NCl-H23) xenograft model in nude mice

[0120] Collect cells in the logarithmic growth phase and replace the culture medium when the cell density reaches 80-90%. After collecting NCl-H23 cells, resuspend them twice in pre-cooled PBS solution. Mix serum-free 1640 medium and matrix gel at a 1:1 ratio and inoculate approximately 5 × 10⁵ cells into the left axilla of each nude mouse. 6 Each cell was individually counted. After tumor formation, the longest and shortest diameters of the transplanted tumor were measured periodically using calipers. When the tumor volume reached approximately 70-100 mm... 3 At that time, 18 nude mice with good growth and uniform tumor size were selected and randomly divided into 3 groups of 6 mice each.

[0121] 2) Drug administration and result processing

[0122] Negative control group: The same volume of normal saline was injected once a day for two weeks.

[0123] Positive control group: Cisplatin (2 mg / kg), administered every other day for two weeks.

[0124] Treatment group: Platinum complex IC (10 mg / kg) was administered once daily for two weeks.

[0125] Tumor diameter and weight of nude mice were measured every other day. Two weeks later, all mice were euthanized by cervical dislocation, tumors were removed, weighed, and dissected. The collected heart, spleen, lungs, and kidneys were preserved in 4% tissue fixative for subsequent HE staining and sectioning experiments. The formula for calculating tumor volume (TV) is: TV = 1 / 2 × a × b 2 (a is the length of the tumor, b is the width of the tumor).

[0126] Experimental results are as follows Figure 2 and Figure 3 As shown, both platinum complex IC and CDDP can inhibit tumor growth. The tumor inhibition rates of platinum complex IC and CDDP were 71.6% and 65.8%, respectively. The results show that the tumor inhibition effect of platinum complex IC is slightly better than that of cisplatin, and there was no significant change in the body weight of mice during the administration process, indicating that platinum complex IC has good tolerability.

[0127] 3) Hematoxylin-eosin staining experiment

[0128] Tissue fixation: The tissue specimen to be stained is fixed with formalin at a concentration of 10%.

[0129] Dehydration: The fixed tissue specimen is dehydrated by passing it through a series of ethanol solutions with increasing concentrations, so that the water in the tissue is gradually replaced by ethanol. The volume concentrations of ethanol are 75%, 85%, 90%, and 95% respectively, with the final solution being anhydrous ethanol.

[0130] Osmosis: The dehydrated tissue specimen is permeated through a series of xylene solutions with increasing concentrations.

[0131] Embedding: After melting paraffin, the wax blocks were embedded and cut into paraffin sections (3 μm) using a microtome. The sections were then baked at 65 °C for 4.5 h.

[0132] Staining process: The sections were dewaxed with xylene for 10 min, then dehydrated with alcohol of decreasing concentration for 5 min each time. The tissue specimens were then immersed in hematoxylin staining solution for staining, followed by decolorization with alcohol of decreasing concentration. The sections were then washed with water, and the washed tissue specimens were then immersed in eosin staining solution for staining, followed by decolorization and washing again.

[0133] Mounting: The cleaned tissue specimens are treated sequentially with a series of ethanol and xylene solutions of decreasing concentration. The permeated tissue specimens are then placed in a clearing agent and mounted with neutral resin to fix the tissue specimens on the slides for easy observation.

[0134] Experimental results are as follows Figure 4 As shown: Compared with the negative control group, mice treated with platinum complex IC showed normal myocardial tissue structure, but slight damage to liver, spleen, lung, and kidney tissues. In contrast, mice in the cisplatin group showed slight myocardial tissue damage, but more severe overall damage to liver, spleen, lung, and kidney tissues. The experimental results indicate that platinum complex IC is safe at a dose of 10 mg / kg.

Claims

1. A platinum complex with a β-carbaline derivative as a ligand having the structure shown in formula (I) below, or a pharmaceutically acceptable salt thereof: （I）； in, R represents a C1~C6 alkyl group, or a group represented by the following formula (II); (II), in formula (II), n = 0~4, R1 represents hydrogen, trifluoroalkyl, trifluoroalkoxy or C1~C6 alkyl.

2. The platinum complex with a β-carbaline derivative as a ligand according to claim 1, characterized in that, In formula (II), n = 0~4, and R1 represents hydrogen, trifluoroalkyl, trifluoromethoxy or C1~C4 alkyl.

3. The platinum complex with a β-carbaline derivative as a ligand according to claim 2, characterized in that, R1 represents hydrogen, trifluoroalkyl, trifluoromethoxy, methyl, or tert-butyl.

4. The method for synthesizing the platinum complex with β-carboline derivative as ligand as described in claim 1, characterized in that, A β-carbaline derivative with the structure shown in formula (L) and dichlorobis(dimethyl sulfoxide) platinum were placed in a reaction vessel, a mixed solvent was added, and the reaction was carried out under heating conditions to obtain the target complex. （L）； Wherein, R represents a C1~C6 alkyl group, or a group represented by the following formula (II); (II), in formula (II), n = 0~4, R1 represents hydrogen, trifluoroalkyl, trifluoroalkoxy or C1~C6 alkyl; The mixed solvent is a combination of ethanol and acetonitrile or chloroform, wherein the proportion of ethanol in the mixed solvent is greater than or equal to 30 v / v%.

5. The synthesis method according to claim 4, characterized in that, In the composition of the mixed solvent, the proportion of ethanol in the mixed solvent is greater than or equal to 50 v / v%.

6. The synthesis method according to claim 4, characterized in that, The reaction is carried out at a temperature greater than or equal to 50°C.

7. A crystalline form of platinum complex I-E, which belongs to monoclinic system, space group P21 / c, with unit cell parameters: a = 8.9396(10) A, b = 11.4562(10) A, c = 21.3714(2) A, a = 90 o , b = 98.6670(10) o , g = 90 o .

8. The method for synthesizing the Pt-IE crystal form of the platinum complex according to claim 7, characterized in that, Take the β-carbaline derivative with the structure shown in formula (L) and dichlorobis(dimethyl sulfoxide) platinum in a reaction vessel, add a mixed solvent, and react under heating conditions. After the reactants are cooled, crystals precipitate out. Collect the crystals, which are the target products. （L）； Where R represents ; The mixed solvent is a composition of ethanol and acetonitrile in a volume ratio of 2:1 to 1:

1.

9. The use of the platinum complex with β-carboline derivative as ligand as described in claim 1 or the crystal form of the platinum complex IE as described in claim 7 in the preparation of antitumor drugs or Mcl-1 inhibitors.

10. A pharmaceutical composition comprising the crystal form of the platinum complex of claim 1 with a β-carboline derivative as a ligand or the platinum complex IE of claim 7.

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