CN111187303B - Platinum (II) complex with high antitumor activity of cryptolepine, and synthetic method and application thereof - Google Patents

Abstract

The invention relates to a platinum (II) complex of phyllophylline with high antitumor activity, the chemical formula is [Pt(T)R]Cl, and the ligand T is the synthesis of phyllophylline derivative and lutidine amine derivative The compound, R is halogen. The method for synthesizing the complex is that the phyllophylline derivative and the lutidine amine derivative react in the presence of a solvent and a strong base to generate a yellow solid powder ligand T; The platinum (II) compound is coordinated in the presence of a polar solvent to obtain a yellow target product selenium platinum (II) complex. The selenium platinum (II) complex exhibits superior anti-tumor activity and targeting in vitro and in vivo, has potential medicinal value, and is expected to be used in the preparation of various anti-tumor drugs.

Description

High antitumor activity selenium platinum (II) complex and its synthesis method and application

technical field

The present invention relates to a complex, in particular to a platinum (II) complex of phyllophylline with high antitumor activity. Meanwhile, the present invention also relates to the synthesis method and application of the complex.

Background technique

Cisplatin-based anti-tumor drugs are widely used in clinical treatment due to their unique anti-tumor mechanism, significant anti-tumor effect and broad anti-tumor spectrum (Wheate N J, Walker S, Craig G E, et al. platinum anticancer drugs in the clinic and in clinical trials[J]. Dalton transactions, 2010, 39(35):8113-8127.). At present, more than 50% of chemotherapy regimens involve the use of platinum drugs, among which FDA-approved cisplatin (CDDP), carboplatin (carboplatin) and oxaliplatin (oxaliplatin) are the pillars of clinical chemotherapy regimens for malignant tumors Drugs, which mainly cause tumor cell apoptosis by interacting with tumor DNA (Liu Fengfan, Su Weike. Research progress on functional anti-tumor platinum complexes [J]. China Journal of Pharmaceutical Industry, 2019, 50(8): 823- 833.). The listed platinum drugs lack selectivity, low bioavailability, serious adverse reactions in the course of treatment, and easily lead to drug resistance and cross-resistance of tumor cells, which limit their further expansion. In order to overcome the clinical defects of classic cisplatin drugs, domestic and foreign scholars have synthesized a large number of platinum complexes on the basis of the structure of platinum antitumor drugs on the market, in order to obtain higher biological activity, lower toxicity and overcome drug resistance. Or cross-resistant antitumor platinum drugs.

Selmenine alkaloids have a wide range of physiological activities such as antibacterial, antiviral, anti-trypanosome, anti-inflammatory, etc., and there are no reported metal complexes using Selmenine and its derivatives as ligands.

SUMMARY OF THE INVENTION

One of the objectives of the present invention is to provide a platinum (II) complex of semenine with high antitumor activity.

Specifically, a high antitumor activity selemenine platinum (II) complex, its chemical formula is [Pt(T)R]Cl (abbreviated as T-Pt), and the chemical structural formula is shown in the following formula:

Wherein, the ligand Tm is a compound synthesized by a phyllophylline derivative and a dipyridylmethylamine derivative, n is a non-zero natural number, and R is a halogen.

The second purpose of the present invention is to provide a method for synthesizing a platinum (II) complex of semenine with high antitumor activity.

Specifically, the method for synthesizing the high antitumor activity selemenine platinum (II) complex comprises the following steps:

(1) The selemenine derivative (SM) reacts with the lutidine derivative in the presence of a solvent and a strong base to generate a yellow solid powder ligand T;

(2) The ligand T and the platinum (II) compound in the same amount are coordinated in the presence of a polar solvent to obtain a yellow target product-selenium platinum (II) complex T-Pt.

The synthetic route of the present invention is as follows:

n为不为零的自然数。The structural formula of the lutidine amine derivative:

n is a non-zero natural number.

In step (1), the molar ratio of the selemenine derivative (SM) to the lutidine derivative is 1:1-1.5.

In step (1), the selemenine derivative (SM) and the lutidine amine derivative are reacted at 20-30° C. for 1-10 hours.

In step (2), the platinum (II) compound includes, but is not limited to, dichlorobis(dimethylsulfoxide)platinum (II) solid (Pt(DMSO) ₂ Cl ₂ ).

In step (2), the coordination reaction temperature is 30-100°C, and the reaction time is 10-80h.

In step (2), the polar solvent is any one of methanol, ethanol, water, dimethyl sulfoxide and acetone or a mixed solution in pairs, wherein the two solvents in the mixed solution are in an arbitrary ratio. As an embodiment of the present invention, the polar solution is a mixed solution of methanol and water or acetone, or a mixed solution of ethanol and water or acetone, or a mixed solution of dimethyl sulfoxide and methanol or ethanol.

The third object of the present invention is to provide the application of the platinum (II) complex of selemenine. Specifically, the application of the selemenine platinum (II) complex in the preparation of antitumor drugs is provided. More specifically, the application of the selemenine zinc-platinum (II) complex in the preparation of a medicament for targeted treatment of breast cancer is provided.

The beneficial effects of the present invention are:

Compared with the prior art, the jatrorrhizine derivative active ligand T provided by the present invention is used as a ligand to synthesize its platinum complex [Pt(T)R]Cl(T-Pt). The inventors investigated the effect of complex T-Pt on human cervical cancer cells HeLa, human breast cancer cells (MCF-7 and MDA-MB-231), human ovarian cancer drug-resistant SK-OV-3/DDP cells and human normal liver cells. Viability and toxicity experiments of HL-7702 cells. The results of MTT experiment showed that the complex T-Pt has high antitumor activity against human breast cancer cells HeLa, MCF-7, MDA-MB-231 and SK-OV-3/DDP, and its in vitro antitumor activity is far greater In addition, the complex T-Pt has little toxicity to normal cells HL-7702 (IC ₅₀ >100μM), showing a good target inhibition of human breast Cancer proliferation. The complex T-Pt exhibits superior in vitro and in vivo antitumor activity and targeting, has potential medicinal value, and is expected to be used in the preparation of various antitumor drugs.

Description of drawings

Fig. 1 is the T3 hydrogen nuclear magnetic resonance spectrogram obtained in Example 1 of the present invention;

Fig. 2 is the T3 carbon nuclear magnetic resonance spectrogram obtained in Example 1 of the present invention;

Fig. 3 is the electrospray mass spectrum of the complex T3-Pt prepared in Example 1 of the present invention;

Fig. 4 is the hydrogen nuclear magnetic resonance spectrogram of T3-Pt obtained in Example 1 of the present invention;

Fig. 5 is the carbon nuclear magnetic resonance spectrum of T3-Pt prepared in Example 1 of the present invention;

Fig. 6 is the T4 hydrogen nuclear magnetic resonance spectrogram obtained in Example 4 of the present invention;

Fig. 7 is the T4 carbon nuclear magnetic resonance spectrogram obtained in Example 4 of the present invention;

Figure 8 is the electrospray mass spectrum of the complex T4-Pt prepared in Example 4 of the present invention;

Fig. 9 is the hydrogen nuclear magnetic resonance spectrogram of T4-Pt obtained in Example 4 of the present invention;

Fig. 10 is the carbon nuclear magnetic resonance spectrum of T4-Pt prepared in Example 4 of the present invention.

Detailed ways

The present invention will be further described below with specific examples, but the present invention is not limited to these examples.

The raw material selemenine derivative SM involved in the synthesis method of the present invention is referred to the existing literature (Gu, L.-Q.; et al. J. Med. Chem., 2005, 48: 7315-7321. ) to prepare. In addition, dichlorobis(dimethylsulfoxide)platinum (II) can be carried out by referring to existing literature (Al-Allaf, TAK; et al. Transit. Met. Chem., 1998, 23:403-406.). Preparation, abbreviated cis-PtCl ₂ (DMSO) ₂ or PtCl ₂ (DMSO) ₂ in this application.

Example 1

(1) Synthesis and characterization of ligand T3:

In a 25.0 mL round-bottomed flask, weigh 1.0 mol of compound SM, 1.05 mol of lutidine amine derivative and 2.00 mol of NaH, dissolved in 5.0 mL of dimethylacetamide solution (DMA) at 25.0 °C After 10.0 hours of reaction, a yellow solid powder of T3 ligand was obtained with a yield of 53.0%.

Identification of the resulting T3:

(1) H NMR spectrum, as shown in Figure 1.

¹ H NMR (400MHz, CHCl ₃ -d) δ 8.49 (d, J=4.9Hz, 2H), 8.35 (dd, J=8.0, 17.5Hz, 2H), 8.20 (d, J=8.6Hz, 1H) ,7.70(t,J＝7.7Hz,1H),7.65-7.54(m,4H),7.53-7.41(m,4H),7.12-7.06(m,2H),5.29(s,1H),4.93(t , J=6.4Hz, 2H), 3.81(s, 4H), 2.61(t, J=6.9Hz, 2H), 1.91(quin, J=6.9Hz, 2H), 1.73-1.54(m, 4H).

(2) Carbon NMR spectrum, as shown in Figure 2.

¹³ C NMR (101MHz, CHCl ₃ -d) δ159.99, 158.66, 147.38, 144.12, 136.31, 134.51, 130.58, 128.64, 128.42, 124.76, 123.48, 123.19, 122.86, 122.33 (d, J=15.4) ,121.39,111.99,72.78,60.57,54.30,29.93,26.91,23.70.

(3) The results of elemental analysis are shown in Table 1.

Elemental analysis results of compounds T3 and T3-Pt in the examples of Table 1

Therefore, it can be determined that the obtained yellow target product is compound T3, and its structural formula is as follows:

(2) Synthesis and characterization of the complex T3-Pt:

Weigh 1.0 mmol of ligand T3 and 1.0 mmol of dichloro·bis(dimethyl sulfoxide) platinum(II) solid (cis-Pt(DMSO) ₂ Cl ₂ ) and dissolve them in 30 mL of a mixed solution of methanol and acetone (volume ratio of 20:1), the coordination reaction was carried out at 40 °C for 36 h, and the product was dried with 5.0 mL of ether for 3 times in a vacuum drying oven at 45 °C to obtain the yellow target product T3-Pt. The yield was 91.3%.

Identification of the obtained T3-Pt:

(1) Electrospray mass spectrometry, the spectrum of which is shown in FIG. 3 .

ESI-MS m/z: 731.9 [M-Cl] ⁺ , where M is the molecular weight of compound T3-Pt.

(2) H NMR spectrum, as shown in FIG. 4 .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.76 (dd, J=5.8, 1.6 Hz, 2H), 8.29-8.22 (m, 3H), 8.20 (dd, J=8.9, 1.2 Hz, 1H), 8.14–8.10 (m, 1H), 7.79 (d, J=7.9Hz, 2H), 7.78–7.72 (m, 3H), 7.65–7.60 (m, 2H), 7.57 (ddd, J=8.2, 6.7, 1.2 Hz,1H),7.53(ddd,J=7.9,6.5,1.5Hz,1H),5.41(d,J=15.9Hz,2H),4.89(d,J=15.8Hz,2H),4.79(t,J =6.1Hz,2H),3.15-3.07(m,2H),1.77(dq,J=12.2,6.3Hz,2H),1.65(dq,J=13.8,7.1Hz,2H),1.51(q,J= 7.8Hz, 2H).

(3) Carbon NMR spectrum, as shown in Figure 5.

¹³ C NMR(126MHz,DMSO-d ₆ )δ166.34,158.54,149.44,148.79,147.20,143.63,141.73,134.33,131.75,129.11,128.93,125.76,125.61,124.41,123.91,122.87,122.51,122.30,121.12,112.87 ,72.78,68.29,64.57,40.92,40.51,40.34,40.18,40.01,39.84,39.68,39.51,29.47,27.13,22.94.

(4) The results of elemental analysis are shown in Table 1.

Therefore, it can be determined that the obtained yellow target product is the complex T3-Pt, and its structural formula is as follows:

Example 2

Weigh 1.0 mmol of ligand T3 and 1.0 mmol of dichlorobis(dimethyl sulfoxide) platinum(II) solid (Pt(DMSO) ₂ Cl ₂ ), and dissolve them in 15 mL of a mixture of ethanol and dimethyl sulfoxide. In the mixed solution (volume ratio of 2:1), the coordination reaction was carried out at 80 °C for 5 h, and the product was dried with 5.0 mL of ether for 3 times in a vacuum drying oven at 45 °C to obtain the yellow target product T3-Pt. The yield was 75.2%.

Example 3

Weigh 1.0 mmol of ligand T3 and 1.0 mmol of dichlorobis(dimethyl sulfoxide) platinum(II) solid (Pt(DMSO) ₂ Cl ₂ ), and dissolve them in 80 mL of a mixed solution of ethanol and acetone ( The volume ratio is 50:3), the coordination reaction was carried out at 30 °C for 72 h, the product was dried with 5.0 mL of diethyl ether 3 times in a vacuum drying oven at 45 °C, and the yellow target product T3-Pt was obtained. The yield was 88.3%.

Experimental example 1

Experiment on the Inhibitory Activity of Selenium Platinum(II) Complex T3-Pt on Various Human Tumor Cell Lines

1. Cell Lines and Cell Culture

In this experiment, human cervical cancer HeLa cells, human ovarian cancer cisplatin-resistant SK-OV-3/DDP cells, human breast cancer cells (MCF-7 and MDA-MB-231) and human normal liver HL-7702 cells were selected. human cell lines.

All human cell lines were cultured in RPMI-1640 medium containing 100 U/mL penicillin, 10 wt% calf blood, and 100 U/mL streptomycin, and cultured in a 37°C incubator with a volume concentration of 5% CO ₂ .

2. Preparation of compounds to be tested

The purity of the used ligand T3 and complex T3-Pt should be ≥95%. Dilute their DMSO stock solution with physiological buffer to a final solution of 20 μmol/L (the final concentration of DMSO is ≤1%), and test the concentration. The degree of inhibition of the growth of normal cells or selected tumor cells by each compound is shown below.

3. Cell growth inhibition assay (MTT method)

(1) Take normal cells or tumor cells in logarithmic growth phase, digest with trypsin, prepare a cell suspension with a concentration of 5000 cells/mL with a culture medium containing 10% calf serum, and inoculate 190 μL per well in In a 96-well culture plate, the density of the cells to be tested is adjusted to 1000-10000 wells (the edge wells are filled with sterile PBS);

(2) Incubate with 5% CO ₂ at 37°C for 24h, until the cell monolayer covers the bottom of the well, add 10 μL of the drug with a certain concentration gradient to each well, and set up 4 duplicate wells for each concentration gradient;

(3) 5% CO ₂ , incubated at 37°C for 48 hours, and observed under an inverted microscope;

(4) Add 10 μL of MTT solution (5 mg/mL PBS, ie 0.5% MTT) to each well, and continue to culture for 4 hours;

(5) Terminate the culture, carefully aspirate the culture medium in the wells, add 150 μL of DMSO to each well to dissolve the formazan precipitate, and after mixing with a shaker, measure the concentration of each well using a microplate reader with a wavelength of 570 nm and a reference wavelength of 450 nm. optical density value;

(6) At the same time, set up zero adjustment wells (medium, MTT, DMSO) and control wells (cells, culture medium, MTT, drug dissolution medium with the same concentration, DMSO).

(7) According to the measured optical density value (OD value), the number of living cells is judged. The larger the OD value, the stronger the cell activity. Use the formula:

Calculate the inhibitory rate of each compound on the growth of the selected cells, and then calculate the IC ₅₀ values of each tested ligand T3 and complex T3-Pt on each selected cell line by Bliss method. The results are shown in Table 2 below.

Table 2. _IC50 values (μM) of ligand T3 and complex T3-Pt against various cell lines

Judging from the IC ₅₀ activity screening results, the complex T3-Pt was effective against four tested human tumor cell lines (human cervical cancer HeLa cells, human ovarian cancer cisplatin-resistant SK-OV-3/DDP cells, and human breast cancer cells). The proliferation inhibitory activity of cells (MCF-7 and MDA-MB-231)) was significantly higher than that of metal salt cis-Pt(DMSO) ₂ Cl ₂ , ligand T3 and cisplatin, reflecting the coordination between ligand T3 and platinum central atom effect. The MTT results showed that the complex T3-Pt had high antitumor activity against human breast cancer cells HeLa, MCF-7, MDA-MB-231 and SK-OV-3/DDP, with _IC50 values ranging from 0.05- 2.35μM, its antitumor activity in vitro is much greater than that of T3 ligand and the clinical classic metal-based anticancer drug cisplatin; in addition, the complex T3-Pt has little toxicity to normal cells HL-7702 (IC ₅₀ >100μM), It shows a good target inhibition of the proliferation of human breast cancer. In conclusion, the complex T3-Pt exhibits superior in vitro and in vivo antitumor activity and targeting, has potential medicinal value, and is expected to be used in the preparation of various antitumor drugs.

Example 4

(1) Synthesis and characterization of ligand T4:

In a 50.0 mL round-bottomed flask, weigh 1.0 mol of compound SM, 1.20 mol of lutidine amine derivative and 2.20 mol of NaH, dissolved in 5.0 mL of dimethylacetamide solution (DMA) at 25.0 °C After 1.7 hours of reaction, yellow solid powder T4 ligand was obtained with a yield of 61.0%.

Identification of the resulting T4:

(1) H NMR spectrum, as shown in Figure 6.

¹ H NMR (400MHz, CHCl ₃ -d) δ 8.48 (br d, J=4.4Hz, 2H), 8.35 (t, J=9.2Hz, 2H), 8.18 (d, J=8.6Hz, 1H), 7.68(dt,J=1.3,7.7Hz,1H),7.64-7.57(m,3H),7.55-7.46(m,3H),7.46-7.38(m,1H),7.10(dd,J=5.5,6.6 Hz, 2H), 4.94(t, J＝6.5Hz, 2H), 3.78(s, 4H), 3.47(s, 1H), 2.57-2.44(m, 2H), 2.02-1.87(m, 2H), 1.65 -1.44(m,4H),1.42-1.32(m,2H),1.32-1.19(m,6H).

(2) Carbon NMR spectrum, as shown in Figure 7.

¹³ C NMR (101MHz, CHCl ₃ -d)δ160.12,158.63,149.15-148.75(m,1C),147.29,144.22,136.37,134.48,130.59,128.48(d,J=5.9Hz,1C),124.75,123.48, 123.11,122.84,122.37(d,J=18.3Hz,1C),121.85,121.38,111.97,72.95,60.48,54.53,50.57,30.09,29.63-29.17(m,1C),27.19(d,J=24.9Hz, 1C), 25.91.

(3) The results of elemental analysis are shown in Table 3.

Elemental analysis results of compounds T4 and T4-Pt in the examples of Table 3

Therefore, it can be determined that the obtained yellow target product is compound T4, and its structural formula is as follows:

(2) Synthesis and characterization of the complex T4-Pt:

Weigh 1.0 mmol of ligand T4 and 1.0 mmol of dichlorobis(dimethyl sulfoxide) platinum(II) solid (Pt(DMSO) ₂ Cl ₂ ) and dissolve them in 50 mL of a mixed solution of methanol and water ( The volume ratio is 100:1), the coordination reaction was carried out at 50 °C for 20 h, filtered, and the product was dried with 5.0 mL of diethyl ether 3 times in a vacuum drying oven at 40 °C to obtain the yellow target product T4-Pt. Yield: 90.9%.

Identification of the obtained T4-Pt:

(1) Electrospray mass spectrometry, the spectrum of which is shown in FIG. 8 .

ESI-MS m/z: 788.0 [M-Cl] ⁺ , where M is the molecular weight of compound T4-Pt.

(2) H NMR spectrum, as shown in FIG. 9 .

¹ H NMR (500MHz, DMSO-d ₆ ) δ 8.79 (dt, J=6.0, 1.8 Hz, 2H), 8.32-8.24 (m, 4H), 8.17-8.11 (m, 1H), 7.83 (d, J = 7.9Hz, 2H), 7.77–7.73 (m, 2H), 7.68–7.65 (m, 2H), 7.55 (dddd, J=30.5, 8.0, 6.9, 1.2Hz, 2H), 5.39 (d, J=15.7 Hz, 2H), 4.95–4.81 (m, 4H), 3.03–2.98 (m, 2H), 1.84 (dq, J=13.6, 6.7Hz, 2H), 1.46 (q, J=10.9, 7.2Hz, 4H) ,1.25(t,J=7.2Hz,2H),1.16–1.07(m,6H).

(3) Carbon NMR spectrum, as shown in Figure 10.

¹³ C NMR(126MHz,DMSO-d ₆ )δ166.36,158.56,149.47,148.80,147.24,143.78,141.78,134.38,131.72,129.10,128.95,125.81,125.57,124.39,123.93,122.90,122.49,122.28,121.20,112.86 ,73.06,68.33,64.68,40.94,40.53,40.36,40.20,40.03,39.86,39.69,39.53,29.81,29.09,29.06,28.90,27.44,26.24,25.69.

(4) The results of elemental analysis are shown in Table 3.

Therefore, it can be determined that the obtained yellow target product is the complex T4-Pt, and its structural formula is as follows:

Example 5

Weigh 1.0 mmol of ligand T4 and 1.0 mmol of dichlorobis(dimethyl sulfoxide) platinum(II) solid (Pt(DMSO) ₂ Cl ₂ ) and dissolve them in 100 mL of a mixed solution of ethanol and acetone ( The volume ratio is 100:9), the coordination reaction was carried out at 30 °C for 80 h, filtered, and the product was dried with 5.0 mL of diethyl ether 3 times in a vacuum drying oven at 40 °C to obtain the yellow target product T4-Pt. Yield: 50.2%.

Example 6

Weigh 1.0 mmol of ligand T4 and 1.0 mmol of dichloro·bis(dimethyl sulfoxide) platinum(II) solid (Pt(DMSO) ₂ Cl ₂ ) and dissolve them in 10 mL of a mixed solution of methanol and acetone ( The volume ratio is 50:3), carry out the coordination reaction at 100°C for 10h, filter, use 5.0mL of ether for three times, and dry the product in a vacuum drying oven at 40°C to obtain the yellow target product T4-Pt. Yield: 80.0%.

Experimental example 2

Experiment on the Inhibitory Activity of T4-Pt of T4-Pt with High Antitumor Activity on Various Human Tumor Cell Lines

1. Cell Lines and Cell Culture

In this experiment, human cervical cancer HeLa cells, human ovarian cancer cisplatin-resistant SK-OV-3/DDP cells, human breast cancer cells (MCF-7 and MDA-MB-231) and human normal liver HL-7702 cells were selected. human cell lines.

All human cell lines were cultured in RPMI-1640 medium containing 100 U/mL penicillin, 10 wt% calf blood, and 100 U/mL streptomycin, and cultured in a 37°C incubator with a volume concentration of 5% CO ₂ .

2. Preparation of compounds to be tested

The purity of the used ligand T4 and complex T4-Pt should be ≥95%. Dilute their DMSO stock solution with physiological buffer to a final solution of 20 μmol/L (the final concentration of DMSO is ≤1%), and test the concentration. The degree of inhibition of the growth of normal cells or selected tumor cells by each compound is shown below.

3. Cell growth inhibition assay (MTT method)

(1) Take normal cells or tumor cells in logarithmic growth phase, digest with trypsin, prepare a cell suspension with a concentration of 5000 cells/mL with a culture medium containing 10% calf serum, and inoculate 190 μL per well in In a 96-well culture plate, the density of the cells to be tested is adjusted to 1000-10000 wells (the edge wells are filled with sterile PBS);

(2) Incubate with 5% CO ₂ at 37°C for 24h, until the cell monolayer covers the bottom of the well, add 10 μL of the drug with a certain concentration gradient to each well, and set up 4 duplicate wells for each concentration gradient;

(3) 5% CO ₂ , incubated at 37°C for 48 hours, and observed under an inverted microscope;

(4) Add 10 μL of MTT solution (5 mg/mL PBS, ie 0.5% MTT) to each well, and continue to culture for 4 hours;

(5) Terminate the culture, carefully remove the culture medium in the wells, add 150 μL of DMSO to each well to fully dissolve the formazan precipitate, and after mixing with a shaker, use a microplate reader with a wavelength of 570 nm and a reference wavelength of 450 nm to measure the concentration of each well. optical density value;

(6) At the same time, set up zero adjustment wells (medium, MTT, DMSO) and control wells (cells, culture medium, MTT, drug dissolution medium with the same concentration, DMSO).

(7) According to the measured optical density value (OD value), the number of living cells is judged. The larger the OD value, the stronger the cell activity. Use the formula:

Calculate the inhibitory rate of each compound on the growth of the selected cells, and then calculate the IC ₅₀ value of each test compound on each selected cell line by Bliss method. The results are shown in Table 4 below.

Table 4. _IC50 values (μM) of ligand T4 and complex T4-Pt against various cell lines

From the results of IC ₅₀ activity screening, the complex T4-Pt showed that the complex T4-Pt was effective against 4 tested human tumor cell lines (human cervical cancer HeLa cells, human ovarian cancer cisplatin-resistant SK-OV-3/DDP cells, human breast cancer cells The proliferation inhibitory activity of cells (MCF-7 and MDA-MB-231)) was significantly higher than that of metal salt cis-Pt(DMSO) ₂ Cl ₂ , ligand T4 and cisplatin, reflecting the coordination between ligand T4 and platinum central atom effect. The results of the activity screening experiment showed that the complex T4-Pt had high antitumor activity against human breast cancer cells HeLa, MCF-7, MDA-MB-231 and SK-OV-3/DDP, and its IC ₅₀ value ranged from 0.01-1.89μM, its antitumor activity in vitro is much greater than that of T4 ligand and the clinical classic metal-based anticancer drug cisplatin; in addition, the complex T4-Pt has little toxicity to normal cells HL-7702 (IC ₅₀ >100μM ), showing a good targeted inhibition of the proliferation of human breast cancer. In conclusion, the complex T4-Pt exhibits superior in vitro and in vivo antitumor activity and targeting, has potential medicinal value, and is expected to be used in the preparation of various antitumor drugs.

Claims (1)

1. The application of the platinum (II) chelidonine complex in preparing the medicine for targeted therapy of breast cancer is characterized in that the platinum (II) chelidonine complex has the following chemical structural formula:

wherein m is a non-zero natural number, n is a non-zero natural number, and R is halogen.

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