5-amino-8-hydroxyquinoline platinum complex as well as synthesis method and application thereof

Abstract

The invention discloses a 5-amino-8-hydroxyquinoline platinum complex as well as a synthesis method and application thereof. The preparation method comprises the following steps: by taking 5-amino-8-hydroxyquinoline as an active ligand, reacting with cis-Pt (DMSO) 2Cl2 platinum salt, and synthesizing to obtain the 8-hydroxyquinoline platinum complex. The 5-amino-8-hydroxyquinoline platinum complex can inhibit the growth of human ovarian adenocarcinoma cis-platinum drug-resistant cells SK-OV-3 / DDP in a targeted manner, shows excellent anti-tumor activity, has potential medicinal value, and is expected to be used for preparing various anti-tumor drugs.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to a 5-amino-8-hydroxyquinoline platinum complex and a synthesis method and application thereof. Background Art

[0002] The toxic side effects of cisplatin in clinical treatment have inspired researchers to develop new platinum-based targeted anticancer drugs. In addition, this type of platinum complex urgently needs to address the drug resistance of cisplatin-based drugs.

[0003] A large number of literature reports show that 8-hydroxyquinoline metal complexes have high anticancer activity, and the anticancer activity of some compounds is as low as nM level (Zhou, X. Med. Journal of Inorganic Biochemistry, 2023, 238, 112051.), but their selectivity is poor, and there have been no reports on the study of 5-amino-8-hydroxyquinoline (H-Ah) complexes and their anticancer activity. Summary of the invention

[0004] One of the objects of the present invention is to provide a 5-amino-8-hydroxyquinoline platinum complex.

[0005] Specifically, the 5-amino-8-hydroxyquinoline platinum complex has a chemical formula of [Pt(Ah)Cl2](AhPt), and a chemical structure as shown below:

[0006]

[0007] The second object of the present invention is to provide a method for synthesizing the above-mentioned 5-amino-8-hydroxyquinoline platinum complex.

[0008] Specifically, the synthesis method of the above-mentioned 5-amino-8-hydroxyquinoline platinum complex is to take 5-amino-8-hydroxyquinoline (H-Ah) and cis-Pt(DMSO)2Cl2 platinum salt, then add a solvent, react at 45°C for 2 days and at 68°C for 1 day under sealed conditions, cool to 37°C, filter, and obtain 5-amino-8-hydroxyquinoline platinum complex.

[0009] Its synthetic route is as follows:

[0010]

[0011] The solvent is methanol (CH3OH) and dimethyl sulfoxide (DMSO), or methanol (CH3OH) and acetone.

[0012] Another object of the present invention is to provide the application of the above 5-amino-8-hydroxyquinoline platinum complex.

[0013] Specifically, it relates to the use of the above 5-amino-8-hydroxyquinoline platinum complex in the preparation of anti-tumor drugs. It relates to the use of the above 5-amino-8-hydroxyquinoline platinum complex in the preparation of targeted drugs for the treatment of ovarian cancer.

[0014] Compared with the prior art, the present invention uses 5-amino-8-hydroxyquinoline (H-Ah) as an active ligand to react with platinum salt cis-Pt(DMSO)2Cl2 to synthesize 5-amino-8-hydroxyquinoline platinum complex AhPt, and investigates its activity and toxicity experiments on human ovarian adenocarcinoma cells SK-OV-3, human ovarian adenocarcinoma cisplatin-resistant cells SK-OV-3 / DDP and normal liver cells HL-7702. The experimental results show that the complex AhPt has the best inhibitory effect on SK-OV-3 / DDP cancer cells, and its IC 50 The value is 9.14±0.58μM, which is much more active than H-Ah (>50μM), cis-Pt(DMSO)2Cl2 (>50μM) and clinical anticancer drug cisplatin (>50μM); and it has almost no toxicity to normal HL-7702 cells (>50μM); indicating that 5-amino-8-hydroxyquinoline platinum complex AhPt can target and inhibit the growth of human ovarian adenocarcinoma cisplatin-resistant cells SK-OV-3 / DDP. In short, the new 5-amino-8-hydroxyquinoline platinum complex AhPt exhibits excellent antitumor activity, has potential medicinal value, and is expected to be used in the preparation of various antitumor drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of AhPt prepared in Example 1 of the present invention;

[0016] Figure 2 This is the carbon nuclear magnetic resonance spectrum of AhPt prepared in Example 1 of the present invention;

[0017] Figure 3 This is the infrared spectrum of AhPt prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0018] The present invention will be further described below with reference to specific examples, but the present invention is not limited to these examples.

[0019] Example 1

[0020] Weigh 0.1 mmol of 5-amino-8-hydroxyquinoline (H-Ah) and 0.1 mmol of cis-Pt(DMSO)2Cl2, place in a 15.0 cm thick-walled pressure tube, then add 1.5 mL of CH3OH and 0.1 mL of DMSO, cover with a lid, react at 45°C for 2 days and at 68°C for 1 day, cool to 37°C, open the lid of the tube, filter, and then obtain 5-amino-8-hydroxyquinoline platinum complex (complex AhPt) with a yield of 81.6%.

[0021] The obtained complex AhPt was identified:

[0022] (1) The H NMR spectrum of the complex AhPt is shown in the following figure: Figure 1 shown.

[0023] 1 H NMR (600MHz, DMSO-d6) δ9.45 (d, J=5.2Hz, 1H), 8.74 (d, J=8.4Hz, 1H), 7.80 (dd, J= 8.5,5.3Hz,1H),7.34(d,J=8.1Hz,1H),6.98(d,J=8.3Hz,1H),2.50(overlap,6H).

[0024] (2) The carbon NMR spectrum of the complex AhPt is as follows: Figure 2 shown.

[0025] 13 C NMR (151MHz, DMSO-d6) δ148.50,143.06,136.30,135.36,130.92,127.64,122.79,121.26,113.43.

[0026] (3) Infrared spectrum of the complex AhPt, as shown in the figure Figure 3 shown.

[0027] IR(KBr):3896,3888,3866,3856,3850,3834,3818,3812,3804,3798,3747 ,3741,3707,3685,3672,3666,3645,3625,3424,3078,3008,2921,2593,1 589,1576,1541,1514,1475,1433,1417,1399,1384,1334,1293,1257,113 5,1106,1060,1029,981,926,830,772,744,697,657,632,573,508,491cm -1 .

[0028] (4) Elemental analysis results are shown in Table 1.

[0029] Table 1. Elemental analysis results of the complex AhPt

[0030]

[0031] Thus, the obtained complex AhPt can be determined, and its structural formula is as follows:

[0032]

[0033] Example 2

[0034] Weigh 0.1 mmol of 5-amino-8-hydroxyquinoline (H-Ah) and 0.1 mmol of cis-Pt(DMSO)2Cl2, place in a 15.0 cm thick-walled pressure tube, then add 1.5 mL of CH3OH and 0.1 mL of acetone, cover the tube, react at 45°C for 2 days and at 68°C for 1 day, cool to 37°C, open the tube lid, filter, and then obtain 5-amino-8-hydroxyquinoline platinum complex with a yield of 75.0%.

[0035] In order to fully illustrate the use of the 5-amino-8-hydroxyquinoline platinum complex AhPt of the present invention in pharmaceutical manufacturing, the applicant conducted in vitro and in vivo anti-tumor activity experiments on it.

[0036] 1. Experimental study on the proliferation inhibition activity of 5-amino-8-hydroxyquinoline platinum complex AhPt on three human cell lines

[0037] 1. Cell lines and cell culture

[0038] In this experiment, three human cell lines were selected, including human ovarian adenocarcinoma cell lines SK-OV-3, human ovarian adenocarcinoma cisplatin-resistant cells SK-OV-3 / DDP and normal liver cells HL-7702.

[0039] All human cell lines were cultured in RPMI-1640 culture medium containing 100 U / mL penicillin, 10 wt% calf blood, and 100 U / mL streptomycin, and cultured in an incubator at 37° C. containing 5% CO 2 by volume.

[0040] 2. Preparation of test compounds

[0041] The purity of all compounds used must be ≥95%. Their DMSO stock solutions are diluted with physiological buffer to a final solution of 20 μmol / L (final DMSO concentration ≤1%), and the degree of inhibition of the growth of normal cells or selected tumor cells by each compound at this concentration is tested.

[0042] 3. Cell Growth Inhibition Experiment

[0043] The specific steps are as follows:

[0044] (1) Cell digestion, counting, and preparation to a concentration of 5×10 4 100 μL of cell suspension was added to each well of a 96-well cell culture plate, and the plate was placed in a 37° C., 5.0% CO 2 incubator for 24.0 h.

[0045] (2) Dilute the drug to the desired concentration using RPMI-1640 medium, add 100 μL of the corresponding drug-containing medium to each well of a 96-well plate to achieve final concentrations of 0, 1.0, 2.5, 5.0, 10.0, 20.0 and 50.0 μM, respectively. Set up 6 parallel experiments for each concentration. After adding the drug, continue culturing in a 37°C, 5% CO2 incubator for 48 h.

[0046] (3) Perform CCK-8 staining and measure the OD value at a wavelength of λ = 450nm: add 10μL CCK-8 to each well, continue to culture in the incubator for 2h, shake for 10min to gently mix, then measure the OD value of each well at a wavelength of λ = 450nm using an enzyme marker to calculate the inhibition rate of each compound on the growth of the selected cell line, and then calculate the IC value of each test compound on the selected cell line using the Bliss method. 50 The results are shown in Table 2 below.

[0047] Table 2. IC values ​​of platinum complex AhPt against various cell lines 50 Value (μM)

[0048]

[0049] The activity screening results showed that the complex AhPt had a good inhibitory effect on human ovarian adenocarcinoma cell line SK-OV-3 and human ovarian adenocarcinoma cisplatin-resistant cell line SK-OV-3 / DDP. Its IC 50 The values ​​were 9.14±0.58 and 11.08±1.07μM, respectively, and the inhibitory effect on SK-OV-3 / DDP was the strongest. Its activity was much greater than that of H-Ah (>50μM), cis-Pt(DMSO)2Cl2 (>50μM) and the clinical anticancer drug cisplatin (>50μM); and its toxicity to normal HL-7702 cells was very small (>50μM); indicating that the complex AhPt can target the proliferation of human ovarian adenocarcinoma cisplatin-resistant cells SK-OV-3 / DDP.

Claims

1. 5-amino-8-hydroxyquinoline platinum complex, characterized in that: The chemical structure is shown below:

2. The method for synthesizing the 5-amino-8-hydroxyquinoline platinum complex according to claim 1, characterized in that: Take 5-amino-8-hydroxyquinoline and cis-Pt(DMSO)2Cl2 platinum salt, then add solvent, react at 45°C for 2 days under sealed conditions, then react at 68°C for 1 day, cool to 37°C, filter, and obtain 5-amino-8-hydroxyquinoline platinum complex.

3. The method for synthesizing the 5-amino-8-hydroxyquinoline platinum complex according to claim 2, characterized in that: The solvent is methanol and dimethyl sulfoxide, or methanol and acetone.

4. The method for synthesizing the 5-amino-8-hydroxyquinoline platinum complex according to claim 3, characterized in that: The solvent is 1.5 mL of methanol and 0.1 mL of dimethyl sulfoxide.

5. The method for synthesizing the 5-amino-8-hydroxyquinoline platinum complex according to claim 3, characterized in that: The solvent was 1.5 mL of methanol and 0.1 mL of acetone.

6. Use of the 5-amino-8-hydroxyquinoline platinum complex according to claim 1 in the preparation of antitumor drugs.

7. Use of the 5-amino-8-hydroxyquinoline platinum complex according to claim 1 in the preparation of a drug for the targeted treatment of ovarian cancer.

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