2-amino-8-hydroxyquinoline nickel complex against drug-resistant ovarian cancer and preparation method thereof

Abstract

The application discloses 2-amino-8-hydroxyquinoline nickel complexes for resisting drug-resistant ovarian cancer and a preparation method thereof. The application takes 2-amino-8-hydroxyquinoline as a first ligand, and takes 4,7-dichloro-1,10-phenanthroline, 5 5'-dimethyl-2,2'-dipyridyl, 5-chloro-phenanthroline, 4,4'-dimethoxy-2,2'-dipyridyl, 1,10-phenanthroline-5-amino, 1,10-ortho-phenanthroline, 2,9-dimethyl-ortho-phenanthroline (L7) and 4,7-diphenyl-1,10-phenanthroline as auxiliary ligands, synthesizes eight kinds of 2-amino-8-hydroxyquinoline nickel complexes (Ni-1-Ni-8) for treating drug-resistant strain cells of ovarian cancer. Experimental results show that Ni-1-Ni-8 has good inhibiting effect on ovarian cancer drug-resistant strain cells SK-OV-3 / DDP, and the toxicity of the normal HL-7702 cells is much smaller than that of tumor cells, which indicates that the complexes have good tumor selectivity on tumor cells, exhibit superior anti-tumor activity, have potential medicinal value, and are expected to be used for preparing various anti-tumor drugs.

Description

Technical Field

[0001] This invention relates to 8-hydroxyquinoline derivative metal complexes, and particularly to 2-amino-8-hydroxyquinoline nickel complexes for anti-drug-resistant ovarian cancer and their preparation methods. Background Technology

[0002] With the rapid rise in global cancer incidence and mortality rates, the design and development of novel, highly effective, and low-toxicity non-platinum anti-tumor drugs has become a key research topic in chemistry, biology, and medicine (Guo, Z.; et al. Chem. Soc. Rev., 2013, 42: 202–224.). In the field of bioinorganic chemistry, a large number of novel and high-quality complexes provide abundant materials for this research, such as copper complexes used as artificial nucleases for gene detection and therapy, and copper-nickel complexes used as anti-cancer drugs for the treatment of malignant tumors (Guo, Z.; et al. Chem. Soc. Rev., 2013, 42: 202–224.).

[0003] In addition, metal complexes of 8-hydroxyquinoline derivatives have good anti-cancer activity against tumors (Chen Zhenfeng, et al. Science in China: Chemistry, 2017, 47(02): 172-182.), however, there are no reports in the literature on the study of metal complexes of 2-amino-8-hydroxyquinoline and their anti-cancer activity. Summary of the Invention

[0004] One of the technical problems to be solved by the present invention is to provide a 2-amino-8-hydroxyquinoline nickel complex for treating drug-resistant ovarian cancer.

[0005] Specifically, the 2-amino-8-hydroxyquinoline nickel complexes for resisting drug-resistant ovarian cancer described in this invention have the chemical formulas [Ni(AQ)2(L1)](Ni-1), [Ni(AQ)2(L2)](Ni-2), [Ni(AQ)2(L3)]·3CH3OH(Ni-3), [Ni(AQ)2(L4)]·3CH3OH(Ni-4), [Ni(AQ)2(L5)]·CH3OH(Ni-5), [Ni(AQ)2(L6)](Ni-6), [Ni(AQ)2(L7)]·2CH3OH(Ni-7), and [Ni(AQ)2(L8)]·3CH3OH(Ni-8), and their chemical structural formulas are shown below:

[0006]

[0007] The second technical problem to be solved by the present invention is to provide a method for preparing the above-mentioned 2-amino-8-hydroxyquinoline nickel complex.

[0008] Specifically, the preparation method of the 2-amino-8-hydroxyquinoline nickel complex involves weighing 0.200 mmol of 2-amino-8-hydroxyquinoline (H-AQ), 0.100 mmol of NiCl2·6H2O, and 0.100 mmol of the auxiliary ligand into a 15.0 cm thick-walled drug-resistant tube, adding 2.5 mL of MeOH, 0.5 mL of CH2Cl2, and 0.5 mL of triethylamine, evacuating the tube, sealing the opening, and carrying out the coordination reaction at 80 °C for 3 days to obtain the final product.

[0009] The auxiliary ligands include 4,7-dichloro-1,10-phenanthroline (L1), 5,5'-dimethyl-2,2'-bipyridine (L2), 5-chloro-o-phenanthroline (L3), 4,4'-dimethoxy-2,2'-bipyridine (L4), 1,10-phenanthroline-5-amino (L5), 1,10-o-phenanthroline (L6), 2,9-dimethyl-o-phenanthroline (L7), or 4,7-diphenyl-1,10-phenanthroline (L8).

[0010] The synthetic route of this invention is as follows:

[0011]

[0012] The third technical problem to be solved by the present invention is to provide the application of the above-mentioned 2-amino-8-hydroxyquinoline nickel complex.

[0013] Specifically, this involves the application of the aforementioned 2-amino-8-hydroxyquinoline nickel complex in the preparation of targeted drugs for the treatment of ovarian cancer. It further involves the application of the aforementioned 2-amino-8-hydroxyquinoline nickel complex in the preparation of targeted drugs for the treatment of drug-resistant strains of ovarian cancer.

[0014] This invention uses 2-amino-8-hydroxyquinoline (H-AQ) as the first ligand and 4,7-dichloro-1,10-phenanthroline (L1), 5,5'-dimethyl-2,2'-bipyridine (L2), 5-chloro-o-phenanthroline (L3), 4,4'-dimethoxy-2,2'-bipyridine (L4), 1,10-phenanthroline-5-amino (L5), 1,10-o-phenanthroline (L6), 2,9-dimethyl-o-phenanthroline (L7), and 4,7-diphenyl-1,10-phenanthroline (L8) as auxiliary ligands to synthesize eight novel 2-amino-8-hydroxyquinoline nickel complexes Ni-1–Ni-8 for the treatment of drug-resistant ovarian cancer cells. The activity and toxicity of these complexes against drug-resistant human ovarian cancer cell lines SK-OV-3 / DDP and normal HL-7702 cells were investigated. Experimental results showed that Ni-8 had the most significant inhibitory effect on the drug-resistant ovarian cancer cell line SK-OV-3 / DDP, with an IC50 concentration of 100%. 50The toxicity value was 5.09 ± 0.26 μM, significantly higher than that of Ni-1–Ni-7, H-AQ, L1–L8, NiCl2·6H2O, and the clinical drug cisplatin. Furthermore, the toxicity to normal HL-7702 cells was much lower than that to tumor cells, indicating that these complexes exhibit good tumor selectivity. In conclusion, the 2-amino-8-hydroxyquinoline nickel complex Ni-1–Ni-8 demonstrates superior antitumor activity and has potential pharmaceutical value, holding promise for the preparation of various antitumor drugs. Attached Figure Description

[0015] Figure 1 This is an X-ray single-crystal structure diagram of the complex Ni-1 obtained in Example 1 of the present invention;

[0016] Figure 2 This is an X-ray single-crystal structure diagram of the complex Ni-2 obtained in Example 1 of the present invention;

[0017] Figure 3 This is an X-ray single-crystal structure diagram of the complex Ni-3 obtained in Example 1 of the present invention;

[0018] Figure 4 This is an X-ray single-crystal structure diagram of the complex Ni-4 obtained in Example 1 of the present invention;

[0019] Figure 5 This is an X-ray single-crystal structure diagram of the complex Ni-5 obtained in Example 1 of the present invention;

[0020] Figure 6 This is an X-ray single-crystal structure diagram of the complex Ni-6 obtained in Example 1 of the present invention;

[0021] Figure 7 This is an X-ray single-crystal structure diagram of the complex Ni-7 obtained in Example 1 of the present invention;

[0022] Figure 8 This is an X-ray single-crystal structure diagram of the complex Ni-8 obtained in Example 1 of the present invention;

[0023] Figure 9 The infrared spectrum of the complex Ni-1 obtained in Example 1 of this invention;

[0024] Figure 10 The infrared spectrum of the complex Ni-2 obtained in Example 1 of this invention;

[0025] Figure 11 The infrared spectrum of the complex Ni-3 obtained in Example 1 of this invention;

[0026] Figure 12 The infrared spectrum of the complex Ni-4 obtained in Example 1 of this invention;

[0027] Figure 13 The infrared spectrum of the complex Ni-5 obtained in Example 1 of this invention;

[0028] Figure 14 The infrared spectrum of the complex Ni-6 obtained in Example 1 of this invention;

[0029] Figure 15 The infrared spectrum of the complex Ni-7 obtained in Example 1 of this invention;

[0030] Figure 16 The infrared spectrum of the complex Ni-8 obtained in Example 1 of this invention is shown. Detailed Implementation

[0031] The present invention will be further described below with reference to specific embodiments, but the present invention is not limited to these embodiments.

[0032] Example 1

[0033] In a 15.0 cm thick-walled drug-resistant tube, weigh out 0.200 mmol of 2-amino-8-hydroxyquinoline (H-AQ), 0.100 mmol of NiCl2·6H2O, and 0.100 mmol of 4,7-dichloro-1,10-phenanthroline (L1), 5,5'-dimethyl-2,2'-bipyridine (L2), 5-chloro-o-phenanthroline (L3), 4,4'-dimethoxy-2,2'-bipyridine (L4), 1,10-phenanthroline-5-amino (L5), 1,10-o-phenanthroline (L6), 2,9-dimethyl-o-phenanthroline (L7), or 4,7-diphenyl-1,10-phenanthroline (L8), respectively. Add 2.5 mL of MeOH and 0.5 mL of... CH2Cl2 and 0.5 mL of triethylamine were added, the tube was evacuated, sealed, and subjected to a coordination reaction at 80 °C for 3 days to obtain the target products Ni-1–Ni-8 in reddish-brown blocky crystals. The yields ranged from 50.9% to 78.6%.

[0034] The obtained product was identified as follows:

[0035] (1) X-ray single crystal structure diagram of compound Ni-1–Ni-8, its spectrum is as follows Figure 1 –8 is shown.

[0036] (2) The infrared spectrum of compound Ni-1–Ni-8 is shown in the figure below. Figure 9 –16 is shown.

[0037] Data for Ni-1.Yield:50.9% IR(KBr):3454,3042,1620,1569,1509,1474,1438,1370,1323,1305,1278,1214,1092,1051,890,840,826,793,750,595,551,473,439,406cm -1 .

[0038] Data for Ni-2.Yield:78.6%.IR(KBr):3451,3035,1619,1508,1474,1436,1368,1322,1304,1276,1091,1046,990,890,840,825,743,714,648,592,565,548,514,469,441,420cm -1 .

[0039] Data for Ni-3.Yield:62.8%.IR(KBr):3450,3042,1621,1565,1508,1473,1457,1368,1322,1304,1277,1211,1179,1142,1091,1053,959,889,828,806,742,639,588,568,544,515,473,423cm -1 .

[0040] Data for Ni-4.Yield:55.3%.IR(KBr):3454,3066,1619,1564,1509,1474,1436,1369,1339,1323,1304,1278,1245,1225,1091,1039,888,837,827,745,592,551,514,469,439cm -1 .

[0041] Data for Ni-5.Yield:78.0%.IR(KBr):3460,3381,3159,3070,1619,1557,1509,1475,1437,1367,1322,1302,1276,1220,1118,1091,1054,1041,889,857,826,797,743,727,662,546,514,471,441cm -1 .

[0042] Data for Ni-6.Yield:70.3%.IR(KBr):3331,3142,3056,1626,1561,1511,1472,1439,1364,1321,13 03,1274,1209,1137,1092,1056,889,848,821,736,727,639,595,581,547,515,475,441cm -1 .

[0043] Data for Ni-7.Yield:67.1%.IR(KBr):3435,3160,3046,2928,1625,1580,1508,1472,1437,1365,1 322,1303,1275,1212,1146,1092,1055,1032,888,855,827,742,648,600,567,550,514cm -1 .

[0044] Data for Ni-8.Yield:54.9%.IR(KBr):3641,3442,3315,3043,1627,1558,1509,1473,143 81367,1321,1303,1275,1231,1090,888,828,765,740,702,630,545,514,471cm -1 .

[0045] (3) Elemental analysis results are shown in Table 1.

[0046] Table 1 shows the elemental analysis results of compounds Ni-1–Ni-8 in the examples.

[0047]

[0048] Therefore, the target product Ni-1–Ni-8 obtained from the reddish-brown blocky crystals can be determined, and its structural formula is as follows:

[0049]

[0050] To fully illustrate the pharmaceutical applications of the eight novel 2-amino-8-hydroxyquinoline nickel complexes Ni-1–Ni-8 described in this invention for treating drug-resistant ovarian cancer cell lines, the applicant conducted in vitro and in vivo antitumor activity experiments on them.

[0051] I. Experimental Study on the Inhibitory Activity of 2-Amino-8-hydroxyquinoline Nickel Complex Ni-1–Ni-8 on the Proliferation of Two Human Cell Lines

[0052] 1. Cell lines and cell culture

[0053] This experiment used two human cell lines: drug-resistant human ovarian cancer cell line SK-OV-3 / DDP and normal HL-7702 cells.

[0054] All human cell lines were cultured in RPMI-1640 medium containing 100 U / mL penicillin, 10 wt% fetal blood, and 100 U / mL streptomycin, and incubated at 37°C in an incubator containing 5% CO2 by volume.

[0055] 2. Preparation of the test compound

[0056] All compounds used must have a purity of ≥95%. Their DMSO stock solutions were diluted with physiological buffer to a final solution of 20 μmol / L (final DMSO concentration ≤1%), and the inhibitory effect of each compound on the growth of normal cells or selected tumor cells at this concentration was tested.

[0057] 3. Cell growth inhibition assay (MTT method)

[0058] (1) Take normal cells or tumor cells in the logarithmic growth phase, digest them with trypsin, and prepare a cell suspension with a concentration of 5000 cells / mL using culture medium containing 10% fetal bovine serum. Seed 190 μL per well in a 96-well culture plate to make the cell density to be tested 1000-10000 wells (fill the edge wells with sterile PBS).

[0059] (2) Incubate at 37°C for 24 hours with 5% CO2 until the cell monolayer covers the bottom of the well. Add 10 μL of drug at a certain concentration gradient to each well, and set 4 replicates for each concentration gradient.

[0060] (3) Incubate at 37°C with 5% CO2 for 48 hours and observe under an inverted microscope;

[0061] (4) Add 10 μL of MTT solution (5 mg / mL PBS, i.e. 0.5% MTT) to each well and continue culturing for 4 h;

[0062] (5) Terminate the culture, carefully aspirate the culture medium from the well, add 150 μL of DMSO to each well to fully dissolve the formazan precipitate, mix with a shaker, and then measure the optical density of each well using a microplate reader with a wavelength of 570 nm and a reference wavelength of 450 nm.

[0063] (6) Simultaneously set up zeroing wells (culture medium, MTT, DMSO) and control wells (cells, culture medium, MTT, drug dissolution medium of the same concentration, DMSO).

[0064] (7) The number of live cells is determined based on the measured optical density value (OD value). The higher the OD value, the stronger the cell activity. The formula is:

[0065]

[0066] The inhibition rate of each compound on the growth of the selected cells was calculated, and then the IC50 of each tested compound on each selected cell line was calculated using the Bliss method. 50 The values ​​are shown in Table 2 below.

[0067] Table 2. IC50 of compounds Ni-1–Ni-8 for various cell lines 50 Value (μM)

[0068]

[0069] From IC 50 Based on the activity screening results, Ni-8 showed the most significant inhibitory effect on the drug-resistant ovarian cancer cell line SK-OV-3 / DDP, with an IC50 concentration of 100%. 50 The value was 5.09±0.26 μM, significantly higher than that of Ni-1–Ni-7, H-AQ, L1–L8, NiCl2·6H2O, and the clinical drug cisplatin. Furthermore, Ni-1–Ni-8 exhibited low toxicity to normal HL-7702 cells, indicating good tumor selectivity for tumor cells. In conclusion, the 2-amino-8-hydroxyquinoline nickel complex Ni-1–Ni-8 demonstrates superior antitumor activity and has potential pharmaceutical value, holding promise for the preparation of various antitumor drugs.

Claims

The application of 1,2-amino-8-hydroxyquinoline nickel complex in the preparation of drugs for targeted therapy of drug-resistant ovarian cancer strains, characterized in that... The chemical structural formula of the 2-amino-8-hydroxyquinoline nickel complex is shown below: 。

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