8-hydroxyquinoline-based anticancer zinc(ii) complexes, methods for their synthesis and use

Abstract

The application discloses an 8-hydroxyquinoline anticancer zinc (II) complex and a synthesis method and application thereof. The 8-hydroxyquinoline anticancer zinc (II) complex is synthesized by taking 5,7-diiodo-8-hydroxyquinoline, 5,7-dichloro-8-hydroxyquinoline, 5-chloro-7-iodo-8-hydroxyquinoline, 5,7-dibromo-8-hydroxyquinoline and 5-chloro-8-hydroxyquinoline as a first ligand and taking 4,4'-dimethoxy-2,2'-bipyridine, 4,4-di-tert-butyl-2,2-bipyridine, 5,5'-dimethyl-2,2-bipyridine, 2,2-bipyridine and 4,4'-dimethyl-2,2'-bipyridine as auxiliary ligands. The 8-hydroxyquinoline anticancer zinc (II) complex has good inhibiting effect on SK-OV-3CR cells of an ovarian cancer drug-resistant strain, is higher than that of cisplatin drugs, overcomes drug resistance of clinical drugs, has potential medicinal value and can be used for preparation of various antitumor drugs.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to 8-hydroxyquinoline anticancer zinc(II) complexes, their synthesis methods, and applications. Background Technology

[0002] Cancer is generally treated with a variety of methods, including radiotherapy, surgery, and chemotherapy. However, surgery and radiotherapy are important means of local treatment. While platinum-based drugs inhibit tumor cell growth during chemotherapy, they also have varying degrees of toxicity to different types of normally proliferating cells in the body. Therefore, the development and treatment of targeted non-platinum drugs in recent years have shown promising prospects (Guo, Z.; et al. Chem. Soc. Rev., 2013, 42:202-224.). However, they are currently still in the clinical trial stage, and further in-depth observation and accumulation are needed for clinical use. Therefore, there is still a significant gap before large-scale clinical promotion and use.

[0003] Currently, research on the anticancer activity of 8-hydroxyquinoline zinc complex against SK-OV-3 / DDP remains lacking. Summary of the Invention

[0004] One of the objectives of this invention is to provide 8-hydroxyquinoline anticancer zinc(II) complexes.

[0005] Specifically, this invention uses 5,7-diiodo-8-hydroxyquinoline (H-Q1), 5,7-dichloro-8-hydroxyquinoline (H-Q2), 5-chloro-7-iodo-8-hydroxyquinoline (H-Q3), 5,7-dibromo-8-hydroxyquinoline (H-Q4), and 5-chloro-8-hydroxyquinoline (H-Q5) as the first ligands, and 4,4'-dimethoxy-2,2'-bipyridine (D1), 4,4-di-tert-butyl-2,2-bipyridine (D2), and 5,7'-diisothio-8-hydroxyquinoline (H-Q5) as the second ligands, respectively. Novel zinc(II) complexes targeting 8-hydroxyquinoline anticancer agents were synthesized using 5'-dimethyl-2,2-bipyridine (D3), 2,2-bipyridine (D4), and 4,4'-dimethyl-2,2'-bipyridine (D5) as auxiliary ligands: [Zn(Q1)2(D1)](DQ1), [Zn(Q1)2(D2)](DQ2), [Zn(Q2)2(D3)](DQ3), [Zn(Q3)2(D3)]·CH3OH(DQ4), and [Zn(Q3)2(D4)]·CH3OH(DQ4). ](DQ5), [Zn(Q3)2(D2)]·CH3OH(DQ6), [Zn(Q3)2(D1)](DQ7), [Zn(Q4)2(D4)](DQ8), [Zn(Q4)2(D5)](DQ9 ), [Zn(Q4)2(D1)](DQ10), [Zn(Q4)2(D3)](DQ11), [Zn(Q4)2(D2)](DQ12) and [Zn(Q5)2(D4)]·CH3OH(DQ13).

[0006] The chemical structural formula of the above compound is shown below:

[0007]

[0008] The second objective of this invention is to provide a method for synthesizing the above-mentioned 8-hydroxyquinoline anticancer zinc(II) complex as follows: 0.1 mmol of the auxiliary ligand and 0.1 mmol of the metal salt Zn(NO3)2·6H2O are weighed into a 15.0 cm long thick-walled drug-resistant tube. Then, 3.5 mL of a mixed solution of MeOH and CH2Cl2 in a volume ratio of 6:1 is added. The tube is capped and the coordination reaction is carried out at 65 °C for 3 days. After the reaction is completed, the tube is cooled to room temperature, the cap is opened, and then 0.2 mmol of the first ligand 8-hydroxyquinoline derivative and 0.1 mL of triethylamine are added. The tube is capped again and the reaction is carried out at 80 °C for 3 days. After cooling and standing for 48 h, the target product in yellow blocky crystals is obtained.

[0009] The 8-hydroxyquinoline derivative is 5,7-diiodo-8-hydroxyquinoline (H-Q1), 5,7-dichloro-8-hydroxyquinoline (H-Q2), 5-chloro-7-iodo-8-hydroxyquinoline (H-Q3), 5,7-dibromo-8-hydroxyquinoline (H-Q4) or 5-chloro-8-hydroxyquinoline (H-Q5).

[0010] The auxiliary ligand is 4,4'-dimethoxy-2,2'-bipyridine (D1), 4,4-di-tert-butyl-2,2-bipyridine (D2), 5,5'-dimethyl-2,2-bipyridine (D3), 2,2-bipyridine (D4), or 4,4'-dimethyl-2,2'-bipyridine (D5).

[0011] The synthetic route of this invention is as follows:

[0012]

[0013] It is worth noting that:

[0014] (1) Triethylamine should be 0.1 mL. If less than this amount, the overall reaction yield will be very low. If more than this amount, a large amount of powder will be produced, indicating that the reaction is incomplete.

[0015] (2) All reaction temperatures were explored, and only the given temperature was suitable for obtaining the target product of yellow blocky crystals. At other temperatures, the reaction yield was low or the reaction was messy.

[0016] (3) MeOH and CH2Cl2 must be present at the same time, and the volume ratio v:v = 6:1. The product obtained from the reaction has few impurities and is easy to separate.

[0017] Another object of the present invention is to provide the application of the above-mentioned 8-hydroxyquinoline anticancer zinc(II) complex.

[0018] Specifically, the application of 8-hydroxyquinoline anticancer zinc(II) complexes in the preparation of targeted therapies for ovarian cancer. Further, the application of 8-hydroxyquinoline anticancer zinc(II) complexes in the preparation of targeted therapies for drug-resistant ovarian cancer strains is discussed.

[0019] This invention uses 5,7-diiodo-8-hydroxyquinoline (H-Q1), 5,7-dichloro-8-hydroxyquinoline (H-Q2), 5-chloro-7-iodo-8-hydroxyquinoline (H-Q3), 5,7-dibromo-8-hydroxyquinoline (H-Q4), and 5-chloro-8-hydroxyquinoline (H-Q5) as the first ligands, and 4,4'-dimethoxy-2,2'-bipyridine (D1), 4,4-di-tert-butyl-2,2-bipyridine (D2), and 5,7'-diisothio-8-hydroxyquinoline (H-Q5) as the second ligands, respectively. Thirteen novel 8-hydroxyquinoline anticancer zinc(II) complexes were synthesized using 5'-dimethyl-2,2-bipyridine (D3), 2,2-bipyridine (D4), and 4,4'-dimethyl-2,2'-bipyridine (D5) as auxiliary ligands. Their activity and toxicity against the drug-resistant human ovarian cancer cell line SK-OV-3 / DDP (abbreviated as SK-OV-3CR) and normal HL-7702 cells were investigated. The results showed that DQ3 had the most significant inhibitory effect on the drug-resistant ovarian cancer cell line SK-OV-3CR, with an IC50 concentration of [missing value]. 50 The value was 6.78±0.59 μM, which was much higher than that of DQ1–DQ2, DQ4–DQ13, H-Q1–H-Q5, D1–D5, the metal salt Zn(NO3)2·6H2O, and the clinical drug cisplatin. Furthermore, it showed very low toxicity to normal HL-7702 cells (>50 μM). Literature reports that four 8-hydroxyquinoline derivative anticancer zinc complexes are highly toxic to normal HL-7702 cells, with IC50 values ​​of 6.78±0.59 μM. 50 The concentration was below 1.78±0.05 μM (Chen, Z.-F..; et al. Eur. J. Med. Chem., 2013, 69: 554-563.), indicating that this type of complex is selective for tumor cells SK-OV-3CR, exhibiting good anticancer activity, low toxicity to normal cells, and high selectivity, thus possessing significant advantages. Furthermore, the novel 8-hydroxyquinoline anticancer zinc(II) complexes DQ1–DQ13 showed good inhibitory effects on drug-resistant ovarian cancer cell lines SK-OV-3CR, exceeding those of cisplatin (60.37±1.14 μM), overcoming drug resistance in clinical use. In conclusion, the novel 8-hydroxyquinoline anticancer zinc(II) complexes DQ1–DQ13 exhibit superior antitumor activity and have potential pharmaceutical value, showing promise for the preparation of various antitumor drugs. Attached Figure Description

[0020] Figure 1 This is an X-ray single-crystal structure diagram of the complex DQ1 obtained in Example 1 of the present invention;

[0021] Figure 2 This is an X-ray single-crystal structure diagram of the complex DQ2 obtained in Example 1 of the present invention;

[0022] Figure 3This is an X-ray single-crystal structure diagram of the complex DQ3 obtained in Example 1 of the present invention;

[0023] Figure 4 This is an X-ray single-crystal structure diagram of the complex DQ4 obtained in Example 1 of the present invention;

[0024] Figure 5 This is an X-ray single-crystal structure diagram of the complex DQ5 obtained in Example 1 of the present invention;

[0025] Figure 6 This is an X-ray single-crystal structure diagram of the complex DQ6 obtained in Example 1 of the present invention;

[0026] Figure 7 This is an X-ray single-crystal structure diagram of the complex DQ7 obtained in Example 1 of the present invention;

[0027] Figure 8 This is an X-ray single-crystal structure diagram of the complex DQ8 obtained in Example 1 of the present invention;

[0028] Figure 9 This is an X-ray single-crystal structure diagram of the complex DQ9 obtained in Example 1 of the present invention;

[0029] Figure 10 This is an X-ray single crystal structure diagram of the complex DQ10 obtained in Example 1 of the present invention;

[0030] Figure 11 This is an X-ray single-crystal structure diagram of the complex DQ11 obtained in Example 1 of the present invention;

[0031] Figure 12 This is an X-ray single-crystal structure diagram of the complex DQ12 obtained in Example 1 of the present invention;

[0032] Figure 13 This is an X-ray single-crystal structure diagram of the complex DQ13 obtained in Example 1 of the present invention;

[0033] Figure 14 The infrared spectrum of complex DQ1 obtained in Example 1 of this invention;

[0034] Figure 15 The infrared spectrum of complex DQ2 obtained in Example 1 of this invention;

[0035] Figure 16 The infrared spectrum of complex DQ3 obtained in Example 1 of this invention;

[0036] Figure 17 The infrared spectrum of complex DQ4 obtained in Example 1 of this invention;

[0037] Figure 18The infrared spectrum of complex DQ5 obtained in Example 1 of this invention;

[0038] Figure 19 The infrared spectrum of complex DQ6 obtained in Example 1 of this invention;

[0039] Figure 20 The infrared spectrum of complex DQ7 obtained in Example 1 of this invention;

[0040] Figure 21 The infrared spectrum of complex DQ8 obtained in Example 1 of this invention;

[0041] Figure 22 The infrared spectrum of complex DQ9 obtained in Example 1 of this invention;

[0042] Figure 23 The infrared spectrum of complex DQ10 obtained in Example 1 of this invention;

[0043] Figure 24 The infrared spectrum of complex DQ11 obtained in Example 1 of this invention;

[0044] Figure 25 The infrared spectrum of complex DQ12 obtained in Example 1 of this invention;

[0045] Figure 26 The infrared spectrum of complex DQ13 obtained in Example 1 of this invention. Detailed Implementation

[0046] The present invention will be further described below with reference to specific embodiments, but the present invention is not limited to these embodiments.

[0047] Example 1

[0048] In a 15.0 cm long thick-walled drug-resistant tube, weigh out 0.1 mmol of 4,4'-dimethoxy-2,2'-bipyridine (D1), 4,4-di-tert-butyl-2,2-bipyridine (D2), 5,5'-dimethyl-2,2-bipyridine (D3), 2,2-bipyridine (D4), or 4,4'-dimethyl-2,2'-bipyridine (D5), and 0.1 mmol of the metal salt Zn(NO3)2·6H2O, then add 3.5 mL of the solution. A mixed solution of MeOH and CH2Cl2 (v:v = 6:1) was prepared, capped, and subjected to a coordination reaction at 65°C for 3 days. After the reaction was completed, the mixture was cooled to room temperature, the cap was opened, and then 0.2 mmol of 5,7-diiodo-8-hydroxyquinoline (H-Q1), 5,7-dichloro-8-hydroxyquinoline (H-Q2), 5-chloro-7-iodo-8-hydroxyquinoline (H-Q3), 5,7-dibromo-8-hydroxyquinoline (H-Q4), or 5-chloro-8-hydroxyquinoline (H-Q5) and 0.1 mL of triethylamine were added, respectively. The cap was closed again, and the mixture was subjected to a reaction at 80°C for 3 days. After cooling and standing for 48 h, the target product was obtained as yellow blocky crystals. The yield was 60.1%–85.0%.

[0049] The obtained product was identified as follows:

[0050] (1) X-ray single crystal structure diagram of compound DQ1–DQ13, and its spectrum is shown in Figure 1. Figure 1 –13 is shown.

[0051] (2) The infrared spectrum of compound DQ1–DQ13 is shown in the figure below. Figure 14 –26 is shown.

[0052] Data for DQ1.Yield:60.1%.IR(KBr):3402,3069,3008,1609,1563,1533,1500,1472,1442,1386,1348,1288,12 57,1250,1232,1202,1133,1105,1049,1031,928,920,884,841,828,807,790,738,673,652,634,559cm -1 .

[0053] Data for DQ2.Yield:75.2%.IR(KBr):3414,3053,2965,1610,1534,1471,1443,1387,1372,1344,1297,1278,1251,1201,1134,1107,1049,1033,1013,939,923,888,879,849,841,906,789,739,671,651,605,558cm -1 .

[0054] Data for DQ3.Yield:83.4%.IR(KBr):3381,3111,3066,3044,3031,2953,2743,2611,2557,1945,1891,1763,1607,1596,1572,1548,1488,1433,1356,1309,1286,1248,1220,1200,1189,1159,1145,1114,1045,977,962,880,824,813,805,742,714,690,673,649,589cm -1 .

[0055] Data for DQ4.Yield:77.9%.IR(KBr):3654,3263,3052,3023,2922,2815,2550,1750,1629,1593,1569,1546,1480,1440,1391,1375,1356,1314,1249,1233,1210,1164,1134,1107,1067,1040,963,879,845,821,805,786,742,702,667,647,599,573,538cm -1 .

[0056] Data for DQ5.Yield:80.0%.IR(KBr):3392,3110,3056,3016,2552,1958,1878,1744,1668,1601,1577,1565,1547,1483,1439,1393,1380,1356,1315,1280,1249,1214,1156,1107,1088,1043,1019,961,906,870,846,837,806,787,765,741,701,668,645,627,598,573,545,505cm -1 .

[0057] Data for DQ6.Yield:85.0%.IR(KBr):3392,3075,3053,3016,2630,1991,1958,1867,1784,1744,1669,1602,1579,1550,1501,1484,1453,1394,1384,1368,1315,1249,1219,1208,1159,1131,1110,1088,1044,967,959,874,836,805,786,740,705,662,645,598,619,577,545,505cm -1 .

[0058] Data for DQ7.Yield:84.4%.IR(KBr):3115,3080,3011,2982,2940,2844,2550,2346,2089,1607,1564,1543,1499,1483,1440,1390,1381,1352,1339,1314,1290,1279,1269,1256,1230,1211,1195,1150,1136,1107,1046,1022,1003,960,919,891,876,861,844,835,815,803,792,785,740,698,668,642,582,571cm -1 .

[0059] Data for DQ8.Yield:64.7%.IR(KBr):3069,2939,2825,2529,1957,1739,1634,1593,1557,1483,1445,1390,1375,1361,1281,1251,1237,1219,1168,1137,1108,1051,1030,981,948,874,861,806,787,737,692,667,642,592,576,503cm -1 .

[0060] Data for DQ9.Yield:63.7%.IR(KBr):3394,3064,3041,2958,2915,2826,2731,2599,2554,2303,1939,1795,1755,1615,1591,1548,1484,1451,1393,1378,1352,1305,1291,1248,1211,1138,1106,1048,1033,1017,940,919,906,880,857,837,827,807,789,741,684,670,640,593,571,548,515cm -1 .

[0061] Data for DQ10.Yield:71.1%.IR(KBr):3402,3072,1610,1564,1548,1501,1449,1391,1378,1353,1337,1290,1257,1232,1211,1137,1106,1049,1031,943,919,881,857,833,808,786,740,685,673,640,571cm -1 .

[0062] Data for DQ11.Yield:87.0%.IR(KBr):3067,2941,2825,1956,1740,1593,1552,1484,1446,1390,1375,1361,1311,1282,1251,1237,1219,1211,1155,1138,1108,1050,1042,1030,949,941,881,874,859,829,806,787,737,692,668,642,592,574,503cm -1 .

[0063] Data for DQ12.Yield:70.0%.IR(KBr):3070,2953,2825,1956,1739,1633,1611,1593,1557,1484,1445,1390,1375,1361,1282,1251,1237,1219,1137,1109,1051,1030,981,948,881,874,862,806,787,737,692,667,642,605,592,577,505cm -1 .

[0064] Data for DQ13.Yield:88.5%.IR(KBr):3646,3191,3105,3074,2816,2646,2578,2061,1944,1849,1748,1659,1595,1565,1493,1457,1440,1394,1 382,1324,1254,1242,1225,1173,1153,1128,1101,1084,1059,1039 ,1020,957,929,891,825,812,783,766,735,663,652,627,596,536cm -1 .

[0065] (3) Elemental analysis results are shown in Table 1.

[0066] Table 1. Elemental analysis results of compounds DQ1–DQ13 in the examples.

[0067]

[0068] Therefore, the target product DQ1–DQ13 of the obtained yellow blocky crystals can be identified, and its structural formula is as follows:

[0069]

[0070] To fully illustrate the pharmaceutical applications of the novel 8-hydroxyquinoline anticancer zinc(II) complex DQ1–DQ13 described in this invention, the applicant conducted in vitro and in vivo antitumor activity experiments on it.

[0071] I. Experimental Study on the Inhibitory Activity of Novel 8-Hydroxyquinoline Anticancer Zinc(II) Complexes DQ1–DQ13 on the Proliferation of Two Human Cell Lines

[0072] 1. Cell lines and cell culture

[0073] This experiment used two human cell lines: drug-resistant human ovarian cancer cell line SK-OV-3CR and normal HL-7702 cells.

[0074] 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.

[0075] 2. Preparation of the test compound

[0076] 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.

[0077] 3. Cell growth inhibition assay (MTT method)

[0078] (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).

[0079] (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.

[0080] (3) Incubate at 37°C with 5% CO2 for 48 hours and observe under an inverted microscope;

[0081] (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;

[0082] (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.

[0083] (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).

[0084] (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:

[0085]

[0086] 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 Tables 2 and 3 below.

[0087] Table 2. IC50 of compounds DQ1–DQ13 on various cell lines 50 Value (μM, 24h)

[0088]

[0089] Table 3. IC50 of compounds on various cell lines 50 Value (μM, 24h)

[0090]

[0091] From Tables 2 and 3, IC 50 Based on the activity screening results, DQ3 showed the most significant inhibitory effect on the drug-resistant ovarian cancer cell line SK-OV-3CR, with an IC50 concentration of 100%. 50 The value was 6.78±0.59 μM, which is much higher than that of DQ1–DQ2, DQ4–DQ13, H-Q1–H-Q5, D1–D5, the metal salt Zn(NO3)2·6H2O, and the clinical drug cisplatin. Furthermore, it showed very low toxicity to normal HL-7702 cells (>50 μM), indicating that this type of complex is selective for tumor cells SK-OV-3CR. In contrast, existing literature reports four anticancer zinc complexes of 8-hydroxyquinoline derivatives, which exhibit high anticancer activity (IC50). 50 =44±1nM), but it is highly toxic to normal cells HL-7702, IC50 = 44±1nM. 50 The concentration was below 1.78±0.05 μM (Chen, Z.-F..; et al. Eur. J. Med. Chem., 2013, 69: 554-563.). It lacked tumor selectivity and exhibited high toxicity. Therefore, the reported combination showed better selectivity than the complexes reported in the literature, with lower toxicity to normal cells and higher selectivity, making it more advantageous. Furthermore, the novel 8-hydroxyquinoline anticancer zinc(II) complexes DQ1–DQ13 showed good inhibitory effects on the drug-resistant ovarian cancer cell line SK-OV-3CR, exceeding those of cisplatin (60.37±1.14 μM), overcoming drug resistance in clinical use. In conclusion, the novel 8-hydroxyquinoline anticancer zinc(II) complexes DQ1–DQ13 exhibited superior antitumor activity and have potential pharmaceutical value, showing promise for the preparation of various antitumor drugs.

Claims

1. An anticancer zinc (II) complex of 8-hydroxyquinoline characterized in that, The chemical structural formula is shown in the following formula: 。 2. The method for synthesizing the 8-hydroxyquinoline anticancer zinc complex according to claim 1, characterized in that, in 15.0 cm long thick-walled drug-resistant tube, respectively, 0.1 mmol of auxiliary ligand and 0.1 mmol of metal salt Zn(NO3)2·6H2O, followed by 3.5 mL of MeOH and CH2Cl2 mixed solution with a volume ratio of 6:1, cover the lid, the coordination reaction at 65°C for 3 days, after the reaction is cooled to room temperature, open the cover of the system, then respectively 0.2 mmol of the first ligand 8-hydroxyquinoline derivatives and 0.1 mL of triethylamine, cover the lid again, at 80°C for 3 days, after cooling and standing for 48 h, the target product of yellow block crystal is obtained; The 8-hydroxyquinoline derivative is 5,7-diiodo-8-hydroxyquinoline, 5,7-dichloro-8-hydroxyquinoline, 5-chloro-7-iodo-8-hydroxyquinoline, 5,7-dibromo-8-hydroxyquinoline or 5-chloro-8-hydroxyquinoline; The auxiliary ligand is 4,4'-dimethoxy-2,2'-bipyridine, 4,4-di-tert-butyl-2,2-bipyridine, 5 5'-dimethyl-2,2-bipyridine, 2,2-bipyridine or 4,4'-dimethyl-2,2'-bipyridine.

3. The use of the 8-hydroxyquinoline anticancer zinc (II) complex of claim 1 in the preparation of a drug for targeted treatment of drug-resistant strains of ovarian cancer, characterized in that, The drug-resistant strain is SK-OV-3CR.

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