8-hydroxyquinoline-n-oxide copper(ii) complex, method of preparation and use

Abstract

The application discloses an 8-hydroxyquinoline-N-oxide copper (II) complex and a preparation method thereof, and belongs to the technical field of medicines, and solves the technical problem of drug resistance in the use process of existing platinum drugs. 50 The application discloses an 8-hydroxyquinoline-N-oxide copper (II) complex and a preparation method thereof, and belongs to the technical field of medicines, and solves the technical problem of drug resistance in the use process of existing platinum drugs. The application discloses an 8-hydroxyquinoline-N-oxide copper (II) complex and a preparation method thereof, and belongs to the technical field of medicines, and solves the technical problem of drug resistance in the use process of existing platinum drugs. The application discloses an 8-hydroxyquinoline-N-oxide copper (II) complex and a preparation method thereof, and belongs to the technical field of medicines, and solves the technical problem of drug resistance in the use process of existing platinum drugs. The application discloses an 8-hydroxyquinoline-N-oxide copper (II) complex and a preparation method thereof, and belongs to the technical field of medicines, and solves the technical problem of drug resistance in the use process of existing platinum drugs. The application discloses an 8-hydroxyquinoline-N-oxide copper (II) complex and a preparation method thereof, and belongs to the technical field of medicines, and solves the technical problem of drug resistance in the use process of existing platinum drugs. The application discloses an 8-hydroxyquinoline-N-oxide copper (II) complex and a preparation method thereof, and belongs to the technical field of medicines, and solves the technical problem of drug resistance in the use process of existing platinum drugs. The application discloses an 8-hydroxyquinoline-N-oxide copper (II) complex and a preparation method thereof, and belongs to the technical field of medicines, and solves the technical problem of drug resistance in the use process of existing platinum drugs. The application discloses an 8-hydroxyquinoline-N-oxide copper (II) complex and a preparation method thereof, and belongs to the technical field of medicines, and solves the technical problem of drug resistance in the use process of existing platinum drugs. The application discloses an 8-hydroxyquinoline-N-oxide copper (II) complex and a preparation method thereof, and belongs to the technical field of medicines, and solves the technical problem of

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, more particularly, it relates to a novel 8-hydroxyquinoline-N-oxide copper (II) complex and a preparation method thereof. BACKGROUND

[0002] The incidence of cancer is increasing year by year, and patients urgently need drugs with better efficacy and lower toxicity for treatment. However, the currently used clinical drug cisplatin and platinum drugs have great toxicity, which limits their use in cancer treatment, so it is necessary to develop a series of anticancer drugs with good selectivity and high efficiency.

[0003] In addition, the literature reports that the 8-hydroxyquinoline zinc complex has obvious inhibitory effect on SK-OV-3 / DDP tumor cells, and the IC 50 value is 2.25±0.13 μM, and from the current research, 8-hydroxyquinoline-N-oxide is active, and there are few metal anticancer complexes synthesized therefrom, except for rare earth metal complexes, and no related reports on other metal complexes. SUMMARY

[0004] One of the purposes of the present application is to provide a 8-hydroxyquinoline-N-oxide copper (II) complex.

[0005] The second purpose of the present application is to provide a preparation method of the 8-hydroxyquinoline-N-oxide copper (II) complex.

[0006] The third purpose of the present application is to provide an application of the 8-hydroxyquinoline-N-oxide copper (II) complex in preparing an antitumor drug.

[0007] The first purpose of the present application is achieved by the following technical scheme: a 8-hydroxyquinoline-N-oxide copper (II) complex, the chemical structural formula of which is as follows:

[0008]

[0009] The second purpose of the present application is achieved by the following technical scheme: a preparation method of the 8-hydroxyquinoline-N-oxide copper (II) complex, comprising the following steps:

[0010] (1) mixing an active ligand, an auxiliary ligand, methanol, triethylamine, dichloromethane, Cu(NO3)2·3H2O or CuCl2·2H2O; the active ligand is 8-hydroxyquinoline-N-oxide; the auxiliary ligand is 4,4'-dimethyl-2,2'-dipyridyl, 1,10-phenanthroline, 2,2-dipyridyl or 5,5'-dimethyl-2,2'-dipyridyl;

[0011] (2) The obtained mixed solution is subjected to coordination reaction at 75-80℃ under sealed condition.

[0012] (3) After the reaction is completed, the solution is cooled to room temperature.

[0013] As a further improvement, the molar ratio of the active ligand, the auxiliary ligand, Cu(NO3)2·3H2O and CuCl2·2H2O in step (1) is 1:1:1:1.

[0014] Further, the amount of methanol used in step (1) is 1.5 mL, the amount of triethylamine used is 0.2 mL, and the amount of dichloromethane used is 0.3 mL.

[0015] Further, the reaction temperature of step (2) is 80℃.

[0016] Further, the reaction time of step (2) is 3 days.

[0017] The third object of the present application is achieved by the use of 8-hydroxyquinoline-N-oxide copper (II) complexes in the preparation of antitumor drugs.

[0018] The chemical formula of the 8-hydroxyquinoline-N-oxide copper (II) complexes (NQCu1-NQCu7) of the present application is [Cu(ONQ)(QD1)(NO3)] (NQCu1), [Cu(ONQ)(QD2)(NO3)] (NQCu2), [Cu(ONQ)(QD3)(NO3)]·CH3OH (NQCu3), [Cu(ONQ)(QD4)(NO3)] (NQCu4), [Cu(NQ)(QD4)Cl] (NQCu5), [Cu(ONQ)(QD3)Cl] (NQCu6) and [Cu(ONQ)(QD2)Cl] (NQCu7), and the chemical structural formula is as shown in Figure 1

[0019] Advantages

[0020] ​The application has the advantages that the application provides seven novel 8-hydroxyquinoline-N-oxide copper (II) complexes [Cu(ONQ)(QD1)(NO3)] (NQCu1), [Cu(ONQ)(QD2)(NO3)] (NQCu2), [Cu(ONQ)(QD3)(NO3)]·CH3OH (NQCu3), [Cu(ONQ)(QD4)(NO3)] (NQCu4), [Cu(NQ)(QD4)Cl] (NQCu5), [Cu(ONQ)(QD3)Cl] (NQCu6) and [Cu(ONQ)(QD2)Cl] (NQCu7), and a preparation method and application thereof, and the activity and toxicity experiments of the complexes on human ovarian cancer drug-resistant strain cells SK-OV-3 / DDP and normal HL-7702 cells are investigated. 50 The experimental results show that the complexes NQCu1-NQCu7 have good inhibition effects on the ovarian cancer drug-resistant strain cells SK-OV-3 / DDP, the IC 50 values are 0.17-4.23 μM, especially the inhibition effect of NQCu7 is the most obvious, the IC values are 0.17±0.05 μM, far greater than QD1-QD4 and the clinical drug cisplatin (IC50 value > 50 μM), and the toxicity on the normal HL-7702 cells is very small, which indicates that the complexes have tumor selectivity on the tumor cells SK-OV-3 / DDP and overcome the drug resistance of the clinical drug. The novel 8-hydroxyquinoline-N-oxide copper (II) complexes NQCu1-NQCu7 have superior antitumor activity, have potential medicinal value, and are expected to be used for the preparation of various antitumor drugs. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 The structural formulae of NQCu1-NQCu7 are target products of the application;

[0022] Figure 2 The synthetic route map of the application is shown in the following figure:

[0023] Figure 3 The single crystal structure diagram of NQCu1 of the application is shown in the following figure:

[0024] Figure 4 The single crystal structure diagram of NQCu2 of the application is shown in the following figure:

[0025] Figure 5 The single crystal structure diagram of NQCu3 of the application is shown in the following figure:

[0026] Figure 6 The single crystal structure diagram of NQCu4 of the application is shown in the following figure:

[0027] Figure 7 The single crystal structure diagram of NQCu5 of the application is shown in the following figure:

[0028] Figure 8 A single crystal structure diagram of NQCu6 of the present application;

[0029] Figure 9 A single crystal structure diagram of NQCu7 of the present application. DETAILED DESCRIPTION

[0030] The present application will be further described below in connection with specific embodiments in the accompanying drawings.

[0031] Example 1

[0032] (1) The active ligand, auxiliary ligand, methanol, triethylamine, dichloromethane, Cu(NO3)2·3H2O or CuCl2·2H2O are mixed; the active ligand is 8-hydroxyquinoline-N-oxide; the auxiliary ligand is 4,4'-dimethyl-2,2'-bipyridine (QD1), 1,10-phenanthroline (QD2), 2,2-bipyridine (QD3) or 5,5'-dimethyl-2,2'-bipyridine (QD4).

[0033] Specifically, first, 1.5 mL of methanol, 0.2 mL of triethylamine, 0.3 mL of dichloromethane and 1.0 mmol of active ligand are added to each of the 7 15 mL thick-walled high-temperature pressure tubes; second, 1.0 mmol of Cu(NO3)2·3H2O is added to each of 4 of the pressure tubes, and 1.0 mmol of CuCl2·2H2O is added to each of the remaining 3 pressure tubes; finally, 1.0 mmol of auxiliary ligand (QD1-QD4) is added to each of the 4 pressure tubes, and 1.0 mmol of auxiliary ligand (QD2-QD4) is added to each of the 3 pressure tubes, to obtain the corresponding mixed solutions.

[0034] Specifically, the reaction system should be methanol, if ethanol or acetonitrile or acetone or water is used instead, the reaction time needs to be increased by 3 times to complete the reaction, and the cost consumption is large.

[0035] Specifically, 0.2 mL of triethylamine must be contained in the reaction, if the amount of triethylamine is less than 0.2 mL, it is difficult for the hydroxyl group of the active ligand to be removed and react with copper; if no triethylamine is added, the system does not react after 3 days; if the amount of triethylamine added exceeds 0.2 mL, there is too much solid in the solution, which leads to low dissolution of raw materials, low yield, and too much solid precipitated, which is difficult to separate from the raw materials.

[0036] (2) The mixed solution obtained is subjected to coordination reaction at 75-80°C under sealed conditions.

[0037] Specifically, the reaction temperature of the coordination reaction is preferably 80°C. If the reaction temperature is lower than 80°C, the yield is low and the raw material is difficult to separate. If the reaction temperature is higher than 80°C, the product is easy to paste.

[0038] (3) After the reaction is completed and cooled to room temperature, the target complex NQCu1, NQCu2, NQCu3, NQCu4, NQCu5, NQCu6, NQCu7 of dark green block crystal can be obtained, and the yield is 61.2%-92.5%.

[0039] The obtained complexes NQCu1-NQCu7 are identified:

[0040] (1) The single crystal structure diagram of the complexes NQCu1-NQCu7 is shown in Figures 3-9 .

[0041] (2) The infrared spectrum of the complexes NQCu1-NQCu7.

[0042] Specifically, the infrared spectrum data of each complex is as follows:

[0043] The data of the complex NQCu1: the yield is 77.0%; IR (KBr): 3418, 3044, 1623, 1617, 1568, 1511, 1489, 1456, 1385, 1352, 1303, 1290, 1249, 1199, 1056, 1038, 1030, 834, 821, 743, 563, 516, 510 cm -1 .

[0044] The data of the complex NQCu2: the yield is 85.4%; IR (KBr): 3435, 3048, 3009, 1627, 1568, 1516, 1455, 1430, 1386, 1328, 1228, 1169, 1153, 1137, 874, 858, 823, 788, 752, 725, 713, 649, 635, 614, 600, 510, 429 cm -1 .

[0045] The data of the complex NQCu3: the yield is 92.5%; IR (KBr): 3550, 3110, 3077, 3052, 3034, 1603, 1568, 1510, 1498, 1474, 1456, 1446, 1385, 1348, 1335, 1321, 1166, 1155, 1053, 1033, 1022, 820, 788, 779, 749, 732, 714, 661, 650, 642, 635, 599, 578, 510, 423 cm -1 .

[0046] Data for complex NQCu4: yield 61.2%; IR (KBr): 3436, 3044, 1603, 1582, 1563, 1507, 1480, 1454, 1423, 1385, 1351, 1328, 1309, 1296, 1255, 1232, 1194, 1162, 1092, 1055, 1050, 1037, 858, 828, 785, 751, 727, 714, 661, 653, 634, 614, 599, 579, 536, 508, 484, 422 cm -1 .

[0047] Data for complex NQCu5: yield 70.6%; IR (KBr): 3438, 3053, 1635, 1608, 1562, 1505, 1474, 1455, 1421, 1389, 1351, 1306, 1242, 1225, 1206, 1196, 1175, 1158, 1148, 1136, 1050, 1035, 948, 846, 833, 827, 788, 758, 730, 711, 698, 658, 652, 641, 617, 596, 579, 550, 534, 508, 487, 462, 433, 419 cm -1 .

[0048] Data for complex NQCu6: yield 90.0%; IR (KBr): 3277, 3106, 3075, 3048, 3034, 2983, 2931, 2819, 1602, 1566, 1509, 1495, 1472, 1453, 1445, 1386, 1347, 1309, 1300, 1253, 1229, 1210, 1195, 1168, 1129, 1107, 1053, 1039, 1032, 986, 816, 786, 776, 746, 732, 710, 661, 652, 638, 615, 595, 577, 535, 508, 421 cm -1 .

[0049] Data of complex NQCu7: yield 87.1%; IR (KBr): 3427, 3045, 3004, 1627, 1584, 1567, 1518, 1510, 1454, 1427, 1387, 1347, 1311, 1301, 1227, 1195, 1169, 1151, 1128, 1054, 1039, 1028, 987, 906, 874, 854, 820, 787, 749, 737, 709, 649, 637, 616, 595, 574, 535, 508, 472, 445, 432, 419 cm -1 .

[0050] (3) Elemental analysis results, as shown in Table 1.

[0051] Table 1. Elemental analysis results of compounds NQCu1-NQCu7 in the examples

[0052]

[0053] Therefore, the target products NQCu1-NQCu7 of the obtained dark green block crystals can be determined, and the structural formulae thereof are as shown in Figure 1 .

[0054] In order to fully illustrate the use of the seven 8-hydroxyquinoline-N-oxide copper (II) complexes NQCu1-NQCu7 described in the application in pharmacy, the applicant has carried out in-vivo and in-vitro anti-tumor activity experiments.

[0055] 1. Cell strains and cell culture

[0056] In this experiment, two human cell strains, human ovarian cancer drug-resistant strain cell SK-OV-3 / DDP and normal HL-7702 cells, were selected.

[0057] All human cell strains were cultured in RPMI-1640 culture solution containing 100 U / mL penicillin, 10 wt% calf blood and 100 U / mL streptomycin, and were placed in a 37°C incubator containing 5% CO2 by volume.

[0058] 2. Preparation of the tested compounds

[0059] The purity of all the compounds used needs to be ≥95.0%, and the DMSO stock solution thereof is diluted with a physiological buffer to a final solution of 20 μmol / L (the final concentration of DMSO ≤1%), and the degree of inhibition of the growth of normal cells or selected tumor cells by each compound at this concentration is tested.

[0060] 3. Cell growth inhibition experiment

[0061] (1) Cell digestion, counting and preparation into a solution with a concentration of 8 x 104 A cell suspension of 1 x 105cells / mL was prepared, and 100 μL of the cell suspension was added to each well of a 96-well cell culture plate;

[0062] (2) The 96-well cell culture plate was placed in a 37°C, 5% CO2incubator for 24 h;

[0063] (3) The drug was diluted with complete culture medium to the desired concentration, and 100 μL of the corresponding drug-containing culture medium was added to each well, while a negative control group was set up;

[0064] (4) The 96-well cell culture plate was placed in a 37°C, 5% CO2incubator for 48 h;

[0065] (5) The 96-well plate was subjected to CCK-8 staining, λ = 450 nm, and the OD value was measured;

[0066] i) 10 μL of CCK-8 was added to each well, and incubation in the incubator was continued for 2 h;

[0067] ii) The mixture was gently mixed on a shaker for 10 min;

[0068] iii) λ = 450 nm, and the OD value of each well was read on an enzyme-labeled instrument, and the inhibition rate was calculated;

[0069] iv) The number of living cells was determined according to the measured optical density value (OD value), and the greater the OD value, the stronger the cell activity. The formula:

[0070]

[0071] The inhibition rate of each compound on the growth of the selected cells was calculated, and the IC 50 values of each tested compound on the selected cells were calculated by Bliss method. The results are shown in Table 2 below.

[0072] Table 2. IC 50 values (μM) of compounds NQCu1-NQCu7 on various cell lines

[0073]

[0074] From the IC 50 activity screening results, NQCu1-NQCu7 had a stronger inhibitory effect on SK-OV-3 / DDP tumor cells than the ligand H-ONQ, QD1-QD4, and metal salts Cu(NO3)2·3H2O and CuCl2·2H2O, which reflected the synergistic effect of the ligand and copper ions; in addition, NQCu7 had the best inhibitory effect on SK-OV-3 / DDP, with an IC 50The value is 0.17±0.05 μM, which is much greater than NQCu1-NQCu6, H-ONQ, Cu(NO3)2·3H2O, CuCl2·2H2O, QD1-QD4 and the clinical drug cisplatin. It is worth noting that NQCu1-NQCu7 has little toxicity (>50 μM) to normal HL-7702 cells, indicating that NQCu1-NQCu7 has good selectivity to SK-OV-3 / DDP tumor cells and can overcome the drug resistance of clinical drugs. In summary, 8-hydroxyquinoline-N-oxide zinc complexes NQCu1-NQCu7 exhibit superior anticancer activity, have potential pharmaceutical value, and are expected to be used in the preparation of various anticancer drugs.

[0075] The above merely describes the preferred embodiments of the present application, and it should be noted that those skilled in the art can make several modifications and improvements without departing from the structure of the present application, and these will not affect the effect of the implementation of the present application and the practicality of the patent.

Claims

1. A copper (II) complex of 8-hydroxyquinoline-N-oxide, characterized in that, The chemical structural formula is shown in the following formula: 。 2. The process for the preparation of a copper (II) complex of 8-hydroxyquinoline-N-oxide according to claim 1, characterized in that, The method comprises the following steps: (1) mixing an active ligand, an auxiliary ligand, methanol, triethylamine, dichloromethane, Cu(NO3)2·3H2O or CuCl2·2H2O; the active ligand is 8-hydroxyquinoline-N-oxide; the auxiliary ligand is 4,4'-dimethyl-2,2'-bipyridine, 1,10-phenanthroline, 2,2-bipyridine or 5,5'-dimethyl-2,2'-bipyridine; (2) performing a coordination reaction on the obtained mixed solution under a sealed condition at 75-80 DEG C; (3) after the reaction is completed, cooling to room temperature.

3. The process for the preparation of a copper (II) complex of 8-hydroxyquinoline-N-oxide according to claim 2, characterized in that, The molar ratio of the active ligand, the auxiliary ligand, Cu(NO3)2·3H2O and CuCl2·2H2O in the step (1) is 1:1:1:

1.

4. The method for preparing the 8-hydroxyquinoline-N-oxide copper(II) complex according to claim 2, characterized in that, The amount of methanol used in the step (1) is 1.5 mL, the amount of triethylamine used is 0.2 mL, and the amount of dichloromethane used is 0.3 mL.

5. The method for preparing the 8-hydroxyquinoline-N-oxide copper(II) complex according to claim 2, characterized in that, The reaction temperature of the step (2) is 80 DEG C.

6. The method for preparing the 8-hydroxyquinoline-N-oxide copper(II) complex according to claim 2, characterized in that, The reaction time of the step (2) is 3 days.

7. Use of the 8-hydroxyquinoline-N-oxide copper (II) complex according to claim 1 for the preparation of a medicament for the treatment of a drug-resistant strain of ovarian cancer, characterized in that, The drug-resistant strain is SK-OV-3CR / DDP.

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