8-hydroxyquinoline-n-oxide zinc complex, preparation method and application thereof

Abstract

The application discloses an 8-hydroxyquinoline-N-oxide zinc 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 zinc 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 zinc 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 zinc 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 zinc 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 zinc 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 zinc 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 zinc 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 zinc 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 zinc complex and a preparation method thereof, and belongs to the technical field of medicines, and solves

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 zinc complex and a preparation method thereof. BACKGROUND

[0002] Cancer threatens human health, and the cases of the disease are rising sharply at present, and the mortality rate cannot be ignored. Due to the side effects and drug resistance in the clinical use of platinum, the design of targeted and low-toxicity non-platinum drugs is also a hot topic at present.

[0003] In addition, the literature reports that the novel 8-hydroxyquinoline-N-oxide rare earth metal complex has good anti-cancer activity on A549 / DDP tumor cells, and has very low toxicity to normal cells HL-7702, which indicates that the 8-hydroxyquinoline-N-oxide rare earth metal complex has tumor targeting on A549 / DDP tumor cells; however, the anti-cancer activity of the novel 8-hydroxyquinoline-N-oxide metal complex on ovarian cancer cell drug-resistant strains is still lacking in the literature, and the synthesis and anti-cancer activity of the 8-hydroxyquinoline-N-oxide zinc complex have not been reported in the literature. SUMMARY

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

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

[0006] The third purpose of the present application is to provide an application of the 8-hydroxyquinoline-N-oxide zinc complex in preparing an anti-tumor drug.

[0007] The first purpose of the present application is achieved by the following technical scheme: a 8-hydroxyquinoline-N-oxide zinc 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 zinc complex, comprising the following steps:

[0010] (1) mixing an active ligand, zinc chloride, methanol, triethylamine, dichloromethane and an auxiliary ligand; the active ligand is 8-hydroxyquinoline-N-oxide; and the auxiliary ligand is 4,4'-dimethyl-2,2'-bipyridine, 1,10-phenanthroline, 2,2-bipyridine, 5,5'-dimethyl-2,2'-bipyridine, 4,4-dimethoxy-2,2-bipyridine, 5-chloro-1,10-phenanthroline or red phenanthroline;

[0011] (2) The obtained mixed solution is subjected to coordination reaction at 75-80°C 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 and zinc chloride in step (1) is 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 time of step (2) is 3 days.

[0016] Further, the reaction temperature of step (2) is 80°C.

[0017] The third object of the present application is achieved by the use of 8-hydroxyquinoline-N-oxide zinc complex in the preparation of an antitumor drug.

[0018] The chemical formula (NQZn1-NQZn7) of the 8-hydroxyquinoline-N-oxide zinc complex of the present application is [Zn(ONQ)(QD5)Cl] (NQZn1), [Zn(ONQ)(QD3)Cl] (NQZn2), [Zn(ONQ)(QD1)Cl] (NQZn3), [Zn(ONQ)(QD4)Cl] (NQZn4), [Zn(ONQ)(QD6)Cl] (NQZn5), [Zn(ONQ)(QD7)Cl] (NQZn6) and [Zn(ONQ)(QD2)Cl] (NQZn7), and the chemical structural formula is as shown in Figure 1

[0019] Advantages

[0020] ​Compared with the prior art, the present invention has the following advantages: The present invention provides seven novel 8-hydroxyquinoline-N-oxide zinc complexes (NQZn1-NQZn7) namely [Zn(ONQ)(QD5)Cl](NQZn1), [Zn(ONQ)(QD3)Cl](NQZn2), [Zn(ONQ)(QD1)Cl](NQZn3), [Zn(ONQ)(QD4)Cl](NQZn4), [Zn(ONQ)(QD6)Cl](NQZn5), [Zn(ONQ)(QD7)Cl](NQZn6) and [Zn(ONQ)(QD2)Cl](NQZn7), as well as their preparation methods and applications; and the activity and toxicity of these seven zinc complexes against human ovarian cancer drug-resistant cell line SK-OV-3 / DDP and normal HL-7702 cells were investigated. Experimental results showed that the complexes NQZn1-NQZn7 had a good inhibitory effect on SK-OV-3 / DDP, with an IC50 concentration of 100 mg / L. 50 Values ​​ranged from 0.47 to 11.67 μM, with NQZn6 showing the best inhibitory effect on SK-OV-3 / DDP, and IC50 value being 0.47-11.67 μM. 50 The value was 0.47±0.09 μM, significantly higher than that of QD1-QD7 and the clinical drug cisplatin. Furthermore, NQZn1-NQZn7 exhibited very low toxicity to normal HL-7702 cells (>50 μM), indicating that NQZn1-NQZn7 showed good selectivity for SK-OV-3 / DDP tumor cells and overcame drug resistance in clinical trials. The novel 8-hydroxyquinoline-N-oxide zinc complex NQZn1-NQZn7 demonstrated superior anticancer activity and has potential pharmaceutical value, holding promise for the preparation of various antitumor drugs. Attached Figure Description

[0021] Figure 1 The chemical structural formulas of the target complexes NQZn1-NQZn7 of this invention are shown below;

[0022] Figure 2 This is a synthetic route diagram of the present invention;

[0023] Figure 3 This is a single-crystal structure diagram of NQZn1 of the present invention;

[0024] Figure 4 This is a single-crystal structure diagram of NQZn2 according to the present invention;

[0025] Figure 5 This is a single-crystal structure diagram of NQZn3 of the present invention;

[0026] Figure 6 This is a single-crystal structure diagram of NQZn4 according to the present invention;

[0027] Figure 7 This is a single-crystal structure diagram of NQZn5 of the present invention;

[0028] Figure 8 A single crystal structure diagram of NQZn6 of the present application;

[0029] Figure 9 A single crystal structure diagram of NQZn7 of the present application. DETAILED DESCRIPTION

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

[0031] Example 1

[0032] (1) The active ligand, zinc chloride, methanol, triethylamine, dichloromethane and auxiliary ligand are mixed to obtain a mixed solution; the active ligand is 8-hydroxyquinoline-N-oxide (H-ONQ); the auxiliary ligand is 4,4'-dimethyl-2,2'-bipyridine (QD1), 1,10-phenanthroline (QD2), 2,2-bipyridine (QD3), 5,5'-dimethyl-2,2'-bipyridine (QD4), 4,4-dimethoxy-2,2-bipyridine (QD5), 5-chloro-1,10-phenanthroline (QD6) or red phenanthroline (QD7).

[0033] Specifically, first, 1.0 mmol of zinc chloride, 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 thick-walled high-temperature pressure tubes; second, 1.0 mmol of auxiliary ligand (QD1-QD7) is added to each of the pressure tubes to obtain the corresponding mixed solution.

[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 zinc; if no triethylamine is added, the system does not react after three days; if the amount of triethylamine added exceeds 0.2 mL, there are too many solids in the solution, which leads to low dissolution of raw materials, low yield, and too many solids precipitated, which are difficult to separate from the raw materials.

[0036] (2) The lid of the pressure tube is tightly closed, and the coordination reaction is carried out at 75-80℃.

[0037] Specifically, the optimal reaction temperature for the coordination reaction is 80℃, if the reaction temperature is lower than 80℃, the yield is much lower, the raw materials are difficult to separate from the product; if the reaction temperature is higher than 80℃, the product is easy to be paste.

[0038] (3) After the reaction is completed, the target complexes NQZn1, NQZn2, NQZn3, NQZn4, NQZn5, NQZn6, NQZn7 in the form of yellow block crystals can be obtained after cooling to room temperature, with a yield of 65.5%-89.4%.

[0039] The obtained complexes NQZn1-NQZn7 are identified:

[0040] (1) The single crystal structure diagram of the complexes NQZn1-NQZn7 is as shown in Figures 3-9 .

[0041] (2) The infrared spectrum of the complexes NQZn1-NQZn7.

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

[0043] The data of the complex NQZn1: yield 65.5%; IR (KBr): 3435, 3113, 3066, 2999, 2983, 2950, 2844, 1601, 1583, 1563, 1497, 1477, 1457, 1434, 1412, 1384, 1361, 1351, 1334, 1314, 1306, 1283, 1262, 1248, 1229, 1218, 1193, 1157, 1095, 1061, 1035, 1005, 919, 881, 863, 840, 816, 786, 740, 702, 635, 614, 580, 524, 505, 474, 434, 413 cm -1 .

[0044] The data of the complex NQZn2: yield 70.9%; IR (KBr): 3432, 3104, 3053, 3031, 1605, 1596, 1583, 1566, 1509, 1492, 1475, 1456, 1443, 1422, 1387, 1348, 1315, 1305, 1286, 1266, 1252, 1221, 1205, 1189, 1173, 1165, 1151, 1116, 1092, 1056, 1038, 1022, 978, 878, 818, 814, 785, 764, 754, 736, 697, 652, 638, 630, 621, 579, 568, 524, 498, 419 cm -1 .

[0045] Data for complex NQZn3: yield 86.2%; IR (KBr): 3437, 3104, 3057, 3041, 2955, 1612, 1580, 1565, 1506, 1485, 1453, 1414, 1387, 1350, 1302, 1292, 1248, 1220, 1190, 1173, 1162, 1127, 1114, 1084, 1055, 1036, 1021, 992, 972, 919, 891, 822, 785, 753, 741, 731, 696, 669, 639, 621, 576, 554, 543, 517, 497, 445, 418 cm -1 .

[0046] Data for complex NQZn4: yield 88.8%; IR (KBr): 3429, 3072, 3058, 2996, 2914, 1598, 1579, 1564, 1504, 1476, 1455, 1419, 1387, 1349, 1306, 1232, 1246, 1202, 1189, 1158, 1135, 1089, 1054, 1045, 1035, 949, 893, 846, 828, 812, 786, 757, 733, 697, 650, 622, 579, 566, 536, 522, 501, 481, 413 cm -1 .

[0047] Data for complex NQZn5: yield 73.9%; IR (KBr): 3413, 3056, 1990, 1804, 1709, 1610, 1603, 1579, 1565, 1517, 1484, 1454, 1425, 1386, 1349, 1339, 1305, 1260, 1205, 1182, 1149, 1112, 1090, 1054, 1038, 990, 957, 905, 890, 875, 819, 785, 748, 732, 698, 667, 642, 617, 575, 525, 500, 471, 427, 405 cm -1 .

[0048] Data of complex NQZn6: yield 82.0%; IR (KBr): 3488, 3088, 1618, 1564, 1521, 1494, 1455, 1428, 1421, 1387, 1347, 1305, 1282, 1270, 1262, 1235, 1212, 1192, 1093, 1077, 1056, 1042, 1028, 1006, 877, 862, 841, 817, 786, 772, 739, 707, 665, 631, 616, 596, 576, 549, 523, 516, 502, 480, 461, 454, 446, 435, 427, 419 cm -1 .

[0049] Data of complex NQZn7: yield 89.4%; IR (KBr): 3427, 3053, 2990, 1625, 1580, 1564, 1516, 1496, 1454, 1425, 1386, 1349, 1306, 1300, 1225, 1200, 1175, 1166, 1153, 1139, 1105, 1055, 1037, 954, 869, 852, 840, 821, 785, 772, 763, 748, 722, 695, 641, 619, 569, 522, 436, 426, 411 cm -1 .

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

[0051] Table 1. Elemental analysis results of compounds NQZn1-NQZn7 in the examples

[0052]

[0053] Therefore, it can be determined that the target product of the obtained yellow block crystal is the complex NQZn1-NQZn7, the structural formula of which is shown in Figure 1 .

[0054] In order to fully illustrate the application of the novel 8-hydroxyquinoline-N-oxide zinc complex 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 lines were cultured in RPMI-1640 medium containing 100 U / mL penicillin, 10 wt% calf blood, 100 U / mL streptomycin, and incubated at 37°C in a 5% CO2 incubator.

[0058] 2. Preparation of test compounds

[0059] All compounds used should be ≥95.0% pure, and their DMSO stock solutions were diluted with 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 at this concentration was tested.

[0060] 3. Cell growth inhibition experiment

[0061] (1) The cells were digested, counted, and prepared into a cell suspension with a concentration of 8 x 10 4 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 incubated in a 37°C, 5% CO2 incubator for 24 h;

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

[0064] (4) The 96-well cell culture plate was incubated in a 37°C, 5% CO2 incubator 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 marker, 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 test compound on the selected cell lines were calculated by Bliss method, respectively. The results are shown in Table 2 below.

[0072] Table 2. IC50 of compounds NQZn1-NQZn7 for various cell lines 50 Value (μM)

[0073]

[0074] From Table 2 IC 50 Based on the activity screening results, the complexes NQZn1-NQZn7 showed better anticancer activity against SK-OV-3 / DDP than the ligands H-ONQ, QD1-QD7, and the metal salt ZnCl2, demonstrating the synergistic effect of the ligands and metal Zn. Furthermore, NQZn6 exhibited the best inhibitory effect on SK-OV-3 / DDP, with an IC50 value of [missing value]. 50 The value was 0.47±0.09 μM, significantly higher than that of NQZn1-NQZn5, H-ONQ, NQZn7, ZnCl2, QD1-QD7, and the clinical drug cisplatin. The 8-hydroxyquinoline zinc complex reported in the literature exhibited the best IC50 activity against SK-OV-3 / DDP antitumor activity. 50 The effective value was 2.25±0.13 μM, while that of NQZn6 was 0.47±0.09 μM, which is superior to the anticancer activity reported in the literature. Furthermore, NQZn1-NQZn7 showed very low toxicity to normal HL-7702 cells (>50 μM), indicating that NQZn1-NQZn7 has good selectivity for SK-OV-3 / DDP tumor cells and overcomes drug resistance in clinical trials. In conclusion, the 8-hydroxyquinoline-N-oxide zinc complex NQZn1-NQZn7 exhibits superior anticancer activity and tumor selectivity, possessing potential pharmaceutical value and promising applications in the preparation of various anticancer drugs.

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

Claims

1. An 8-hydroxyquinoline-N-oxide zinc complex, characterized by, The chemical structural formula is shown as follows: 。 2. The method for preparing the 8-hydroxyquinoline-N-oxide zinc complex according to claim 1, characterized in that, The method comprises the following steps: (1) mixing an active ligand, zinc chloride, methanol, triethylamine, dichloromethane and an auxiliary ligand; the active ligand is 8-hydroxyquinoline-N-oxide; the auxiliary ligand is 4,4'-dimethyl-2,2'-bipyridine, 1,10-phenanthroline, 2,2-bipyridine, 5,5'-dimethyl-2,2'-bipyridine, 4,4-dimethoxy-2,2-bipyridine, 5-chloro-1,10-phenanthroline or red phenanthroline; (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 method for preparing the 8-hydroxyquinoline-N-oxide zinc complex according to claim 2, characterized in that, The mass ratio of the active ligand, the auxiliary ligand and zinc chloride in step (1) is 1:1:

1.

4. The method for preparing the 8-hydroxyquinoline-N-oxide zinc complex according to claim 2, characterized in that, 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.

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

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

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

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