8-hydroxyquinoline binuclear calcium complex as well as preparation method and application thereof

Abstract

The invention discloses an 8-hydroxyquinoline binuclear calcium complex as well as a preparation method and application thereof. According to the invention, an 8-hydroxyquinoline derivative is used as a main ligand, 4, 7-diphenyl-1, 10-phenanthroline and 1, 10-phenanthroline are used as auxiliary ligands, and the main ligand and the auxiliary ligands react with Ca (NO3) 2.4 H2O to synthesize the 8-hydroxyquinoline binuclear calcium complex. Compared with human ovarian SK-OV-3 cancer cells, the 8-hydroxyquinoline binuclear calcium complex has a good anti-cancer effect on the SK-OV-3 / DDP cancer cells and almost has no toxicity on normal HL-7702 cells, it is indicated that the 8-hydroxyquinoline binuclear calcium complex can inhibit proliferation of the SK-OV-3 / DDP cancer cells in a targeted mode, shows excellent anti-tumor activity and has potential medicinal value, and the 8-hydroxyquinoline binuclear calcium complex has good application prospects. The compound is expected to be used for preparing various anti-tumor drugs.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to 8-hydroxyquinoline binuclear calcium complexes, their preparation methods, and applications. Background Technology

[0002] Metallic calcium ions are one of the essential trace elements for the human body. Metallic calcium complexes not only have excellent anti-cancer and antibacterial activities, but also have a safety profile that is unmatched by other metals. Therefore, the design and development of calcium-targeted anti-cancer drugs is urgently needed.

[0003] In recent years, numerous studies have reported that 8-hydroxyquinoline metal complexes have shown good inhibitory effects on various cancer cells (Du LQ, Yang Y, Ruan L, et al. Insights into the antineoplastic activity and mechanisms of action of coumarin-coordinated 8-hydroxyquinoline ruthenium(II / III) compounds[J]. Journal of Inorganic Biochemistry, 2024, 259:112659.). However, research on the synthesis and anticancer properties of 8-hydroxyquinoline calcium metal complexes remains lacking. Summary of the Invention

[0004] One of the objectives of this invention is to provide an 8-hydroxyquinoline binuclear calcium complex.

[0005] The 8-hydroxyquinoline binuclear calcium complex of this invention has the chemical formula [Ca2(μ2-O)2(QM](μ2-O)2(QM)2. x )4(QH y [CaQ1, x = 1, y = 1; CaQ2, x = 2, y = 1; CaQ3, x = 3, y = 2; CaQ4, x = 2, y = 2; CaQ5, x = 4, y = 2; CaQ6, x = 1, y = 2], its chemical structural formula is shown below:

[0006]

[0007] The second objective of this invention is to provide a method for preparing 8-hydroxyquinoline binuclear calcium complexes.

[0008] The preparation method of 8-hydroxyquinoline binuclear calcium complex involves adding 4,7-diphenyl-1,10-phenanthroline (QH) to a CH3OH-DMF mixed solution. 1 ) and 1,10-phenanthroline (QH 2The reaction was carried out at 68℃ for 72 hours. After the reaction was completed, it was cooled to room temperature, and an 8-hydroxyquinoline derivative was added. The reaction was continued at 68-80℃ for 72 hours. After cooling to room temperature, it was filtered to obtain the 8-hydroxyquinoline binuclear calcium complex.

[0009] The 8-hydroxyquinoline derivative is 5,7-dibromo-8-hydroxyquinoline (H-QM) 1 ), 5,7-dichloro-8-hydroxyquinoline (H-QM) 2 ), 5,7-diiodo-8-hydroxyquinoline (H-QM) 3 ) and 5-chloro-7-iodo-8-hydroxyquinoline (H-QM) 4 ).

[0010] Its synthetic route is as follows:

[0011]

[0012] Another object of the present invention is to provide the use of 8-hydroxyquinoline binuclear calcium complexes.

[0013] Specifically, this relates to the application of the aforementioned 8-hydroxyquinoline binuclear calcium complex in the preparation of antitumor drugs; the application of the aforementioned 8-hydroxyquinoline binuclear calcium complex in the preparation of targeted therapies for ovarian adenocarcinoma; and the application of the aforementioned 8-hydroxyquinoline binuclear calcium complex in the preparation of targeted therapies for drug-resistant ovarian adenocarcinoma.

[0014] Compared with the prior art, the present invention uses 5,7-dibromo-8-hydroxyquinoline (H-QM) 1 ), 5,7-dichloro-8-hydroxyquinoline (H-QM) 2 ), 5,7-diiodo-8-hydroxyquinoline (H-QM) 3 ) and 5-chloro-7-iodo-8-hydroxyquinoline (H-QM) 4 ) as the main ligand, with 4,7-diphenyl-1,10-phenanthroline (QH) as the main ligand. 1 ) and 1,10-phenanthroline (QH 2 Using α as an auxiliary ligand, six 8-hydroxyquinoline binuclear calcium complexes were synthesized by reacting with Ca(NO3)2·4H2O, with the general chemical formula [Ca2(μ2-O)2(QM]. x )4(QH y[2](CaQ1, x = 1, y = 1; CaQ2, x = 2, y = 1; CaQ3, x = 3, y = 2; CaQ4, x = 2, y = 2; CaQ5, x = 4, y = 2; CaQ6, x = 1, y = 2), and their anticancer activity and toxicity against human ovarian SK-OV-3 cancer cells, cisplatin-resistant human ovarian adenocarcinoma SK-OV-3 / DDP cells, and normal liver HL-7702 cells were investigated. The results showed that, compared to human ovarian SK-OV-3 cancer cells, the complexes CaQ1-CaQ6 exhibited better anticancer effects against SK-OV-3 / DDP cancer cells, with an IC50 value of [missing value]. 50 The values ​​were 3.59±0.67, 2.73±0.25, 8.11±0.50, 4.56±0.21, 5.99±0.31, and 6.48±0.69 μM, respectively, and their activity was much greater than that of H-QM. 1 -H-QM 4 QH 1 Clinical drugs cisplatin, QH 2 The six 8-hydroxyquinoline binuclear calcium complexes, CaQ1-CaQ6, exhibited excellent antitumor activity and potential pharmaceutical value, and are expected to be used in the preparation of various antitumor drugs. Furthermore, they showed almost no toxicity to normal HL-7702 cells, indicating that they could target and inhibit the proliferation of SK-OV-3 / DDP cancer cells. In conclusion, the six 8-hydroxyquinoline binuclear calcium complexes, CaQ1-CaQ6, demonstrated excellent antitumor activity and have potential pharmaceutical value, and are expected to be used in the preparation of various antitumor drugs. Attached Figure Description

[0015] Figure 1 The X-ray single-crystal diffraction pattern of the complex CaQ1 obtained in Example 1 of this invention;

[0016] Figure 2 The X-ray single-crystal diffraction pattern of the complex CaQ2 obtained in Example 1 of this invention;

[0017] Figure 3 The X-ray single-crystal diffraction pattern of the complex CaQ3 obtained in Example 1 of this invention;

[0018] Figure 4 The X-ray single-crystal diffraction pattern of the complex CaQ4 obtained in Example 1 of this invention;

[0019] Figure 5 The X-ray single-crystal diffraction pattern of the complex CaQ5 obtained in Example 1 of this invention;

[0020] Figure 6 The X-ray single-crystal diffraction pattern of the complex CaQ6 obtained in Example 1 of this invention;

[0021] Figure 7 The infrared spectrum of the complex CaQ1 obtained in Example 1 of this invention;

[0022] Figure 8 The infrared spectrum of the complex CaQ2 obtained in Example 1 of this invention;

[0023] Figure 9 The infrared spectrum of the complex CaQ3 obtained in Example 1 of this invention;

[0024] Figure 10 The infrared spectrum of the complex CaQ4 obtained in Example 1 of this invention;

[0025] Figure 11 The infrared spectrum of the complex CaQ5 obtained in Example 1 of this invention;

[0026] Figure 12 The infrared spectrum of the complex CaQ6 obtained in Example 1 of this invention is shown. Detailed Implementation

[0027] The present invention will be further described below with reference to specific embodiments, but the present invention is not limited to these embodiments.

[0028] Example 1

[0029] 0.1 mmol of 4,7-diphenyl-1,10-phenanthroline (QH) was added to a thick-walled, drug-resistant tube approximately 15.0 cm in length. 1 ) and 1,10-phenanthroline (QH 2 Then, 3.2 mL of CH3OH-DMF mixed solution (v:v, 3.0 mL / 0.2 mL) was added, the lid was closed, and the mixture was reacted at 68 °C for 72 h (6 parallel experiments were conducted). After the reaction was completed, the mixture was cooled to room temperature, and 0.2 mmol of 5,7-dibromo-8-hydroxyquinoline (H-QM) was added to different tubes. 1 ), 5,7-dichloro-8-hydroxyquinoline (H-QM) 2 ), 5,7-diiodo-8-hydroxyquinoline (H-QM) 3 ) and 5-chloro-7-iodo-8-hydroxyquinoline (H-QM) 4 The reaction proceeded at 80°C for 72 hours, with 0.1 mL of triethylamine added to each tube. After capping the tubes, the reaction was continued. The mixture was cooled to room temperature, filtered, and the yellow blocky crystals were washed with 10 mL of cold ethanol and ether, respectively. After drying, six 8-hydroxyquinoline binuclear calcium complexes, CaQ1-CaQ6, were obtained. The yields were: CaQ1 (81.2%), CaQ2 (77.7%), CaQ3 (63.4%), CaQ4 (70.1%), CaQ5 (80.0%), and CaQ6 (65.9%).

[0030] The obtained complexes CaQ1-CaQ6 were identified as follows:

[0031] (1) X-ray single-crystal diffraction pattern of the complex CaQ1-CaQ6, the spectrum is as follows: Figure 1-6 As shown.

[0032] (2) The infrared spectrum of the complex CaQ1-CaQ6 is shown in the figure below. Figure 7-12 As shown.

[0033] Data for CaQ1.Yield:81.2%.IR(KBr):3639.12,3379.96,3058.42,3032.12,1643.69,1619.27,1590.62,1579.27,1545.81,1519 .37,1482.50,1446.33,1426.10,1388.79,1375.65,1345.97,1338.94,1308.61,1282.72,1245.84,1232.99,1207.22,11 81.56,1158.95,1137.37,1098.02,1089.22,1075.57,1046.23,1031.96,931.30,866.53,853.01,831.68,805.43,790. 22,763.43,738.61,699.53,684.22,674.01,627.14,594.56,573.83,563.84,544.22,500.67,489.80,465.85,440.82cm -1 .

[0034] Data for CaQ2.Yield:77.7%.IR(KBr):3646.52,3591.64,3385.66,3060.47,2588.00,1957.30,1646.87,1619.94,1591.09,1550.05,1519.13,1488.95,1446.13,1425.55,1394.45,1377.26,1351.97,1344.02,1283.11,1247.87,1233.33 1182.09,1159.15,1140.03,1101.15,1089.07,1075.79,1047.24,1029.39,1000.96,980.71,951.72,926.45,875.22,852.72,831.62,806.50,790.88,763.39,742.58,700.01,679.61,641.84,626.60,594.92,574.14,544.61,500.89,488.82,441.20cm -1 .

[0035] Data for CaQ3.Yield:63.4%.IR(KBr):3401.71,3049.15,1955.60,1748.06,1621.82,1588.73,1571.41,1531.36,1512.23,1474.62,1452.18,1438.34,1384.03,1371.93,1344.82,1334.43,1279.80,1268.42,1246.86,1194.44,1138.83,1097.98,1043.65,980.95,950.41,919.34,883.65,877.70,860.62,842.54,806.66,790.63,766.98,732.48,717.86,672.98,647.01,631.88,586.16,552.28,500.43,479.81,458.79,448.25,431.98,422.30,406.91cm -1 .

[0036] Data for CaQ4.Yield:70.1%.IR(KBr):3409.33,3067.74,3046.04,2590.24,1749.63,1623.68,1589.41,1551.26,1513.11,1488.00,1459.96,1441.17,1421.91,1392.82,1375.37,1355.34,1343.16,1283.41,1250.80,1237.53,1218.75,1191.87,1142.75,1100.98,1084.17,1045.10,996.63,982.25,953.08,873.80,860.50,842.97,814.00,804.00,793.97,788.51,767.01,740.68,731.29,719.05,678.05,640.04,633.83,599.14,582.35,553.83,506.84,493.86,431.14,416.87cm -1 .

[0037] Data for CaQ5.Yield:80.0%.IR(KBr):3399.12,3046.50,1957.80,1727.34,1622.09,1588.94,1541.44,1511.73,1483.02,1458.19,1437.89,1387.77,1372.44,1341.02,1281.99,1247.00,1206.00,1190.35,1139.17,1097.42,1043.11,985.43,951.78,878.44,860.43,841.97,807.89,791.64,766.15,739.86,731.55,717.08,697.13,692.20,670.97,633.67,593.52,565.04,500.28,479.57,430.07,415.84cm -1 .

[0038] Data for CaQ6.Yield:65.9%.IR(KBr):3363.14,3058.93,3042.02,2920.02,1622.38,1588.85,1545.94,1511.77,1482.58,145 9.58,1444.00,1419.38,1388.95,1376.34,1345.38,1337.20,1284.87,1277.05,1247.78,1203.95,1189.85,1157.68, 1139.35,1098.62,1084.00,1043.90,994.62,981.94,951.96,932.48,882.91,868.53,858.94,852.15,841.48,804.1 0,789.47,765.33,736.67,731.45,717.14,683.92,671.20,633.69,603.94,593.46,564.42,553.86,502.67,414.89cm -1 .

[0039] (3) Elemental analysis results are shown in Table 1.

[0040] Table 1 shows the elemental analysis results of the complexes CaQ1-CaQ6 in the examples.

[0041]

[0042] Therefore, the structural formula of the resulting complex CaQ1-CaQ6 can be determined as follows:

[0043]

[0044] Example 2

[0045] 0.1 mmol of 4,7-diphenyl-1,10-phenanthroline (QH) was added to a thick-walled, drug-resistant tube approximately 15.0 cm in length. 1 ) and 1,10-phenanthroline (QH 2 Then, 3.2 mL of CH3OH-DMF mixed solution (v:v, 3.0 mL / 0.2 mL) was added, the lid was closed, and the mixture was reacted at 68 °C for 72 h (6 parallel experiments were conducted). After the reaction was completed, the mixture was cooled to room temperature, and 0.2 mmol of 5,7-dibromo-8-hydroxyquinoline (H-QM) was added to different tubes. 1 ), 5,7-dichloro-8-hydroxyquinoline (H-QM) 2 ), 5,7-diiodo-8-hydroxyquinoline (H-QM) 3) and 5-chloro-7-iodo-8-hydroxyquinoline (H-QM) 4 The reaction proceeded at 68°C for 72 hours, with 0.1 mL of triethylamine added to each tube. After capping the tubes, the reaction was continued. The mixture was then cooled to room temperature, filtered, and the yellow blocky crystals were washed with 10 mL of cold ethanol and ether, respectively. After drying, six 8-hydroxyquinoline binuclear calcium complexes, CaQ1-CaQ6, were obtained. The yields were: CaQ1 (80.0%), CaQ2 (72.0%), CaQ3 (63.6%), CaQ4 (68.1%), CaQ5 (76.2%), and CaQ6 (63.9%).

[0046] To fully illustrate the pharmaceutical applications of the six 8-hydroxyquinoline binuclear calcium complexes CaQ1-CaQ6 described in this invention, the applicant conducted antitumor activity experiments on them.

[0047] I. Experimental Study on the Inhibitory Activity of Six 8-Hydroxyquinoline Binuclear Calcium Complexes CaQ1-CaQ6 on the Proliferation of Three Human Cell Lines

[0048] 1. Cell lines and cell culture

[0049] This experiment used three human cell lines: human ovarian SK-OV-3 cancer cells, human ovarian adenocarcinoma cisplatin-resistant SK-OV-3 / DDP cells, and normal liver HL-7702 cells.

[0050] 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.

[0051] 2. Preparation of the test compound

[0052] 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.

[0053] 3. Cell growth inhibition experiment

[0054] The specific steps are as follows:

[0055] (1) Cells were digested, counted, and prepared to a concentration of 5×10⁻⁶. 4 Add 100 μL of cell suspension per well to each well of a 96-well cell culture plate and incubate at 37°C in a 5.0% CO2 incubator for 24.0 h.

[0056] (2) Dilute the drug to the required concentration with RPMI-1640 medium, add 100 μL of the corresponding drug-containing medium to each well of a 96-well plate, so that the final concentrations reach 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, place it in a 37℃, 5% CO2 incubator and continue to incubate for 48 h.

[0057] (3) Perform CCK-8 staining and measure OD values ​​at a wavelength of λ = 450 nm: Add 10 μL of CCK-8 to each well, continue incubation in an incubator for 2 h, gently mix on a shaker for 10 min, and then measure the OD value of each well at a wavelength of λ = 450 nm using an ELISA reader. Calculate the inhibition rate of each compound on the growth of the selected cell lines, and then calculate the IC50 of each tested compound on the selected cell lines using the Bliss method. 50 Values. The results are shown in Table 2 below.

[0058] Table 2. IC50 of six 8-hydroxyquinoline binuclear calcium complexes CaQ1-CaQ6 on various cell lines 50 Value (μM)

[0059]

[0060] From IC 50 Based on the activity screening results, the complex CaQ1-CaQ6 showed good anti-cancer effects against SK-OV-3 / DDP cancer cells compared to human ovarian SK-OV-3 cancer cells, with an IC50 value of [missing information]. 50 The values ​​were 3.59±0.67, 2.73±0.25, 8.11±0.50, 4.56±0.21, 5.99±0.31, and 6.48±0.69 μM, respectively, and their activity was much greater than that of H-QM. 1 -H-QM 4 QH 1 Clinical drugs cisplatin, QH 2 The six 8-hydroxyquinoline binuclear calcium complexes, CaQ1-CaQ6, exhibited excellent antitumor activity and potential pharmaceutical value, and are expected to be used in the preparation of various antitumor drugs. Furthermore, they showed almost no toxicity to normal HL-7702 cells, indicating that they could target and inhibit the proliferation of SK-OV-3 / DDP cancer cells. In conclusion, the six 8-hydroxyquinoline binuclear calcium complexes, CaQ1-CaQ6, demonstrated excellent antitumor activity and have potential pharmaceutical value, and are expected to be used in the preparation of various antitumor drugs.

Claims

1,8-Hydroxyquinoline binuclear calcium complex, characterized in that, Its chemical structural formula is as follows: A method for preparing 2,8-hydroxyquinoline binuclear calcium complexes, characterized in that, In a CH3OH-DMF mixed solution, 4,7-diphenyl-1,10-phenanthroline and 1,10-phenanthroline were added and reacted at 68 °C for 72 h. After the reaction was completed, the mixture was cooled to room temperature, and an 8-hydroxyquinoline derivative was added. The reaction was continued at 68-80 °C for 72 h. After cooling to room temperature, the mixture was filtered to obtain the 8-hydroxyquinoline binuclear calcium complex.

3. The method for preparing the 8-hydroxyquinoline binuclear calcium complex according to claim 2, characterized in that, The 8-hydroxyquinoline derivative is 5,7-dibromo-8-hydroxyquinoline, 5,7-dichloro-8-hydroxyquinoline, 5,7-diiodo-8-hydroxyquinoline, or 5-chloro-7-iodo-8-hydroxyquinoline.

4. The use of the 8-hydroxyquinoline binuclear calcium complex according to claim 1 in the preparation of antitumor drugs.

5. The use of the 8-hydroxyquinoline binuclear calcium complex according to claim 1 in the preparation of a targeted therapy for ovarian adenocarcinoma.

6. The use of the 8-hydroxyquinoline binuclear calcium complex according to claim 1 in the preparation of targeted therapy for drug-resistant ovarian adenocarcinoma.

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