5-Bromo-8-hydroxyquinoline cobalt complex with high anticancer activity, synthesis method and application thereof

Abstract

The present invention discloses a 5-bromo-8-hydroxyquinoline cobalt complex with high anticancer activity, its synthesis method and application. The present invention uses 5-bromo-8-hydroxyquinoline as an active ligand to synthesize a 5-bromo-8-hydroxyquinoline cobalt complex [Co(BrQ)3]·CH3OH with high anticancer activity, and investigates its activity and toxicity against human ovarian cancer resistant cell line SK-OV-3 / DDP and normal HL-7702 cells. The experimental results show that [Co(BrQ)3]·CH3OH has a very significant inhibitory effect on ovarian cancer resistant cell line SK-OV-3 / DDP, with IC 50 The value is as low as 0.27±0.09μM, which is much larger than H‑BrQ, CoCl2·6H2O and clinical drug cisplatin, and has low toxicity to normal HL‑7702 cells, indicating that the complex has good tumor selectivity for tumor cells.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a 5-bromo-8-hydroxyquinoline cobalt complex with high anticancer activity, a synthesis method and application thereof. Background Art

[0002] Cancer is typically treated with a variety of methods, including radiotherapy, surgery, and chemotherapy. However, surgery and radiotherapy are only important local treatments. Platinum-based chemotherapy, while inhibiting tumor cell growth, also has varying degrees of toxicity to normal cells in the body. Consequently, the development and treatment of targeted non-platinum drugs has shown promising prospects in recent years (Guo, Z.; et al. Chem. Soc. Rev., 2013, 42:202-224). However, these drugs are still in the clinical trial stage and require further observation and accumulation before they can be widely adopted in clinical practice.

[0003] Cobalt (Co) is a metal element located in the fourth period and group VIII of the periodic table. Its complexes have been widely studied in the fields of sterilization, anti-cancer, chemical catalysis, etc. Compared with traditional cisplatin anticancer drugs, it has the advantages of less side effects and greater safety (Guo, Z.; et al. Chem. Soc. Rev., 2013, 42: 202–224; Ji Yanhua, et al. Chemical Reagents, 2021, 43(10): 1348-1352.).

[0004] It is reported that 8-hydroxyquinoline cobalt complexes have good anticancer activity (Ling, F.-P.; et al. ACS Med. Chem. Lett., 2019, 10: 1603-1608; Qin, Q.-P.; et al. ACS Med. Chem. Lett., 2019, 10: 1603-1608. Inorg. Chem. Commun., 2020, 115: 107854.), however, the anticancer activity of 5-bromo-8-hydroxyquinoline cobalt complexes remains unknown. Summary of the Invention

[0005] One of the purposes of the present invention is to provide a 5-bromo-8-hydroxyquinoline cobalt complex having high anticancer activity.

[0006] Specifically, the 5-bromo-8-hydroxyquinoline cobalt complex provided by the present invention has a chemical formula of [Co(BrQ)3]·CH3OH, and its chemical structure is shown below:

[0007]

[0008] A second object of the present invention is to provide a method for synthesizing the above-mentioned 5-bromo-8-hydroxyquinoline cobalt complex, which comprises weighing 0.300 mmol of 5-bromo-8-hydroxyquinoline (H-BrQ) and 0.100 mmol of CoCl2·6H2O in a 15.0 cm long 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 tube, and conducting a coordination reaction at 80°C for 3 days to obtain the target product [Co(BrQ)3]·CH3OH as reddish-brown block crystals.

[0009] The synthetic route is as follows:

[0010]

[0011] Another object of the present invention is to provide the application of the above-mentioned 5-bromo-8-hydroxyquinoline cobalt complex.

[0012] Specifically, the invention relates to the use of a 5-bromo-8-hydroxyquinoline cobalt complex in the preparation of a drug for the targeted treatment of ovarian cancer, and further relates to the use of a 5-bromo-8-hydroxyquinoline cobalt complex in the preparation of a drug for the targeted treatment of drug-resistant ovarian cancer.

[0013] Compared with the existing technology, the present invention uses 5-bromo-8-hydroxyquinoline (H-BrQ) as the active ligand to synthesize a 5-bromo-8-hydroxyquinoline cobalt complex [Co(BrQ)3]·CH3OH with high anticancer activity. The activity and toxicity of the complex on human ovarian cancer resistant cell line SK-OV-3 / DDP and normal HL-7702 cells were investigated. The experimental results showed that [Co(BrQ)3]·CH3OH had a very significant inhibitory effect on the ovarian cancer resistant cell line SK-OV-3 / DDP, with an IC of 1. 50 The value was as low as 0.27±0.09 μM, significantly greater than that of H-BrQ, CoCl2·6H2O, and the clinical drug cisplatin. Furthermore, the complex exhibited low toxicity towards normal HL-7702 cells, indicating that the complex exhibited excellent tumor selectivity for tumor cells. In summary, the 5-bromo-8-hydroxyquinoline cobalt complex exhibited excellent antitumor activity and has potential medicinal value, with potential applications in the preparation of various antitumor drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 This is the X-ray single crystal structure of the complex prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0015] The present invention will be further described below with reference to specific examples, but the present invention is not limited to these examples.

[0016] Example 1

[0017] In a 15.0 cm thick-walled, chemical-resistant tube, 0.300 mmol of 5-bromo-8-hydroxyquinoline (H-BrQ) and 0.100 mmol of CoCl2·6H2O were weighed, followed by the addition of 2.5 mL of MeOH, 0.5 mL of CH2Cl2, and 0.5 mL of triethylamine. The tube was then evacuated, sealed, and the coordination reaction was carried out at 80°C for 3 days to obtain the desired product, [Co(BrQ)3]·CH3OH, as reddish-brown blocky crystals. The yield was 87.9%.

[0018] Identification of the obtained product:

[0019] (1) X-ray single crystal structure diagram of the complex, its spectrum is as follows Figure 1 shown.

[0020] (2) Elemental analysis results are shown in Table 1.

[0021] Table 1 Elemental analysis results of the complexes in the examples

[0022]

[0023] Therefore, the complex of the obtained reddish-brown block crystals can be determined, and its structural formula is as follows:

[0024]

[0025] In order to fully illustrate the use of the 5-bromo-8-hydroxyquinoline cobalt complex with high anticancer activity provided by the present invention in pharmaceutical manufacturing, the applicant conducted an antitumor activity experiment on it.

[0026] 1. Experimental study on the proliferation inhibition activity of the target substance on two human cell lines

[0027] 1. Cell lines and cell culture

[0028] In this experiment, two human cell lines were selected: human ovarian cancer drug-resistant cell line SK-OV-3 / DDP and normal HL-7702 cells.

[0029] All human cell lines were cultured in RPMI-1640 medium containing 100 U / mL penicillin, 10 wt% calf blood, and 100 U / mL streptomycin in an incubator at 37° C. with a volume concentration of 5% CO 2 .

[0030] 2. Preparation of test compounds

[0031] The purity of all compounds used must be ≥95%. Their DMSO stock solutions are diluted with physiological buffer to a final solution of 20 μmol / L (final DMSO concentration ≤1%), and the degree of inhibition of each compound on the growth of normal cells or selected tumor cells at this concentration is tested.

[0032] 3. Cell growth inhibition assay (MTT assay)

[0033] (1) Normal cells or tumor cells in the logarithmic growth phase were digested with trypsin and prepared into a cell suspension with a concentration of 5000 cells / mL in a culture medium containing 10% calf serum. 190 μL of the suspension was inoculated into each well of a 96-well culture plate to a cell density of 1000 to 10,000 wells (the edge wells were filled with sterile PBS);

[0034] (2) Incubate at 37°C with 5% CO2 for 24 h until the cell monolayer covers the bottom of the well. Add 10 μL of a drug of a certain concentration gradient to each well, with four replicate wells for each concentration gradient.

[0035] (3) Incubate at 37°C with 5% CO2 for 48 hours and observe under an inverted microscope;

[0036] (4) Add 10 μL of MTT solution (5 mg / mL PBS, i.e., 0.5% MTT) to each well and continue incubation for 4 h;

[0037] (5) Terminate the culture, carefully remove the culture medium from the wells, add 150 μL of DMSO to each well to fully dissolve the formazan precipitate, mix on an oscillator, and measure the optical density of each well using a microplate reader at a wavelength of 570 nm and a reference wavelength of 450 nm.

[0038] (6) Set up zero-adjustment wells (culture medium, MTT, DMSO) and control wells (cells, culture medium, MTT, drug dissolution medium of the same concentration, DMSO) at the same time;

[0039] (7) The number of living cells can be determined based on the measured optical density (OD value). The larger the OD value, the stronger the cell activity. Use the formula:

[0040]

[0041] Calculate the inhibition rate of each compound on the selected cell growth, and then calculate the IC of each test compound on each selected cell line using the Bliss method. 50 The results are shown in Table 2 below.

[0042] Table 2. IC values of compounds against various cell lines 50 Value (μM)

[0043]

[0044] From Table 2, IC 50 The activity results show that the complex [Co(BrQ)3]·CH3OH has a very significant inhibitory effect on the drug-resistant ovarian cancer cell line SK-OV-3 / DDP, IC 50The value was as low as 0.27±0.09μM, and its activity against SK-OV-3 / DDP was much greater than the anticancer activity of the ligand H-BrQ, metal salt CoCl2·6H2O, clinical drug cisplatin and cobalt complexes reported in the literature on this cell line (IC 50 The value is >0.3μM; Ling, F.-P.; et al. ACS Med. Chem. Lett., 2019, 10:1603-1608; Zou, H.-H.; et al. Dalton Trans., 2022, 51, 8840–8847.). The complex [Co(BrQ)3]·CH3OH has low toxicity to normal HL-7702 cells, and its IC 50 The value was >50.0 μM, indicating that [Co(BrQ)₃]·CH₃OH has good tumor selectivity against tumor cells. In conclusion, 5-bromo-8-hydroxyquinoline cobalt complex 1 exhibits excellent antitumor activity and has potential medicinal value, and is expected to be used in the preparation of various antitumor drugs.

Claims

1. The use of a 5-bromo-8-hydroxyquinoline cobalt complex with high anticancer activity in the preparation of a drug for the targeted treatment of drug-resistant ovarian cancer, characterized in that: The chemical structural formula of the 5-bromo-8-hydroxyquinoline cobalt complex is shown below:

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