8-hydroxyquinoline derivative zinc complex as well as preparation method and application thereof
By synthesizing novel 8-hydroxyquinoline derivative zinc complexes QhBr1-QhBr3, the problem of insufficient anticancer effect against human skin melanoma cells in existing technologies has been solved, achieving significant in vitro anticancer activity and in vivo tumor inhibition effect, showing good pharmaceutical prospects.
Patent Information
- Application Number
- CN202510956380.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-11
- Publication Date
- 2025-10-31
AI Technical Summary
Existing 8-hydroxyquinoline metal complexes have insufficient in vitro and in vivo anticancer effects on human skin melanoma cells, and cisplatin-based drugs have problems with nephrotoxicity and drug resistance.
Three novel 8-hydroxyquinoline derivative zinc complexes, [Zn(QBr1)2(pyr1)]·2CH3OH, [Zn(QBr2)2(pyr2)]·2CH3OH, and [Zn(H0.5QBr2)2(pyr3)2](NO3)·CH3OH·H2O, were synthesized. These complexes, QhBr1-QhBr3, exhibit excellent anticancer activity and were formed by reacting with ligands such as o-phenanthroline, 4,4'-dimethyl-2,2'-bipyridine, and 2-(1H-pyrazol-3-yl)pyridine.
The novel 8-hydroxyquinoline derivative zinc complexes QhBr1-QhBr3 exhibited significant anticancer activity against human skin melanoma cells, with IC50 values of 5.04±0.16, 3.48±0.07 and 2.70±0.19 μM, respectively, and an in vivo tumor inhibition rate of 54.2%. They also showed low toxicity to normal cells and have potential medicinal value.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical technology, specifically to zinc complexes of 8-hydroxyquinoline derivatives, their preparation methods, and applications. Background Technology
[0002] Nephrotoxicity and drug resistance are drawbacks of cisplatin-based drugs, prompting scientists to develop a series of novel non-platinum-based targeted anticancer drugs. Zinc is also an essential trace element for the human body, involved in various health issues such as enzymes, immunity, loss of appetite, night blindness, child growth, arteriosclerosis, and anemia. Furthermore, in recent years, an increasing number of zinc anticancer complexes have been synthesized, and their structures, targeting effects, and mechanisms have been continuously published, revealing their excellent anticancer activity and targeting properties.
[0003] In recent years, inventors have reported a series of 8-hydroxyquinoline zinc complexes, and studies have found that they have good anti-cancer effects against ovarian cancer (Du LQ, Zeng CJ, Mo DY, et al. 8-hydroxyquinoline-N-oxide copper(II)-and zinc(II)-phenanthroline and bipyridine coordination compounds: Design, synthesis, structures, and antitumor evaluation[J]. Journal of Inorganic Biochemistry, 2024, 251: 112443.). However, the in vitro and in vivo anti-cancer effects of 8-hydroxyquinoline metal complexes on human skin melanoma cells (SK-MEL-5) are still lacking. Summary of the Invention
[0004] One of the objectives of this invention is to provide zinc complexes of 8-hydroxyquinoline derivatives.
[0005] The 8-hydroxyquinoline derivative zinc complexes of this invention have the chemical formulas [Zn(QBr1)2(pyr1)]·2CH3OH(QhBr1), [Zn(QBr2)2(pyr2)]·2CH3OH(QhBr2), and [Zn(H 0.5 The chemical structural formula of QhBr3 is shown below: [QBr2)2(pyr3)2](NO3)·CH3OH·H2O(QhBr3)
[0006]
[0007] The second objective of this invention is to provide a method for synthesizing zinc complexes of 8-hydroxyquinoline derivatives.
[0008] The method for synthesizing 8-hydroxyquinoline derivative zinc complex involves taking 8-hydroxyquinoline derivative, CH3OH, CH2Cl2, triethylamine, Zn(NO3)2 and ligand, capping the bottle with the drug-resistant cap, incubating at 80.0℃ for 72 hours, then cooling to 25℃ and standing for 24 hours to obtain the product.
[0009] The ligands are o-phenanthroline (pyr1), 4,4'-dimethyl-2,2'-bipyridine (pyr2) and 2-(1H-pyrazol-3-yl)pyridine (pyr3).
[0010] Its synthetic route is as follows:
[0011]
[0012] Another object of the present invention is to provide the application of the above-mentioned 8-hydroxyquinoline derivative zinc complex.
[0013] Specifically, this relates to the application of the aforementioned 8-hydroxyquinoline derivative zinc complexes in the preparation of antitumor drugs. It also relates to the application of the aforementioned 8-hydroxyquinoline derivative zinc complexes in the preparation of targeted therapies for cutaneous melanoma.
[0014] Compared with existing technologies, this invention synthesizes 8-hydroxyquinoline derivatives H-QBr1 and H-QBr2, and uses them as active ligands, with o-phenanthroline (pyr1), 4,4'-dimethyl-2,2'-bipyridine (pyr2), and 2-(1H-pyrazol-3-yl)pyridine (pyr3) as auxiliary ligands, to react with the metal salt Zn(NO3)2 to synthesize three novel 8-hydroxyquinoline derivative zinc complexes QhBr1-QhBr3. The anticancer activity and toxicity of these complexes against human skin melanoma SK-MEL-5 cells and normal liver HL-7702 cells were investigated. The experimental results showed that the complexes QhBr1-QhBr3 exhibited good anticancer activity against human skin melanoma SK-MEL-5 cells, with an IC50 value of [missing information]. 50 The effective values were 5.04±0.16, 3.48±0.07, and 2.70±0.19 μM, indicating that the complex QhBr1-QhBr3 exhibited significantly higher activity than H-QBr1, H-QBr2, Zn(NO3)2, pyr1-pyr3, and cisplatin. Furthermore, they showed low toxicity to normal HL-7702 cells, suggesting that the complex QhBr1-QhBr3 can target and inhibit the proliferation of SK-MEL-5 cancer cells. In vivo tumor suppression experiments showed that the complex QhBr3 had a good tumor-suppressing effect on a nude mouse model of cutaneous melanoma SK-MEL-5, with an inhibition rate as high as 54.2%. In conclusion, the novel 8-hydroxyquinoline derivative zinc complex QhBr3 exhibits superior in vitro and in vivo antitumor activity and has potential pharmaceutical value, holding promise for the preparation of various antitumor drugs. Attached Figure Description
[0015] Figure 1 The X-ray single-crystal diffraction pattern of the complex QhBr1 prepared in Example 1 of this invention (two free methanol molecules have been removed from the figure for clearer structural display);
[0016] Figure 2 The X-ray single-crystal diffraction pattern of the complex QhBr2 prepared in Example 1 of this invention (two free methanol molecules were removed from the plot for clearer structural display);
[0017] Figure 3 The X-ray single-crystal diffraction pattern of the complex QhBr3 prepared in Example 1 of this invention (to make the structure clearer, one free water molecule and one methanol molecule were removed from the plot, and one external NO3 molecule was also removed). - ion);
[0018] Figure 4 The infrared spectrum of the complex QhBr1 obtained in Example 1 of this invention;
[0019] Figure 5 The infrared spectrum of the complex QhBr2 obtained in Example 1 of this invention;
[0020] Figure 6 The infrared spectrum of the complex QhBr3 obtained in Example 1 of this invention is shown. Detailed Implementation
[0021] The 8-hydroxyquinoline derivatives H-QBr1 and H-QBr2 were synthesized according to the literature (Wu RC, Zhang JM, Huang XQ, et al. Synthesis and antitumormechanisms of two new 8-hydroxyquinoline platinum(II) derivatives[J]. New Journal of Chemistry, 2025, 49(16): 6561-6567.).
[0022] Immediately afterward, 0.2 mmol of H-QBr1, 2.0 mL of CH3OH, 0.5 mL of CH2Cl2, 0.1 mL of triethylamine (NEt3), 0.10 mmol of Zn(NO3)2, and 0.10 mmol of the auxiliary ligand pyr1 were added to a 15.0 cm thick-walled drug-resistant tube. After capping the drug-resistant tube, it was incubated at 80.0 °C for 72 hours, then cooled to 25 °C. After 24 hours, the cap was opened, and the target zinc complex QhBr1 (yellow, yield: 79.6%) was obtained.
[0023] Take a 15.0 cm thick-walled drug-resistant tube, add 0.2 mmol of H-QBr2, CH3OH (2.0 mL), CH2Cl2 (0.5 mL), triethylamine (NEt3, 0.1 mL), Zn(NO3)2 (0.10 mmol), and auxiliary ligand pyr2 (0.10 mmol), cap the drug-resistant bottle, incubate at 80.0 °C for 72 hours, then cool to 25 °C. After 24 hours, open the bottle cap to obtain the target zinc complex QhBr2 (yellow, yield: 80.6%).
[0024] In a 15.0 cm thick-walled drug-resistant tube, 0.1 mmol of H-QBr2, CH3OH (2.0 mL), CH2Cl2 (0.5 mL), triethylamine (NEt3, 0.1 mL), Zn(NO3)2 (0.10 mmol), and auxiliary ligand pyr3 (0.10 mmol) were weighed. After capping the drug-resistant tube, it was incubated at 80.0 °C for 72 hours, then cooled to 25 °C. After 24 hours, the cap was opened, and the target zinc complex QhBr3 (reddish-brown, yield: 84.4%) was obtained.
[0025] The obtained products QhBr1-QhBr3 were identified as follows:
[0026] (1) X-ray single-crystal diffraction patterns of compounds QhBr1-QhBr3 are shown in the figure. Figure 1-3 As shown.
[0027] (2) The infrared spectra of compounds QhBr1-QhBr3 are shown in the figure below. Figure 4-6 As shown.
[0028] Data for QhBr1(yellow).Yield:79.6%.IR(KBr):3193,3053,1580,1547,1454,1387,1342,1281,1147,1090,938,841,730,639,507cm -1 .
[0029] Data for QhBr2(yellow).Yield:80.6%.IR(KBr):3401,3241,1570,1532,1443,1420,1370,1339,1141,1112,1101,1037,930,838,783,743,647,521,504cm -1 .
[0030] Data for QhBr3(red-brown).Yield:84.4%.IR(KBr):3401,3205,1606,1570,1531,1502,1416,1384,1266,1151,1116,840,759,645,486cm -1 .
[0031] (3) Elemental analysis results are shown in Table 1.
[0032] Table 1 shows the elemental analysis results of compounds QhBr1-QhBr3 in the examples.
[0033]
[0034] Therefore, the structural formula of the obtained products QhBr1-QhBr3 can be determined as follows:
[0035]
[0036] To fully illustrate the pharmaceutical applications of the three novel 8-hydroxyquinoline derivative zinc complexes QhBr1-QhBr3 described in this invention, the applicant conducted in vitro and in vivo antitumor activity experiments on them.
[0037] I. Experimental Study on the Inhibitory Activity of Three Novel 8-Hydroxyquinoline Derivative Zinc Complexes QhBr1-QhBr3 on Two Human Cell Lines
[0038] 1. Cell lines and cell culture
[0039] This experiment used two human cell lines: human skin melanoma SK-MEL-5 cells and normal liver HL-7702 cells.
[0040] 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.
[0041] 2. Preparation of the test compound
[0042] 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.
[0043] 3. Cell growth inhibition experiment
[0044] The specific steps are as follows:
[0045] (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.
[0046] (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.
[0047] (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.
[0048] Table 2. IC50 of zinc complexes QhBr1-QhBr3 for various cell lines 50 Value (μM)
[0049]
[0050] From IC 50 Based on the activity screening results, the complexes QhBr1-QhBr3 showed good anticancer activity against human skin melanoma SK-MEL-5 cells, with an IC50 value of [missing information]. 50 The values were 5.04±0.16μM, 3.48±0.07μM, and 2.70±0.19μM, respectively, and their activity was much greater than that of H-QBr1 (>50μM), H-QBr2 (>50μM), Zn(NO3)2 (>50μM), pyr1-pyr3 (>50μM), and cisplatin (9.05±0.46μM); moreover, they had low toxicity to normal HL-7702 cells; indicating that the complex QhBr1-QhBr3 can target and inhibit the proliferation of human skin melanoma SK-MEL-5 cells.
[0051] II. In vivo tumor suppression experiment in tumor-bearing nude mice
[0052] Human skin melanoma SK-MEL-5 cells in the logarithmic growth phase were collected and cultured in serum-free medium to form cells of 5.0 × 10⁻⁶. 7A suspension with a live cell concentration of 1 × 10⁶ cells / mL. 0.2 mL of the suspension is drawn using a 1.0 mL syringe, containing approximately 1 × 10⁶ cells / mL. 7 One live cell was then inoculated subcutaneously into the right axilla of a nude mouse, and the subcutaneous tumor was allowed to grow to approximately 1 cm. 3 The tumor source, used as a subcutaneous xenograft tumor model, was passaged in nude mice. Human skin melanoma SK-MEL-5 cells were passaged four times in nude mice until growth stabilized. Mice bearing tumors with vigorous growth and no ulceration were selected, euthanized by cervical dislocation, and the animal skin was disinfected with 75.0% medical alcohol. The tissue block was dissected, necrotic parts were removed, and the tumor tissue was cut into 1.5mm pieces. 3 Small pieces were inoculated subcutaneously into the right axilla of nude mice using a cannula. The diameter of the transplanted tumor was measured with electronic calipers. The tumor volume was monitored until it reached 100-300 mm. 3 At that time, the animals were randomly grouped.
[0053] Nude mice bearing human cutaneous melanoma SK-MEL-5 cell tumors were randomly divided into a solvent group, a drug-treated group, and a cisplatin-positive control group, with 7 animals in each group. Intraperitoneal injection of the drug was initiated on the day of grouping, with the compound administered every two days and cisplatin administered every other day. Tumor diameter and body weight were measured every three days using electronic calipers. On day 21, the mice were euthanized by cervical dislocation, the tumors were dissected, weighed, photographed, and the tumor inhibition rate was calculated.
[0054] Tumor volume calculation formula: V=a×b 2 / 2, where a is the major axis and b is the minor axis;
[0055] Relative tumor volume RTV = V t / V0, where V t V0 represents the volume at each measurement, and V0 represents the volume when grouping.
[0056] Relative tumor proliferation rate T / C% = (T RTV / C RTV )×100%;
[0057] Tumor growth inhibition rate (%) = (average tumor weight in the solvent group - average tumor weight in the treatment group) / average tumor weight in the solvent group × 100%.
[0058] Table 3. In vivo tumor inhibition results of complex QhBr3 on nude mice bearing human cutaneous melanoma SK-MEL-5.
[0059]
[0060] Table 3 shows that the in vivo tumor inhibition experiment demonstrated that the complex QhBr3 exhibited a certain tumor-inhibiting effect on a nude mouse model of human skin melanoma SK-MEL-5, with an inhibition rate of 54.2%. Furthermore, no significant changes in mouse weight or mortality occurred during the experiment. In conclusion, the complex QhBr3 exhibited superior in vitro and in vivo antitumor activity and possesses potential pharmaceutical value, making it a promising candidate for the preparation of various antitumor drugs.
[0061] In summary, the three novel 8-hydroxyquinoline derivative zinc complexes QhBr1-QhBr3 described in this invention exhibit excellent in vitro and in vivo antitumor activity and selectivity, as well as good cytotoxicity selectivity, and have good potential pharmaceutical value, and are expected to be used in the preparation of various antitumor drugs.
Claims
1. 8-Hydroxyquinoline derivative zinc complex, characterized in that, Its chemical structural formula is as follows: A method for synthesizing zinc complexes of 2,8-hydroxyquinoline derivatives, characterized in that, Take 8-hydroxyquinoline derivative, CH3OH, CH2Cl2, triethylamine, Zn(NO3)2 and ligand, cap the resistant bottle, incubate at 80.0℃ for 72 hours, then cool to 25℃ and stand for 24 hours to obtain the product.
3. The method for synthesizing the 8-hydroxyquinoline derivative zinc complex according to claim 1, characterized in that, The ligand is o-phenanthroline, 4,4'-dimethyl-2,2'-bipyridine, or 2-(1H-pyrazol-3-yl)pyridine.
4. The use of the 8-hydroxyquinoline derivative zinc complex according to claim 1 in the preparation of antitumor drugs.
5. The use of the 8-hydroxyquinoline derivative zinc complex according to claim 1 in the preparation of a targeted therapy for cutaneous melanoma.