8-hydroxyquinoline iron complex and its synthesis method and application

Abstract

This invention discloses an 8-hydroxyquinoline iron complex, its synthesis method, and its applications. The method involves reacting 5,7-dichloro-2-methyl-8-hydroxyquinoline, FeCl3·6H2O, CH3OH, N,N-dimethylformamide, and NaOH under sealed conditions at 80°C for 3 days. After cooling to 37°C, the mixture is purified by silica gel column chromatography and eluted with CH3OH / CH2Cl2 to obtain the 8-hydroxyquinoline iron complex. The 8-hydroxyquinoline iron complex described in this invention can target and inhibit the growth of human cervical SiHa cancer cells and exhibits superior in vitro and in vivo antitumor activity, possessing potential pharmaceutical value and promising applications in the preparation of various antitumor drugs.

Description

Technical Field

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

[0002] In recent years, numerous quinoline metal complexes and their anticancer activities have been reported. Among them, the 5-nitro-8-hydroxyquinoline mononuclear iron complex has shown good inhibitory effects on SK-OV-3, BEL-7404, HeLa, T-24, and MGC80-3 cancer cells, especially showing the best inhibitory effect on human bladder T-24 cancer cells, with an IC50 value of [missing value]. 50 The value was 9.24 ± 0.07 μM (H.-R. Zhang, T.Meng, Y.-C. Liu, Q.-P. Qin, Z.-F. Chen, Y.-N. Liu, H. Liang, Synthesis, Structure Characterization and Antitumor Activity Study of a New Iron(III) Complex of 5-Nitro-8-hydroxylquinoline (HNOQ)[J]. Chem. Pharm. Bull. 64(2016) 1208-1217.); Two mononuclear iron complexes synthesized with aminobisphenol A ester and 8-hydroxyquinoline as ligands also showed good inhibitory effects on HeLa and MDA-MB-231 cancer cells, with IC50 values ​​of 9.24 ± 0.07 μM. 50 The value was as low as 2.17 ± 0.25 μM (CPMatos, Y. Yildizhan, Z. Adiguzel, FR Pavan, DL Campos, JC Pessoa, LP Ferreira, AI Tomaz, I. Correia, C. Acilan, New ternary iron(III)aminobisphenolate hydroxyquinoline complexes as potential therapeutic agents[J]. Dalton Trans. 48 (2019) 8702-8716.); More importantly, 5,7-dichloro-2-methyl-8-hydroxyquinoline mononuclear iron complexes are also inhibitors of Hep-G2, BEL-7404, NCI-H460, A549 and T-24 cancer cells, IC50 50The effective concentration ranged from 5.04 to 14.35 μM, and it inhibited tumor cell apoptosis through c-myc G-tetrachain (B.-Q. Zou, Q.-P. Qin, Y.-X. Bai, Q.-Q. Cao, Y. Zhang, Y.-C. Liu, Z.-F. Chen, H. Liang, Synthesis and antitumor mechanism of a new iron(III) complex with 5,7-dichloro-2-methyl-8-quinolinol as ligands[J]. Med. Chem. Commun. 8 (2017) 633-639.). However, the design, synthesis, and anticancer mechanism of quinoline-based binuclear iron are still lacking. Summary of the Invention

[0003] One of the objectives of this invention is to provide 8-hydroxyquinoline iron complexes, their synthesis methods, and applications.

[0004] The 8-hydroxyquinoline iron complex of the present invention has the following chemical structural formula:

[0005] The second objective of this invention is to provide a method for synthesizing 8-hydroxyquinoline iron complexes.

[0006] The synthesis method of 8-hydroxyquinoline iron complex involves taking 5,7-dichloro-2-methyl-8-hydroxyquinoline (H-Dmq), FeCl3·6H2O, CH3OH, N,N-dimethylformamide (DMF), and NaOH, reacting at 80°C for 3 days under sealed conditions, cooling to 37°C, purifying by silica gel column chromatography, and eluting with CH3OH / CH2Cl2 to obtain the final product.

[0007] Its synthetic route is as follows:

[0008] Another object of the present invention is to provide the application of 8-hydroxyquinoline iron complexes.

[0009] Specifically, this relates to the application of the aforementioned 8-hydroxyquinoline iron complex in the preparation of anti-cervical cancer drugs. Specifically, it relates to the application of the aforementioned 8-hydroxyquinoline iron complex in the preparation of anti-cervical squamous cell carcinoma (SiHa carcinoma) drugs.

[0010] This invention synthesizes a novel binuclear iron complex, FeGa2, by reacting 5,7-dichloro-2-methyl-8-hydroxyquinoline (H-Dmq) with iron salt FeCl3·6H2O as the active ligand. Its anticancer activity and toxicity against human cervical SiHa cancer cells and normal human hepatocytes HL-7702 were investigated. The results showed that FeGa2 effectively inhibited the growth of SiHa cancer cells, with an IC50 value of [missing information]. 50 The effective values ​​were 0.11 ± 0.01 and 2.15 ± 0.72 μM, respectively, indicating that FeGa2 exhibited greater activity than H-Dmq, FeCl3·6H2O, the clinical drug cisplatin, and iron complexes reported in the literature. Furthermore, the FeGa2 complex showed very low toxicity to normal HL-7702 cells (>50.00 μM), suggesting that FeGa2 can target and inhibit the growth of human cervical SiHa cancer cells. In conclusion, FeGa2 demonstrated 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. Attached Figure Description

[0011] Figure 1 This is an X-ray single-crystal structure diagram of the complex FeGa2 obtained in Example 1 of the present invention; Figure 2 The infrared spectrum of the complex FeGa2 obtained in Example 1 of this invention is shown. Detailed Implementation

[0012] The present invention will be further described below with reference to specific embodiments, but the present invention is not limited to these embodiments.

[0013] Example 1 Take two 15.0 cm thick-walled drug-resistant tubes and weigh in H-Dmq (45.6 mg, 0.2 mmol) and FeCl3·6H2O (27.0 mg, 0.1 mmol). Then add CH3OH (2.0 mL), DMF (0.2 mL), and NaOH (1.0 M, 0.1 mL) to each tube. After capping, react at 80 °C for 3 days. After cooling to 37 °C, after the reaction is complete, purify the two crude products by silica gel column chromatography and elute with CH3OH / CH2Cl2 to obtain the target product FeGa2 (black blocky crystals, yield: 84.3%).

[0014] Identification of the obtained FeGa2: (1) X-single crystal structure diagram of FeGa2, the structure diagram is as follows: Figure 1 As shown.

[0015] (2) The infrared spectrum of FeGa2 is shown in the figure below. Figure 2 As shown.

[0016] CompoundFeGa2, 43.7 mg, yield: 84.3%. IR (KBr): 3429, 3065, 1581,1557, 1496, 1424, 1377, 1331, 1278, 1248, 1200, 1252, 1113, 1033, 968, 948,871, 831, 783, 755, 705, 664, 603, 541, 514, 469 and 425 cm 1 ; elementalanalysis: cald (%) values ​​for Fe2C 40 H 24 O5C l8 N4 were C 46.38, H 2.34, and N 5.41; observed values: C 46.36, H 2.37, and N 5.43. (3) Elemental analysis results are shown in Table 1.

[0017] Table 1 Elemental analysis results of FeGa2

[0018] Therefore, it can be determined that the obtained product is FeGa2, and its structural formula is as follows:

[0019] To fully illustrate the use of FeGa2 in pharmaceuticals as described in this invention, the applicant conducted antitumor activity experiments on it.

[0020] I. Experiment on the inhibitory activity of FeGa2 on the proliferation of two human cell lines 1. Cell lines and cell culture This experiment used two human cell lines: human cervical SiHa cancer cells and human normal liver cells HL-7702.

[0021] 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.

[0022] 2. Preparation of the test compound All compounds used must have a purity of ≥95.0%. Their DMSO stock solutions were diluted with physiological buffer to a final solution of 20.0 µmol / L (final DMSO concentration ≤1.0%), and the inhibitory effect of each compound on the growth of normal cells or selected tumor cells at this concentration was tested.

[0023] 3. Cell growth inhibition experiment Take 100 μL of logarithmic phase cell suspension (5 × 10⁻⁶ cells / mL) 4 Add the compound (at a concentration of 10 cells / mL) to a 96-well cell culture plate. After culturing for 24.0 h, add final concentrations of 0, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 20.0, and 50.0 μM, respectively, with six replicates for each concentration. After adding the drug, incubate for 48 h. Then, add 10 μL of CCK-8 staining solution to each well, incubate for 2 h, mix on a shaker, and measure the OD value (λ=450 nm) of each well after 10 min using a microplate reader. Calculate the inhibitory rate of the compound on cells, and then calculate the IC50 of each compound on the selected cells using the Bliss assay. 50 Values. The results are shown in Table 2 below.

[0024] Table 2. IC50 of FeGa2 for various cell lines 50 Value (µM)

[0025] From IC 50 Based on the activity screening results, FeGa2 can effectively inhibit the growth of SiHa cancer cells, and its IC50 value is [missing information]. 50The values ​​were 0.11 ± 0.01 and 2.15 ± 0.72 μM, respectively, and their activities were greater than those of H-Dmq, FeCl3·6H2O, the clinical drug cisplatin, and iron complexes reported in the literature (H.-R. Zhang, T. Meng, Y.-C. Liu, Q.-P. Qin, Z.-F. Chen, Y.-N. Liu, H.Liang, Synthesis, Structure Characterization and Antitumor Activity Study of a New Iron(III) Complex of 5-Nitro-8-hydroxylquinoline (HNOQ)[J]. Chem.Pharm. Bull. 64 (2016) 1208-1217.; CP Matos, Y. Yildizhan, Z. Adiguzel, FR Pavan, DL Campos, JC Pessoa, LP Ferreira, AI Tomaz, I. Correia, C. Acilan, New ternary iron(III) aminobisphenolate hydroxyquinoline complexes as potential therapeutic agents[J]. Dalton Trans. 48 (2019) 8702-8716.;B.-Q. Zou, Q.-P. Qin, Y.-X. Bai, Q.-Q. Cao, Y. Zhang, Y.-C. Liu, Z.-F. Chen, H. Liang, Synthesis and antitumor mechanism of a new iron(III) complex with 5,7-dichloro-2-methyl-8-quinolinol as ligands[J]. Med. Chem. Commun. 8(2017) 633-639.)); and the complex FeGa2 showed very low toxicity to normal HL-7702 cells (>50.00 μM); indicating that the complex FeGa2 can target and inhibit the growth of SiHa cancer cells.

[0026] II. In vivo tumor suppression experiment in tumor-bearing nude mice SiHa tumor tissue was cut into 1.5 mm pieces. 3Small 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 100-150 mm. 3 Animals were randomly divided into two groups: a solvent group and a FeGa1-treated group, with six animals in each group. Intraperitoneal injection of FeGa1 began on the day of grouping, with administration every two days. Tumor diameter and body weight were measured every three days using electronic calipers. On day 21, animals were euthanized by cervical dislocation, the tumor was dissected, weighed, photographed, and the tumor inhibition rate was calculated.

[0027] The formula for calculating tumor volume is: V = a × b² / 2, where a is the major axis and b is the minor axis; Relative tumor volume RTV = Vt / V0, where Vt is the volume at each measurement and V0 is the volume at the grouping. Relative tumor proliferation rate T / C% = (TRTV / CRTV) × 100%; 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%.

[0028] In summary, the FeGa2 of the present invention exhibits superior in vitro and in vivo antitumor activity, has potential pharmaceutical value, and is expected to be used in the preparation of various antitumor drugs.

Claims

1,8-Hydroxyquinoline iron complex, characterized in that, The chemical structural formula is shown below: 。 2. The method for synthesizing the 8-hydroxyquinoline iron complex according to claim 1, characterized in that, Take 5,7-dichloro-2-methyl-8-hydroxyquinoline, FeCl3·6H2O, CH3OH, N,N-dimethylformamide and NaOH, and react at 80°C for 3 days under sealed conditions. After cooling to 37°C, purify by silica gel column chromatography and elute with CH3OH / CH2Cl2 to obtain the final product.

3. The use of the 8-hydroxyquinoline iron complex according to claim 1 in the preparation of anti-cervical cancer drugs.

4. The use of the 8-hydroxyquinoline iron complex according to claim 1 in the preparation of an anti-cervical squamous cell carcinoma drug.

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