5-Chloro-8-hydroxyquinoline rhodium complex for drug-resistant lung cancer, its preparation method and application

Abstract

This invention discloses an anti-drug-resistant lung cancer compound, its preparation method, and its applications. The invention involves reacting 5-chloro-8-hydroxyquinoline, dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, methanol, dimethyl sulfoxide, and triethylamine under sealed conditions at 80 °C for 3 days. After cooling to 37 °C, the mixture is filtered and dried to obtain the final product. The 5-chloro-8-hydroxyquinoline rhodium complex exhibits superior antitumor activity by targeting and inhibiting the growth of lung cancer cells A549 and cisplatin-resistant lung cancer cells A549 / DDP, while showing low toxicity to normal HL-7702 cells. It possesses potential pharmaceutical value and is expected to be used in the preparation of various antitumor drugs.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a rhodium complex for treating drug-resistant lung cancer with 5-chloro-8-hydroxyquinoline, its preparation method, and its application. Background Technology

[0002] Recent literature reports that the 8-hydroxyquinoline-triphenylphosphine-rhodium complexes GUPT1-GUPT4 exhibit good inhibitory effects on human lung cancer A549 and cisplatin-resistant lung cancer cells A549 / DDP, especially on A549 / DDP cancer cells, with an IC500 of [missing information]. 50 The values ​​ranged from 5.11 to 14.59 μM (Zhen-Feng Wang, Xiao-Qiong Huang, Run-Chun Wu, Shu-Hua Zhan. Newrhodium(III)-triphenylphosphine complexes with 5-halogenate-8-hydroxyquinoline as ligands: synthesis, characterization, cytotoxicity, and mechanism of action[J]. Bioorganic Chemistry, 2025, 163, 108789.); however, the synthesis and anticancer activity of 5-chloro-8-hydroxyquinoline organorhodium complexes have not been reported. Summary of the Invention

[0003] One of the objectives of this invention is to provide a 5-chloro-8-hydroxyquinoline rhodium complex.

[0004] The 5-chloro-8-hydroxyquinoline rhodium complex of the present invention has the following chemical structural formula:

[0005]

[0006] The second objective of this invention is to provide a method for preparing 5-chloro-8-hydroxyquinoline rhodium complexes.

[0007] The preparation method of 5-chloro-8-hydroxyquinoline rhodium complex involves taking 5-chloro-8-hydroxyquinoline (H-ClQ), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (η5-Cpa), methanol, dimethyl sulfoxide (DMSO), and triethylamine, reacting them at 80 °C for 3 days under sealed conditions, cooling to 37 °C, filtering, and drying to obtain the final product.

[0008] Its synthetic route is as follows:

[0009] Another object of the present invention is to provide the use of 5-chloro-8-hydroxyquinoline rhodium complexes.

[0010] Specifically, this relates to the application of the aforementioned 5-chloro-8-hydroxyquinoline rhodium complex in the preparation of anti-lung cancer drugs. It also relates to the application of the aforementioned 5-chloro-8-hydroxyquinoline rhodium complex in the preparation of drugs for treating drug-resistant lung cancer.

[0011] Furthermore, the application of the aforementioned 5-chloro-8-hydroxyquinoline rhodium complex in the preparation of drugs for treating cisplatin-resistant lung cancer is discussed.

[0012] This invention uses 5-chloro-8-hydroxyquinoline (H-ClQ) as the active ligand, reacting it with a rhodium salt dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (η5-Cpa) to obtain the 5-chloro-8-hydroxyquinoline rhodium complex ClRh. Its anticancer activity and toxicity against human lung cancer cells A549, cisplatin-resistant lung cancer cells A549 / DDP, and normal human hepatocytes HL-7702 were investigated. The results showed that the rhodium complex ClRh exhibited good inhibitory effects on A549 and A549 / DDP cancer cells, with an IC50 value of [missing information]. 50 The effective values ​​were 4.21 ± 0.12 and 2.64 ± 0.10 μM, respectively, indicating that ClRh's activity was significantly greater than that of its ligand H-ClQ, rhodium salt η5-Cpa, and the clinical drug cisplatin. Furthermore, ClRh exhibited minimal toxicity to normal HL-7702 cells (>50.00 μM), demonstrating that the 5-chloro-8-hydroxyquinoline rhodium complex ClRh can target and inhibit the growth of lung cancer cells A549 and cisplatin-resistant lung cancer cells A549 / DDP. In vivo tumor suppression experiments showed that ClRh had a significant inhibitory effect on lung cancer A549 tumors in nude mice, with an in vivo inhibition rate of 49.2%. In conclusion, the 5-chloro-8-hydroxyquinoline organorhodium complex ClRh exhibits superior in vitro and in vivo antitumor activity and has potential pharmaceutical value, making it promising for the preparation of various antitumor drugs. Attached Figure Description

[0013] Figure 1 The X-ray single-crystal structure diagram of the 5-chloro-8-hydroxyquinoline organorhodium complex ClRh prepared in Example 1 of this invention is shown. Figure 2 The 1H NMR spectrum of the 5-chloro-8-hydroxyquinoline organorhodium complex ClRh prepared in Example 1 of this invention; Figure 3 The infrared spectrum of the 5-chloro-8-hydroxyquinoline organorhodium complex ClRh prepared in Example 1 of this invention is shown. Detailed Implementation

[0014] The present invention will be further described below with reference to specific embodiments, but the present invention is not limited to these embodiments.

[0015] Example 1 Take a thick-walled drug-resistant tube of about 15.0 cm, open the cap, and add 0.1 mmol of 5-chloro-8-hydroxyquinoline (H-ClQ), 0.1 mmol of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (η5-Cpa), 1.0 mL of methanol, 0.3 mL of dimethyl sulfoxide (DMSO), and 0.1 mL of triethylamine. After capping, react at 80 °C for 3 days. After cooling to 37 °C, filter and dry to obtain the reddish-brown blocky crystal product ClRh, with a yield of 88.6%.

[0016] The obtained 5-chloro-8-hydroxyquinoline organorhodium complex ClRh was identified as follows: (1) X-single crystal structure diagram of the complex ClRh, as shown in the figure. Figure 1 As shown.

[0017] (2) The proton NMR spectrum of the complex ClRh is shown in the figure below. Figure 2 As shown.

[0018] 1 H NMR (400 MHz, DMSO- d 6): δ 8.85 (d, J = 4.6 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H), 7.70 (dd, J = 8.6, 4.8 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 6.66 (d, J = 8.6 Hz, 1H), 1.64 (s, 15H). (3) The infrared spectrum of the complex ClRh is shown in the figure below. Figure 3 As shown.

[0019] IR (KBr): 3434, 3051, 3005, 2980, 2920, 1590, 1560, 1493, 1451, 1401,1372, 1356, 1320, 1213, 1087, 1044, 1023, 965, 828, 819, 785, 741, 673, 612,540, 456, 442, and 422 cm 1 . (4) Elemental analysis results are shown in Table 1.

[0020] Table 1 shows the elemental analysis results of the complex ClRh in the examples.

[0021] Therefore, the structural formula of the obtained complex ClRh can be determined as follows:

[0022] To fully illustrate the use of the complex ClRh described in this invention in pharmaceutical applications, the applicant conducted antitumor activity experiments on it.

[0023] I. Experiment on the inhibitory activity of one complex ClRh on the proliferation of two human cell lines 1. Cell lines and cell culture This experiment used two human cell lines: human lung cancer cell line A549, cisplatin-resistant lung cancer cell line A549 / DDP, and normal human liver cell line HL-7702.

[0024] 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.

[0025] 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.

[0026] 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 and incubate for 24.0 h. Then, add final concentrations of 0, 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. Subsequently, add 10 μL of CCK-8 staining solution to each well and incubate for 2 h. Mix well on a shaker, and after 10 min, measure the OD value (λ=450nm) of each well 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.

[0027] Table 2. IC50 of complex ClRh for various cell lines 50 Value (µM)

[0028] From IC 50The activity screening results showed that the rhodium complex ClRh had a good inhibitory effect on A549 and A549 / DDP cancer cells, especially on A549 / DDP cancer cells, where the effect was most significant, with an IC50 of 100%. 50 The concentration was 2.64 ± 0.10 μM, indicating that its anticancer activity was significantly greater than that of the ligand H-ClQ (>50.00 μM), the rhodium salt η5-Cpa (>50.00 μM), and the clinical drug cisplatin (>50.00 μM). The study also found that ClRh exhibited minimal toxicity to normal HL-7702 cells (>50.00 μM), suggesting that the 5-chloro-8-hydroxyquinoline rhodium complex ClRh can target and inhibit the growth of lung cancer cells A549 and cisplatin-resistant lung cancer cells A549 / DDP.

[0029] II. In vivo tumor suppression experiment in tumor-bearing nude mice The lung cancer tumor tissue was cut into 1.5 mm 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 100-200 mm. 3 Animals were randomly divided into two groups: a solvent group and a drug-treated group, with six animals in each group. Intraperitoneal injection of the compound was administered on the day of grouping, with the compound administered 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.

[0030] Tumor volume calculation formula: V = a × b 2 / 2, where a is the major axis and b is the minor axis; Relative tumor volume RTV = V t / V0, where V t V0 represents the volume at each measurement, and V0 represents the volume when grouping. Relative tumor proliferation rate T / C% = (T RTV / C RTV ) × 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%.

[0031] Table 3. In vivo antitumor effect of rhodium complex ClRh on nude mice bearing human lung cancer A549 tumors.

[0032] Table 3 shows that in vivo tumor inhibition experiments have a significant inhibitory effect on A549 lung cancer tumors in nude mice, with an in vivo inhibition rate of 49.2%, and it is expected to be used in the preparation of various anti-tumor drugs.

[0033] In summary, the 5-chloro-8-hydroxyquinoline rhodium complex ClRh described in this 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. A 5-chloro-8-hydroxyquinoline rhodium complex for treating drug-resistant lung cancer, characterized in that... The chemical structural formula is shown below: 。 2. The method for preparing the 5-chloro-8-hydroxyquinoline rhodium complex according to claim 1, characterized in that, Take 5-chloro-8-hydroxyquinoline, dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, methanol, dimethyl sulfoxide and triethylamine, and react them at 80 °C for 3 days under closed conditions. After cooling to 37 °C, filter and dry to obtain the product.

3. The use of the 5-chloro-8-hydroxyquinoline rhodium complex according to claim 1 in the preparation of anti-lung cancer drugs.

4. The use of the 5-chloro-8-hydroxyquinoline rhodium complex according to claim 1 in the preparation of drugs for treating drug-resistant lung cancer.

5. The use of the 5-chloro-8-hydroxyquinoline rhodium complex according to claim 1 in the preparation of a drug for treating lung cancer resistant to cisplatin.

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