Rhodium complex, process for its preparation and use thereof

Abstract

The application discloses a rhodium complex and a preparation method and application thereof. The rhodium complex is prepared by taking 5-bromo-8-hydroxyquinoline, dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer, methanol, dimethyl sulfoxide and triethylamine, and reacting under a closed condition at 80 DEG C for 3 days. After cooling to 37 DEG C, the rhodium complex is filtered and dried. The rhodium complex has a good inhibitory effect on endometrial carcinoma Ishikawa nude mouse tumors, and the in-vivo inhibition rate is 58.4%, which is obviously higher than that of clinical drug cisplatin (53.6%). It can be seen that the rhodium complex has superior in-vivo and in-vitro anti-tumor activities, has potential medicinal value, and can be used for the preparation of various anti-tumor drugs.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a rhodium complex, its preparation method, and its application. Background Technology

[0002] Numerous studies have reported that 8-hydroxyquinoline metal anticancer drugs have good inhibitory effects on corresponding tumors, and its rhodium complex is also a good tumor inhibitor. However, current research shows that in vivo and in vitro studies of 8-hydroxyquinoline rhodium complex against endometrial cancer cells are still lacking and require further investigation. Summary of the Invention

[0003] Its potential medicinal value suggests it could be used in the preparation of various anti-tumor drugs.

[0004] One of the objectives of this invention is to provide a rhodium complex (CpRh).

[0005] The rhodium complex of the present invention has the following chemical structural formula:

[0006]

[0007] The second objective of this invention is to provide a method for preparing the above-mentioned rhodium complex.

[0008] The rhodium complex was prepared by taking 5-bromo-8-hydroxyquinoline (H-OBr), 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.

[0009] Its synthetic route is as follows:

[0010] Another object of the present invention is to provide applications of the above-mentioned rhodium complexes.

[0011] Specifically, this relates to the application of the aforementioned rhodium complex in the preparation of drugs for treating endometrial cancer.

[0012] This invention synthesizes a rhodium complex CpRh by chelating the active ligand 5-bromo-8-hydroxyquinoline (H-OBr) with a dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (η5-Cpa). Its antiproliferative activity and toxicity against endometrial cancer Ishikawa cells and normal human liver HL-7702 cells were investigated. Experimental data show that the rhodium complex CpRh has a strong inhibitory effect on the proliferation of endometrial cancer Ishikawa cells, with an IC50 value of [missing data]. 50The concentration was 1.64 ± 0.17 μM, indicating that its activity was significantly greater than that of H-OBr, η5-Cpa, and cisplatin. Furthermore, the rhodium complex CpRh exhibited very low toxicity to normal HL-7702 cells (>50.00 μM), suggesting that it can target and inhibit the growth of endometrial cancer Ishikawa cells. In vivo experiments showed that the rhodium complex CpRh had a good inhibitory effect on endometrial cancer Ishikawa nude mouse tumors, with an in vivo inhibition rate of 58.4%, significantly higher than that of the clinical drug cisplatin (ca. 53.6%). In conclusion, the rhodium complex CpRh exhibits superior in vitro and in vivo antitumor activity and has potential pharmaceutical value, making it a promising candidate for the preparation of various antitumor drugs. Attached Figure Description

[0013] Figure 1 This is an X-ray single-crystal structure diagram of the rhodium complex CpRh obtained in Example 1 of the present invention; Figure 2 The infrared spectrum of the rhodium complex CpRh obtained 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 In a thick-walled, drug-resistant tube of approximately 15.0 cm, 5-bromo-8-hydroxyquinoline (H-OBr, 0.1 mmol), an equimolar amount of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (η5-Cpa), methanol (1.0 mL), dimethyl sulfoxide (DMSO, 0.3 mL), and triethylamine (0.1 mL) were added. After capping, the mixture was reacted at 80 °C for 3 days. After cooling to 37 °C, the mixture was filtered and dried to obtain reddish-brown blocky crystals ClRh (yield: 87.2%).

[0016] The obtained rhodium complex CpRh was identified as follows: (1) X-ray single-crystal structure diagram of the rhodium complex CpRh, as shown in the figure. Figure 1 As shown.

[0017] (2) The infrared spectrum of the rhodium complex CpRh is shown in the figure below. Figure 2 As shown.

[0018] IR (KBr): 3006, 2978, 1588, 1563, 1492, 1452, 1400, 1372, 1353, 1321,1210, 1086, 1045, 1024, 946, 831, 785, 741, 653, 614, 532, 440, and 421 cm 1 . (4) Elemental analysis results are shown in Table 1.

[0019] Table 1 shows the elemental analysis results of the rhodium complex CpRh in the examples.

[0020] Therefore, the structural formula of the obtained rhodium complex CpRh can be determined as follows:

[0021] To fully illustrate the use of the rhodium complex CpRh described in this invention in pharmaceutical applications, the applicant conducted antitumor activity experiments on it.

[0022] I. Experiment on the inhibitory activity of rhodium complex CpRh on the proliferation of two human cell lines 1. Cell lines and cell culture This experiment used two human cell lines: Ishikawa cells (endometrial cancer) and HL-7702 cells (normal human liver).

[0023] 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.

[0024] 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.

[0025] 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.

[0026] Table 2. IC50 of rhodium complex CpRh for various cell lines50 Value (µM)

[0027] Based on the CCK-8 results, the rhodium complex CpRh showed excellent inhibitory effects on Ishikawa endometrial cancer cells, with an IC50 value of [missing information]. 50 The value was 1.64 ± 0.17 μM, and its activity was much greater than that of H-OBr (>50.00 μM), η5-Cpa (>50.00 μM) and cisplatin (8.56 ± 0.75 μM); moreover, the rhodium complex CpRh had very low toxicity to normal HL-7702 cells (>50.00 μM); indicating that the rhodium complex CpRh can target and inhibit the growth of endometrial cancer Ishikawa cells.

[0028] II. In vivo tumor suppression experiment in tumor-bearing nude mice Ishikawa tissue from endometrial cancer 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 drug was initiated on the day of grouping, with the rhodium complex CpRh 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.

[0029] 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%.

[0030] Table 3. In vivo antitumor effect of rhodium complex CpRh on nude mice bearing Ishikawa endometrial cancer.

[0031] Table 3 shows that the in vivo tumor inhibition experiments of the rhodium complex CpRh have a good inhibitory effect on Ishikawa nude mouse endometrial cancer, with an in vivo inhibition rate of 58.4%, which is significantly higher than that of the clinical drug cisplatin (ca. 53.6%). In summary, the rhodium complex CpRh exhibits superior in vitro and in vivo antitumor activity and has potential pharmaceutical value, and is expected to be used in the preparation of various antitumor drugs.

Claims

1. A rhodium complex, characterized in that, The chemical structural formula is shown below: 。 2. The method for preparing the rhodium complex according to claim 1, characterized in that, Take 5-bromo-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 rhodium complex according to claim 1 in the preparation of a drug for treating endometrial cancer.

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