10-hydroxybenzoquinoline platinum complex as well as synthesis method and application thereof

Abstract

The invention provides a 10-hydroxybenzoquinoline platinum complex as well as a synthesis method and application thereof, and belongs to the technical field of medicines, and the chemical formula of the 10-hydroxybenzoquinoline platinum complex is C15H15ClNO2 PtS. The platinum compound L-Pt shows a remarkable inhibition effect on MDA-MB-231 cancer cells, and the IC50 value of the platinum compound L-Pt is 0.092 + / -0.01 [mu] M and is far lower than that of a clinical anti-tumor drug cis-platinum (8.86 + / -0.79 [mu] M); compared with the prior art, synthesis raw material ligands L and cis-Pt (DMSO) 2Cl2 of the platinum compound L-Pt almost have no inhibition effect on MDA-MB-231 cancer cells, the platinum compound L-Pt has high tumor selectivity on the MDA-MB-231 cancer cells, the 10-hydroxybenzoquinoline platinum compound L-Pt shows excellent anti-tumor activity, the potential value of the 10-hydroxybenzoquinoline platinum compound L-Pt as medicine development is shown, and the application prospect is broad. And the compound is expected to become a candidate substance for preparing various anti-tumor drugs.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a 10-hydroxybenzoquinoline platinum complex, a synthesis method and an application thereof. Background Art

[0002] Although platinum-based drugs have achieved tremendous success in the clinical treatment of cancer, they suffer from serious toxic side effects and the susceptibility to drug resistance. Quinoline alkaloids, such as the antimalarial drug quinine and the anticancer drug camptothecin, are a class of alkaloids with a quinoline ring as their basic nucleus. Hydroxyquinoline derivatives are intermediates for a variety of drugs and exhibit a wide range of pharmacological activities, including anticancer, anti-AIDS, antifungal, anti-schistosomal, antioxidant, and neuroprotective activities. Therefore, there is a need to design hydroxybenzoquinoline platinum complexes, their synthesis methods, and their applications. Summary of the Invention

[0003] The purpose of the present invention is to provide a 10-hydroxybenzoquinoline platinum complex and a synthesis method and application thereof, so as to solve the technical problem that there is no effective drug for the treatment of breast cancer.

[0004] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0005] 10-Hydroxybenzoquinoline platinum complex, chemical formula: C 15 H 15 ClNO2PtS, chemical structure is:

[0006]

[0007] Synthesis of 10-hydroxybenzoquinoline platinum complexes, synthesis of the platinum intermediate [Pt(DMSO)2Cl2]: Weigh 0.3 g of K2PtCl4 and dissolve it in 10 mL of H2O. Stir continuously at room temperature. After 10 minutes, add dimethyl sulfoxide (DMSO) dropwise until the solution turns yellow. Heat to 65°C, stir for 30 minutes, cool to room temperature, and refrigerate at 4°C. Filter the solution the next day and wash three times with acetone.

[0008] Synthesis of platinum complex L-Pt: Weigh 0.39 g of ligand L and dissolve it in 10 mL of ethanol and 5 mL of acetone, and 0.85 g of platinum intermediate [Pt(DMSO)2Cl2] (2 mmol) and dissolve it in 5 mL of ethanol and 5 mL of acetone. Slowly add [Pt(DMSO)2Cl2] solution dropwise to the L solution at room temperature. The reaction temperature is controlled at 63-67°C. At this time, the solution is light yellow. Reflux the solution under stirring in a water bath for 6 hours, cool overnight, and filter the solution the next day. Transfer the filtrate to a beaker, seal it with plastic wrap, and then slowly evaporate it at room temperature for 7 days to precipitate yellow needle-like crystals, which are 10-hydroxybenzoquinoline platinum complex.

[0009] Application of 10-hydroxybenzoquinoline platinum complex, 10-hydroxybenzoquinoline platinum complex is used in the preparation of anti-breast cancer drugs.

[0010] Furthermore, the 10-hydroxybenzoquinoline platinum complex was used to prepare anti-breast cancer drugs, and the proliferation inhibition activity of human breast cancer cells MDA-MB-231 was first tested.

[0011] Furthermore, the specific process of the proliferation inhibition activity experiment is as follows:

[0012] (2) Preparation of L-Pt solution: Weigh an appropriate amount of L-Pt complex and dissolve it in DMSO to prepare 10 mmol·L -1 of solution;

[0013] (2) MDA-MB-231 tumor cells in the logarithmic growth phase were taken, washed twice with 5 mL of PBS buffer, digested with 1 mL of trypsin, and terminated with 5 mL of culture medium. The adherent cells were gently blown off, and the cells were mixed and inoculated into a 96-well culture plate;

[0014] (3) Observe the cell growth under a microscope. When the cell confluence reaches more than 80%, pipette 20 μL of the prepared L-Pt into each well. Set up 5 replicate wells in parallel for the drug-treated group and the blank group, and repeat the experiment three times.

[0015] (4) Place the culture plate in a 37°C, 5% CO2 incubator for 48 h. Remove the plate, add 20 μL of 5 mg / mL [4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide reagent, pat the plate evenly, and return the plate to the incubator for 4 h.

[0016] (5) Remove the plate, discard the culture medium, add 200 μL of DMSO solution to each well, place the plate on a horizontal shaker, and gently shake for 15 minutes;

[0017] (6) Use an enzyme-labeled instrument to measure the absorbance at 570 nm.

[0018] The present invention has the following beneficial effects due to the adoption of the above technical solution:

[0019] The platinum compound L-Pt of the present invention showed a significant inhibitory effect on MDA-MB-231 cancer cells, and its IC 50The value was 0.092±0.01μM, which was much lower than the clinical anti-tumor drug cisplatin (8.86±0.79μM); in comparison, the synthetic raw materials ligand L and cis-Pt(DMSO)2Cl2 of the platinum complex L-Pt had almost no inhibitory effect on MDA-MB-231 cancer cells. The platinum complex L-Pt had high tumor selectivity for MDA-MB-231 cancer cells. The 10-hydroxybenzoquinoline platinum complex L-Pt exhibited excellent anti-tumor activity, showing its potential value as a drug development, and is expected to become a candidate substance for the preparation of various anti-tumor drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The figure is a crystal structure diagram of the 10-hydroxybenzoquinoline platinum complex of the present invention. DETAILED DESCRIPTION

[0021] To make the objectives, technical solutions, and advantages of the present invention more clearly understood, the present invention is further described in detail below with reference to the accompanying drawings and by way of preferred embodiments. However, it should be noted that many of the details listed in this specification are merely provided to help the reader gain a thorough understanding of one or more aspects of the present invention, and these aspects of the present invention can be practiced even without these specific details.

[0022] 1. Synthesis of 10-Hydroxybenzoquinoline Platinum Complex

[0023] Synthesis of platinum intermediate [Pt(DMSO)2Cl2]: Weigh 0.3g K2PtCl4 and dissolve it in 10mL H2O. Stir continuously at room temperature. After 10 minutes, add dimethyl sulfoxide (DMSO) dropwise until the solution turns yellow. Heat to 65℃, stir for 30 minutes, cool to room temperature, transfer to a 4℃ refrigerator, filter the solution the next day, and wash three times with acetone.

[0024] Synthesis of platinum complex L-Pt: Weigh 0.39g ligand L (2mmol) and dissolve it in 10mL ethanol and 5mL acetone, 0.85g platinum intermediate [Pt(DMSO)2Cl2] (2mmol) and dissolve it in 5mL ethanol and 5mL acetone, slowly add [Pt(DMSO)2Cl2] solution to the L solution at room temperature, and control the reaction temperature at about 65℃. At this time, the solution is light yellow, and refluxes for 6h under stirring in a water bath, cools overnight, and filters the next day. The filtrate is transferred to a small beaker, sealed with plastic wrap, and then slowly evaporated at room temperature for 7d to precipitate yellow needle-shaped crystals with a yield of about 55%. Select suitable single crystals for X-ray diffraction analysis to determine the crystal structure, such as Figure 1 shown.

[0025] 2. Experimental study on the proliferation inhibitory activity of platinum complex L-Pt on human breast cancer cells MDA-MB-231

[0026] (1) Preparation of L-Pt solution: Weigh an appropriate amount of L-Pt complex and dissolve it in DMSO to prepare 10 mmol·L -1 of solution.

[0027] (2) MDA-MB-231 tumor cells in the logarithmic growth phase were taken, washed twice with 5 mL of PBS buffer, digested with 1 mL of trypsin, and terminated with 5 mL of culture medium. The adherent cells were gently blown off, and the cells were mixed and inoculated into a 96-well culture plate;

[0028] (3) Observe the cell growth under a microscope. When the cell confluence reaches more than 80%, pipette 20 μL of the prepared L-Pt into each well. Set up 5 replicate wells in parallel for the drug-treated group and the blank group, and repeat the experiment three times.

[0029] (4) Place the culture plate in a 37°C, 5% CO2 incubator for 48 h. Remove the plate, add 20 μL of 5 mg / mL MTT ([4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) reagent, pat the plate evenly, and return the plate to the incubator for 4 h.

[0030] (5) Remove the plate, discard the culture medium, add 200 μL of DMSO solution to each well, place the plate on a horizontal shaker, and gently shake for 15 minutes;

[0031] (6) Use an enzyme-labeled instrument to measure the absorbance at 570 nm.

[0032] 3.1 Structural characterization of platinum complexes

[0033] Analysis of X-ray single crystal diffraction data shows that L-Pt belongs to the monoclinic system with a space group of P21 / c. 10-Hydroxybenzoquinoline (L) reacts with [Pt(DMSO)2Cl2] to synthesize [Pt(DMSO)LCl]. Pt(II) coordinates with the hydroxyl O atom in 10-hydroxybenzo[h]quinoline and the N atom of the quinoline heterocycle, while retaining the original DMSO and Cl atoms to form a tetracoordinate complex. The crystal structure of L-Pt is shown in Figure 1. Figure 1 The crystallographic data and structural modification parameters are shown in Table 1, and some bond lengths and bond angles are shown in Table 2.

[0034] Table 1 L-Pt crystallographic data and structural correction parameters

[0035]

[0036]

[0037] Table 2 Partial bond lengths of L-Pt and bond angle (°)

[0038]

[0039] 3.2 Experimental results of L-Pt inhibition of tumor cell growth

[0040] Table 3. IC50 values (μM) of compounds against MDA-MB-231 cell lines

[0041]

[0042]

[0043] According to IC 50 Activity screening results showed that the platinum compound L-Pt exhibited significant inhibitory effect on MDA-MB-231 cancer cells, with an IC 50 The value was 0.092±0.01μM, far lower than the clinical anti-tumor drug cisplatin (8.86±0.79μM). In comparison, the synthetic raw materials of the platinum complex L-Pt, ligand L and cis-Pt(DMSO)2Cl2, had almost no inhibitory effect on MDA-MB-231 cancer cells. This result indicates that the platinum complex L-Pt has high tumor selectivity for MDA-MB-231 cancer cells. In summary, the 10-hydroxybenzoquinoline platinum complex L-Pt exhibits excellent anti-tumor activity, demonstrating its potential value as a drug development candidate and its potential as a candidate for the preparation of various anti-tumor drugs.

[0044] Matters not covered by the present invention are known technologies.

[0045] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. 10-Hydroxybenzoquinoline platinum complex, characterized by: The chemical formula is: C15H15ClNO2PtS, and the chemical structure is:

2. The method for synthesizing a 10-hydroxybenzoquinoline platinum complex according to claim 1, wherein: Synthesis of platinum intermediate [Pt(DMSO)2Cl2]: Weigh 0.3g K2PtCl4 and dissolve it in 10mL H2O. Stir continuously at room temperature. After 10 minutes, add dimethyl sulfoxide (DMSO) dropwise until the solution turns yellow. Heat to 65°C, stir for 30 minutes, cool to room temperature, and refrigerate at 4°C. Filter the solution the next day and wash three times with acetone. Synthesis of platinum complex L-Pt: Weigh 0.39 g of ligand L and dissolve it in 10 mL of ethanol and 5 mL of acetone, and 0.85 g of platinum intermediate [Pt(DMSO)2Cl2] (2 mmol) and dissolve it in 5 mL of ethanol and 5 mL of acetone. Slowly add [Pt(DMSO)2Cl2] solution dropwise to the L solution at room temperature. The reaction temperature is controlled at 63-67°C. At this time, the solution is light yellow. Reflux the solution under stirring in a water bath for 6 hours, cool overnight, and filter the solution the next day. Transfer the filtrate to a beaker, seal it with plastic wrap, and then slowly evaporate it at room temperature for 7 days to precipitate yellow needle-like crystals, which are 10-hydroxybenzoquinoline platinum complex.

3. Application of 10-hydroxybenzoquinoline platinum complex, characterized by: 10-Hydroxybenzoquinoline platinum complexes are used to prepare anti-breast cancer drugs.

4. The use of the 10-hydroxybenzoquinoline platinum complex according to claim 3, characterized in that: 10-Hydroxybenzoquinoline platinum complex is used in the preparation of anti-breast cancer drugs, and the proliferation inhibitory activity of human breast cancer cells MDA-MB-231 is first tested.

5. The use of the 10-hydroxybenzoquinoline platinum complex according to claim 4, characterized in that: The specific process of the proliferation inhibition activity experiment is as follows: (1) Preparation of L-Pt solution: Weigh an appropriate amount of L-Pt complex and dissolve it in DMSO to prepare 10 mmol·L -1 of solution; (2) MDA-MB-231 tumor cells in the logarithmic growth phase were taken, washed twice with 5 mL of PBS buffer, digested with 1 mL of trypsin, and terminated with 5 mL of culture medium. The adherent cells were gently blown off, and the cells were mixed and inoculated into a 96-well culture plate; (3) Observe the cell growth under a microscope. When the cell confluence reaches more than 80%, pipette 20 μL of the prepared L-Pt into each well. Set up 5 replicate wells in parallel for the drug-treated group and the blank group, and repeat the experiment three times. (4) Place the culture plate in a 37°C, 5% CO2 incubator for 48 h. Remove the plate, add 20 μL of 5 mg / mL [4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide reagent, pat the plate evenly, and return the plate to the incubator for 4 h. (5) Remove the plate, discard the culture medium, add 200 μL of DMSO solution to each well, place the plate on a horizontal shaker, and gently shake for 15 minutes; (6) Use an enzyme-labeled instrument to measure the absorbance at 570 nm.

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