8-hydroxyquinoline derivative platinum complex as well as synthesis method and application thereof
By synthesizing 8-hydroxyquinoline derivative platinum complex YLN3, the high toxicity and drug resistance of cisplatin drugs were solved, effective inhibition and low toxicity of human breast cancer cells were achieved, and its anti-tumor treatment was demonstrated potential value in.
Patent Information
- Application Number
- CN202411292891.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-14
- Publication Date
- 2025-01-03
AI Technical Summary
Existing cisplatin drugs have high toxicity and drug resistance problems in the treatment of cancer. The 8-hydroxyquinoline derivative platinum complex has low selectivity in the field of tumors and has not been used for clinical anti-cancer applications.
Design and synthesize the 8-hydroxyquinoline derivative platinum complex [PtCl2(phyq)] by mixing 8-hydroxyquinoline-2-formaldehyde with 2-hydrazine pyrimidine 5-chloro-2-hydrazine pyridine, followed by Coordination reaction with cis-Pt(DMSO) 2Cl2 in the presence of acetonitrile to produce a novel platinum compound YLN3, and the reaction conditions are optimized to improve yield and selectivity.
Platinum YLN3 has a significant inhibitory effect on human breast cancer cell MDA-MB-231, with an IC50 value of 2.79±0.07μM, which is much lower than cis-Pt(DMSO)2Cl2 and cisplatin, and it is also used to normal hepatocyte HL-7702 It has low toxicity and shows superior anti-tumor selectivity and potential medicinal value.
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Abstract
Description
Technical Field
[0001] The invention relates to the technical field of medicines, and in particular to an 8-hydroxyquinoline derivative platinum complex and a synthesis method and application thereof. Background Art
[0002] Cisplatin drugs have achieved very good therapeutic effects in clinical cancer treatment, but they produce great toxicity and drug resistance during the treatment process (Guo, Z.; et al. Chem. Soc. Rev., 2013, 42: 202-224.), so it is necessary to design new high-efficiency and low-toxic platinum anticancer drugs.
[0003] In addition, 8-hydroxyquinoline derivative platinum complexes have certain effects in the field of tumors (Chen Zhenfeng, et al. Chinese Science: Chemistry, 2017, 47(02): 172-182.), but their selectivity is low and their in vivo clinical anti-cancer applications are still lacking, so it is necessary to develop new targeted 8-hydroxyquinoline platinum complexes. Summary of the invention
[0004] One of the objects of the present invention is to provide a platinum complex of an 8-hydroxyquinoline derivative.
[0005] Specifically, the 8-hydroxyquinoline derivative platinum complex, [PtCl2(phyq)](YLN3), has a chemical structure as shown below:
[0006]
[0007] The second object of the present invention is to provide a method for synthesizing the above-mentioned 8-hydroxyquinoline derivative platinum complex.
[0008] Specifically, the synthesis method of the above-mentioned 8-hydroxyquinoline derivative platinum complex is as follows: 8-hydroxyquinoline-2-carboxaldehyde is mixed with 2-hydrazinopyrimidine 5-chloro-2-hydrazinopyridine, the mixed solution is stirred at 80°C, reacted for 12 hours, cooled to room temperature, the solution is removed, recrystallized with 20.0 mL of ethanol, filtered, and dried to obtain the ligand phyq; the ligand phyq is subjected to coordination reaction with cis-Pt(DMSO)2Cl2 in the presence of acetonitrile (CH3CN) at 55-80°C for 3 days to obtain the 8-hydroxyquinoline derivative platinum complex YLN3.
[0009] Its synthetic route is as follows:
[0010]
[0011] In the present invention, when the platinum compound YLN3 is synthesized by coordination reaction, acetonitrile must be contained to generate the target complex; the reaction system may contain other solvents, which may be acetone, DMF, DMSO, dichloromethane, chloroform or distilled water, and the volume thereof is 0.1-0.5 mL; wherein 3.0 mL acetonitrile and 0.1 mL DMSO are the best solvent conditions, the product is higher, and the target is easier to separate. The reaction system is subjected to coordination reaction at 55-80°C for 3 days, and the yield is best at a reaction temperature of 65°C, while the yield is very low at a temperature below 55°C or above 80°C.
[0012] Another object of the present invention is to provide the application of the above-mentioned 8-hydroxyquinoline derivative platinum complex.
[0013] Specifically, the application of 8-hydroxyquinoline derivative platinum complex in the preparation of targeted drugs for the treatment of breast cancer.
[0014] Compared with the prior art, the present invention synthesizes 8-hydroxyquinoline derivatives (phyq) and uses them as active ligands to react with cis-Pt(DMSO)2Cl2 to synthesize a new platinum compound YLN3, and investigates their activity and toxicity experiments on human breast cancer cells MDA-MB-231 and normal liver cells HL-7702. The experimental results show that the platinum compound YLN3 has a good inhibitory effect on MDA-MB-231 cancer cells, IC 50 The value is 2.79±0.07μM, which is much larger than cis-Pt(DMSO)2Cl2 (>100μM), phyq (50.14±1.04μM) and clinical drug cisplatin (9.46±0.88μM), and has little toxicity to normal HL-7702 cells (>100μM), indicating that the platinum complex YLN3 has good tumor selectivity for MDA-MB-231 cancer cells. In short, 8-hydroxyquinoline platinum complex YLN3 exhibits excellent antitumor activity, has potential medicinal value, and is expected to be used in the preparation of various antitumor drugs. BRIEF DESCRIPTION OF THE DRAWINGS
[0015] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of the ligand phyq prepared in Example 1 of the present invention;
[0016] Figure 2 The hydrogen nuclear magnetic resonance spectrum of the complex YLN3 prepared in Example 1 of the present invention;
[0017] Figure 3 The X-ray single crystal structure diagram of the complex YLN3 prepared in Example 1 of the present invention;
[0018] Figure 4 This is the infrared spectrum of the complex YLN3 prepared in Example 1 of the present invention. DETAILED DESCRIPTION
[0019] The present invention will be further described below with reference to specific examples, but the present invention is not limited to these examples.
[0020] Example 1
[0021] In a 250mL round-bottom flask, 0.01mol 8-hydroxyquinoline-2-carboxaldehyde (1.7317g), 0.1mL acetic acid, 50.0mL ethanol and 2-hydrazinopyrimidine 5-chloro-2-hydrazinopyridine (2.3594g, 8.9mmol, 89.0%) were added. The mixture was stirred at 80°C and reacted for 12h. The mixture was cooled to room temperature, the solution was removed, and the mixture was recrystallized with 20.0mL ethanol. The mixture was filtered and dried to obtain a light yellow ligand phyq with a yield of 89.0%.
[0022] Subsequently, 0.1 mmol of ligand phyq (26.51 mg, 0.1 mmol) and cis-Pt(DMSO)2Cl2 (42.20 mg, 0.1 mmol) were weighed into a 15.0 cm thick-walled drug-resistant tube, CH3CN (3.0 mL) and 0.1 mL DMSO were added, the tube was covered, and the reaction was carried out at 65°C for 3 days to obtain reddish brown block crystals YLN3. The yield was 80.2%.
[0023] Identification of the obtained product:
[0024] (1) H NMR spectra of 8-hydroxyquinoline derivatives (phyq) and their new platinum complex YLN3. Figure 1 and 2 shown.
[0025] Data of phyq. 1 H NMR (400MHz, DMSO-d6): δ11.76 (s, 1H), 9.75 (s, 1H), 8.54 (d, J = 4.7
[0026] Hz,2H),8.38(s,1H),8.28(d,J=8.7Hz,1H),8.09(d,J=8.7Hz,1H),7.45–7.32(m,2H),7.10(dd,J=7.2,1.4Hz,1H),6.93(t,J=4.7Hz,1H).
[0027] Data of YLN3. 1 H NMR (400MHz, DMSO-d6): δ11.68 (s, 1H), 9.05 (d, J = 5.9Hz, 1H), 8.82
[0028] (dd,J=4.3,1.9Hz,1H),8.74(m,2H),8.14(d,J=8.7Hz,1H),7.69(t,J=7.9Hz,1H),7.57(d,J=8.1Hz,1H),7.28(d,J=7.7Hz,1H),7.13(m,1H).
[0029] (2) X-ray single crystal structure of platinum compound YLN3, its spectrum is as follows Figure 3 shown.
[0030] (3) Infrared spectrum of platinum compound YLN3, as shown in the following figure Figure 4 shown.
[0031] IR(KBr):3907,3856,3841,3823,3809,3754,3738,3714,3692,3678,3652,3631,3393,3067,2783,2346,1619,1598,1585,1552,1501,1446 ,1431,1354,1334,1274,1213,1165,1150,1126,1112,1084,1070,105 4,973,906,880,829,801,785,760,718,689,625,577,542,461,418cm -1 .
[0032] Therefore, it can be determined that the obtained 8-hydroxyquinoline derivative (phyq) and its novel platinum complex YLN3 have the following structural formula:
[0033]
[0034] Example 2
[0035] In a 250mL round-bottom flask, 0.01mol 8-hydroxyquinoline-2-carboxaldehyde (1.7317g), 0.1mL acetic acid, 50.0mL ethanol and 2-hydrazinopyrimidine 5-chloro-2-hydrazinopyridine (2.3594g, 8.9mmol, 89.0%) were added. The mixture was stirred at 80°C and reacted for 12h. The mixture was cooled to room temperature, the solution was removed, and the mixture was recrystallized with 20.0mL ethanol. The mixture was filtered and dried to obtain a light yellow ligand phyq with a yield of 89.0%.
[0036] Subsequently, 0.1 mmol of ligand phyq (26.51 mg, 0.1 mmol) and cis-Pt(DMSO)2Cl2 (42.20 mg, 0.1 mmol) were weighed into a 15.0 cm thick-walled drug-resistant tube, CH3CN (3.0 mL) and 0.5 mL of acetone were added, the tube was covered, and the reaction was carried out at 80°C for 3 days to obtain reddish brown block crystals YLN3. The yield was 85.0%.
[0037] Example 3
[0038] In a 250mL round-bottom flask, 0.01mol 8-hydroxyquinoline-2-carboxaldehyde (1.7317g), 0.1mL acetic acid, 50.0mL ethanol and 2-hydrazinopyrimidine 5-chloro-2-hydrazinopyridine (2.3594g, 8.9mmol, 89.0%) were added. The mixture was stirred at 80°C and reacted for 12h. The mixture was cooled to room temperature, the solution was removed, and the mixture was recrystallized with 20.0mL ethanol. The mixture was filtered and dried to obtain a light yellow ligand phyq with a yield of 89.0%.
[0039] Subsequently, 0.1 mmol of ligand phyq (26.51 mg, 0.1 mmol) and cis-Pt(DMSO)2Cl2 (42.20 mg, 0.1 mmol) were weighed into a 15.0 cm thick-walled drug-resistant tube, CH3CN (3.0 mL) and 0.3 mL of dichloromethane were added, the tube was covered, and the reaction was carried out at 55°C for 3 days to obtain reddish brown block crystals YLN3. The yield was 75.3%.
[0040] In order to fully illustrate the use of the 8-hydroxyquinoline derivative (phyq) and its novel platinum complex YLN3 described in the present invention in pharmaceutical manufacturing, the applicant conducted in vitro and in vivo anti-tumor activity experiments on them.
[0041] 1. Experimental study on the proliferation inhibition activity of an 8-hydroxyquinoline derivative (phyq) and its novel platinum complex YLN3 against two human cell lines
[0042] 1. Cell lines and cell culture
[0043] In this experiment, two human cell lines, human breast cancer cells MDA-MB-231 and normal liver cells HL-7702, were selected.
[0044] All human cell lines were cultured in RPMI-1640 culture medium containing 100 U / mL penicillin, 10 wt% calf blood, and 100 U / mL streptomycin in an incubator at 37° C. containing 5% CO 2 by volume.
[0045] 2. Preparation of test compounds
[0046] The purity of all compounds used must be ≥95%. Their DMSO stock solutions are diluted with physiological buffer to a final solution of 20 μmol / L (final DMSO concentration ≤1%), and the degree of inhibition of the growth of normal cells or selected tumor cells by each compound at this concentration is tested.
[0047] 3. Cell Growth Inhibition Experiment
[0048] The specific steps are as follows:
[0049] (1) Cell digestion, counting, and preparation to a concentration of 5×10 4 100 μL of cell suspension was added to each well of a 96-well cell culture plate and cultured in a 37°C, 5% CO2 incubator for 24 h.
[0050] (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 the 96-well plate to make the final concentrations reach 0, 1.0, 2.5, 5.0, 10.0, 20.0, 50.0 and 100.0 μM, respectively. Set up 6 parallel experiments for each concentration. After adding the drug, place it in a 37°C, 5% CO2 incubator for 48 h;
[0051] (3) Perform CCK-8 staining and measure the OD value at a wavelength of λ = 450nm: add 10μL CCK-8 to each well, continue to culture in the incubator for 2h, shake for 10min to gently mix, then measure the OD value of each well at a wavelength of λ = 450nm using an enzyme marker to calculate the inhibition rate of each compound on the growth of the selected cell line, and then calculate the IC value of each test compound on the selected cell line using the Bliss method. 50 The results are shown in Table 2 below.
[0052] Table 2. IC values of compounds against various cell lines 50 Value (μM)
[0053]
[0054] From IC 50 According to the results of activity screening, the platinum compound YLN3 has a good inhibitory effect on MDA-MB-231 cancer cells, IC 50The value is 2.79±0.07μM, which is much larger than cis-Pt(DMSO)2Cl2 (>100μM), phyq (50.14±1.04μM) and clinical drug cisplatin (9.46±0.88μM), and has little toxicity to normal HL-7702 cells (>100μM), indicating that the platinum complex YLN3 has good tumor selectivity for MDA-MB-231 cancer cells. In short, 8-hydroxyquinoline platinum complex YLN3 exhibits excellent antitumor activity, has potential medicinal value, and is expected to be used in the preparation of various antitumor drugs.
Claims
1. 8-Hydroxyquinoline derivative platinum complex, characterized in that: The chemical structure is shown below:
2. The method for synthesizing the 8-hydroxyquinoline derivative platinum complex according to claim 1, characterized in that: 8-hydroxyquinoline-2-carboxaldehyde and 2-hydrazinopyrimidine 5-chloro-2-hydrazinopyridine were mixed, the mixed solution was stirred at 80° C., reacted for 12 hours, cooled to room temperature, the solution was removed, recrystallized with 20.0 mL of ethanol, filtered, and dried to obtain a ligand phyq; the ligand phyq was subjected to a coordination reaction with cis-Pt(DMSO)2Cl2 in the presence of acetonitrile at 55-80° C. for 3 days to obtain a platinum complex of an 8-hydroxyquinoline derivative; The structural formula of the ligand phyq is:
3. The method for synthesizing the 8-hydroxyquinoline derivative platinum complex according to claim 2, characterized in that: The reaction system of the coordination reaction contains other solvents, including acetone, DMF, DMSO, dichloromethane, chloroform or distilled water, with a volume of 0.1-0.5 mL.
4. The method for synthesizing the 8-hydroxyquinoline derivative platinum complex according to claim 3, characterized in that: The solvent conditions for the coordination reaction were 3.0 mL acetonitrile and 0.1 mL DMSO.
5. The method for synthesizing the 8-hydroxyquinoline derivative platinum complex according to claim 2, 3 or 4, characterized in that: The temperature of the coordination reaction was 65°C.
6. Use of the 8-hydroxyquinoline derivative platinum complex according to claim 1 in the preparation of drugs for targeted treatment of breast cancer.