8-hydroxyquinoline derivative platinum complex as well as synthesis method and application thereof

Abstract

The invention discloses an 8-hydroxyquinoline derivative platinum complex as well as a synthesis method and application thereof. According to the invention, an 8-hydroxyquinoline derivative platinum complex is used as an active ligand and reacts with cis-Pt (DMSO) 2Cl2 to synthesize the 8-hydroxyquinoline derivative platinum complex. The 8-hydroxyquinoline derivative platinum complex has a good inhibition effect on human breast cancer cells MDA-MB-231, shows excellent in-vivo and in-vitro anti-tumor activity, has potential medicinal value, and is expected to be used for preparing various anti-tumor drugs.

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, a large number of 8-hydroxyquinoline derivatives of platinum anticancer drugs have high anticancer activity against cancer cells (Chen Zhenfeng, et al. Chinese Science: Chemistry, 2017, 47(02): 172-182..); however, the synthesis of platinum complexes with 8-hydroxyquinoline derivatives (QCl, QBr) as ligands is still a blank. 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 complexes have the chemical formulas of [Pt(QCl)Cl 2 ]·CH 3 OH(YLN1) and [Pt(QBr)Cl 2 ]·CH 3 OH(YLN2), its chemical structure is 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 8-hydroxyquinoline derivative platinum complex is as follows: 8-hydroxyquinoline-2-carboxaldehyde is mixed with 5-chloro-2-hydrazinopyridine or 2-hydrazino-5-bromopyridine, the mixed solution is stirred and reacted at 68° C. for 24 hours, cooled to room temperature, filtered, washed with 10 mL of ethanol three times, and dried to obtain a ligand; the ligand is reacted with cis-Pt(DMSO) 2 Cl 2 The coordination reaction is carried out at 45-90° C. for 3 days in the presence of methanol to obtain a platinum complex of an 8-hydroxyquinoline derivative.

[0009] Its synthetic route is as follows:

[0010]

[0011] In the present invention, when the platinum compounds YLN1 and YLN2 are synthesized by coordination reaction, methanol must be contained to generate the target complex; the reaction system may contain other solvents, which may be acetone, DMF, DMSO, dichloromethane, chloroform, distilled water, and the volume thereof is 0.1-0.8 mL; wherein 2.5 mL methanol and 0.4 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 45-90° C. for 3 days, and the yield is best at a reaction temperature of 68° 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 and uses them as active ligands to react with cis-Pt(DMSO) 2 Cl 2 The new platinum compounds YLN1 and YLN2 were synthesized by reaction, and their activity and toxicity experiments on MDA-MB-231 (human breast cancer cells) and HL-7702 (normal liver cells) were investigated. The experimental results showed that the platinum compounds YLN1 and YLN2 had a good inhibitory effect on MDA-MB-231 cancer cells, IC 50 The values ​​were 5.49±0.14μM and 7.09±0.24μM, which were much larger than cis-Pt(DMSO) 2 Cl 2 The results showed that the platinum compounds YLN1 and YLN2 had good tumor selectivity against MDA-MB-231 tumor cells. In conclusion, the 8-hydroxyquinoline derivative (QCl, QBr) platinum compounds YLN1 and YLN2 showed excellent antitumor activity, had potential medicinal value, and were expected to be used in the preparation of various antitumor drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the ligand QCl prepared in Example 1 of the present invention;

[0016] Figure 2 The hydrogen nuclear magnetic resonance spectrum of the ligand QBr prepared in Example 1 of the present invention;

[0017] Figure 3 The hydrogen nuclear magnetic resonance spectrum of the complex YLN1 prepared in Example 1 of the present invention;

[0018] Figure 4 The nuclear magnetic resonance hydrogen spectrum of the complex YLN2 prepared in Example 1 of the present invention;

[0019] Figure 5 The X-ray single crystal structure of the complex YLN1 prepared in Example 1 of the present invention;

[0020] Figure 6 The X-ray single crystal structure diagram of the complex YLN2 prepared in Example 1 of the present invention;

[0021] Figure 7 This is the infrared spectrum of the complex YLN1 prepared in Example 1 of the present invention;

[0022] Figure 8 This is the infrared spectrum of the complex YLN2 prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0023] The present invention will be further described below with reference to specific examples, but the present invention is not limited to these examples.

[0024] Example 1

[0025] In a 500mL round-bottom flask, 0.0289mol of 8-hydroxyquinoline-2-carboxaldehyde (Qd, 5.0000g), 1.0mL of acetic acid, 300.0mL of methanol and 0.0289mol of 5-chloro-2-hydrazinopyridine (Clpy, 5.4291g) or 2-hydrazino-5-bromopyridine (Brpy, 4.1456g, 0.0289mol) were added, and then the mixed solution was stirred and reacted at 68°C for 24h, cooled to room temperature, filtered, washed three times with 10mL of ethanol, and dried to obtain light yellow ligands QCl (yield: 91.8%) and QBr (yield: 91.6%).

[0026] Subsequently, 0.2 mmol of ligand QCl or QBr and cis-Pt(DMSO) were weighed into a 15.0 cm thick-walled drug-resistant tube. 2 Cl 2 (0.2 mmol), added 2.5 mL of methanol and 0.4 mL of DMSO, covered with a lid, and carried out coordination reaction at 68° C. for 3 days to obtain black rod-shaped crystalline platinum compounds YLN1 (yield 89.4%) and YLN2 (yield 83.5%), respectively.

[0027] Identification of the obtained product:

[0028] (1) H NMR spectra of two 8-hydroxyquinoline derivatives (QCl, QBr) and their new platinum compounds YLN1 and YLN2. Figure 1-4 shown.

[0029] Data of QCl.Yield:91.8%(9.0981g). 1 H NMR(400MHz,DMSO-d 6 ):δ11.60(s,1H),9.71(s,1H),8.27(s,1H),8.25(s,1H),8.20(d,J=2.0Hz,1H),8.13(d,J=8.7Hz,1H),7.78(dd,J=8.9,2.5Hz,1H),7.39(m,3H),7.09(dd,J=7.2,1.6Hz,1H).

[0030] Data of QBr.Yield:91.6%(7.9042g). 1 H NMR(400MHz,DMSO-d 6 ):δ11.60(s,1H),9.72(br s,1H),8.26(m,3H),8.13(d,J=8.7Hz,1H),7.87(dd,J=8.9,2.4Hz,1H),7.39(m,3H),7.09(dd,J=7.2,1.5Hz,1H).

[0031] Data of YLN1.Yield:89.4%. 1 H NMR(400MHz,DMSO-d 6 ):δ11.91(s,1H),8.71(m,2H),8.60(s,1H),8.12(d,J=9.0Hz,1H),8.04(d,J=8.5Hz,1H),7.68(t,J=7.9Hz,1H),7.58(d,J=8.2Hz,1H),7.35(d,J=7.7Hz,1H),7.21(d,J=8.9Hz,1H).

[0032] Data of YLN2.Yield:83.5%. 1 H NMR(400MHz,DMSO-d 6 ):δ11.88(s,1H),8.72(s,1H),8.69(s,1H),8.58(s,1H),8.17(d,J=8.8Hz,1H),8.00(d,J=8.6Hz,1H),7.67(t,J=8.0Hz,1H),7.55(d,J=8.1Hz,1H),7.33(d,J=7.7Hz,1H),7.12(d,J=8.9Hz,1H).

[0033] (2) X-ray single crystal structure diagram of platinum compounds YLN1 and YLN2, and their spectra are shown in Figure 5 and 6 shown.

[0034] (3) Infrared spectra of platinum compounds YLN1 and YLN2, as shown in the following figure Figure 7 and 8 shown.

[0035] Data of YLN1.IR(KBr):3849,3833,3817,3802,3746,3671,3645,3393,3067,2970,2835,2782,2683,1587,1547,1468,1451,1392,1362 ,1270,1245,1221,1167,1148,1132,1097,1074,1007,970,920,845,831,789,743,727,701,687,655,585,573,543,462,419cm -1 .

[0036] Data of YLN2.IR(KBr):3850,3747,3394,3087,2774,2670,2346,1587,1547,1465,1388,1363,1277,1245,1219 ,1148,1134,1093,1073,1036,1007,972,953,918,845,831,744,727,694,652,585,541,529,461,419cm -1 .

[0037] Therefore, the obtained two 8-hydroxyquinoline derivatives (QCl, QBr) and their novel platinum compounds YLN1 and YLN2 can be determined, and their structural formulas are as follows:

[0038]

[0039] Example 2

[0040] In a 500mL round-bottom flask, 0.0289mol of 8-hydroxyquinoline-2-carboxaldehyde (Qd, 5.0000g), 1.0mL of acetic acid, 300.0mL of methanol and 0.0289mol of 5-chloro-2-hydrazinopyridine (Clpy, 5.4291g) or 2-hydrazino-5-bromopyridine (Brpy, 4.1456g, 0.0289mol) were added, and then the mixed solution was stirred and reacted at 68°C for 24h, cooled to room temperature, filtered, washed three times with 10mL of ethanol, and dried to obtain light yellow ligands QCl (yield: 91.8%) and QBr (yield: 91.6%).

[0041] Subsequently, 0.2 mmol of ligand QCl or QBr and cis-Pt(DMSO) were weighed into a 15.0 cm thick-walled drug-resistant tube. 2 Cl 2 (0.2mmol), added 2.5mL methanol and 0.8mL acetone, covered with a lid, and carried out coordination reaction at 90°C for 3 days to obtain black rod-shaped crystalline platinum compounds YLN1 (yield 86.0%) and YLN2 (yield 84.1%), respectively.

[0042] Example 3

[0043] In a 500mL round-bottom flask, 0.0289mol of 8-hydroxyquinoline-2-carboxaldehyde (Qd, 5.0000g), 1.0mL of acetic acid, 300.0mL of methanol and 0.0289mol of 5-chloro-2-hydrazinopyridine (Clpy, 5.4291g) or 2-hydrazino-5-bromopyridine (Brpy, 4.1456g, 0.0289mol) were added, and then the mixed solution was stirred and reacted at 68°C for 24h, cooled to room temperature, filtered, washed three times with 10mL of ethanol, and dried to obtain light yellow ligands QCl (yield: 91.8%) and QBr (yield: 91.6%).

[0044] Subsequently, 0.2 mmol of ligand QCl or QBr and cis-Pt(DMSO) were weighed into a 15.0 cm thick-walled drug-resistant tube. 2 Cl 2 (0.2 mmol), added 2.5 mL of methanol and 0.1 mL of DMF, covered with a lid, and carried out coordination reaction at 45° C. for 3 days to obtain black rod-shaped crystalline platinum compounds YLN1 (yield 83.5%) and YLN2 (yield 83.9%), respectively.

[0045] In order to fully illustrate the use of the two 8-hydroxyquinoline derivatives (QCl, QBr) and their novel platinum compounds YLN1 and YLN2 described in the present invention in pharmaceutical manufacturing, the applicant conducted in vitro and in vivo anti-tumor activity experiments on them.

[0046] 1. Experimental study on the proliferation inhibition activity of two 8-hydroxyquinoline derivatives (QCl, QBr) and their new platinum complexes YLN1 and YLN2 on two human cell lines

[0047] 1. Cell lines and cell culture

[0048] Two human cell lines, MDA-MB-231 (human breast cancer cells) and HL-7702 (normal liver cells), were used in this experiment.

[0049] All human cell lines were cultured in RPMI-1640 medium containing 100 U / mL penicillin, 10 wt% calf blood, and 100 U / mL streptomycin at 37°C with 5% CO 2 Culture in an incubator.

[0050] 2. Preparation of test compounds

[0051] 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.

[0052] 3. Cell Growth Inhibition Experiment

[0053] The specific steps are as follows:

[0054] (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 placed at 37°C with 5% CO 2 Culture in an incubator for 24 h;

[0055] (2) Dilute the drug to the required concentration using RPMI-1640 medium, add 100 μL of the corresponding drug-containing medium to each well of a 96-well plate to make the final concentrations reach 0, 1.0, 2.5, 5.0, 10.0, and 20.0 μM, respectively. Set up 6 parallel experiments for each concentration. After adding the drug, continue culturing in a 37°C, 5% CO2 incubator for 48 h;

[0056] (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.

[0057] Table 2. IC values ​​of compounds against various cell lines 50 Value (μM)

[0058]

[0059] From IC 50 According to the results of activity screening, the platinum compounds YLN1 and YLN2 have a good inhibitory effect on MDA-MB-231 cancer cells, IC 50 The values ​​were 5.49±0.14μM and 7.09±0.24μM, which were much larger than cis-Pt(DMSO) 2 Cl 2 The results showed that the platinum compounds YLN1 and YLN2 had good tumor selectivity against MDA-MB-231 tumor cells. In conclusion, the 8-hydroxyquinoline derivative (QCl, QBr) platinum compounds YLN1 and YLN2 showed excellent antitumor activity, had potential medicinal value, and were 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 is mixed with 5-chloro-2-hydrazinopyridine or 2-hydrazino-5-bromopyridine, the mixed solution is stirred and reacted at 68° C. for 24 hours, cooled to room temperature, filtered, washed with 10 mL of ethanol for three times, and dried to obtain a ligand; the ligand is subjected to coordination reaction with cis-Pt(DMSO)2Cl2 in the presence of methanol at 45-90° C. for 3 days to obtain a platinum complex of an 8-hydroxyquinoline derivative.

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 0.1-0.8 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 2.5 mL of methanol and 0.4 mL of 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 68°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.

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