CN115850347A - Lung cancer cell inhibitor and preparation method and application thereof - Google Patents
Lung cancer cell inhibitor and preparation method and application thereof Download PDFInfo
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- CN115850347A CN115850347A CN202211672570.6A CN202211672570A CN115850347A CN 115850347 A CN115850347 A CN 115850347A CN 202211672570 A CN202211672570 A CN 202211672570A CN 115850347 A CN115850347 A CN 115850347A
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Abstract
The invention discloses a lung cancer cell inhibitor, which has a chemical structural formula shown as the following formula:
the invention also discloses a preparation method and application of the lung cancer cell inhibitor. The lung cancer cell inhibitor shows excellent in-vivo and in-vitro anti-lung cancer activity and targeting property, has potential medicinal value, and can be used for preparing various anti-lung cancer medicines.
Description
Technical Field
The invention relates to a complex, and particularly relates to a lung cancer cell inhibitor. Meanwhile, the invention also relates to a preparation method and application of the lung cancer cell inhibitor.
Background
Since 1965, rosenberg discovered that cisplatin has anti-tumor activity, so far, it still has important significance for cancer treatment and development of platinum anti-tumor drugs, and cisplatin is still considered as one of important drugs for cancer treatment in clinic. However, clinical use of cisplatin and its derivatives is associated with serious adverse effects including neurotoxicity, nephrotoxicity, hematological toxicity, and drug resistance, among others (Guo, z.; et al, chem.soc.rev.,2013, 42. Therefore, the development of a zinc metal anticancer complex with high efficiency and low toxicity is urgently needed.
The document reports that the metal complexes of the 8-hydroxyquinoline and the derivatives thereof have good antitumor and antibacterial activities (Chen Shao, et al, chinese science: chemistry, 2017,47 (02): 172-182.), however, the complexes are deficient in the research of the cisplatin-resistant strains (A549/DDP or A549R) of the human lung adenocarcinoma.
Disclosure of Invention
One of the technical problems to be solved by the invention is to provide a lung cancer cell inhibitor which has high activity in vivo and in vitro and targets cisplatin-resistant cells of human lung cancer, and the lung cancer cell inhibitor is a 5-substituted-8-hydroxyquinoline platinum complex which is synthesized by taking 5- (ethoxymethyl) -8-hydroxyquinoline as an active ligand.
Specifically, the chemical structural formula of the lung cancer cell inhibitor is shown as the following formula:
the second technical problem to be solved by the present invention is to provide a method for preparing the lung cancer cell inhibitor.
In particular to a preparation method of a lung cancer cell inhibitor,
0.1mmol of ligand 5- (ethoxymethyl) -8-hydroxyquinoline and 0.1mmol of the metal salt cis-Pt (DMSO) are weighed out 2 Cl 2 Dissolving in 1.5-10.0mL of methanol or a mixed solution of methanol and acetone, water or DMSO (volume ratio is arbitrary), performing coordination reaction at 45-85 deg.C for 1-7 days, filtering, and drying in a vacuum drying oven at 45 deg.C to obtain yellow bulk crystals PtL1.
The invention also provides the application of the lung cancer cell inhibitor.
In particular to application of the lung cancer cell inhibitor in preparing a medicament for targeted therapy of lung cancer. Further relates to application of the lung cancer cell inhibitor in preparing a medicine for targeted therapy of cisplatin-resistant strain lung cancer.
The invention relates to a method for synthesizing a 5-substituted-8-hydroxyquinoline platinum complex [ Pt (L1) (DMSO) Cl ] targeting a human lung cancer cis-platinum-resistant strain by using 5- (ethoxymethyl) -8-hydroxyquinoline (H-L1), 5-bromo-8-hydroxyquinoline (H-L2) and 8-hydroxyquinoline (H-L3) as active ligands](PtL1)、[Pt(L2)(DMSO)Cl](PtL 2) and [ Pt (L3) (DMSO) Cl](PtL 3) and examined the activity and toxicity experiments of human lung cancer A549, cisplatin-resistant strain A549R and normal HL-7702 cells. The experimental result shows that PtL1 can inhibit the growth of the cisplatin-resistant strain A549R of the human lung adenocarcinoma in a targeted way, and the IC of the cisplatin-resistant strain A549R 50 The value is 1.3 +/-0.7 mu M, and the activity is far greater than that of H-L1 and cis-Pt (DMSO) 2 Cl 2 H-L2, H-L3, cisplatin, ptL2 and PtL3, and its inhibitory effect on normal HL-7702 cells is small: (>50 mu M), which shows that the 5- (ethoxymethyl) -8-hydroxyquinoline platinum complex PtL1 can target and inhibit the proliferation of the human lung adenocarcinoma cis-platinum-resistant strain A549R and also has better anticancer activity. More importantly, in vivo tumor inhibition experiments show that PtL1 has good tumor inhibition effect on a nude mouse model carrying human lung cancer A549, and the inhibition rate is up to 68.2 percent and is far higher than the inhibition effect (50.0 percent) of clinical medicine cisplatin. In summary, 5- (ethoxymethyl) -8-hydroxyquinoline platinum complexes PtL1 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 medicaments.
Drawings
FIG. 1 shows a schematic diagram of an X-ray single crystal of the complex PtL1 obtained in example 1 of the present invention;
FIG. 2 is a structural view of an X-ray single crystal of a complex PtL2 obtained in example 1 of the present invention;
FIG. 3 is a structural view of an X-ray single crystal of a complex PtL3 obtained in example 1 of the present invention;
FIG. 4 is an infrared spectrum of a complex PtL1 prepared in example 1 of the present invention;
FIG. 5 is an infrared spectrum of a complex PtL2 prepared in example 1 of the present invention;
FIG. 6 is an infrared spectrum of a complex PtL3 prepared in example 1 of the present invention.
Detailed Description
The present invention is further illustrated by the following specific examples, but the present invention is not limited to these examples.
The metal salt cis-Pt (DMSO) involved in the synthetic method of the invention 2 Cl 2 The preparation can be carried out with reference to the existing literature (Al-Allaf, T.A.K.; et Al. Transit. Met.chem.,1998, 23.
Example 1
0.1mmol of ligand H-L1, H-L2 or H-L3 and 0.1mmol of metal salt cis-Pt (DMSO) are added into a thick-wall pressure-resistant pipe with the length of 15cm 2 Cl 2 And 4.5mL of methanol, performing coordination reaction at 55 ℃ for 5 days, filtering, and drying in a vacuum drying oven at 45 ℃ to obtain yellow blocky crystals PtL1-PtL3 respectively. The yields of PtL1, ptL2 and PtL3 were 78.3%, 83.6% and 62.4%, respectively.
The synthetic route is as follows:
the resulting product was characterized:
(1) The structure diagram of the X-ray single crystal of the complex PtL1 is shown in figure 1.
(2) The structure diagram of the X-ray single crystal of the complex PtL2 is shown in figure 2.
(3) The structure diagram of the X-ray single crystal of the complex PtL2 is shown in figure 3.
(4) The infrared spectrum of the complex PtL1 is shown in FIG. 4.
IR(KBr):3922,3131,3013,2917,1627,1599,1576,1506,1460,1400,1322,1168,1131,1022,980,936,920,816,762,734,683,648,569,448cm -1 .
(5) The infrared spectrum of the complex PtL2 is shown in FIG. 5.
IR(KBr):3130,3009,2916,1619,1583,1573,1499,1459,1400,1366,1320,1266,1233,1200,1137,1123,1088,1047,1037,981,957,934,922,815,767,755,694,664,544,450cm -1 .
(6) The infrared spectrum of the complex PtL3 is shown in FIG. 6.
IR(KBr):3130,3004,2915,1592,1578,1507,1472,1399,1322,1283,1243,1175,1125,1035,978,928,856,820,804,777,748,699,650,632,585,530,452,418cm -1 .
(7) The results of elemental analysis are shown in Table 1.
Table 1 elemental analysis results of complexes PtL1-PtL3 in examples
Thus, the resulting yellow complex PtL1-PtL3 can be identified, which has the following structural formula:
example 2
0.1mmol of ligand H-L1 and 0.1mmol of metal salt cis-Pt (DMSO) are added into a thick-wall pressure-resistant pipe with the length of 15cm 2 Cl 2 And 10mL of a mixed solution of methanol and water (volume ratio: 95: 1) were subjected to a coordination reaction at 55 ℃ for 5 days, filtered, dried in a vacuum oven at 45 ℃,this gave, in each case, ptL1 as yellow, massive crystals in a yield of 70.1%.
Example 3
0.1mmol of ligand H-L1 and 0.1mmol of metal salt cis-Pt (DMSO) are added into a thick-wall pressure-resistant pipe with the length of 15cm 2 Cl 2 And 1.5mL of a mixed solution of methanol and DMSO (volume ratio 1).
Example 4
0.1mmol of ligand H-L1 and 0.1mmol of metal salt cis-Pt (DMSO) are added into a thick-wall pressure-resistant pipe with the length of 15cm 2 Cl 2 And 8.0mL of a mixed solution of methanol and DMF (volume ratio 50.
In order to fully illustrate the application of the three targeted cisplatin-resistant cell 8-hydroxyquinoline derivative platinum (II) complexes PtL1-PtL3 of the human lung cancer in pharmacy, the applicant performs in vivo and in vitro antitumor activity experiments on the complexes.
1. Proliferation inhibition activity experiment of three targeted human lung cancer cis-platinum-resistant cell 8-hydroxyquinoline derivative platinum (II) complexes PtL1-PtL3 on three human cell strains
1. Cell lines and cell cultures
3 human cell strains such as human lung cancer A549, cisplatin-resistant strain A549R, normal HL-7702 cells and the like are selected.
All human cell lines were cultured in RPMI-1640 medium containing 100U/mL penicillin, 10wt% calf blood, and 100U/mL streptomycin, and placed at 37 deg.C with 5% CO by volume 2 Culturing in an incubator.
2. Preparation of test Compounds
All compounds used had a purity of 95.0% or more, their DMSO stock solutions were diluted with physiological buffer to 20. Mu. Mol/L final solutions (DMSO final concentration. Ltoreq.1.0%) and the degree of inhibition of growth of normal cells or selected tumor cells by each compound at this concentration was tested.
3. Cell growth inhibition assay (MTT method)
(1) Taking normal cells or tumor cells in logarithmic growth phase, digesting with trypsin, preparing a cell suspension with the concentration of 5000/mL by using a culture solution containing 10% calf serum, inoculating 190 mu L of the cell suspension into a 96-hole culture plate per hole, and enabling the cell density to be detected to reach 1000-10000 holes (the edge holes are filled with sterile PBS);
(2)5％ CO 2 incubating at 37 ℃ for 24h until cell monolayers are paved on the bottoms of the wells, adding 10 mu L of medicine with a certain concentration gradient into each well, and arranging 4 multiple wells in each concentration gradient;
(3)5％ CO 2 incubating at 37 ℃ for 48 hours, and observing under an inverted microscope;
(4) Add 10. Mu.L of MTT solution (5 mg/mL PBS, i.e., 0.5% MTT) to each well and continue culturing for 4h;
(5) Terminating the culture, carefully removing the culture solution in the wells, adding 150 μ L of DMSO into each well to sufficiently dissolve formazan precipitate, mixing uniformly with an oscillator, and measuring the optical density of each well with a microplate reader at a wavelength of 570nm and a reference wavelength of 450 nm;
(6) Simultaneously, a zero setting hole (culture medium, MTT, DMSO) and a control hole (cells, culture solution, MTT, a drug dissolving medium with the same concentration, DMSO) are arranged.
(7) The number of living cells was judged from the measured optical density values (OD values), and the larger the OD value, the stronger the cell activity. Using the formula:
calculating the inhibition rate of each compound on the growth of the selected cells, and calculating the IC of each tested compound on each selected cell strain by a Bliss method 50 The value is obtained. The results are shown in table 2 below.
TABLE 2 IC of Compounds on various cell lines 50 Value (μ M)
IC from Table 2 50 As shown by the activity screening result, the PtL1 can target and inhibit the growth of the human lung adenocarcinoma cis-platinum-resistant strain A549R, and the IC thereof 50 The value is 1.3 +/-0.7 mu M, and the activity of the compound is far greater than that of H-L1 and cis-Pt (DMSO) 2 Cl 2 H-L2, H-L3, cisplatin, ptL2, ptL3 and all 8-hydroxyquinoline platinum complexes reported in the literature (Y. -C.Liu., et al. Med. Chem. Commun.,2016,7, 1802-1811.), and its inhibitory effect on normal HL-7702 cells is small (see that the compounds have little effect on normal HL-7702 cells, see that the compounds have no side effect on the growth of the cells>50 mu M), which shows that the 5- (ethoxymethyl) -8-hydroxyquinoline platinum complex PtL1 can target and inhibit the proliferation of the human lung adenocarcinoma cis-platinum-resistant strain A549R and also has better anticancer activity. In a word, the 5- (ethoxymethyl) -8-hydroxyquinoline platinum complex PtL1 shows excellent in-vitro anti-tumor activity and targeting property, has potential medicinal value and is expected to be used for preparing various anti-tumor medicaments.
2. In vivo tumor suppression experiment for tumor-bearing nude mice
Collecting human lung cancer strain A549 in logarithmic growth phase, and modulating with serum-free medium cell to 5 × 10 6 Viable cell concentration suspension per mL. 0.2mL of the suspension, approximately 1X 10, was withdrawn using a 1.0mL syringe 7 The living cells are inoculated to the subcutaneous part of the right armpit of the nude mouse until the subcutaneous tumor grows to about 1cm 3 In time, the tumor source was generated as a subcutaneous tumor model and passaged on nude mice. Human lung cancer A549 is propagated for 4 generations on nude mice, and after the nude mice grow stably, tumor-bearing mice with vigorous tumor growth and no burst are selected, cervical vertebra dislocation is killed, animal skin is disinfected with 75.0% medical alcohol, tissue blocks are dissected, necrotic parts are removed, and tumor tissues are cut into 1.5mm 3 The left and right small blocks are inoculated under the skin of the right axilla of the nude mouse by a trocar. Measuring the tumor diameter of the transplanted tumor by using an electronic vernier caliper until the tumor volume grows to 100-300mm 3 At time, animals were randomly grouped.
Nude mice with human lung cancer A549 tumor were randomly divided into a vehicle group, a PtL1 medicated group and a blank control group, each group consisting of 6 animals. The administration by intraperitoneal injection was started on the day of grouping, and was administered once every 1 day. The tumor diameter was measured every three days with an electronic vernier caliper, and the body weight was measured. On day 21, cervical dislocation was sacrificed, tumors were dissected away, weighed, photographed, and tumor inhibition rate was calculated.
Tumor volume calculation formula: v = a × b 2 A is a long diameter, and b is a short diameter;
relative tumor volume RTV = V t /V 0 In which V is t Volume at each measurement, V 0 Volume when grouped;
relative tumor proliferation rate T/C% = (T) RTV /C RTV )×100％；
Tumor growth inhibition (%) = (mean tumor weight in vehicle group-mean tumor weight in treatment group)/mean tumor weight in vehicle group × 100%.
TABLE 3 in vivo tumor inhibition rate of PtL1 complex on A549 tumor-bearing nude
In vivo tumor inhibition experiments in Table 3 show that PtL1 has good tumor inhibition effect on a nude mouse model with human lung cancer A549, and the inhibition rate is as high as 68.2%, which is far higher than the inhibition effect (50.0%) of clinical drug cisplatin. Wherein the in vivo anticancer data of cisplatin is derived from literature reports ((a) J.Qi, Y.ZHEN, B.Li, L.Wei, J.Li, X.xu, S.ZHao, X.ZHEN and Y.Wang, eur.J.Med.Chem.,2022,237,114415. (b) J.ZHou, L.Rao, G.Yu, T.R.Cook, X.Chen and F.Huang, chem.Soc.Rev.,2021,50,2839-2891. (c) Y.Li, S.Cre, S.Zhang, Z.gan, X.Wang, X.ZHao, Y.ZHu, M.Cao, X.Wang and W.Li, dalton train., 2021,50,11180-11188. Seid (F.J., Y.Zhu, Y.H.6751, Y.J.J.D.6752, J.H.J.H.6751, J.J.H.D.H.6791, 20251, D.D.52). In a word, the 5- (ethoxymethyl) -8-hydroxyquinoline platinum complex PtL1 shows excellent in-vivo anti-tumor activity, has potential medicinal value and is expected to be used for preparing various anti-tumor medicaments.
In conclusion, the 5- (ethoxymethyl) -8-hydroxyquinoline platinum complex PtL1 shows excellent in-vitro and in-vivo antitumor activity and selectivity and good cytotoxicity selectivity, and the design concept and the synthesis method of the synthesized novel antitumor 5- (ethoxymethyl) -8-hydroxyquinoline platinum complex PtL1 are feasible. The 5- (ethoxymethyl) -8-hydroxyquinoline platinum complex PtL1 has good potential medicinal value due to the antitumor activity, and is expected to be used for preparing various antitumor medicaments.
Claims (4)
1. The lung cancer cell inhibitor is characterized by having a chemical structural formula as shown in the following formula:
2. the method for preparing the lung cancer cell inhibitor according to claim 1, wherein 0.1mmol of the ligand 5- (ethoxymethyl) -8-hydroxyquinoline and 0.1mmol of the metal salt cis-Pt (DMSO) are weighed out 2 Cl 2 Dissolving in 1.5-10.0mL of methanol or a mixed solution of methanol and acetone, water or DMSO, performing coordination reaction at 45-85 deg.C for 1-7 days, filtering, and drying in a vacuum drying oven at 45 deg.C to obtain yellow bulk crystal PtL1.
3. The use of the lung cancer cell inhibitor of claim 1 in the preparation of an antitumor medicament.
4. The use of the lung cancer cell inhibitor of claim 1 in the preparation of a medicament for the targeted treatment of cisplatin-resistant cell line lung cancer.
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