CN114539294A - Targeted human lung adenocarcinoma cis-platinum-resistant cell solanum lyratum-phenanthroline zinc (II) complex, and synthesis method and application thereof - Google Patents
Targeted human lung adenocarcinoma cis-platinum-resistant cell solanum lyratum-phenanthroline zinc (II) complex, and synthesis method and application thereof Download PDFInfo
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- 201000005249 lung adenocarcinoma Diseases 0.000 title claims abstract description 39
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 7
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- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/06—Zinc compounds
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention discloses a targeted human lung adenocarcinoma cis-platinum-resistant cell solanum lyratum-phenanthroline zinc (II) complex, a synthesis method and application thereof, and relates to the complex and the synthesis method thereof, wherein the method specifically comprises the following steps: (1) adding 5ml of pyridine into 1, 10-phenanthroline-5-amino, 7-hydroxyheptanoic acid and 1-ethyl-3 (3-dimethylpropylamine) carbodiimide, reacting to obtain a compound 1, dissolving the compound 1, the compound BQ and NaH in a solvent, and performing a coordination reaction to obtain a ligand BQA; (2) and (3) dissolving the ligand BQA, curcumin and zinc chloride (II) solid in methanol and KOH solution, carrying out coordination reaction, washing and drying to obtain the target complex. The research finds that the complex Zn (BQACur) can target and inhibit the growth of the human lung adenocarcinoma cis-platinum-resistant strain A549R, and the IC thereof50The value is 0.08 + -0.02 μ M, the activity is much higher than cisPlatinum, curcumin, ligands BQA, AP and Zn (APCur), has little inhibition effect on human lung adenocarcinoma A549 cells and normal HL-7702 cells, has potential medicinal value and is expected to be used for preparing various anti-lung adenocarcinoma medicaments.
Description
Technical Field
The invention relates to a complex and a synthetic method thereof, in particular to a targeted human lung adenocarcinoma cis-platinum resistant cell solanum lyratum-phenanthroline zinc (II) complex and a synthetic method thereof. The invention also relates to an application of the solanum lyratum-phenanthroline zinc (II) complex in preparation of an anti-lung adenocarcinoma drug.
Background
The drug resistance of cisplatin drugs obviously restricts the curative effect and long-term use of the cisplatin drugs, so that non-platinum drugs are attracted more and more attention in cancer treatment. In addition, zinc is a necessary trace element, plays a very important physiological role in vivo, can form a complex with macromolecular protein, becomes an active center of enzyme, can participate in the constitution of certain vitamins, and shows good selectivity and anticancer activity.
Disclosure of Invention
One of the purposes of the invention is to provide a targeted human lung adenocarcinoma cis-platinum-resistant cell solanum lyratum-phenanthroline zinc (II) complex.
In order to achieve the first object of the present invention, the present invention provides the following technical solutions:
a targeted cisplatin-resistant cell white leaf vine-phenanthroline zinc (II) complex for human lung adenocarcinoma has a chemical structural formula shown in formula 1:
another targeted human lung adenocarcinoma cis-platinum-resistant cell solanum lyratum-phenanthroline zinc (II) complex has a chemical structural formula shown in the following formula 2:
the invention also aims to provide a synthetic method of the targeted human lung adenocarcinoma cis-platinum-resistant cell solanum lyratum-phenanthroline zinc (II) complex.
In order to achieve the second object of the present invention, the present invention provides the following technical solutions: a synthetic method of a targeted human lung adenocarcinoma cis-platinum cell solanum lyratum-phenanthroline zinc (II) complex comprises the following steps:
(1) adding 5ml of pyridine into 1, 10-phenanthroline-5-amino, 7-hydroxyheptanoic acid and 1-ethyl-3 (3-dimethylpropylamine) carbodiimide, reacting to obtain a compound 1, dissolving the compound 1, a byssurine derivative (BQ) and NaH in 2ml of dimethylacetamide solution, and carrying out coordination reaction to obtain a ligand BQA;
(2) and (3) dissolving the ligand BQA, curcumin and zinc chloride (II) solid in methanol and KOH solution, performing coordination reaction, washing and drying to obtain the target complex.
Further, in the step (1), the molar ratio of 1, 10-phenanthroline-5-amino, 7-hydroxyheptanoic acid and 1-ethyl-3 (3-dimethylpropylamine) carbodiimide is 1:1.1: 2; the mol ratio of the compound 1, the bynine derivative (BQ) and NaH is 1:1.2: 5; the solvent is 2ml of dimethylacetamide solution.
Further, in the step (1), the reaction temperature for preparing the compound 1 is 70 ℃, and the reaction time is 12 hours; the reaction temperature of the coordination reaction is 100 ℃, and the reaction time is 185 min.
Further, in the step (2), the molar ratio of the ligand BQA, the curcumin and the zinc (II) chloride solid is 1:1:1, and the volume ratio of the methanol to the KOH is 1.5-15: 0.1.
Further, in the step (2), the reaction temperature of the coordination reaction is 50-90 ℃, and the reaction time is 12-48 h.
Further, in the step (2), the washing is carried out for 3 times by using 5ml of ether solution, and the drying temperature is 45 ℃.
The invention also aims to provide an application of targeted human lung adenocarcinoma cis-platinum-resistant cell solanum lyratum-phenanthroline zinc (II) complex in preparation of anti-lung adenocarcinoma drugs.
In order to realize the third purpose of the invention, the application of the solanum lyratum-phenanthroline zinc (II) complex in preparing the anti-lung adenocarcinoma medicine is realized.
Advantageous effects
Compared with the prior art, the invention synthesizes a novel leucas albecana derivative (BQA), takes the novel leucas albecana derivative as an active ligand and curcumin (H-Cur) as a second ligand, and synthesizes a novel leucas albecana-phenanthroline zinc complex Zn (BQACur) targeting a human lung adenocarcinoma cis-platinum-resistant strain; and the activity and toxicity test of the compound in human lung adenocarcinoma A549, cis-platinum resistant strain A549R and normal HL-7702 cells is examined. Experimental result shows that the novel cryptolepine-phenanthroline zinc complex Zn (BQACur) can be used for targeted inhibition of growth of human lung adenocarcinoma cis-platinum-resistant strain A549R and IC thereof50The values are respectively 0.08 +/-0.02 mu M, the activity of the compound is far greater than that of cisplatin, curcumin (H-Cur), ligands BQA, AP and Zn (APCur), and the compound has little inhibition effect on human lung adenocarcinoma A549 and normal HL-7702 cells; the cryptolepine-phenanthroline zinc complex Zn (BQACur) can be used for targeted inhibition of proliferation of the human lung adenocarcinoma cis-platinum-resistant strain A549R. In a word, the cryptolepine-phenanthroline zinc complex Zn (BQACur) shows excellent antitumor activity and tumor selectivity, has potential medicinal value and is expected to be used for preparing various antitumor medicaments.
Drawings
FIG. 1 is a structural formula of a bynine derivative (BQ) according to the present invention;
FIG. 2 is a structural formula of compound BQA obtained in example 1 of the present invention;
FIG. 3 is a structural formula of a compound Zn (BQACur) prepared in example 1 of the present invention;
FIG. 4 shows the structural formula of compound Zn (APCur) prepared in example 1;
FIG. 5 is an electrospray mass spectrum of Compound 1 prepared in example 1 of the present invention;
FIG. 6 is an electrospray mass spectrum of compound BQA prepared in example 1 of the present invention;
FIG. 7 is a NMR spectrum of BQA obtained in example 1 of the present invention;
FIG. 8 is a NMR spectrum of BQA obtained in example 1 of the present invention;
FIG. 9 is an electrospray mass spectrum of a compound Zn (BQACur) prepared in example 1 of the present invention;
FIG. 10 shows the NMR spectrum of Zn (BQACur) compound obtained in example 1 of the present invention;
FIG. 11 is an electrospray mass spectrum of a compound Zn (APCur) prepared in example 1 of the present invention;
FIG. 12 shows the NMR spectrum of Zn (APCur) compound obtained in example 1 of the present invention;
FIG. 13 shows the NMR spectrum of Zn (APCur) compound obtained in example 1 of the present invention;
fig. 14 is a synthetic route map of the present invention.
Detailed Description
The present invention will be further described with reference to the following specific examples.
The synthesis method and the application of the targeted human lung adenocarcinoma cis-platinum-resistant cell leucinolone acetonide-phenanthroline zinc (II) complex are characterized in that a leucinodine derivative (BQ) is synthesized by referring to the existing literature (Qin, Q. -P.; et al, chem. Commun.,2020,56,3999-4002.), and the structural formula of the complex is shown in figure 1.
Example 1
Synthesis of ligand BQA:
1.00mol of 1, 10-phenanthroline-5-amino (compound AP), 1.10mol of 7-hydroxyheptanoic acid, 2.00mol of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (EDCI) and 5.0mL of pyridine are respectively weighed and reacted for 12.0 hours at 70.0 ℃ to obtain a yellow compound 1 with the yield of 71.4 percent; then, 1.00mol of Compound 1, 1.20mol of Compound BQ, and 5.00mol of NaH were each weighed out, dissolved in 2.0mL of Dimethylacetamide (DMA), reacted at 100.0 ℃ for 185min, and then passed through a column to give yellow ligand BQA in 7.30% yield.
The resulting product was characterized:
(1) the electrospray mass spectrum of the compound 1 is shown in figure 5.
ESI-MS m/z:324.0[M+H]+Wherein M is the molecular weight of Compound 1.
(2) An electrospray mass spectrum of compound BQA is shown in FIG. 6.
ESI-MS m/z:541.2[M+H]+Wherein M is the molecular weight of compound BQA.
(3) The NMR spectrum of compound BQA is shown in FIG. 7.
1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),9.23(dd,J＝1.1,4.5Hz,1H),9.16(dd,J＝1.3,4.9Hz,1H),9.03-8.94(m,2H),8.54(s,1H),8.29(t,J＝7.5Hz,2H),8.17-8.05(m,3H),7.82-7.72(m,3H),7.61-7.51(m,2H),5.02(t,J＝6.2Hz,2H),2.65(t,J＝7.2Hz,2H),2.02(quin,J＝6.8Hz,2H),1.81(quin,J＝7.3Hz,2H),1.70(quin,J＝7.3Hz,2H),1.64–1.52(m,2H)。
(4) The NMR spectrum of compound BQA is shown in FIG. 8.
13C NMR(101MHz,DMSO-d6)δ173.18,159.63,159.28,158.93,158.58,158.38,149.25,146.56,145.93,145.22,143.13,142.66,138.97,135.25(br s,1C),134.09,133.79,132.83,130.60,129.79,126.03,125.60,125.44–125.01(m,1C),124.60,122.75(br d,J＝10.2Hz,1C),120.19,119.99,117.96,117.38(br s,1C),115.05,112.86,73.82,36.40,29.63,28.75,25.47(d,J＝5.8Hz,1C)。
(5) Elemental analysis results, as shown in table 1:
results of elemental analysis of compound BQA in example 1
Thus, the resulting yellow ligand BQA can be identified, and its structural formula is shown in FIG. 2.
Synthesizing a target complex:
in a 15.0mL high-temperature pressure-resistant tube, weighing 1.0mmol of ligand BQA, 1.0mmol of curcumin (H-Cur) and 1.0mmol of zinc chloride (II) solid, adding 3.5mL of methanol and 0.1mL of KOH (0.1M) solution, carrying out coordination reaction for 24H at 65.0 ℃, washing the product with 5.0mL of diethyl ether solution for 3 times, and drying in a vacuum drying oven at 45 ℃ to obtain a yellow target product Zn (BQACur), wherein the yield is 68.3%.
Weighing 1.0mmol of AP, 1.0mmol of curcumin (H-Cur) and 1.0mmol of zinc chloride (II) solid in a 15.0mL high-temperature pressure-resistant tube, adding 3.5mL of methanol and 0.1mL of KOH (0.1M) solution, carrying out coordination reaction at 65.0 ℃ for 24H, washing the product with 5.0mL of diethyl ether solution for 3 times, and drying in a vacuum drying oven at 45 ℃ to obtain a yellow target product Zn (APCur), wherein the yield is 71.5%.
(1) Electrospray ionization mass spectrum of compound Zn (BQACur) is shown in FIG. 9.
ESI-MS:m/z＝971.45for[M-Cl]+Wherein M is the molecular weight of the compound Zn (BQACur).
(2) The NMR spectrum of the compound Zn (BQACur) is shown in FIG. 10.
1H NMR(500MHz,DMSO-d6)δ10.34(s,1H),9.39(d,J＝49.4Hz,2H),8.97(s,2H),8.78(s,2H),8.46(s,2H),8.27(dd,J＝25.9,7.5Hz,3H),8.14–8.05(m,2H),7.82–7.64(m,4H),7.51(d,J＝30.8Hz,4H),7.31(s,1H),7.14(s,2H),6.81(s,4H),4.97(s,2H),3.84(s,6H),2.62(s,2H),1.99(s,2H),1.79(s,2H),1.67(s,2H),1.56(s,2H),0.95(t,J＝7.1Hz,2H)。
(3) Electrospray mass spectrum of compound Zn (APCur) is shown in figure 11.
ESI-MS:m/z＝626.25for[M-Cl]+Wherein M is the molecular weight of the compound Zn (APCur).
(4) The NMR spectrum of the compound Zn (APCur) is shown in FIG. 12.
1H NMR(500MHz,DMSO-d6)δ9.70(s,1H),9.51(s,1H),9.16–9.00(m,2H),8.42(d,J＝7.8Hz,2H),8.24–7.94(m,2H),7.76(s,1H),7.60–7.54(m,1H),7.35(s,2H),7.17(d,J＝7.8Hz,2H),7.06(s,1H),6.86(d,J＝7.9Hz,2H),6.78(d,J＝15.9Hz,2H),6.71(s,3H),3.86(d,J＝9.0Hz,6H)。
(6) The nuclear magnetic resonance carbon spectrum of the compound Zn (APCur) is shown in FIG. 13.
13C NMR(126MHz,DMSO-d6)δ183.85,183.68,149.83,148.47,148.36,144.32,141.16,140.96,136.30,135.02,134.90,134.51,126.82,125.78,124.94,124.68,123.62,121.57,116.19,116.09,111.80,101.47,101.37,56.19,40.50,40.33,40.16,40.00,39.83,39.66,39.50。
(7) Elemental analysis results, as shown in table 2:
table 2 elemental analysis results of the compounds Zn (BQACur) and Zn (APCur) in the examples
Therefore, the obtained yellow Zn (BQACur) and Zn (APCur) can be determined, and the structural formulas are shown in figures 3 and 4.
Example 2
In a 15.0mL high-temperature pressure-resistant tube, weighing 1.0mmol of ligand BQA, 1.0mmol of curcumin (H-Cur) and 1.0mmol of zinc chloride (II) solid, adding 14.5mL of methanol and 0.1mL of KOH (0.1M) solution, carrying out coordination reaction for 48H at 90.0 ℃, washing the product with 5.0mL of diethyl ether solution for 3 times, and drying in a vacuum drying oven at 45 ℃ to obtain a yellow target product Zn (BQACur), wherein the yield is 60.0%.
Example 3
In a 15.0mL high-temperature pressure-resistant tube, weighing 1.0mmol of ligand BQA, 1.0mmol of curcumin (H-Cur) and 1.0mmol of zinc chloride (II) solid, adding 1.5mL of methanol and 0.1mL of KOH (0.1M) solution, carrying out coordination reaction for 12H at 50.0 ℃, washing the product with 5.0mL of diethyl ether solution for 3 times, and drying in a vacuum drying oven at 45 ℃ to obtain a yellow target product Zn (BQACur), wherein the yield is 72.5%.
In order to fully illustrate the application of the two novel solanum lyratum-phenanthroline zinc (II) complexes in pharmacy, in vivo and in vitro anti-tumor activity experiments are performed on the complexes.
1. Cell lines and cell cultures
The experiment selects 3 human cell strains such as human lung adenocarcinoma A549, a cisplatin-resistant strain A549R, normal HL-7702 cells and the like.
All human cell lines were cultured in RPMI-1640 medium containing 100U/mL penicillin, 10 wt% calf blood, and 100U/mL streptomycin, and placed at 37 deg.C with 5% CO by volume2Culturing in an incubator.
2. Preparation of test Compounds
All compounds used had to be more than 95% pure, their DMSO stock solutions were diluted to 20. mu. mol/L final solution (DMSO final concentration. ltoreq.1%) in physiological buffer, and the degree of inhibition of growth of normal cells or selected tumor cells by each compound was tested at this concentration.
3. Cell growth inhibition assay (MTT method)
(1) Taking normal cells or tumor cells in a logarithmic growth phase, digesting the cells or tumor cells by 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, and enabling the density of cells to be detected to reach 1000-10000 holes (the edge holes are filled with sterile PBS);
(2)5％CO2incubating for 24h at 37 ℃ until a cell monolayer is paved on the bottom of each well, adding 10 mu L of medicine with a certain concentration gradient into each well, and arranging 4 compound wells in each concentration gradient;
(3)5％CO2incubating for 48h at 37 ℃, and observing under an inverted microscope;
(4) add 10. mu.L of MTT solution (5mg/mL PBS, i.e., 0.5% MTT) to each well and continue culturing for 4 h;
(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) setting zero adjusting holes (culture medium, MTT and DMSO) and control holes (cells, culture solution, MTT, drug dissolving medium with the same concentration and DMSO);
(7) judging the number of living cells according to the measured optical density value (OD value), wherein the larger the OD value is, the stronger the cell activity is, and the formula is used:
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 method50The results are shown in table 3 below:
TABLE 3 IC of Compounds on various cell lines50Value (μ M)
Slave IC50According to the result of activity screening, the novel cryptolepine-phenanthroline zinc complex Zn (BQACur) can be used for targeted inhibition of the growth of the human lung adenocarcinoma cis-platinum-resistant strain A549R and the IC of the complex50The values are respectively 0.08 +/-0.02 mu M, the activity of the compound is far greater than that of cisplatin, curcumin (H-Cur), ligands BQA, AP and Zn (APCur), and the compound has little inhibition effect on human lung adenocarcinoma A549 and normal HL-7702 cells; in addition, the activity of the novel cryptolepine-phenanthroline zinc complex Zn (BQACur) is far greater than that of all cryptolepine zinc and platinum complexes reported in the literature, and the cryptolepine-phenanthroline zinc complex Zn (BQACur) can be used for targeted inhibition of proliferation of the human lung adenocarcinoma cis-platinum-resistant strain A549R. In a word, the cryptolepine-phenanthroline zinc complex Zn (BQACur) shows excellent antitumor activity and tumor selectivity, has potential medicinal value and is expected to be used for preparing various anti-lung adenocarcinoma medicaments.
The above is only a preferred embodiment of the present invention, and it should be noted that it is obvious to those skilled in the art that several variations and modifications can be made without departing from the structure of the present invention, which will not affect the effect and practicality of the present invention.
Claims (10)
1. A targeted cisplatin-resistant cell white leaf vine-phenanthroline zinc (II) complex for human lung adenocarcinoma is characterized in that the chemical structural formula is shown as the following formula 1:
2. a targeted cisplatin-resistant cell white vine-phenanthroline zinc (II) complex for human lung adenocarcinoma is characterized in that the chemical structural formula is shown as the following formula 2:
3. the method for synthesizing the rattan-phenanthroline zinc (II) complex targeting the human lung adenocarcinoma cis-platin resistant cell according to claim 1 or 2, which is characterized by comprising the following steps:
(1) adding 5ml of pyridine into 1, 10-phenanthroline-5-amino, 7-hydroxyheptanoic acid and 1-ethyl-3 (3-dimethylpropylamine) carbodiimide, reacting to obtain a compound 1, dissolving the compound 1, the compound BQ and NaH in 2ml of dimethylacetamide solution, and carrying out coordination reaction to obtain a ligand BQA;
(2) and (3) dissolving the ligand BQA, curcumin and zinc chloride (II) solid in methanol and KOH solution, performing coordination reaction, washing and drying to obtain the target complex.
4. The method for synthesizing the rattan-phenanthroline zinc (II) complex targeting the human lung adenocarcinoma cis-platin resistant cell according to claim 3, wherein in the step (1), the molar ratio of 1, 10-phenanthroline-5-amino, 7-hydroxyheptanoic acid and 1-ethyl-3 (3-dimethylpropylamine) carbodiimide is 1:1.1: 2; the molar ratio of the compound 1, the compound BQ and NaH is 1:1.2: 5.
5. The synthesis method of the targeted human lung adenocarcinoma cisplatin-resistant cell leucoxene-phenanthroline zinc (II) complex as claimed in claim 3, wherein in the step (1), the reaction temperature for preparing the compound 1 is 70 ℃, and the reaction time is 12 h; the reaction temperature of the coordination reaction is 100 ℃, and the reaction time is 185 min.
6. The synthesis method of the targeted human lung adenocarcinoma cis-platin resistant cell leucoxene-phenanthroline zinc (II) complex as claimed in claim 3, wherein in the step (2), the molar ratio of the ligand BQA, the curcumin and the zinc (II) chloride solid is 1:1:1, and the volume ratio of the methanol to the KOH is 1.5-15: 0.1.
7. The method for synthesizing the rattan-phenanthroline zinc (II) complex targeting the human lung adenocarcinoma cis-platin resistant cell according to claim 3, wherein in the step (2), the reaction temperature of the coordination reaction is 50-90 ℃, and the reaction time is 12-48 h.
8. The method for synthesizing the rattan-phenanthroline zinc (II) complex targeting the human lung adenocarcinoma cis-platin resistant cell according to claim 3, wherein in the step (2), the washing is carried out for 3 times by using 5ml of ether solution, and the drying temperature is 45 ℃.
9. The use of the targeted human lung adenocarcinoma cisplatin-resistant cell leucoxene-phenanthroline zinc (II) complex as claimed in claim 1 or 2 in the preparation of a medicament for resisting lung adenocarcinoma.
10. The use of the targeted human lung adenocarcinoma cisplatin-resistant cell leuconostoc-phenanthroline zinc (II) complex as an active ingredient in the preparation of in vitro and in vivo anti-lung adenocarcinoma drugs according to claim 1 or 2.
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| CN115160347B (en) * | 2022-08-11 | 2023-09-12 | 玉林师范学院 | Glycosyl white vine zinc (II) complex and application |
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Application publication date: 20220527 Assignee: Guangxi Junlang Agricultural Technology Co.,Ltd. Assignor: Yulin Normal University Contract record no.: X2023980045979 Denomination of invention: Targeting Human Lung Adenocarcinoma Cisplatin-resistant Cells with Leukophyllum Phenanthroline Zinc (II) Complex, Synthesis Method and Its Application Granted publication date: 20231020 License type: Common License Record date: 20231106 |
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