CN111116636B - Preparation method and application of tricyclohexyltin indole-6-formate complex - Google Patents
Preparation method and application of tricyclohexyltin indole-6-formate complex Download PDFInfo
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- AYOHIQLKSOJJQH-UHFFFAOYSA-N dibutyltin Chemical compound CCCC[Sn]CCCC AYOHIQLKSOJJQH-UHFFFAOYSA-N 0.000 description 1
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/22—Tin compounds
- C07F7/2224—Compounds having one or more tin-oxygen linkages
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
The invention discloses a preparation method and application of tricyclohexyl tin indole-6-formate complex, which is a complex with the following structural formula (I)
Description
Technical Field
The invention relates to a tricyclohexyltin indole-6-formate complex, a preparation method thereof and application of the complex in preparing antitumor drugs.
Background
Since Brown first discovered organotin carboxylates (CH 3 CO 2 SnPh 3 ) The synthesis, structure and biological activity research of the organotin carboxylate complex are widely focused by scientists since the biological activity of inhibiting the tumor of mice is inhibited. However, the known organotin compounds are generally highly toxic and therefore limited in application. Studies have shown that the structure, reactivity and biological activity of organotin compounds are related to both the hydrocarbon-based structure directly attached to the tin atom and the nature of the ligand. The organic tin complex structure is optimized through molecular design, so that the balance between toxicity and biological activity of the organic tin complex is regulated, and the organic tin complex is an important direction of current research. The coordination mode of tin atoms can be greatly changed by functionalizing hydrocarbon groups or ligands, so that the biological activity of the organotin complex is affected. Studies have shown that the toxicity of organotin compounds is related to their relative molecular masses, with smaller relative molecular masses being more toxic and larger relative molecular masses being more bulky hydrocarbyl tin. Therefore, the novel large steric hindrance alkyl tin complex is synthesized, and the structure and the biological activity of the complex are researched, so that the complex has important research significance.
It is well known that azacyclic rings are important and common structural units of medicines, pesticides, functional materials, etc., most of which are closely related to life systems, so that studying the structure of organotin derivatives of such ligands can provide useful information not only for the disclosed anticancer mechanism, but also for the development of novel drugs as possible molecular designs. It is necessary to synthesize a novel nitrogen-containing heterocyclic organotin carboxylate compound and conduct a study on the bioactivity of the compound, the nitrogen-containing heteroatom carboxylic acid being an important carboxylic acid ligand. For example, chinese patent CN101402650B discloses an application of a dibutyl tin and quinolinecarboxylic acid complex in preparing medicines for treating gastric cancer, nasopharyngeal carcinoma, human liver cancer or leukemia.
Based on that the tricyclohexyl tin hydroxide is a substance with better biological activity, the tricyclohexyl tin hydroxide is selected to react with the ligand indole-6-formic acid under a certain condition, and the complex with stronger inhibition activity on A549 (human lung cancer cells), hela (human cervical cancer cells) and HGC-27 (human gastric cancer cells) is synthesized, so that a new approach is provided for developing anticancer drugs.
Disclosure of Invention
In view of the above problems of the prior art, a first object of the present invention is to provide a tricyclohexyltin indole-6-carboxylate complex.
The second object of the present invention is to provide a process for preparing the above tricyclohexyltin indole-6-carboxylate complex.
The third object of the invention is to provide the application of the tricyclohexyltin indole-6-formate complex in preparing anticancer drugs.
As a first aspect of the present invention, a tricyclohexyltin indole-6-carboxylate complex having the following structural formula (I):
(I)。
the tricyclohexyltin indole-6-formate complex is subjected to element analysis, infrared spectrum analysis and nuclear magnetic resonance spectrum analysis, and the results are as follows:
elemental analysis (C) 27 H 39 NO 2 Sn): theoretical value: c,61.38; h,7.44; n,2.65. Measurement value: c,61.35; h,7.49; n,2.69.
IR(KBr, v/cm -1 ): 3273.20 (m), 2918.30 (s), 2845.00 (s), 1604.27 (s), 1562.34 (m), 1508.33 (m), 1446.61 (m), 1411.89 (w), 1348.24 (s), 1269.16 (w), 1230.58 (m), 1168.86 (w), 1118.71 (w), 991.41 (w), 898.83 (w), 831.32 (w), 783.10 (m), 736.81 (m), 684.73 (w), 603.72 (w), 570.93 (w), 432.05 (w)。
1 H NMR (CDCl 3 , 500 MHz) δ (ppm): 8.80 (s, 1H), 8.28 (s, 1H), 7.88 (dd, J = 8.5 Hz, J = 1.5 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 7.34 (t, J = 3 Hz, 1H), 6.59 (s,1H), 2.04 - 1.33 (m, 33H)。
13 C NMR(CDCl 3 , 125 MHz) δ (ppm): 172.53, 135.30, 130.94, 126.97, 125.83, 121.71, 119.82, 113.96, 102.70, 33.86, 31.17 (t, J = 7.1 Hz), 28.96 (t, J = 32.3 Hz), 26.94。
119 Sn NMR (CDCl 3 , 186 MHz) δ(ppm): 11.79。
As a preparation method of the tricyclohexyltin indole-6-formate complex, tricyclohexyltin hydroxide, indole-6-formic acid and solvent anhydrous methanol are sequentially added into a microwave reaction tank, and microwave reaction is carried out under the air atmosphere at the radiation power of 800W and the temperature of 100 ℃ for 60-120 min. After the reaction is finished, naturally cooling, filtering, naturally volatilizing and crystallizing the solvent at room temperature to obtain white crystals, namely the tricyclohexyltin indole-6-formate complex.
In a preferred embodiment of the present invention, the mass ratio of the tricyclohexyltin hydroxide to the indole-6-carboxylic acid is 1 (1-1.05).
In a preferred embodiment of the invention, the solvent anhydrous methanol is added in an amount of 10-15 ml per millimole of tricyclohexyl tin hydroxide.
The application of tricyclohexyltin indole-6-formate complex as a third aspect of the invention in preparing anticancer drugs.
The applicant carries out in vitro anti-tumor activity confirmation research on the complex, and confirms that the complex has certain anti-tumor biological activity, namely the application of the complex in preparing anti-tumor drugs, in particular the application in preparing anti-human lung cancer drugs, human cervical cancer cells and human gastric cancer cell drugs.
The tricyclohexyltin indole-6-formate complex of the invention has good anticancer activity on human lung cancer cells, human cervical cancer cells, human gastric cancer cells and the like, and can be used as raw materials for preparing medicines for resisting lung cancer, cervical cancer and gastric cancer. Compared with the currently commonly used platinum anti-cancer drugs, the tricyclohexyltin indole-6-formate complex has the characteristics of high anti-cancer activity, low cost, simple preparation method and the like, and provides a new way for developing anti-cancer drugs.
Drawings
FIG. 1 is an IR spectrum of tricyclohexyltin indole-6-carboxylate complex.
FIG. 2 is a tricyclohexyltin indole-6-carboxylate complex 1 H NMR spectrum.
FIG. 3 is a tricyclohexyltin indole-6-carboxylate complex 13 C NMR spectrum.
FIG. 4 is a tricyclohexyltin indole-6-carboxylate complex 119 Sn NMR spectrum.
FIG. 5 is a TG-DTG curve of tricyclohexyltin indole-6-carboxylate complex.
Detailed Description
The present invention is further illustrated in detail by the following examples, but it should be noted that the scope of the present invention is not limited by any of these examples.
Example 1:
preparation of tricyclohexyltin indole-6-carboxylate complex:
tricyclohexyl tin hydroxide 0.3857 g (1 mmol), indole-6-carboxylic acid 0.1617 g (1 mmol) and solvent anhydrous methanol 10 mL are sequentially added into a microwave reaction tank, and microwave reaction is carried out under the air atmosphere at the radiation power of 800W and the temperature of 100 ℃ for 60 min. After the reaction is finished, naturally cooling, filtering, naturally volatilizing and crystallizing the solvent at room temperature to obtain white crystals, namely the tricyclohexyltin indole-6-formate complex. Yield: 69%, melting point: 216-218 ℃.
Elemental analysis (C) 27 H 39 NO 2 Sn): theoretical value: c,61.38; h,7.44; n,2.65. Measurement value: c,61.35; h,7.49; n,2.69.
IR(KBr, v/cm -1 ): 3273.20 (m), 2918.30 (s), 2845.00 (s), 1604.27 (s), 1562.34 (m), 1508.33 (m), 1446.61 (m), 1411.89 (w), 1348.24 (s), 1269.16 (w), 1230.58 (m), 1168.86 (w), 1118.71 (w), 991.41 (w), 898.83 (w), 831.32 (w), 783.10 (m), 736.81 (m), 684.73 (w), 603.72 (w), 570.93 (w), 432.05 (w)。
1 H NMR (CDCl 3 , 500 MHz) δ (ppm): 8.80 (s, 1H), 8.28 (s, 1H), 7.88 (dd, J = 8.5 Hz, J = 1.5 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 7.34 (t, J = 3 Hz, 1H), 6.59 (s,1H), 2.04 - 1.33 (m, 33H)。
13 C NMR(CDCl 3 , 125 MHz) δ (ppm): 172.53, 135.30, 130.94, 126.97, 125.83, 121.71, 119.82, 113.96, 102.70, 33.86, 31.17 (t, J = 7.1 Hz), 28.96 (t, J = 32.3 Hz), 26.94。
119 Sn NMR (CDCl 3 , 186 MHz) δ(ppm): 11.79。
Example 2:
preparation of tricyclohexyltin indole-6-carboxylate complex:
tricyclohexyltin hydroxide 0.3846 g (1 mmol), indole-6-carboxylic acid 0.1693 g (1.05 mmol) and solvent anhydrous methanol 15 mL are sequentially added into a microwave reaction tank, and microwave reaction is carried out under the air atmosphere at the radiation power of 800W and the temperature of 100 ℃ for 60 min. After the reaction is finished, naturally cooling, filtering, naturally volatilizing and crystallizing the solvent at room temperature to obtain white crystals, namely the tricyclohexyltin indole-6-formate complex. Yield: 70%, melting point: 216-218 ℃.
Elemental analysis (C) 27 H 39 NO 2 Sn): theoretical value: c,61.38; h,7.44; n,2.65. Measurement value: c,61.35; h,7.49; n,2.69.
IR(KBr, v/cm -1 ): 3273.20 (m), 2918.30 (s), 2845.00 (s), 1604.27 (s), 1562.34 (m), 1508.33 (m), 1446.61 (m), 1411.89 (w), 1348.24 (s), 1269.16 (w), 1230.58 (m), 1168.86 (w), 1118.71 (w), 991.41 (w), 898.83 (w), 831.32 (w), 783.10 (m), 736.81 (m), 684.73 (w), 603.72 (w), 570.93 (w), 432.05 (w)。
1 H NMR (CDCl 3 , 500 MHz) δ (ppm): 8.80 (s, 1H), 8.28 (s, 1H), 7.88 (dd, J = 8.5 Hz, J = 1.5 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 7.34 (t, J = 3 Hz, 1H), 6.59 (s,1H), 2.04 - 1.33 (m, 33H)。
13 C NMR(CDCl 3 , 125 MHz) δ (ppm): 172.53, 135.30, 130.94, 126.97, 125.83, 121.71, 119.82, 113.96, 102.70, 33.86, 31.17 (t, J = 7.1 Hz), 28.96 (t, J = 32.3 Hz), 26.94。
119 Sn NMR (CDCl 3 , 186 MHz) δ(ppm): 11.79。
Example 3:
preparation of tricyclohexyltin indole-6-carboxylate complex:
tricyclohexyl tin hydroxide 0.3848 g (1 mmol), indole-6-carboxylic acid 0.1620 g (1 mmol) and solvent anhydrous methanol 12 mL are sequentially added into a microwave reaction tank, and microwave reaction is carried out under the air atmosphere at the radiation power of 800W and the temperature of 100 ℃ for 120 min. After the reaction is finished, naturally cooling, filtering, naturally volatilizing and crystallizing the solvent at room temperature to obtain white crystals, namely the tricyclohexyltin indole-6-formate complex. Yield: 71%, melting point: 216-218 ℃.
Elemental analysis (C) 27 H 39 NO 2 Sn): theoretical value: c,61.38; h,7.44; n,2.65. Measurement value: c,61.35；H，7.49；N，2.69。
IR(KBr, v/cm -1 ): 3273.20 (m), 2918.30 (s), 2845.00 (s), 1604.27 (s), 1562.34 (m), 1508.33 (m), 1446.61 (m), 1411.89 (w), 1348.24 (s), 1269.16 (w), 1230.58 (m), 1168.86 (w), 1118.71 (w), 991.41 (w), 898.83 (w), 831.32 (w), 783.10 (m), 736.81 (m), 684.73 (w), 603.72 (w), 570.93 (w), 432.05 (w)。
1 H NMR (CDCl 3 , 500 MHz) δ (ppm): 8.80 (s, 1H), 8.28 (s, 1H), 7.88 (dd, J = 8.5 Hz, J = 1.5 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 7.34 (t, J = 3 Hz, 1H), 6.59 (s,1H), 2.04 - 1.33 (m, 33H)。
13 C NMR(CDCl 3 , 125 MHz) δ (ppm): 172.53, 135.30, 130.94, 126.97, 125.83, 121.71, 119.82, 113.96, 102.70, 33.86, 31.17 (t, J = 7.1 Hz), 28.96 (t, J = 32.3 Hz), 26.94。
119 Sn NMR (CDCl 3 , 186 MHz) δ(ppm): 11.79。
Example 4:
preparation of tricyclohexyltin indole-6-carboxylate complex:
tricyclohexyl tin hydroxide 0.7707 g (2.0 mmol), indole-6-carboxylic acid 0.3224 g (2 mmol) and solvent anhydrous methanol 25mL are sequentially added into a microwave reaction tank, and microwave reaction is carried out under the air atmosphere at the radiation power of 800W and the temperature of 100 ℃ for 60 min. After the reaction is finished, naturally cooling, filtering, naturally volatilizing and crystallizing the solvent at room temperature to obtain white crystals, namely the tricyclohexyltin indole-6-formate complex. Yield: 70%, melting point: 216-218 ℃.
Elemental analysis (C) 27 H 39 NO 2 Sn): theoretical value: c,61.38; h,7.44; n,2.65. Measurement value: c,61.35; h,7.49; n,2.69.
IR(KBr, v/cm -1 ): 3273.20 (m), 2918.30 (s), 2845.00 (s), 1604.27 (s), 1562.34 (m), 1508.33 (m), 1446.61 (m), 1411.89 (w), 1348.24 (s), 1269.16 (w), 1230.58 (m), 1168.86 (w), 1118.71 (w), 991.41 (w), 898.83 (w), 831.32 (w), 783.10 (m), 736.81 (m), 684.73 (w), 603.72 (w), 570.93 (w), 432.05 (w)。
1 H NMR (CDCl 3 , 500 MHz) δ (ppm): 8.80 (s, 1H), 8.28 (s, 1H), 7.88 (dd, J = 8.5 Hz, J = 1.5 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 7.34 (t, J = 3 Hz, 1H), 6.59 (s,1H), 2.04 - 1.33 (m, 33H)。
13 C NMR(CDCl 3 , 125 MHz) δ (ppm): 172.53, 135.30, 130.94, 126.97, 125.83, 121.71, 119.82, 113.96, 102.70, 33.86, 31.17 (t, J = 7.1 Hz), 28.96 (t, J = 32.3 Hz), 26.94。
119 Sn NMR (CDCl 3 , 186 MHz) δ(ppm): 11.79。
Example 5:
preparation of tricyclohexyltin indole-6-carboxylate complex:
tricyclohexyltin hydroxide 0.7709 g (2.0 mmol), indole-6-carboxylic acid 0.3305 g (2.05 mmol) and solvent anhydrous methanol 25mL are sequentially added into a microwave reaction tank, and microwave reaction is carried out under the air atmosphere at the radiation power of 800W and the temperature of 100 ℃ for 90 min. After the reaction is finished, naturally cooling, filtering, naturally volatilizing and crystallizing the solvent at room temperature to obtain white crystals, namely the tricyclohexyltin indole-6-formate complex. Yield: 71%, melting point: 216-218 ℃.
Elemental analysis (C) 27 H 39 NO 2 Sn): theoretical value: c,61.38; h,7.44; n,2.65. Measurement value: c,61.35; h,7.49; n,2.69.
IR(KBr, v/cm -1 ): 3273.20 (m), 2918.30 (s), 2845.00 (s), 1604.27 (s), 1562.34 (m), 1508.33 (m), 1446.61 (m), 1411.89 (w), 1348.24 (s), 1269.16 (w), 1230.58 (m), 1168.86 (w), 1118.71 (w), 991.41 (w), 898.83 (w), 831.32 (w), 783.10 (m), 736.81 (m), 684.73 (w), 603.72 (w), 570.93 (w), 432.05 (w)。
1 H NMR (CDCl 3 , 500 MHz) δ (ppm): 8.80 (s, 1H), 8.28 (s, 1H), 7.88 (dd, J = 8.5 Hz, J = 1.5 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 7.34 (t, J = 3 Hz, 1H), 6.59 (s,1H), 2.04 - 1.33 (m, 33H)。
13 C NMR(CDCl 3 , 125 MHz) δ (ppm): 172.53, 135.30, 130.94, 126.97, 125.83, 121.71, 119.82, 113.96, 102.70, 33.86, 31.17 (t, J = 7.1 Hz), 28.96 (t, J = 32.3 Hz), 26.94。
119 Sn NMR (CDCl 3 , 186 MHz) δ(ppm): 11.79。
Example 6:
preparation of tricyclohexyltin indole-6-carboxylate complex:
tricyclohexyl tin hydroxide 1.1557 g (3.0 mmol), indole-6-carboxylic acid 0.4835 g (3 mmol) and solvent anhydrous methanol 30 mL are sequentially added into a microwave reaction tank, and microwave reaction is carried out under the air atmosphere at the radiation power of 800W and the temperature of 100 ℃ for 120 min. After the reaction is finished, naturally cooling, filtering, naturally volatilizing and crystallizing the solvent at room temperature to obtain white crystals, namely the tricyclohexyltin indole-6-formate complex. Yield: 72%, melting point: 216-218 ℃.
Elemental analysis (C) 27 H 39 NO 2 Sn): theoretical value: c,61.38; h,7.44; n,2.65. Measurement value: c,61.35; h,7.49; n,2.69.
IR(KBr, v/cm -1 ): 3273.20 (m), 2918.30 (s), 2845.00 (s), 1604.27 (s), 1562.34 (m), 1508.33 (m), 1446.61 (m), 1411.89 (w), 1348.24 (s), 1269.16 (w), 1230.58 (m), 1168.86 (w), 1118.71 (w), 991.41 (w), 898.83 (w), 831.32 (w), 783.10 (m), 736.81 (m), 684.73 (w), 603.72 (w), 570.93 (w), 432.05 (w)。
1 H NMR (CDCl 3 , 500 MHz) δ (ppm): 8.80 (s, 1H), 8.28 (s, 1H), 7.88 (dd, J = 8.5 Hz, J = 1.5 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 7.34 (t, J = 3 Hz, 1H), 6.59 (s,1H), 2.04 - 1.33 (m, 33H)。
13 C NMR(CDCl 3 , 125 MHz) δ (ppm): 172.53, 135.30, 130.94, 126.97, 125.83, 121.71, 119.82, 113.96, 102.70, 33.86, 31.17 (t, J = 7.1 Hz), 28.96 (t, J = 32.3 Hz), 26.94。
119 Sn NMR (CDCl 3 , 186 MHz) δ(ppm): 11.79。
Test example:
the tricyclohexyltin indole-6-formate complex is characterized in that the in-vitro anticancer activity determination is realized by an MTT (methyl thiazolyl tetrazolium) experimental method.
MTT assay:
based on the metabolic reduction of 3- (4, 5-dimethylazol-2-yl) -2,5-diArenyltetrazolium bromide. Succinate dehydrogenase in the mitochondria of living cells reduces exogenous MTT to water insoluble blue-violet crystalline Formazan (Formazan) and deposits in cells, whereas dead cells do not. Dimethyl sulfoxide (DMSO) can dissolve formazan in cells, and the optical density of characteristic wavelength can be measured by an enzyme-labeled instrument, so that the number of living cells can be indirectly reflected.
The inhibitory activity of the tricyclohexyltin indole-6-carboxylate complex prepared in example 1 on human lung cancer cells (A549), human cervical cancer cells (Hela), and human gastric cancer cells (HGC-27) was determined by MTT assay.
Cell lines and culture system: a549, hela, and HGC-27 cell lines were obtained from American Tissue Culture Collection (ATCC). With 10% fetal bovine serum in RPMI1640 (GIBICO) medium at 5% (volume fraction) CO 2 In vitro culture was performed in a saturated humidity incubator at 37 ℃.
The testing process comprises the following steps: the test liquid medicine (0.0625 mu mol/L-0.5 mu mol/L) is added into each hole according to concentration gradient, and 3 parallel holes are arranged for each concentration. The experiments were divided into drug test groups (with different concentrations of test agent added), control groups (with only culture fluid and cells without test agent) and blank groups (with only culture fluid and no cells and test agent). The orifice plate after the drug addition is placed at 37 ℃ and 5 percent CO 2 Culturing in an incubator for 24 hours. The activity of the control drug was determined by the method of the test sample. In the well plate after 48 hours of incubation, MTT 20uL (5 g/L in PBS) was added to each well. After standing at 37℃for 4h, removeClear liquid. 150uL DMSO was added to each well and the mixture was shaken for 10min to dissolve Formazan crystals. Finally, absorbance values of each well were measured at 570nm using a BioTek multifunctional microplate reader.
And (3) data processing: data processing using the GraAr Pad Prism version5.0 program, complex IC 50 Fitting is performed through a nonlinear regression model with S-shaped dose response in the program.
The IC of the human lung cancer cell (A549) cell strain, the human cervical cancer cell (Hela) cell strain and the human gastric cancer cell (HGC-27) cell strain are determined by an MTT assay 50 Values, results are shown in table 1, conclusions are: as can be seen from the data in the table, the tricyclohexyltin indole-6-formate complex provided by the invention is used as an anticancer drug, has high anticancer activity on human lung cancer, human cervical cancer and human gastric cancer, and can be used as a candidate complex of the anticancer drug.
Table 1 tricyclohexyltin indole-6-carboxylate complex anticancer drug in vitro activity test data.
| Human lung cancer cell | Human cervical cancer cell | Human gastric cancer cell | |
| Cell strain | A549 | Hela | HGC-27 |
| IC 50 μM | 0.3035 | 0.1612 | 0.1573 |
The test methods of the anti-cancer activity of the tricyclohexyltin indole-6-formate complex prepared in the other examples on human lung cancer cells (A549), human cervical cancer cells (Hela) and human gastric cancer cells (HGC-27) by using the MTT method are the same as those of the test examples, and the test results are basically the same as those of Table 1.
Claims (1)
1. The application of tricyclohexyltin indole-6-formate complex in preparing anticancer medicine is characterized in that the tricyclohexyltin indole-6-formate complex is a complex with the following structural formula (I):
the cancer cell is cervical cancer Hela.
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| A comparison of the potent in vitro antitumor activity of triphenyltin benzoates with that of related tin compounds;Tranter Carolyn J.等;《Main Group Chemistry》;20060819;165-167 * |
| Tranter Carolyn J.等.A comparison of the potent in vitro antitumor activity of triphenyltin benzoates with that of related tin compounds.《Main Group Chemistry》.2006,165-167. * |
| 氢键构筑网络结构的三正丁基锡羧酸酯的合成、结构及抗癌活性;邝代治等;《无机化学学报》;20150610;1112-1118 * |
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