CN112480019B - 2-benzoxazolone derivative of acanthus ilicifolius alkaloid in marine mangrove, and preparation method and application thereof - Google Patents
2-benzoxazolone derivative of acanthus ilicifolius alkaloid in marine mangrove, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a marine mangrove acanthus ilicifolius alkaloid 2-benzoxazolone derivative, a preparation method and application thereof. The obtained 2-benzoxazolone derivative of the acanthus ilicifolius L.alkaloid has obvious antitumor activity, is a suitable antitumor candidate drug, especially is used as a candidate drug for resisting cervical cancer treatment, has obvious inhibition effect on cervical cancer cells, and can increase the apoptosis rate of the tumor cells.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a 2-benzoxazolone derivative of acanthus ilicifolius L.alkaloid and a preparation method and application thereof.
Background
Acanthus ilicifolius is a mangrove plant growing in tropical coast, and has antioxidant and liver protecting effects, anti-inflammatory and antitumor activities. The alkaloid benzoxazolone compound in the Acanthus ilicifolius L is used as an active substance of a plant secondary metabolite and plays an important role in plant self-defense, and researches show that the benzoxazolone compound has the activities of killing insects, resisting fungi, resisting bacteria and the like, can be used as a lead compound for new pesticide development, and can be used as the lead compound for structural modification and reformation to obtain a compound with better biological activity.
Disclosure of Invention
Based on the content, the invention provides a 2-benzoxazolone derivative of acanthus ilicifolius alkaloid and a preparation method and application thereof. The compound has wide prospect in the development and application of anti-tumor drugs.
One of the technical schemes of the invention is that the ocean mangrove acanthus ilicifolius alkaloid 2-benzoxazolone derivative has a structural formula shown in formula I:
according to the second technical scheme, the preparation method of the 2-benzoxazolone derivative of the acanthus ilicifolius alkaloid is characterized in that o-aminophenol, aromatic aldehyde, trichloroacetic acid and isonitrile are used as raw materials, and the ring closing reaction is carried out after the polymerization reaction to obtain the 2-benzoxazolone derivative of the acanthus ilicifolius alkaloid.
Further, the molar ratio of the o-aminophenol, the aromatic aldehyde, the trichloroacetic acid and the isonitrile is 1:1:1: 1.
Further, the preparation method specifically comprises the following steps:
placing o-aminophenol and aromatic aldehyde in a reaction container, adding methanol, stirring for reaction, sequentially adding trichloroacetic acid and isonitrile for polymerization after precipitation is generated, adding triethylamine for ring closing reaction after the reaction is finished, freezing the product overnight after the reaction is finished, performing suction filtration, washing with water, and recrystallizing to obtain the oceanic mangosteen acanthus alkaloid 2-benzoxazolone derivative.
Further, the molar volume ratio of the o-aminophenol to the methanol is 1 mol: 5L, and the polymerization reaction time is 24 h; the mol ratio of o-aminophenol to triethylamine is 1: 1.5, ring closing reaction time is 24 hours; the product was recrystallized from diethyl ether.
In the third technical scheme of the invention, the application of the 2-benzoxazolone derivative of the acanthus ilicifolius alkaloid in the preparation of antitumor drugs is provided.
Further, the tumor is cervical cancer.
The fourth technical scheme of the invention is that the anti-tumor medicament comprises the ocean mangosteen alkaloid 2-benzoxazolone derivative and pharmaceutically acceptable auxiliary materials.
Compared with the prior art, the invention has the following beneficial effects:
the obtained 2-benzoxazolone derivative of the acanthus ilicifolius L.alkaloid has obvious antitumor activity, is a suitable antitumor candidate drug, especially is used as a candidate drug for resisting cervical cancer treatment, has obvious inhibition effect on cervical cancer cells, and can increase the apoptosis rate of the tumor cells. Compared with a positive control medicament cisplatin, the drug has improved drug inhibition activity on cancer cells. The method for synthesizing the 2-benzoxazolone derivative of the acanthus ilicifolius alkaloid is simple, the raw materials are easy to obtain, the yield of the synthetic route is high, and the operation process is simple and convenient. The compound has wide prospect in the development and application of anti-tumor drugs.
Drawings
FIG. 1 is a synthetic route diagram of acanthus ilicifolius alkaloid 2-benzoxazolone derivatives in the invention;
FIG. 2 is a hydrogen spectrum of Acanthus ilicifolius alkaloid 2-benzoxazolone derivative prepared in example 1 of the present invention;
FIG. 3 is a carbon spectrum of a 2-benzoxazolone derivative of Acanthus ilicifolius alkaloid prepared in example 1 of the present invention;
FIG. 4 is a graph showing the migration effect of 2-benzoxazolone derivatives in Acanthus ilicifolius alkaloids on cervical cancer C-33A cells, prepared in example 1 of the present invention;
FIG. 5 is a graph showing the effect of 2-benzoxazolone derivatives in Acanthus ilicifolius alkaloids on apoptosis factors NOXA and PUMA prepared in example 1 of the present invention.
Detailed Description
Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but as a more detailed description of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. In addition, for numerical ranges in the present disclosure, it is understood that each intervening value, to the upper and lower limit of that range, is also specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the documents are cited. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the present disclosure without departing from the scope or spirit of the disclosure. Other embodiments will be apparent to those skilled in the art from consideration of the specification. The specification and examples are exemplary only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are open-ended terms that mean including but not limited to.
Example 1
Synthesis of acanthus ilicifolius alkaloid 2-benzoxazolone derivative (the synthetic route is shown in figure 1):
weighing o-aminophenol (1mmol) and p-trifluoromethylbenzaldehyde (1mmol) in a 25mL round-bottom flask, adding 5mL methanol, stirring for half an hour, after a precipitate is generated, sequentially adding trichloroacetic acid (1mmol) and cyclohexyl isonitrile (1mmol), and reacting at room temperature for 24 hours; after TLC monitoring polymerization reaction is completed, adding triethylamine (1.5mmol), continuing reaction for 24 hours at room temperature, and after TLC monitoring ring-closing reaction is completed; the reaction solution is put in a refrigerator to be frozen overnight, after the solid is completely separated out, the reaction solution is filtered, washed and recrystallized by ether to obtain the cyclopeptide 2-styryl-5-pyrrolidone-2-amide derivative with the total yield of 83 percent.
The structural formula of the acanthus ilicifolius alkaloid 2-benzoxazolone derivative prepared in the embodiment is shown as formula I:
the compound, a ilicifolius alkaloid 2-benzoxazolone derivative, obtained in this example has a chemical name of N-cyclohexyl-2- (2-benzoxazolone-3-yl) -2-p-trifluoromethyl phenyl acetamide, and its spectral data are as follows: a white solid (0.35g, total yield: 83%); melting point 183-184 ℃. 1 H NMR(CDCl 3 ,400MHz):δ7.64-6.70(m,8H,Ar-H),6.63(s,1H,NH),6.15(s,1H,CH),3.87-3.84(m,1H,CH),2.01-1.13(m,10H,5CH 2 ). 13 C NMR(CDCl 3 ,100MHz):δ165.2,154.8,142.4,137.4,129.3,128.4,128.4,125.9,124.1,123.0,112.0,110.1,60.2,49.2,32.7,25.3,24.7.MS m/z(％):418(M + ,2),292(67),145(33),134(100).Anal.Calcd for C 22 H 21 F 3 N 2 O 3 :C,63.15；H,5.06；N,6.70.Found:C,63.10；H,5.30；N,4.95.
It is composed of 1 HNMR spectra such asAs shown in FIG. 2, which 13 The C NMR spectrum is shown in FIG. 3;
example 2
Experiment of influence of oceanic mangrove acanthus ilicifolius L alkaloid 2-benzoxazolone derivative on cervical cancer C-33A cell proliferation:
cervical cancer cells C-33A in the logarithmic growth phase were collected, digested with 0.25% trypsin, and then centrifuged. Pouring off cell supernatant, preparing into single cell suspension with DMEM medium containing 10% fetal calf serum, and adjusting cell suspension concentration to contain 2 × 10 per ml 5 Individual C-33A cells were seeded into 96-well plates and cultured, 200 μ L of cell suspension was added per well, and the edges of the 96-well plates were filled with sterile PBS. At 5% CO 2 And then incubated in an incubator at 37 ℃ for 24 h. Blanks are set, and the 2-benzoxazolone derivative of the acanthus ilicifolius alkaloid with different concentrations of 10, 20, 30, 40, 50, 60, 70, 80, 90 and 100 mu M and cisplatin with the same final concentration are respectively used for treating the C-33A cells in the logarithmic growth phase for 48 h. Then, MTT reagent was added, and the absorbance was measured by a microplate reader to determine the inhibition ratio at each concentration. The inhibition rate of 2-benzoxazolone derivatives and cisplatin on C-33A cells in Acanthus ilicifolius L.var.argentea L.var.var.argentea L.var.var.var.leiocarpa L.var.f.var.var.franch alkaloid is shown in Table 1.
TABLE 1
Note: n-3, compared to control 1, P < 0.01.
From the table 1, the 2-benzoxazolone derivative of the acanthus ilicifolius L.alkaloid can obviously inhibit the proliferation of the cervical cancer cells C-33A.
According to the result of MTT method, the cervical cancer cell inhibition rate is obviously increased along with the increase of the concentration of the acanthus ilicifolius L.alkaloid 2-benzoxazolone derivative. The concentration of 2-benzoxazolone derivative in the Acanthus ilicifolius L.alkaloid is 10 μ M to 100 μ M, and the inhibition rate of the cervical cancer cell C-33A is respectively increased from (1.25% + -3.01%) to (71.52% + -0.80%).
Example 3
Cervical cancer cells C-33A in the logarithmic growth phase were collected, digested with 0.25% trypsin, and then centrifuged. Pouring off cell supernatant, preparing into single cell suspension with DMEM medium containing 10% fetal calf serum, and adjusting cell suspension concentration to contain 2 × 10 per ml 5 2mL of cell suspension was added per well to each of the C-33A cells in the 6-well plate. 5% CO 2 And then incubated in an incubator at 37 ℃ for 24 h. Setting blank control group and IC of 2-benzoxazolone derivative on C-33A cells according to Acanthus ilicifolius L.var.paniculata L.alkaloid 50 Size settings of (2) cells were treated for 48h at low, medium and high concentrations (20. mu.M, 30. mu.M, 40. mu.M), respectively. After 48h the cells were harvested, digested with Accutase Enzyme and then centrifuged. Operating according to the instructions of the Annexin V-FITC apoptosis detection kit, and determining the effect of the 2-benzoxazolone derivative of the acanthus ilicifolius alkaloid on the C-33A apoptosis by using a flow cytometer. The apoptosis rate of the acanthus ilicifolius alkaloid 2-benzoxazolone derivative on C-33A cells is shown in table 2.
TABLE 2
Note: n-3, P <0.01, compared to control group
As can be seen from Table 2, the apoptosis rate of C-33A cells increased from 7.60% + -0.55% to 62.60% + -1.72% in the flow cytometry results.
Example 4
Effect of Acanthus ilicifolius alkaloids 2-benzoxazolone derivatives on migration of C-33A cells
Cervical cancer cells C-33A in the logarithmic growth phase were collected, digested with 0.25% trypsin, and then centrifuged. Pouring off cell supernatant, preparing into single cell suspension with DMEM medium containing 10% fetal calf serum, and adjusting cell suspension concentration to contain 2 × 10 per ml 5 2mL of cell suspension was added per well to each of the C-33A cells in the 6-well plate.5％CO 2 And then incubated in an incubator at 37 ℃ for 24 h. When the cells fused to about 70%, the cells were placed on a six-well plate with a pre-sterilized ruler, three straight lines were drawn in each well with a 200 μ L pipette tip, the cell supernatant was aspirated, washed twice with PBS, and photographed under a microscope. Setting blank control group and different concentrations of 2-benzoxazolone derivatives of Acanthus ilicifolius alkaloids of marine mangrove of 20 μ M, 30 μ M and 40 μ M to treat cells for 0h, 24h, 48h and 72h respectively, photographing under microscope to observe migration condition of cells, and migration result is shown in FIG. 4.
According to the migration result shown in figure 4, after the 2-benzoxazolone derivatives of the acanthus ilicifolius alkaloids with different concentrations act on the cervical cancer C-33A cells for 0h, 24h, 48h and 72h, compared with the scratch broadband of a control group, the 2-benzoxazolone derivatives of the acanthus ilicifolius alkaloids with different concentrations can inhibit the cell migration to different degrees after acting on the C-33A cells.
Example 5
Action against apoptosis factors NOXA, PUMA
Cervical cancer cells C-33A in the logarithmic growth phase were collected, digested with 0.25% trypsin, and then centrifuged. Pouring off cell supernatant, preparing single cell suspension with DMEM medium containing 10% fetal calf serum, adjusting cell suspension concentration to 2 × 10 per ml 5 For each C-33A cell, 2mL of cell suspension was added per well of 6-well plate. 5% CO 2 And incubating in an incubator at 37 ℃ for 24 h. A blank control group and the 2-benzoxazolone derivatives of the acanthus ilicifolius alkaloids with different concentrations of 20 mu M, 30 mu M and 40 mu M are respectively arranged to treat the cells for 48 h. After 48h, the cells were harvested, total RNA in the cells was extracted, and RT-qPCR was performed. The results were calculated from the amplified CT values, and the amplification results are shown in FIG. 5. As can be seen from fig. 5, expression of both NOXA and PUMA increased, and NOXA and PUMA were pro-apoptotic factors. The experimental result shows that the acanthus ilicifolius L.alkaloid 2-benzoxazolone derivative can induce cell apoptosis by promoting the expression of apoptosis genes NOXA and PUMA.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included therein.
Claims (7)
1. A2-benzoxazolone derivative of acanthus ilicifolius alkaloid in marine mangrove is characterized in that the structural formula is shown as formula I:
2. the preparation method of the 2-benzoxazolone derivative of the acanthus ilicifolius alkaloids in the marine mangrove according to claim 1 is characterized in that o-aminophenol, aromatic aldehyde, trichloroacetic acid and isonitrile are used as raw materials, and the ring closing reaction is carried out after the polymerization reaction to obtain the 2-benzoxazolone derivative of the acanthus ilicifolius alkaloids in the marine mangrove;
the isonitrile is specifically:
3. the preparation method of the 2-benzoxazolone derivative of the acanthus ilicifolius alkaloid as claimed in claim 2, wherein the molar ratio of the o-aminophenol, the aromatic aldehyde, the trichloroacetic acid and the isonitrile is 1:1:1: 1.
4. The preparation method of the 2-benzoxazolone derivative of the acanthus ilicifolius alkaloid as claimed in claim 2, is characterized by comprising the following steps:
putting ortho-aminophenol and aromatic aldehyde into a reaction container, adding methanol, stirring for reaction, sequentially adding trichloroacetic acid and isonitrile for polymerization after precipitation is generated, adding triethylamine for ring closing reaction after the reaction is finished, freezing the product overnight after the reaction is finished, performing suction filtration, washing with water, and recrystallizing to obtain the 2-benzoxazolone derivative of the oceanic mangrove acanthus alkaloid.
5. The preparation method of the 2-benzoxazolone derivative of acanthus ilicifolius L.alkaloid according to claim 4, wherein the molar volume ratio of o-aminophenol to methanol is 1 mol: 5L, and the polymerization reaction time is 24 h; the mol ratio of o-aminophenol to triethylamine is 1: 1.5, ring closure reaction time is 24 hours; the product was recrystallized from diethyl ether.
6. The application of the 2-benzoxazolone derivative of acanthus ilicifolius L as claimed in claim 1 in preparing antitumor drugs, wherein the tumor is cervical cancer.
7. An antitumor drug, which is characterized by comprising the 2-benzoxazolone derivative of the oceanic mangrove acanthus alkaloid of claim 1 and pharmaceutically acceptable auxiliary materials.
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| CN101293876A (en) * | 2008-06-16 | 2008-10-29 | 山西医科大学 | Benzoxazole ketones derivative and preparation method thereof |
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| CN101293876A (en) * | 2008-06-16 | 2008-10-29 | 山西医科大学 | Benzoxazole ketones derivative and preparation method thereof |
Non-Patent Citations (1)
| Title |
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| "One-pot synthesis of Acanthus ilicifolius Linn alkaloid 2-benzoxazolinone derivatives via a tandem Ugi 4-component coupling/haloform cyclization ";Jun Zhu et al.,;《Journal of Chemical Research》;20210630;第1-4页 * |
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