CN109053747B - Compound and preparation method and application thereof - Google Patents
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- CN109053747B CN109053747B CN201811009730.2A CN201811009730A CN109053747B CN 109053747 B CN109053747 B CN 109053747B CN 201811009730 A CN201811009730 A CN 201811009730A CN 109053747 B CN109053747 B CN 109053747B
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Abstract
The invention provides a compound, a preparation method and application thereof, wherein the structural formula of the compound is shown as a formula (I), and the preparation method comprises the following steps: (1) carrying out liquid culture on the white rot fungi; (2) mixing the white rot fungi subjected to liquid culture and a liquid culture medium with dinotefuran, and standing for more than 20 days at 24-30 ℃; (3) separating the liquid culture medium after standing from the white rot fungi, and adding ethyl acetate into the separated liquid for extraction to obtain a supernatant; (4) concentrating the supernatant, performing gradient elution with silica gel chromatography, and tracking metabolites with thin layer chromatography; (5) the product obtained by silica gel chromatography is further separated and purified by preparative liquid chromatography to obtain the compound with high purity. The compound was named: the N- ((4aS,7aS, E) -1-methyl hexahydrofuran [2,3-d ] pyrimidine-2 (1H) -subunit) nitramide can inhibit the survival of bone marrow neuroblastoma cells, and the preparation method utilizes microorganisms and white rot fungi to propagate quickly, can be widely applied, has low production cost, and can be simultaneously used for degrading dinotefuran.
Description
Technical Field
The invention relates to the field of compounds, in particular to a compound and a preparation method and application thereof.
Background
The white rot fungi play an important role in the natural ecosystem, are precious biological resources, and are tools and research mode objects for environmental governance. The white rot fungi can degrade a large number of pollutants with different structures without the need of pre-conditioning specific pollutants before degrading pollutants difficult to degrade, has low requirement on nutritional conditions, and can save cost. The capability of the white rot fungus Phanerochaete sordida YK-624 (hereinafter referred to as YK-624) on a plurality of refractory pollutants such as aflatoxin and the like is higher than that of a model strain Phanerochaete chrysosporium. The white rot fungi has wide prospect in treating organic pollutants, and makes full use of the practical significance of the white rot fungi on environmental remediation.
Disclosure of Invention
The invention aims to provide a compound and a preparation method and application thereof.
In order to achieve the purpose, the technical scheme of the invention is as follows: a compound having the formula (I):
The invention also provides a preparation method of N- ((4aS,7aS, E) -1-methylhexahydropuran [2,3-d ] pyrimidine-2 (1H) -subunit) nitramide, which comprises the following steps:
(1) carrying out liquid culture on white rot fungi (YK-624);
(2) mixing the white rot fungi subjected to liquid culture and a liquid culture medium with dinotefuran, and standing for more than 20 days at 24-30 ℃;
(3) separating the liquid culture medium after standing from the white rot fungi, and adding an organic solvent with octanol/water distribution coefficient logarithmic value range of 0.70-0.80 into the separated liquid for extraction to obtain supernatant;
(4) concentrating the supernatant, performing gradient elution with silica gel chromatography, and tracking metabolites with thin layer chromatography;
(5) and further separating and purifying the product obtained by silica gel chromatographic separation by using a preparative liquid chromatography to obtain the high-purity N- ((4aS,7aS, E) -1-methylhexahydropuran [2,3-d ] pyrimidine-2 (1H) -subunit) nitramide.
The liquid culture medium for liquid culture comprises the following components in parts by weight: 9-11 parts of glucose, 0.2-0.3 part of ammonium tartrate, 1.5-1.7 parts of anhydrous sodium acetate and 95-105 parts of Kirk salt solution.
Wherein the Kirk salt solution comprises the following components in percentage by weight: 1.8-2.2% of monopotassium phosphate, 0.4-0.6% of magnesium sulfate heptahydrate, 0.11-0.15% of calcium chloride dihydrate, 0.0009-0.0011% of thiamine hydrochloride and 1.5-1.8% of Kirk trace element solution.
The Kirk microelement solution comprises the following components in parts by weight: 0.8-1% Nitrilotriacetate (Nitrilotriacetate), 0.30.2-0.4% magnesium sulfate heptahydrate, 0.3-0.5% manganese sulfate monohydrate, 0.5-0.7% sodium chloride, 0.04-0.07% ferrous sulfate heptahydrate, 0.09-0.12% cobalt sulfate heptahydrate, 0.09-0.12% zinc sulfate heptahydrate, 0.05-0.07% calcium chloride dihydrate, 0.005-0.007% copper sulfate pentahydrate, 0.009-0.012% aluminum potassium sulfate dodecahydrate, 0.005-0.007% boric acid, 0.006-0.008% sodium molybdate dihydrate.
Preferably, the liquid culture medium for liquid culture comprises the following components in parts by weight: 10 parts glucose, 0.221 part ammonium tartrate, 1.64 parts anhydrous sodium acetate and 100 parts Kirk's salt solution.
Preferably, the Kirk salt solution comprises the following components in percentage by weight: 2% monopotassium phosphate, 0.5% magnesium sulfate heptahydrate, 0.13% calcium chloride dihydrate, 0.001% thiamine hydrochloride, and 1.67% Kirk microelement solution.
The Kirk microelement solution comprises the following components in parts by weight: 0.9% Nitrilotriacetate, 0.3% magnesium sulfate heptahydrate, 0.42% manganese sulfate monohydrate, 0.6% sodium chloride, 0.06% ferrous sulfate heptahydrate, 0.11% cobalt sulfate heptahydrate, 0.11% zinc sulfate heptahydrate, 0.06% calcium chloride dihydrate, 0.006% copper sulfate pentahydrate, 0.011% aluminum potassium sulfate dodecahydrate, 0.006% boric acid, 0.007% sodium molybdate dihydrate.
Preferably, the liquid culture method of the white rot fungi (YK-624) is as follows: inoculating the white rot fungi hypha slices activated on a Potato Dextrose Agar (PDA) culture medium into the liquid culture medium, and carrying out liquid culture at 24-30 ℃.
Preferably, the method of activation is: activating on Potato Dextrose Agar (PDA) which comprises the following components: 20% of potatoes, 2% of glucose and 2% of agar.
Preferably, the standing temperature in step (2) is 30 ℃.
Preferably, the culturing time in the step (1) is 3-5 days.
Preferably, the temperature of the liquid culture in step (1) is 24-30 ℃.
Preferably, the concentration of the dinotefuran in the liquid culture medium is 0.05-0.15 mmol/L.
Preferably, the concentration of the dinotefuran in the liquid culture medium is 0.1 mmol/L.
Preferably, the organic solvent is ethyl acetate.
Preferably, the method of extraction comprises the steps of: extracting the obtained supernatant with 0.5-2 times of the separated liquid volume of ethyl acetate for 2-3 times.
Preferably, the type of the chromatographic column of the preparative chromatography is: inertsil C30S-Select 5m 20x250 mm.
Preferably, the liquid medium is separated from the white-rot fungi in step (3) by a method selected from centrifugation or filtration.
Preferably, the method of concentrating the supernatant is selected from rotary evaporation or freeze drying.
The invention also provides application of the N- ((4aS,7aS, E) -1-methylhexahydropuran [2,3-d ] pyrimidine-2 (1H) -subunit) nitramide in preparing a medicament for inhibiting survival of human bone marrow neuroblastoma cells.
The invention also provides application of the N- ((4aS,7aS, E) -1-methylhexahydropuran [2,3-d ] pyrimidine-2 (1H) -subunit) nitramide in preparing a medicament for preventing and treating abdominal tumors, breast tumors, paravertebral tumors, paraneoplastic syndromes or metastatic tumor diseases.
The invention has the beneficial effects that: the invention provides a compound and a preparation method, the preparation method of the invention utilizes white rot fungi (YK-624) to act on dinotefuran, qualitative analysis is carried out on the acting product, a new compound, N- ((4aS,7aS, E) -1-methyl hexahydro-furan [2,3-d ] pyrimidine-2 (1H) -subunit) nitramide is prepared, the prepared compound can inhibit survival of bone marrow neuroblastoma cells, the preparation method utilizes microorganisms, the white rot fungi are fast in propagation, the compound can be widely applied, the production cost is low, and the compound can be simultaneously used for degrading dinotefuran.
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FIG. 1 is a structural formula diagram of N- ((4aS,7aS, E) -1-methyl hexahydro-furan [2,3-d ] pyrimidine-2 (1H) -subunit) nitramide.
FIG. 2 is a mass spectrum of N- ((4aS,7aS, E) -1-methylhexahydropuran [2,3-d ] pyrimidin-2 (1H) -ylidene) nitramide.
FIG. 3 shows N- ((4aS,7aS, E) -1-methylhexahydrofuran [2,3-d ]]Process for preparing pyrimidin-2 (1H) -ylidene) nitramides1H-NMR(CD3OD) plot.
FIG. 4 shows N- ((4aS,7aS, E) -1-methylhexahydrofuran [2,3-d ]]Process for preparing pyrimidin-2 (1H) -ylidene) nitramides13C-NMR(CD3OD) plot.
FIG. 5 is a graph showing the effect of N- ((4aS,7aS, E) -1-methylhexahydrofuran [2,3-d ] pyrimidin-2 (1H) -ylidene) nitramide on inhibiting human bone marrow neuroblastoma cell line SH-SY 5Y.
Detailed Description
The present invention will be described in detail with reference to examples, but is not limited thereto.
Example 1
1. Experimental Material
White rot fungus YK-624 is subcultured in potato glucose agar medium (PDA, components: potato 20%, glucose 2%, agar 2%) and stored in refrigerator at 4 deg.C for use.
2. The invention relates to a preparation method of N- ((4aS,7aS, E) -1-methylhexahydropuran [2,3-d ] pyrimidine-2 (1H) -subunit) nitramide, which comprises the following steps:
(1) taking two pieces of hypha sheets of white rot fungi (YK-624) with diameter of 10mm activated on PDA culture medium, and performing liquid culture at 30 deg.C;
(2) mixing the white rot fungi cultured in liquid and the liquid culture medium with dinotefuran, and standing at 30 deg.C for more than 20 days;
(3) separating the liquid culture medium from white-rot fungi after standing, adding equal volume of ethyl acetate into the separated liquid, extracting for 3 times, and combining the supernatants;
(4) concentrating the supernatant by evaporation, performing gradient elution by silica gel chromatography, and tracking metabolite by thin layer chromatography;
(5) the product obtained by silica gel chromatography is further purified by preparative liquid chromatography.
The types of the chromatographic columns of the preparative chromatography are as follows: inertsil C30S-Select 5m 20x250 mm.
The liquid culture medium for liquid culture comprises the following components in parts by weight: 10 parts glucose, 0.221 part ammonium tartrate, 1.64 parts anhydrous sodium acetate and 100 parts Kirk's salt solution.
The Kirk salt solution comprises the following components in percentage by weight: 2% monopotassium phosphate, 0.5% magnesium sulfate heptahydrate, 0.13% calcium chloride dihydrate, 0.001% thiamine hydrochloride, and 1.67% Kirk microelement solution.
The Kirk microelement solution comprises the following components in parts by weight: 0.9% Nitrilotriacetate, 0.3% magnesium sulfate heptahydrate, 0.42% manganese sulfate monohydrate, 0.6% sodium chloride, 0.06% ferrous sulfate heptahydrate, 0.11% cobalt sulfate heptahydrate, 0.11% zinc sulfate heptahydrate, 0.06% calcium chloride dihydrate, 0.006% copper sulfate pentahydrate, 0.011% aluminum potassium sulfate dodecahydrate, 0.006% boric acid, 0.007% sodium molybdate dihydrate.
3. Qualitative analysis of purified Compounds
(1) Mass spectrum [ M-H ] of ESI-TOF-MS analysis]-As shown in FIG. 2, [ M-H ]]-199.02 the molecular weight of the known compound is 200.
(2) By nuclear magnetic resonance spectroscopy in CD3The hydrogen spectrum in OD is shown in FIG. 3, which is in CD3The carbon spectrum in the OD is shown in FIG. 4. The results of the analysis of the hydrogen spectrogram shift response and the carbon spectrogram shift response are shown in table 1.
TABLE 1
By the reaction of compounds1H-NMR(CD3OD) spectrum and13C-NMR(CD3OD) and mass spectrograms, confirming that the structural formula of the prepared compound is as follows:
Example 3
An example of the use of N- ((4aS,7aS, E) -1-methylhexahydrofuran [2,3-d ] pyrimidin-2 (1H) -ylidene) nitramide for the preparation of a medicament for inhibiting the survival of human bone marrow neuroblastoma cells.
When 0.3mM of N- ((4aS,7aS, E) -1-methylhexahydrofuran [2,3-d ] pyrimidine-2 (1H) -subunit) nitramide was added to a human bone marrow neuroblastoma cell line SH-SY5Y and a DMSO solvent containing no nitramide was added to a control group, it was found that 69.3% of the cells survived compared to the control group, indicating that N- ((4aS,7aS, E) -1-methylhexahydrofuran [2,3-d ] pyrimidine-2 (1H) -subunit) nitramide inhibited survival of human bone marrow neuroblastoma cells.
Therefore, N- ((4aS,7aS, E) -1-methylhexahydrofuran [2,3-d ] pyrimidine-2 (1H) -subunit) nitramide can be used for preparing a medicament for inhibiting the survival of human bone marrow neuroblastoma cells, and N- ((4aS,7aS, E) -1-methylhexahydrofuran [2,3-d ] pyrimidine-2 (1H) -subunit) nitramide can be used for preparing a medicament for treating and preventing diseases caused by human bone marrow neuroblastoma cells, wherein the diseases caused by the human bone marrow neuroblastoma cells comprise abdominal tumors, chest tumors, paravertebral tumors, paraneoplastic syndromes or metastatic tumor diseases.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (6)
1. A compound having a structural formula according to formula (i):
2. a process for the preparation of a compound as claimed in claim 1, said process comprising the steps of:
(1) carrying out liquid culture on the white rot fungi;
(2) mixing the white rot fungi subjected to liquid culture and a liquid culture medium with dinotefuran, and standing for more than 20 days at 24-30 ℃;
(3) separating the liquid culture medium after standing from the white rot fungi, and adding an organic solvent with octanol/water distribution coefficient logarithmic value range of 0.70-0.80 into the separated liquid for extraction to obtain supernatant, wherein the organic solvent is ethyl acetate;
(4) concentrating the supernatant, performing gradient elution with silica gel chromatography, and tracking metabolites with thin layer chromatography;
(5) the product obtained by silica gel chromatography is further separated and purified by preparative liquid chromatography to obtain the compound with high purity.
3. The method of claim 2, wherein the extraction process comprises the steps of: extracting the obtained supernatant with 0.5-2 times of the separated liquid volume of ethyl acetate for 2-3 times.
4. The production method according to claim 2, characterized in that the liquid medium for liquid culture comprises the following components in parts by weight: 9-11 parts of glucose, 0.2-0.3 part of ammonium tartrate, 1.5-1.7 parts of anhydrous sodium acetate and 95-105 parts of Kirk salt solution.
5. The method according to claim 2, wherein the liquid culture medium comprises the following components in parts by weight: 10 parts glucose, 0.221 part ammonium tartrate, 1.64 parts anhydrous sodium acetate and 100 parts Kirk's salt solution.
6. Use of a compound according to claim 1 for the preparation of a medicament for inhibiting the survival of human bone marrow neuroblastoma cells.
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| CN114540431B (en) * | 2022-02-18 | 2023-08-04 | 广州大学 | Method for biologically preparing 4,4' -dihydroxybenzophenone by white rot fungi |
| CN114634954B (en) * | 2022-02-18 | 2023-08-08 | 广州大学 | Method for biodegradation and conversion of organic pollutants |
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| CN101781291A (en) * | 2010-02-26 | 2010-07-21 | 上海师范大学 | 1,5-disubstituted hexahydrotriazine-2-N-nitroimine derivative |
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