CN111217878A - Andrastone compounds, preparation method thereof and application thereof in preparing antiallergic drugs - Google Patents
Andrastone compounds, preparation method thereof and application thereof in preparing antiallergic drugs Download PDFInfo
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Abstract
The invention discloses andrastone compounds derived from deep-sea fungi, a preparation method thereof and application thereof in preparing antiallergic drugs. The structure of the andrastone compound 1-14 from the deep sea fungi is respectively shown as formulas I-XIV:
Description
Technical Field
The invention relates to the technical field of anti-allergic drugs, in particular to andrastone compounds, a preparation method thereof and application thereof in preparing anti-allergic drugs.
Background
Food allergy is a common allergic disease, which is caused by the cross-linking of allergen-specific IgE with fce R I, resulting in the release of allergic mediators from effector cells, and in severe cases, anaphylactic shock. Statistically, about 5% of adults and 8% of infants worldwide are allergic to food. Food allergy diseases cannot be completely cured at present, and the more common treatment method is drug control, such as antihistamines, hormones, receptor antagonists and the like. Although the medicine has quick response and obvious curative effect, the medicine has certain adverse reaction and is easy to generate drug resistance. In order to control the increase of allergic diseases, more researchers have developed novel natural active ingredients for preventing food allergic diseases in recent years.
The marine fungi live in special marine environments of high pressure, low temperature, oxygen deficiency and darkness, and often have special metabolic pathways in vivo so as to generate secondary metabolites with novel structures. Alkaloid compounds, terpenoid compounds, flavonoid compounds and the like from deep sea all show strong antiallergic activity. Therefore, the screening and discovery of natural products capable of targeting the antiallergic activity of nuclear receptors in marine fungi have important significance for the development of marine antiallergic drugs.
Disclosure of Invention
The invention aims to provide an andrastone compound, a preparation method thereof and application thereof in preparing an antiallergic medicament aiming at the defects in the prior art, and the andrastone compound can be used for treating diseases related to antiallergic.
The purpose of the invention is realized by the following technical scheme:
the andrastone compound has a structural formula shown as formulas I-XIV: .
The invention also provides a preparation method of the andrastone compound, which comprises the following steps:
s1, carrying out fermentation culture on Penicillium allii-sativi to obtain a fermentation product; the Penicillium Penicillium allii-sativi is preserved in China Marine microorganism culture preservation management center with the preservation number of MCCC3A 00580;
s2, extracting the fermentation product, and separating and purifying the obtained extract to obtain the andrastone compound.
The invention also provides application of the andrastone compound or salts thereof in preparing antiallergic drugs.
The invention also provides an antiallergic drug, which comprises the andrastone compound and the salt thereof or the combination of more than two of the andrastone compound and the salt thereof which are used as active ingredients in effective dose, and a pharmaceutically acceptable carrier.
In particular, the salts include pharmaceutically acceptable salts.
The invention has the beneficial effects that:
the andrastone compound is obtained by separating from deep sea fungus Penicillium allii-sativi fermentation products, and is determined to be 14 compounds with the structures shown in formulas I-XIV through detailed structure analysis. According to the invention, researches show that the andrastone compound has strong efficiency of inhibiting the degranulation of rat basophilic granulocyte, so that a new compound source is provided for the research and development of allergic drugs, and the andrastone compound can be used for preparing the anti-allergic drugs and has a very good application prospect.
Detailed Description
In order to make the objects, technical solutions and technical effects of the present invention more clear, the present invention is described in detail below with reference to embodiments. It should be understood that the embodiments described in this specification are only for the purpose of illustrating the invention and are not to be construed as limiting the invention, and the parameters, proportions and the like of the embodiments may be suitably selected without materially affecting the results.
Example 1: preparation of andrastone compound
(1) Penicillium allii-sativi was cultured on PDA plates at 25 ℃ for 3 days. Fresh mycelium was then inoculated into culture medium containing 400mL of PDB. After 24 hours, 10mL of the seed solution was inoculated into a 1L Erlenmeyer flask (100 flasks) containing 80g of oat and 120mL of 3% seawater per flask and statically cultured at 28 ℃ for 30 days. Carrying out fermentation culture on the Penicillium allii-sativi to obtain a fermentation product;
the Penicillium allii-sativi is preserved in China marine microorganism strain preservation management center, and the preservation number is as follows: MCCC3a 00580.
(2) Extracting the fermented product obtained in the step (1) with ethyl acetate for three times. The organic solvent was evaporated under reduced pressure to give an organic extract (200 g). The extracts were passed through a normal phase column chromatography using petroleum ether, dichloromethane and methanol for elution, respectively. The dichloromethane layer was concentrated to give a crude extract (63.0 g).
(3) Separating the crude extract obtained in the step (2) by using normal phase silica gel column chromatography, and performing gradient elution by using a petroleum ether-ethyl acetate system to obtain 8 crude fractions (Fr.1-Fr.8).
(4) The crude fraction Fr.3(6.3g) in step (3) was separated by ODS column chromatography, and gradient elution was carried out using a water-methanol system. Then, Sephadex LH-20 column chromatography was applied, and the resulting product was separated by elution with methanol and then recrystallized to give Compound 11(434.3 mg).
(5) The crude fraction Fr.4(2.1g) obtained in step (3) was passed through a Sephadex LH-20 gel column and eluted with methanol to give a subfraction Fr.4.1(1.2 g). Fr.4.1 was then subjected to ODS column Chromatography (CH)3OH-H2O, 60 → 100%) to yield 11 subfractions (Fr.4.1.1-Fr.4.1.11). Fr.4.1.2 Produced form HPLC column Chromatography (CH)3CN-H2O, 25 → 50%) to give compound 6(10.0 mg). The same preparative HPLC column chromatography was used to purify compound 2(2.5mg), compound 3(7.9mg), compound 9(3.4mg) and compound 12(39.0mg) from subfractions fr.4.1.8(50.9mg), fr.4.1.9(45.5mg) and fr.4.1.10(55.7mg), respectively.
(6) Subjecting the crude fraction Fr.5(3.5g) obtained in step (3) to ODS column Chromatography (CH)3OH-H2O, 60 → 100%) were separated into 11 sub-fractions. Fr.5.5 passing through Sephadex LH-20 (CH)3OH) column chromatography and preparative HPLC column Chromatography (CH)3-H2O, 50 → 100%) to give compound 4(6.8mg), compound 5(0.5mg), compound 7(27.1 mg). Fr.5.6 also by Sephadex LH-20 (CH)3OH) column chromatography and preparative HPLC column Chromatography (CH)3CN-H2O, 30 → 100%) to give compound 8(29.0mg), compound 10(9.1mg), and compound 13(9.6 mg). Fr.5.7 and Fr.5.8 were separately subjected to preparative HPLC column Chromatography (CH)3CN-H2O, 50 → 100%) to give Compound 1(5.3mg) and Compound 14(14.7 mg).
(7) Respectively analyzing and determining the plane structure of the compound 1-14 obtained in the step by using a 1D NMR spectrum, a 2D NMR spectrum and a high-resolution mass spectrum, and then determining the absolute configuration of the compound by using X-single crystal diffraction, ECD calculation and the like, wherein the detailed description is as follows:
compound 1 is a colorless orthorhombic crystal. Determining the molecular formula of the molecular formula C according to the main ion peak of the molecular formula in the high-resolution mass spectrum29H40O8。1H、13C NMR data (tables 1, 2) and DEPT and HMBC spectra show 29 carbon signals including 7 methyl groups, 2 methoxy groups, 3 methylene groups, 6 methines and 11 quaternary carbons, which are very close to dihydrocyclohybridonol with only one more methyl group on the hydroxyl group at the C-23 position, the absolute configuration was determined by X-ray diffraction (Cu-K α radiation) and was named as citrehydrobridonol B.Compound 2 has the formula C28H36O8，1H、13The C NMR data (tables 1, 2) shows 28 carbons, including 7 methyl groups, 1 methoxy group, 2 methylene groups, 7 methine groups, and 11 quaternary carbons.the signals are very close to andrastin A, but the compound 2 has a hydroxyl at C-6, and a furan ring is formed between C-7 and C-15 through an oxygen bridge, the compound is finally determined to have the structure of 6 α -hydroxy-7 β, 15-epoxyyandrastin A and named andrastin G through detailed 1D and 2D NMR analysis and a method of quantum chemistry calculation26H38O6Which is1H and13the C NMR spectrum was almost identical to that of andrastone A, except that there was one less acetyl group. Through detailed analysis of 1D and 2D NMR, the structure is determined to be 3-O-deacetylandrastone A which is named andrastone B.
The molecular formula of the compound 4 is C28H40O9. It is composed of1H and13the C NMR nuclear magnetic data are very close to that of the compound andrastone A, and the detailed analysis of COSY and HMBC maps confirms that the C-7 and C-23 positions of the compound 4 have two more hydroxyl groups (delta) than the andrastone AC67.6d，δC62.3t), according to the very small coupling constant between H-5 and H-6: (3JH-5，H-62.4Hz), 6-OH is determined to be α configuration, the calculated and tested ECD spectra are further compared, and finally the absolute configuration of the compound 4 is determined to be 6 alpha, 23-dihydroxandrasone a, named andrastone C, the molecular formula of the compound 5 is C28H40O8. Analysis of1H、13C NMR nuclear magnetic data found to be very similar to that of Compound 4, except that there was one less hydroxyl group at the C-6 position in addition, the chemical shift values for C-16 and C-18 were significantly reduced by 3.6 and 5.5ppm, respectively, suggesting that its 16-OH should be in the α configuration rather than the β configuration in Compound 43-22 and H3-20/H2-23 is related, and H-9 is related to H316 correlation, confirming the α configuration of 16-OH Compound 5 was identified as 16-epi-23-hydroxyandtrastone A, named andrastone D, Compound 6 is of formula C28H38O8And (4) Na. It is composed of1H、13C NMR nuclear magnetic data are very similar to 5 except that compound 5 has a hydroxymethyl group at C-23 and an aldehyde group in compound 6. In HMBC mapping, H-23 is associated with C-1 and C-10 confirming the above inference. Thus, Compound 6 was inferred to be 16-epi-23-oxoandrastone, named andrastone E.
The molecular formula of the compound 7 is C28H40O7. It is composed of1H、13The C NMR nuclear magnetic data was very similar to that of 5, except that there was one less hydroxyl group at the C-16 position than at 5, a conclusion that was confirmed by the correlation of COSY and HMBC. In the NOESY spectrum, H-16 is related to H-9, while H3-3' and H3-18/H320, thereby determining the methyl group of C-18 to be in the α configuration, taken together, Compound 7 is structurally identified as 16-hydroxy-23-hydroxyandrastone A and designated andrastone F.
The molecular formulas of the compounds 8 and 9 are respectively C26H38O7And C28H40O6. They showed a close resemblance to Compound 71H、13C NMR nuclear magnetic spectrum. The difference is determined by detailed COSY and HMBC spectrogram correlation analysis that the C-23 position in the compound 7 is hydroxymethyl, the compound 8 is aldehyde group, and the compound 9 is methyl. Further, NOESY confirmed that Compound 8 was 16-dehydroxy-23-oxoandrastone A (named andrastone G) and Compound 9 was 16-dehydroxyandtrastone A (named andrastone H). The other five known compounds 10-14 are identified by comparing the physical and chemical data of NMR nuclear magnetism, optical rotation, mass spectrum, etc. of the reference, respectively: 3-deacetylcitrohydrindiol (compound 10), citrohydrindiol (compound 11), citrohydrindione A (compound 12), 16-epi-citrohydrindione A (compound 13) and andrastin F (compound 14).
TABLE 2 preparation of compounds 1 to 913C NMR data (100MHz)
Determined using an HMBC map;aCD3OD；bCDCl3
example 2: EXAMPLE 1 examination of antiallergic Activity of Compounds 1 to 14 prepared in example 1
Rat Basophilic granulocytes (Rat Basophilic Leukemia-cell, RBL-cell) have good allergic immune response in the study of the diagnosis of food allergy and immunotherapy. The RBL-2H3 cell line has high activity and good homogeneity, and can be used for establishing an allergic reaction cell model. Therefore, the RBL-2H3 cell model is widely applied to the research of the anti-food allergy of natural active components, including degranulation, release of allergic medium and action mechanism thereof. And (3) detecting the degranulation efficiency of the cells after sensitization by using an immunoglobulin (IgE) mediated RBL-2H3 cell model, and calculating the inhibition rate of the compound sample on the degranulation efficiency of the cells so as to judge the anti-allergic activity of the sample.
The detailed steps are as follows:
1) pancreatin digestion to recover RBL-2H3 cells, 6X 105cells/mL, 100uL per well (i.e., 6X 10)4cells/well) into 96-well plates, while adding anti-DNP-IgE to a final concentration of 1. mu.g/mL, incubator (37 ℃, 5% CO)2) Incubate overnight.
2) The wells were washed 3 times with PBS, the samples were dissolved in PBS, 5. mu.L of each sample was mixed with 95. mu.L of Tyrode's buffer (final crude concentration 100. mu.g/mL, final monomer concentration 20. mu.g/mL), and the negative control was 5. mu.L of PBS + 95. mu.L of Tyrode's buffer, 95. mu.L of each sample was added to the plate, and incubation was continued for 1 h. RBL-2H3 cells were stimulated with 1. mu.g/mL DNP-BSA for 6 hours.
3) the activity of beta-aminocaprosidase is detected by using 4-methylumbellife-ryl-N-acetyl-b-Dgluconamide substrate, after recovering cell culture supernatant, 100. mu.L of Tyrode's buffer (containing 0.1% Triton X-100) is added to the culture plate to lyse cells, and finally 25. mu.L of supernatant or cell lysate is added to a 96-well fluorescent plate, 100. mu.L of 4-methylumbellife-ryl-N-acetyl-b-D-gluconamide reagent (1.2mM) is added to each well, and reaction is carried out for 30min (37 ℃), 360nm excitation of each well solution is obtained by using a microplate reader, and the fluorescence value emitted at 450nm is obtained, wherein loratadine is a positive control drug.
4) The particle removal efficiency calculation formula is as follows:
the degranulation efficiency was defined as the fluorescence value of the supernatant/(fluorescence value of the supernatant + fluorescence value of the cell lysate). times.100%
As can be seen from Table 3, compounds 3 and 10 have strong antiallergic activity and can significantly reduce the degranulation efficiency of RBL-2H3 cells, and the IC thereof50The values reached 40.4. mu.M and 14.8. mu.M, respectively, while the IC of the positive control drug loratadine50The concentration was 92.5. mu.M. The compound 14 has an inhibition rate of 35.6% on the cell degranulation efficiency of RBL-2H3, and other compounds show certain antiallergic activity to different degrees.
TABLE 3 antiallergic Activity of Compounds 1-14
NT, not tested
The result shows that the andrastone compound prepared by the invention has very good prospect of being developed into an antiallergic drug.
The above-mentioned embodiments are only for convenience of description, and are not intended to limit the present invention in any way, and those skilled in the art will understand that the technical features of the present invention can be modified or changed by other equivalent embodiments without departing from the scope of the present invention.
Claims (4)
1. An andrastone compound, which is characterized in that: the andrastone compound has a structural formula shown as formulas I-XIV:
2. the process for preparing andrastone compounds as claimed in claim 1, characterized in that: the method comprises the following steps:
s1, carrying out fermentation culture on Penicillium allii-sativi to obtain a fermentation product; the Penicillium Penicillium allii-sativi is preserved in China Marine microorganism culture preservation management center with the preservation number of MCCC3A 00580;
s2, extracting the fermentation product, and separating and purifying the obtained extract to obtain the andrastone compound.
3. The use of the andrastone compound or its salt according to claim 1 in the preparation of antiallergic drugs.
4. An antiallergic drug is characterized in that: the andrastone compound and the salt thereof which are used as active ingredients and are used as the active ingredients, and the pharmaceutically acceptable carrier.
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| CN112047901A (en) * | 2020-09-21 | 2020-12-08 | 自然资源部第三海洋研究所 | Benzothiazole heteroterpenoid and derivative thereof, preparation method and application |
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| CN109942658A (en) * | 2019-04-29 | 2019-06-28 | 自然资源部第三海洋研究所 | A kind of miscellaneous terpene compound and the preparation method and application thereof and anti-tumor drug |
Non-Patent Citations (4)
| Title |
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| SARA KILDGAARD: ""Accurate Dereplication of Bioactive Secondary Metabolites from Marine-Derived Fungi by UHPLC-DAD-QTOFMS and a MS/HRMS Library"", 《MARINE DRUGS》 * |
| SEIJI KOSEMURA: ""Meroterpenoids from Penicillium citreo-viride B. IFO 4692 and 6200 hybrid"", 《TETRAHEDRON》 * |
| SHU-SHAN GAO: ""Secondary Metabolites Produced by Solid Fermentation of the Marine-Derived Fungus Penicillium commune QSD-17"", 《SHU-SHAN GAO ET AL., BIOSCIENCE, BIOTECHNOLOGY, AND BIOCHEMISTRY》 * |
| YUDAI MATSUDA: ""Reconstituted biosynthesis of fungal meroterpenoid andrastin A"", 《TETRAHEDRON》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112047901A (en) * | 2020-09-21 | 2020-12-08 | 自然资源部第三海洋研究所 | Benzothiazole heteroterpenoid and derivative thereof, preparation method and application |
| CN112047901B (en) * | 2020-09-21 | 2023-01-24 | 自然资源部第三海洋研究所 | Benzothiazole heteroterpenoid and derivative thereof, preparation method and application |
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