CN110721191A - Application of diterpene-reducing compound poriferol derived from birch tube-peeling pore fungus - Google Patents
Application of diterpene-reducing compound poriferol derived from birch tube-peeling pore fungus Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/075—Ethers or acetals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C35/22—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system
- C07C35/37—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with a hydroxy group on a condensed system having three rings
- C07C35/42—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with a hydroxy group on a condensed system having three rings derived from the phenanthrene skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes
Abstract
The invention relates to the technical field of microbial medicine chemistry, in particular to a birch tube-peeling hole bacterium (A)Piptoporus betulinus) The six diterpenoid reducing compounds separated and obtained from the fermentation products of the bacterial strains have medical application. The inventionThe six compounds are proved to have remarkable activity of inhibiting the proliferation of T lymphocytes stimulated by the concanavalin A and B lymphocytes stimulated by bacterial lipopolysaccharide by an immunosuppressive activity screening test, have no toxicity to T, B lymphocytes, and have application in preparing novel immunosuppressive medicaments.
Description
Technical Field
The invention relates to the technical field of microbial medicine chemistry, in particular to application of six diterpenoid-reducing compounds derived from birch tube-peeling fungus in the development of drugs with immunosuppressive activity.
Background
The human immune system is composed of immune organs, immune cells and immune molecules, and is an important system for the body to execute immune response and play immune function. The immune system is divided into innate immunity and adaptive immunity, wherein adaptive immunity is divided into humoral immunity and cellular immunity. In the innate immune response, T cells located in lymph fluid, blood and lymph nodes are mainly involved in cellular immune response, and B cells are mainly involved in humoral immune response, which have both unique functions and cooperate with each other to exert immune effects together. The immune system of the normal body can generate immune response to non-self antigens and is in a non-response state or a weak response state to the principle of self-antibodies, and the state is called immune tolerance. At this time, a certain amount of autoreactive T cells and autoantibodies are ubiquitous in the peripheral immune system, help to clear the self-components of aging variation, and have important physiological significance in maintaining the homeostasis of the immune system, a process called autoimmunity.
Immune tolerance is closely related to the occurrence, development and outcome of various clinical diseases. The loss of physiological tolerance of the immune system to self-antigens is the underlying cause of the development of autoimmune diseases. In clinical practice, if the immune system does not attack self tissues or organs, autoimmune diseases may not occur; rejection reactions from organ transplantation can be avoided without attacking the donor organ. Currently, suppression of the immune system by drugs to generate an immune response to self-antigens or transplantation antigens is the primary therapeutic approach.
At present, drugs for treating autoimmune diseases at the first line of clinical treatment, such as cyclosporine, tacrolimus (FK 506), fingolimod and the like, and drugs for treating organ transplant rejection, such as mycophenolic acid, cyclosporine, tacrolimus and rapamycin (rapamycin), and the like, act on T cells to play an immunosuppressive role. However, these drugs have serious side effects, such as 50-70% of the nephrotoxicity of cyclosporin and 10-50% of the liver damage (Chinese comprehensive clinical application 2003,19, 101-102). Mycophenolic acid can cause diarrhea, gastrointestinal dysfunction, leukopenia, etc. (proceedings of Shanghai second college of medicine 2005,25, 714-717). Rapamycin can lead to refractory hyperlipidemia and associated cerebrovascular accidents (southern university of medicine, 2007,27, 1924-1926). Meanwhile, effective medicines for treating autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus are also urgently needed clinically. Therefore, the development of the drug capable of inhibiting T, B cell proliferation can be applied to organ transplantation operation and autoimmune diseases, and has very wide market prospect.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide application of six kinds of diterpenoid compounds prepared from fermentation products of birch tube-peeling fungus (Piptoporus betulinus) in preparing medicines with immunosuppressive activity.
The six diterpenoid reducing compounds are poricolins A-F, and the chemical structural formulas are as follows:
further, the drug having immunosuppressive activity is a drug for the purpose of immunosuppression, for example, rejection after organ transplantation, autoimmune diseases (systemic lupus erythematosus and the like).
The six diterpenoid-reducing compounds, namely the chayol A-F, have the activity of inhibiting T, B lymphocyte proliferation, and can be used as immunosuppressive lead compounds for preparing immunosuppressive drugs.
The six kinds of diterpene reducing compounds are prepared by dissolving the chayol A-F in dichloromethane, chloroform, acetone, methanol, pyridine, dimethyl sulfoxide and the like, but not dissolving in petroleum ether and water.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. currently, immunosuppressive drugs used clinically are mainly cyclic peptides, macrolides and steroids. The invention provides diterpenoid compounds with completely different framework types of immunosuppressive drugs in clinical use at present. The immunosuppressive drug further developed based on the compound can completely avoid the existing drug patents on the market, and provides more choices for the market.
2. The invention discloses that the diterpenoid compound also has immunosuppressive activity for the first time, and the scientific community can look into the diterpenoid compound to search for a lead compound with immunosuppressive activity in future.
3. The immunosuppressive activities of the six compounds are stronger than that of a marketed drug (dexamethasone), and other compounds have certain activities, so that the six compounds have the potential of being developed into a marketed clinical drug; and they are not non-specifically toxic to T, B lymphocyte proliferation.
4. The truffle alcohol to be protected by the invention can be obtained by a microbial fermentation method. The whole production process has no chemical pollution and is green and environment-friendly.
5. The six compounds in the invention have the activity of obviously inhibiting the proliferation of T lymphocytes stimulated by the concanavalin A and B lymphocytes stimulated by the bacterial lipopolysaccharide, have no toxicity to T, B lymphocytes, and have the application of preparing novel immunosuppressive medicaments.
Drawings
FIG. 1 is a graph showing the inhibition of the proliferation of T lymphocytes stimulated by concanavalin A-F.
FIG. 2 is a graph showing the inhibitory effect of Scutellarinol A-F on bacterial lipopolysaccharide-stimulated B lymphocyte proliferation.
Detailed Description
In order to make the purpose and the inventive content of the present application more clear, the following applicant will clearly and completely describe the technical solution of the present invention with reference to the specific embodiments.
The following examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer, and the reagents and equipment used were not specified by the manufacturer, and were all conventional commercially available products.
The animal experiments in the following examples were approved by the university of southern China laboratory animal and biomedical ethics Committee (code 2019-SCUEC-AEC-021).
The six compounds of the tube hole mycol A-F researched by the application of the invention are all derived from fermentation products of the birch tube hole stripping fungus (Piptoporus betulinus). They have the structural formulae:
the compounds belong to the prior art, and are shown in the third chapter of the doctrine of doctrine 'research on terpenoid components of four higher fungi such as stereum fulvum' by the doctrine of Kunming plant institute of Chinese academy of sciences in 2017, and specifically, the correspondence between the six compounds researched in the invention and the compounds extracted and separated in the doctrine of doctor is as follows:
the chayol A corresponds to compound 4;
trufflol B corresponds to compound 6;
trufflol C corresponds to compound 7;
trufflol D corresponds to compound 12;
trufflol E corresponds to compound 17;
trufflol F corresponds to compound 2.
The production strain, namely, the betula platyphylla (Piptoporus betulinus), is stored in the higher fungus chemistry research group of Kunming plant research institute of Chinese academy of sciences, and addresses are as follows: the strain is available to the public from Tokyo Lou 132, Kunming, Yunnan province.
The six kinds of diterpene reducing compounds are prepared by dissolving the chayol A-F in solvents such as dichloromethane, chloroform, acetone, methanol, pyridine, dimethyl sulfoxide and the like, but not dissolving in petroleum ether and water.
Application test example 1
1. The porcellitol a to F obtained in the example were subjected to T, B lymphocyte non-specific toxicity screening by a cell viability assay (MTT method).
2. The test principle is as follows: succinate dehydrogenase in mitochondria of living cells can reduce tetramethylazothiazole blue (MTT) into water-insoluble blue-violet crystalline Formazan (Formazan), while dead cells do not have the function. After the formazan is dissolved by DMSO, the absorbance value of the formazan is measured at the wavelength of 570nm, so that the quantity of living cells can be indirectly reflected. Within a certain range of cell number, the MTT crystal formation amount is in direct proportion to the cell number, and can be used for cytotoxicity analysis. The compounds were tested for mouse spleen lymphocyte cytotoxicity using a cell viability assay (MTT method).
3. The cell viability assay (MTT assay) of this example comprises the following specific steps: the spinal method is used for killing mice, taking spleens of the mice aseptically, grinding the spleens into single cell suspension, removing erythrocytes from erythrocyte lysate, and adjusting the cell concentration. 8X 10 mouse spleen lymphocyte suspension5Inoculating each well in a 96-well plate, adding different concentrations of poriferol A-F, adopting immunosuppressant dexamethasone as positive control drug, and setting corresponding solvent (DMSO) control and culture solution background (RMPI 1640) control (blank control) to make the final volume of each well 200 μ L. At 37 ℃ with 5% CO2The culture was carried out in an incubator for 48 hours. MTT solution was added 4 hours before the end of the culture to give a final MTT concentration of 5 mg/mL. When the culture is finished, the supernatant is removed by suction, 200 mu LDMSO is added into each hole to dissolve purple crystals, and the OD value is measured at 570nm of an enzyme labeling instrument. And calculating the cell survival rate.
4. And (3) test results: the survival rate of T, B lymphocytes is more than 80% when the concentration of the Scutellarinol A-F is 40 mu M, which indicates that the Scutellarinol A-F has no non-specific toxicity to T, B lymphocytes.
Application test example 2
1. By using3The H-TdR incorporation assay measures the effect of each compound on mouse spleen T, B lymphocyte proliferation function.
2. The test principle is as follows: t, B the lymphocyte has recognition antigen and mitogen receptor on its surface, and the corresponding lymphocyte can proliferate and differentiate under the stimulation of specific antigen. Canavalid protein A (ConA) and bacterial Lipopolysaccharide (LPS) are two mitogens that stimulate T, B lymphocytes to proliferate and differentiate, respectively, similar to the process of lymphocyte activation in vivo. Thus, mitogen-induced lymphocyte proliferation is often used as an index to evaluate lymphocyte function.3H-Thymidine (I) ((II))3H-TdR) incorporation refers to the addition of tritiated thymidine to the cell culture medium, then3H-TdR is taken into cells as a raw material for synthesizing DNA, and incorporated into a newly synthesized DNAThe DNA of (1). The method can reflect the synthesis condition of cell DNA, and further detect whether the cell has proliferation. The level of response of lymphocytes to stimuli can be inferred from the amount of isotope incorporated into the cells. Incorporated isotopes3H, measured by liquid scintillation measurement, and calculated3The number of H pulses per minute (cpm), which reflects the extent of lymphocyte proliferation.
3. Preparing a sample to be tested: the chayol A-F was dissolved in DMSO to prepare 1mM stock solutions.
4. Mouse spleen lymphocyte suspension 4X 105Each well was inoculated into a 96-well plate, and ConA (final concentration: 5. mu.g/mL) or LPS (final concentration: 10. mu.g/mL) was added to the plate to calculate the cell growth inhibitory rate. Lymphocyte proliferation assay: mouse spleen lymphocyte suspension 4X 105One well was inoculated into a 96 well plate, and ConA (final concentration 5. mu.g/mL) or LPS (final concentration 10. mu.g/mL) was added to the well, and a stock solution of the test compound was added to make the test concentration of the drug 5 concentrations (0.1, 1.0, 10.0, 40.0, 80.0. mu.M) in the range of 0.01 to 100. mu.M. Corresponding ConA-free, LPS-free control wells and drug-free control wells were also set. At 37 degrees Celsius, 5% (v/v) CO2The culture was carried out in an incubator for 48 hours. At 8 hours before the end of the incubation, 25. mu.L of the solution was added to each well3H-TdR. The culture was continued until the end of the experiment. Collecting cells on a glass fiber membrane by using a cell collecting instrument, adding a scintillation fluid, and reading cell DNA doped in the cells by using a Beta counter3The amount of H-TdR was represented by cpm, and the cell growth inhibition rate was calculated. From the dose-response curves, the median Inhibitory Concentration (IC) was calculated50)。
5. The test data calculation method comprises the following steps:
6. the test results are shown in FIG. 1 and FIG. 2, and specifically, IC of Scutellarinol A for inhibiting T lymphocyte proliferation50IC for inhibition of B lymphocyte proliferation ═ 11.1 μ M5035.1 μ M; IC for inhibiting T lymphocyte proliferation by virtue of Aphyllophoralcohol B50IC for inhibition of B lymphocyte proliferation ═ 21.1 μ M50=51.8μM(ii) a IC for inhibiting T lymphocyte proliferation by virtue of trufflitol C50IC for inhibition of B lymphocyte proliferation ═ 14.9 μ M5049.4 μ M; IC for inhibiting T lymphocyte proliferation by tubular eubacterium alcohol D50IC for inhibition of B lymphocyte proliferation ═ 1.0. mu.M5016.1 μ M; IC for inhibiting T lymphocyte proliferation by virtue of Aphyllophoralcohol E50IC for inhibition of B lymphocyte proliferation ═ 4.0 μ M5046.0 μ M; IC for inhibiting T lymphocyte proliferation by virtue of trufflitol F50IC for inhibition of B lymphocyte proliferation ═ 13.6 μ M50=22.4μM。
7. IC of positive control drug dexamethasone for inhibiting T lymphocyte proliferation50IC for inhibition of B lymphocyte proliferation ═ 1.6 μ M50=0.8μM。
8. As mentioned above, the clitocellol A-F has certain inhibiting effect on T lymphocyte proliferation stimulated by the phaseolin A and B lymphocyte proliferation stimulated by the bacterial lipopolysaccharide. The Scutellaria tubulosa D and Scutellaria tubulosa E have obvious inhibition activity on T lymphocyte proliferation, and the activity of Scutellaria tubulosa D is more obvious than that of a positive control drug dexamethasone.
9. In conclusion, the clitocinol A-F separated from the fermentation extract of a betula (Piptoporus betulinus) strain provided by the invention has activity of inhibiting proliferation of T, B lymphocytes to different degrees, and can be used as a candidate molecule of an immunosuppressive drug lead compound to prepare an immunosuppressive drug.
The embodiments described above are some, but not all embodiments of the invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the claimed invention, but is merely representative of selected embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without any inventive step, are within the scope of the present invention.
Claims (6)
2. the use according to claim 1, wherein said poricol is used in the preparation of a medicament with immunosuppressive type activity, with or without other active ingredients.
4. the use according to claim 3, wherein said poricol is the only active ingredient.
5. Use according to any one of claims 1 to 4, wherein the medicament having immunosuppressive-like activity is a medicament for immunological rejection after organ transplant surgery and/or for the treatment of autoimmune diseases.
6. Use according to any one of claims 1 to 4, wherein the agent with immunosuppressive type activity is an agent inhibiting the proliferation of T and/or B cells.
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CN103360351A (en) * | 2013-07-17 | 2013-10-23 | 云南大学 | Isopimarane diterpenoid compounds and application thereof |
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CN103360351A (en) * | 2013-07-17 | 2013-10-23 | 云南大学 | Isopimarane diterpenoid compounds and application thereof |
Non-Patent Citations (2)
Title |
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GRUNEWALD F等: "Effects of Birch Polypore Mushroom, Piptoporus betulinus (Agaricomycetes), the "Iceman"s Fungus", on Human Immune Cells", 《INTERNATIONAL JOURNAL OF MEDICINAL MUSHROOMS》, vol. 20, no. 12, 31 December 2018 (2018-12-31), pages 2 * |
陈贺平: "褐盖韧革菌等四种高等真菌萜类成分研究", 《中国科学院大学博士学位论文》, 31 December 2017 (2017-12-31) * |
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