CN115246803B - Terphenyl compounds and application thereof in preparation of anti-herpesvirus drugs - Google Patents
Terphenyl compounds and application thereof in preparation of anti-herpesvirus drugs Download PDFInfo
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- CN115246803B CN115246803B CN202110449577.0A CN202110449577A CN115246803B CN 115246803 B CN115246803 B CN 115246803B CN 202110449577 A CN202110449577 A CN 202110449577A CN 115246803 B CN115246803 B CN 115246803B
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- 229940124397 anti-herpes virus drug Drugs 0.000 title claims abstract description 7
- 238000002360 preparation method Methods 0.000 title claims description 7
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- -1 terphenyl compound Chemical class 0.000 claims abstract description 27
- 241000700584 Simplexvirus Species 0.000 claims abstract description 16
- 230000003602 anti-herpes Effects 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 238000000855 fermentation Methods 0.000 claims description 25
- 230000004151 fermentation Effects 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 229940125904 compound 1 Drugs 0.000 claims description 14
- 239000000284 extract Substances 0.000 claims description 14
- 239000001963 growth medium Substances 0.000 claims description 11
- 230000014759 maintenance of location Effects 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 229940125782 compound 2 Drugs 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- 238000010828 elution Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 241001529453 unidentified herpesvirus Species 0.000 claims description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 238000011218 seed culture Methods 0.000 claims description 6
- 239000002024 ethyl acetate extract Substances 0.000 claims description 5
- 241000233866 Fungi Species 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- 239000000287 crude extract Substances 0.000 claims description 4
- 238000002953 preparative HPLC Methods 0.000 claims description 4
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 240000008042 Zea mays Species 0.000 claims description 3
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 claims description 3
- 235000002017 Zea mays subsp mays Nutrition 0.000 claims description 3
- 229940041514 candida albicans extract Drugs 0.000 claims description 3
- 235000005822 corn Nutrition 0.000 claims description 3
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 239000002054 inoculum Substances 0.000 claims description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 3
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 235000013923 monosodium glutamate Nutrition 0.000 claims description 3
- 229940073490 sodium glutamate Drugs 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 239000012138 yeast extract Substances 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000003953 normal phase liquid chromatography Methods 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims 3
- 238000000926 separation method Methods 0.000 claims 1
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- 241000228168 Penicillium sp. Species 0.000 abstract description 11
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 abstract description 8
- 229960004150 aciclovir Drugs 0.000 abstract description 8
- 230000000840 anti-viral effect Effects 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- 238000000338 in vitro Methods 0.000 abstract description 4
- 241000700588 Human alphaherpesvirus 1 Species 0.000 abstract description 2
- 238000011161 development Methods 0.000 abstract description 2
- 230000003389 potentiating effect Effects 0.000 abstract description 2
- 208000029433 Herpesviridae infectious disease Diseases 0.000 abstract 1
- 241000700605 Viruses Species 0.000 description 12
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- 229940126214 compound 3 Drugs 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical group O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 230000000120 cytopathologic effect Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 4
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- 238000005100 correlation spectroscopy Methods 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 3
- 238000001052 heteronuclear multiple bond coherence spectrum Methods 0.000 description 3
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 230000009545 invasion Effects 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000001793 charged compounds Chemical class 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
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- 230000007505 plaque formation Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 210000003501 vero cell Anatomy 0.000 description 2
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- 238000001262 western blot Methods 0.000 description 2
- 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical group O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 1
- PRHJRLIQXXJXKZ-UHFFFAOYSA-N 4,5-diphenylpyran-2-one Chemical compound C=1C=CC=CC=1C1=COC(=O)C=C1C1=CC=CC=C1 PRHJRLIQXXJXKZ-UHFFFAOYSA-N 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- 108010068250 Herpes Simplex Virus Protein Vmw65 Proteins 0.000 description 1
- 208000032420 Latent Infection Diseases 0.000 description 1
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- IKMDFBPHZNJCSN-UHFFFAOYSA-N Myricetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC(O)=C(O)C(O)=C1 IKMDFBPHZNJCSN-UHFFFAOYSA-N 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000011278 co-treatment Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 208000037771 disease arising from reactivation of latent virus Diseases 0.000 description 1
- 238000002518 distortionless enhancement with polarization transfer Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
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- 238000001914 filtration Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 238000009629 microbiological culture Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229940116852 myricetin Drugs 0.000 description 1
- PCOBUQBNVYZTBU-UHFFFAOYSA-N myricetin Natural products OC1=C(O)C(O)=CC(C=2OC3=CC(O)=C(O)C(O)=C3C(=O)C=2)=C1 PCOBUQBNVYZTBU-UHFFFAOYSA-N 0.000 description 1
- 235000007743 myricetin Nutrition 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
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- 238000004321 preservation Methods 0.000 description 1
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- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
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Classifications
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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
- C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
-
- 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
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
-
- 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
-
- 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
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
- C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/02—Oxygen as only ring hetero atoms
- C12P17/04—Oxygen as only ring hetero atoms containing a five-membered hetero ring, e.g. griseofulvin, vitamin C
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/02—Oxygen as only ring hetero atoms
- C12P17/06—Oxygen as only ring hetero atoms containing a six-membered hetero ring, e.g. fluorescein
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- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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Abstract
The invention discloses a terphenyl compound and application thereof in preparing anti-herpesvirus medicaments. The invention discovers that the terphenyl compound (compound 1-3) and the known homolog (compound 4-8) which are separated from the deep sea fungus Penicillium sp.SCSIO 41030 can inhibit diseases caused by two herpes virus infections of herpes simplex virus type I (Herpes simplex virus type, HSV-1) and herpes simplex virus type II (HSV-2). The new compound peniterphenyl A shows stronger antiviral activity in vitro compared with Acyclovir (Acyclovir) and the like which are marketed. Thus, these compounds are ideal candidates for development as highly potent, novel anti-herpesvirus drugs.
Description
Technical field:
the invention belongs to the field of natural products, and particularly relates to a terphenyl compound (compounds 1-3) with a novel structure, a known homolog (compounds 4-8) and application thereof in preparation of anti-herpesvirus medicines.
The background technology is as follows:
herpes viruses (Herpesviruses) are a class of enveloped DNA viruses, known as 120 or more, and are classified into alpha, beta, gamma, unclassified herpes viruses, etc. according to their physicochemical properties. Herpes viruses primarily invade ectodermal-derived tissues, including skin, mucosal and neural tissues. The infection sites and the diseases caused by the infection are various, and the latent infection tends to be serious threat to human health. Deep sea fungi (Deep-sea Derived Fungi) are an extremely important marine microorganism resource and are valuable resources for researching and developing novel antiviral drugs and other human serious diseases.
The invention comprises the following steps:
the invention discloses a novel-structure terphenyl compound (1-3) separated from deep sea fungus Penicillium sp.SCSIO 41030.
The invention relates to a novel structure of terphenyl compound or a medicinal salt thereof, which has a structural formula as any compound in a formula (II):
wherein 1 is compound 1;2 is compound 2;3 is compound 3.
The second object of the present invention is to provide a method for preparing the above-mentioned terphenyl compound, wherein the terphenyl compound is prepared and separated from a fermentation culture of a deep sea fungus Penicillium sp.SCSIO 41030, and the preservation number of the deep sea fungus Penicillium sp.SCSIO 41030 is: GDMCC No.61543.
The method comprises the following specific steps:
a) Preparing a fermentation culture of deep-sea fungus Penicillium sp.SCSIO 41030, separating fermentation liquor and mycelium of the fermentation culture, extracting the fermentation liquor by ethyl acetate, and concentrating the ethyl acetate extract to obtain an extract A; crushing mycelium, extracting with ethyl acetate, concentrating ethyl acetate extract to obtain extract B;
b) Performing medium-pressure normal-phase liquid chromatography on the crude extract obtained by combining the extract A and the extract B, performing gradient elution by using methylene dichloride/methanol as an eluent from a volume ratio of 100:0-0:100, collecting fractions eluted by methylene dichloride/methanol with a volume ratio of 92:8, performing semi-preparative high performance liquid chromatography by using methanol and water with a volume ratio of 49:51 as an elution system at a flow rate of 2mL/min, collecting fractions with a retention time of 35.9min to obtain a compound 3, collecting sub-fractions with a retention time of 12.5min, performing semi-preparative high performance liquid chromatography on the sub-fractions, performing elution by using methanol and water with a volume ratio of 37:63 at a flow rate of 2mL/min, collecting fractions with a retention time of 14.8min to obtain a compound 1, and collecting fractions with a retention time of 22.5min to obtain a compound 2.
The preparation of the fermentation culture of the deep-sea fungus Penicillium sp.SCSIO 41030 of step a) is preferably: inoculating activated Penicillium sp.SCSIO 41030 into seed culture medium, culturing at 28deg.C and 180rpm for 72 hr to obtain seed solution, inoculating the seed solution into fermentation culture medium at 5% inoculum size, standing and culturing at 28deg.C for 30 days to obtain fermentation cultureThe formula of the culture medium and the fermentation culture medium comprises the following components in per liter: mannitol 20g, yeast extract 3g, sodium glutamate 10g, glucose 10g, maltose 20g, corn steep liquor suspension 1g, magnesium sulfate 7H 2 O 0.3g、KH 2 PO 4 0.5g, the balance being water, pH 7.4-7.8.
The third object of the invention is to provide the application of the deep sea fungus Penicillium sp.SCSIO 41030 in preparing the above terphenyl compound.
The invention discovers that the terphenyl compound (compound 1-3) with novel structure and the known homolog (compound 4-8) have stronger inhibition effect on the herpes simplex virus I (HSV-1) and the herpes simplex virus II (HSV-2) through experiments, and no obvious cytotoxicity is discovered under the effective dose. Therefore, the compound can be expected to be developed into a novel non-toxic/low-toxic anti-herpesvirus drug.
The fourth object of the invention is to provide the application of the terphenyl compound or the medicinal salt thereof in preparing the anti-herpesvirus medicament; the structural formula of the terphenyl compound is any one compound in the formula (I):
wherein 1 is compound 1;2 is compound 2;3 is compound 3;4 is compound 4;5 is compound 5;6 is compound 6;7 is compound 7;8 is compound 8.
Preferably, the herpes virus is herpes simplex virus type I or herpes simplex virus type II.
A fifth object of the present invention is to provide an anti-herpes virus drug comprising an effective amount of the above-mentioned terphenyl compound, or a pharmaceutically acceptable salt thereof, as an active ingredient, and a pharmaceutically acceptable carrier; the structural formula of the terphenyl compound is any one compound in the formula (I):
wherein 1 is compound 1;2 is compound 2;3 is compound 3;4 is compound 4;5 is compound 5;6 is compound 6;7 is compound 7;8 is compound 8.
The invention discovers that the terphenyl compound (compound 1-3) and the known homolog (compound 4-8) which are separated from deep sea fungus Penicillium sp.SCSIO 41030 and have novel structures, the structural formulas of which are respectively shown as 4-8 of the formula (I) can inhibit diseases caused by infection of two herpes viruses, namely herpes simplex virus type I (Herpes simplex virus type, HSV-1) and herpes simplex virus type II (HSV-2). Compared with Acyclovir (Acyclovir) and the like which are marketed, the terphenyl compounds (compounds 1-8) show equivalent activity in vitro, and particularly, the novel compound peniterphenyl A shows stronger antiviral activity in vitro compared with Acyclovir (Acyclovir) and the like which are marketed. Thus, these compounds are ideal candidates for development as highly potent, novel anti-herpesvirus drugs.
The deep sea fungus Penicillium sp.SCSIO 41030 of the invention was deposited at the Cantonese microbiological culture Collection center (GDMCC) at year 03 and month 01 of 2021, address: building 5, building 59 of the university of first middle road 100 in Guangzhou city, guangdong province microbiological institute, deposit number is: GDMCC No.61543.
Description of the drawings:
FIG. 1 is a schematic diagram of the key in the structure of the novel terphenyl pentates A-C (Compounds 1-3) 1 H– 1 H COSY (bolded black line) and HMBC (black, i.e. arrow) related signals.
FIG. 2 is a novel compound, pentarphenyl A (Compound 1), antiviral plaque formation assay; wherein + means there is or is added, -means there is no or is not added.
FIG. 3 is an experiment of the inhibition of viral protein expression by novel compound pentarphenyl A (Compound 1); a is the effect of treatment of HSV-1 virus-infected cells with different doses of penteprhenyl A on the mRNA expression levels of the virus-associated proteins gD and VP 16; b is the effect of treatment of HSV-2 virus-infected cells with different doses of penteprhenyl A on the mRNA expression levels of the virus-associated proteins gD and VP 16; c is the protein gD expression level of cells infected with HSV-1 virus treated with different doses of pentaterhenyl A; d is the protein gD expression level of HSV-2 virus infected cells treated with varying doses of pentaterhenyl A.
The specific embodiment is as follows:
the following examples are further illustrative of the invention and are not intended to be limiting thereof.
Example 1: preparation and isolation of New terphenyl pentates A-C (1-3)
1. Seed medium (fermentation medium): each liter of the culture medium contains 20g of mannitol, 3g of yeast extract, 10g of sodium glutamate, 10g of glucose, 20g of maltose, 1g of corn steep liquor suspension (CAS: 66071-94-1), and magnesium sulfate 7H 2 O 0.3g、KH 2 PO 4 0.5g, balance water, pH 7.5. Mixing the above components and contents uniformly, preparing 16L, and sterilizing at 121deg.C under high pressure for 30 min.
2. Fermentation
2.1, seed culture: the activated Penicillium sp.SCSIO 41030 pellet is inoculated into 1000mL conical flask containing 300mL seed culture medium, and subjected to dynamic shaking culture at 28 ℃ and 180rpm for 72 hours to obtain seed solution.
2.2, fermentation culture: the seed solution was inoculated into 16L of a fermentation medium at an inoculum size (volume percent) of 5%, and subjected to stationary culture at a constant temperature of 28℃for 30d, thereby obtaining a fermentation culture.
3. Extraction: filtering the fermentation culture by a Buchner funnel to separate fermentation liquor and mycelium, extracting the fermentation liquor with ethyl acetate for 3 times, combining ethyl acetate extracts, and concentrating by reduced pressure distillation to obtain extract A; crushing mycelium for 3 minutes by using a dispersing machine, performing ultrasonic crushing extraction for 3 times by using ethyl acetate for 30 minutes each time, merging extracting solutions, concentrating the ethyl acetate extracting solutions by reduced pressure distillation to obtain an extract B, merging the extract A and the extract B, and performing reduced pressure distillation to obtain a crude extract (11.2 g).
4. Isolation and characterization of New terphenyl pentates A-C (1-3)
The crude extract (11.2 g) obtained by combining the extract A and the extract B is subjected to medium pressure normal phase column chromatography liquid chromatography (MPLC) and is subjected to gradient elution by using methylene dichloride-methanol as an eluent from a volume ratio of 100:0 to 0:100, and fractions (1.4 g) eluted with the methylene dichloride-methanol volume ratio of 92:8 are collected. This fraction was then further separated and purified by high performance liquid chromatography and semi-preparative column (YMC-pack ODS-A, 10X 250mm,5 μm,2 m/min) to give se:Sup>A sub-fraction (retention time: 12.5 min) and compound 3 (3.2 mg, retention time: 35.9 min) with se:Sup>A volume fraction of 49% of chromatographically pure methanol and water (i.e., se:Sup>A volume ratio of chromatographically pure methanol to water: 49:51) as mobile phases. Further fine purification of the above sub-fractions was also carried out using semi-preparative high performance liquid phase (YMC-pack ODS-A, 10X 250mm,5 μm,2 m/min) under conditions where the elution system was 37% by volume of chromatographically pure methanol and water (i.e., the volume ratio of chromatographically pure methanol and water was 37:63), to finally obtain compounds 1 (1.1 mg, retention time was 14.8 min) and 2 (1.2 mg, retention time was 22.5 min).
And (3) structural identification: the compound pentaterhenyl a (compound 1) is a grey amorphous powder whose nuclear magnetic data is shown in table 1. The high-resolution mass spectrum HRESIMS gives a molecular ion peak M/z 337.0725 ([ M-H)] + ) The molecular formula is determined as follows: c (C) 19 H 14 O 6 The unsaturation was 13. Analysis in combination with DEPT NMR Spectroscopy 13 C NMR data found that the compound pentaterpenyl A has seventeen carbon signals in total, including a methoxy group (delta) C 60.8 Methine groups (. Delta.) on five aromatic rings or olefins C 98.7 107.6, 102.8, 115.6, 130.4) and eleven unsaturated quaternary carbons. Further combine 1 By analysis of the H NMR spectrum, the methine signal delta can be found C 115.6 and 130.4 are two sets of carbon signals symmetrical on the benzene ring. The degree of unsaturation of the binding molecule and the number of carbon analyzed, it is presumed that the pentaterhenyl A has a benzine skeleton structure. In addition by 1 H– 1 The key related signals in the H COSY and HMBC spectra (figure 1) determine the positions of seven methine groups and methoxy groups on the benzene rings respectively, and finally, the number of hydroxyl groups and substitution positions are determined by combining the molecular formula and chemical shift values of quaternary carbon, and the structural formula of the final compound pentaterhenyl A is shown as 1 in the formula (I).
The compound pentaterhenyl B (compound 2) is a yellow oil, the core of whichThe magnetic data attributes are shown in table 1. A molecular ion peak whose molecular formula is given by high resolution mass spectrum HRESIMS is determined as M/z 311.0563 ([ M-H)] + ) Is determined as C 17 H 12 O 6 With 12 unsaturations. By analysis of 13 The C NMR data found that all carbon atoms of the compound were unsaturated, including an ester carbonyl group (delta) C 168.8 Methine groups (delta) on eight benzene rings or olefins C 113.4 135.1, 113.9, 115.8, 118.7, 116.8, 116.0, 123.4) and eight quaternary carbon atoms. And at 1 Four active hydrogen signals (. Delta.) were also found on the H NMR spectrum H 9.17,9.38,9.29,9.48), the molecular formula indicates that all four signals belong to hydroxyl signals. Further pass through 1 H– 1 The key relevant signals in the H COSY and HMBC spectra (FIG. 1) can be deduced that the compound has two 1,2, 4-trisubstituted benzene rings and one 2-pyrone ring in the backbone. By analyzing the chemical shift of the pyrone cycloolefin and the HMBC signal associated with other benzene rings (FIG. 1), the skeleton of the compound pentaterphnyl B is presumed to be 4, 5-diphenyl-2-pyrone. And the structural formula of the final pentaterhenyl B is shown as 2 in the formula (I) by combining the molecular formulas.
The compound pentaterhenyl C (compound 3) is a brown amorphous powder whose nuclear magnetic data is shown in table 1. Similarly, its molecular formula is determined by high resolution mass spectrometry HRESIMS as C 18 H 10 O 6 With 14 unsaturations. Considering that compound 3 has a similar high degree of unsaturation as compound 1, then both will be 13 C NMR 1 As a result of comparison of the H NMR spectra, it was found that both have two benzene ring groups which are similar, and it was presumed that Compound 3 also has a similar biphenyl skeleton. At the position of 1 Three active hydrogen signals (delta) were observed in the H NMR spectrum H 9.77 10.10,9.97) are hydroxyl signals; at the same time, a difference in the olefin methine signal (. Delta.) from Compound 1 was found C/H 130.4/6.73). Bonding of 13 Two low field signals (delta) in the C NMR spectrum C 183.9 175.3) and related HMBC spectrum signals (fig. 1), it is assumed that compound 3 has a p-benzoquinone group in its structure. Finally through two other benzene ringsThe related HMBC signal of the last methyl group (fig. 1) determines the way the two benzene rings are linked to the p-benzoquinone group. Thus, the compound pentaterhenyl C (compound 3) is identified as the p-benzoquinone derivative structure of the terphenyl compound, and the plane structural formula of the p-benzoquinone derivative structure is shown as 3 in the formula (I).
Table 1.peniterphenyls A-C 1 H-sum 13 C-NMR data were assigned, and the solvent was DMSO-d6.
Example 2: determination of anti-herpesvirus Activity of terphenyl Compounds
The terphenyl compounds have significant inhibitory activity against herpes simplex virus type I (Herpes simplex virus type, HSV-1) and herpes simplex virus type II (HSV-2), experimental method references (Li W.M.; xu C.J.; hao C.; zhang Y.; wang Z, Q.; wang S.Y.; wang W.inhibit of herpes simplex virus by myricetin through targeting viral gD protein and cellular EGFR/PI3K/Akt pathway [ J ]. Anti research.177 (2020), 104714). The activity results showed: the novel compounds peniterphenyl A (compound 1) and compound 7 (the structural formula of which is shown as 7 in formula (I)) have stronger in vitro activity for inhibiting herpes viruses (HSV-1 and HSV-2) than Acyclovir (Acyclovir) which is a marketed drug (see Table 2). In addition, the compound pentaterhenyl A does not show obvious cytotoxic activity at an effective dose, so that the compound can be modified to prepare low-toxicity and high-efficiency anti-herpes virus medicines.
TABLE 2 screening results for anti-HSV-1/2 Activity of Compounds 1-8 (n=5)
Example 3: peniterphenyl A anti-HSV-1/2 virus and experiment for inhibiting gD protein expression
The antiviral activity of penteprhenyl A against two human herpes simplex viruses (HSV-1/HSV-2) was evaluated using the cytopathic effect (CPE) method with Vero cells as host cells. The results show that the compound pentaterhenyl a maintains Vero cell morphology in a dose dependent manner, significantly reducing CPE caused by HSV1/2 invasion compared to the control group. Further plaque formation experiments showed (FIG. 2) that at a concentration of 5. Mu.M of penteprhenyl A, almost no plaque (white) was observed for virus HSV-2, whereas more than 10. Mu.M of penteprhenyl A was required for HSV-1 to exhibit the same result. Therefore, the pentaterpenyl A not only can remarkably reduce CPE caused by HSV-1/2 virus, but also can inhibit the proliferation of the virus in host cells, and compared with HSV-1, the sensitivity of HSV-2 to the pentaterpenyl A is higher.
Treatment of cells infected with HSV-1/2 virus with different doses of pentaterhenyl A resulted in a significant reduction in the average mRNA expression of the virus-associated proteins gD and VP16 (FIGS. 3A and B). Similar to the transcription results, detection of the expression level of the gD protein by the western blotting method also confirmed that the gD proteins induced by HSV-1 and HSV-2 respectively disappeared after treatment with 2.5 and 1.25. Mu.M of pentaterhenyl A, respectively (FIGS. 3C and D). The above experiments suggest that the entire process of invasion of the host cell by HSV-1/2 virus may be affected by pentaterhenyl A. To further investigate the mechanism of action of pentaterhenyl a on HSV virus, 4 different treatment conditions were used, pretreatment, co-treatment, post-treatment and co-post-treatment, respectively. The gD protein content was measured under these four conditions using Western blotting and found to be significantly reduced in the co-treated group relative to the other treated groups. The above results demonstrate that the pentaterhenyl a tends to bind to the viral surface glycoprotein gD to prevent the virus from entering the host cell, thereby inhibiting the effect of the virus on invasion into the cell.
Claims (9)
1. A terphenyl compound or a pharmaceutically acceptable salt thereof, which has a structural formula as any one of the compounds of formula (II):
formula (II)
Wherein 1 is compound 1;2 is compound 2.
2. A process for producing the terphenyl compound of claim 1, wherein the terphenyl compound is a compound obtained from a deep sea fungusPenicillium Preparation and separation of sp, SCSIO 41030 fermentation culture, and deep sea fungusPenicilliumsp, deposit number of SCSIO 41030: GDMCC No.61543.
3. The method according to claim 2, characterized by the specific steps of:
a) Preparation of deep sea fungiPenicilliumsp, SCSIO 41030, separating fermentation broth and mycelium of the fermentation broth, extracting the fermentation broth with ethyl acetate, concentrating the ethyl acetate extract to obtain extract A; crushing mycelium, extracting with ethyl acetate, concentrating ethyl acetate extract to obtain extract B;
b) Performing medium-pressure normal-phase liquid chromatography on the crude extract obtained by combining the extract A and the extract B, performing gradient elution by using methylene dichloride/methanol as an eluent from a volume ratio of 100:0-0:100, collecting fractions eluted by methylene dichloride/methanol with a volume ratio of 92:8, performing semi-preparative high performance liquid chromatography by using methanol and water with a volume ratio of 49:51 as an elution system at a flow rate of 2mL/min, collecting sub-fractions with a retention time of 12.5min, performing semi-preparative high performance liquid chromatography on the sub-fractions by using methanol and water with a volume ratio of 37:63 as an elution system at a flow rate of 2mL/min, collecting fractions with a retention time of 14.8min to obtain a compound 1, and collecting fractions with a retention time of 22.5min to obtain a compound 2.
4. According to claim 3The method is characterized in that the deep sea fungi prepared in the step a) are preparedPenicilliumThe fermentation culture of sp, SCSIO 41030 is the deep sea fungus to be activatedPenicilliumsp and SCSIO 41030 are inoculated into a seed culture medium, the seed culture medium is cultured at 28 ℃ and 180rpm for 72h to prepare seed liquid, the seed liquid is inoculated into a fermentation culture medium at the inoculum size of 5 percent, the seed liquid is subjected to static culture for 30 days at the temperature of 28 ℃ to prepare a fermentation culture, and the seed culture medium and the fermentation culture medium comprise the following components in per liter: mannitol 20g, yeast extract 3g, sodium glutamate 10g, glucose 10g, maltose 20g, corn steep liquor suspension 1g, magnesium sulfate 7H 2 O 0.3 g、KH 2 PO 4 0.5g, the balance is water, and the pH is 7.4-7.8.
5. Deep sea fungiPenicilliumApplication of sp, SCSIO 41030 in preparing terphenyl compound in claim 1, and deep sea fungusPenicilliumsp, deposit number of SCSIO 41030: GDMCC No.61543.
6. Application of terphenyl compound or medicinal salt thereof in preparing anti-herpesvirus medicament; the structural formula of the terphenyl compound is any one compound in the formula (I):
(I)
Wherein 1 is compound 1;2 is compound 2;4 is compound 4;5 is compound 5;6 is compound 6;7 is compound 7;8 is compound 8.
7. The use according to claim 6, wherein the herpes virus is herpes simplex virus type I or herpes simplex virus type II.
8. An anti-herpesvirus drug comprising an effective amount of a terphenyl compound as an active ingredient, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; the structural formula of the terphenyl compound is any one compound in the formula (I):
(I)
Wherein 1 is compound 1;2 is compound 2;4 is compound 4;5 is compound 5;6 is compound 6;7 is compound 7;8 is compound 8.
9. Deep sea fungiPenicilliumsp, SCSIO 41030 with deposit number: GDMCC No.61543.
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| WO2001003681A2 (en) * | 1999-07-08 | 2001-01-18 | Prendergast Patrick T | Use of flavones, coumarins and related compounds to treat infections |
| CN102079692A (en) * | 2010-10-22 | 2011-06-01 | 中山大学 | Terphenyl compound and preparation method of terphenyl compound and application of terphenyl compound as alpha-glucosidase inhibitor |
| CN102079735A (en) * | 2010-10-22 | 2011-06-01 | 中山大学 | Terphenyl compound and preparation method thereof and application of compound as acetylcholinesterase inhibitor |
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