CN109574828A - A kind of sesquiterpenoids and its anti-hepatitis purposes - Google Patents
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Abstract
The invention discloses a kind of sesquiterpenoids and its anti-hepatitis purposes.This kind of compound is that is found from the extractive from fermentative of marine-derived fungal Trichoderma harzianum (Trichoderma harzianum) have the sesquiterpenoid of novel chemical skeleton, present invention firstly discovers that this kind of sesquiterpenoid has anti-HCV activity.External activity data shows that such compound can act on the invasion and transcription duplicate stage of HCV virus infection simultaneously, has multiple target point antiviral efficacy, is the drug model molecule of the new object research and development potentiality of a kind of great HCV-Ab IgG.
Description
Technical field
The invention belongs to pharmaceutical fields, and in particular to a kind of sesquiterpenoids and preparation method thereof and the sesquialter
Purposes of the terpenoid in terms of preventing and treating hepatitis (HCV).
Background technique
Hepatitis C Virus (HCV) infection is the important public health problem in the whole world, is caused every year more than 350,000 people death,
Influence the population in the whole world about 3%.The concealment of the HCV course of disease, infection chronicity degree is high, and whole late stage patients are often accompanied by chronic liver disease
Occur, serious person even develops into liver cancer.
The therapeutic agent of hepatitis early stage generally uses Peg-IFN alpha-2b to add Ribavirin, and curative effect is in different genotype
Difference is also larger in crowd, and treatment time length, adverse reaction are more.In recent years, for the targeting medicine of HCV life cycle key protein
Object, i.e., the appearance of the antiviral drugs directly acted on (DAA), makes the treatment of HCV obtain very big improvement, and cure rate mentions significantly
It is high.However, the use of DAA is still limited by some problems, the generation including medicament-resistant mutation strain, subsidiary bad anti-of drug
It answers and high medical expense etc..Therefore, to the Journal of Sex Research that gos deep into of HCV infection process, weeks different for virus infection are developed
The multiple target point newtype drug of phase has important society and economy for ensureing national life security, improving people's living standard
Meaning.
Summary of the invention
The present invention breathes out thatch in the research process for the active chemical components excavated in marine microorganism, from marine-derived fungal
Two sequiterpenes with novel chemical skeleton are had found in the extractive from fermentative of trichoderma (Trichoderma harzianum)
Object is closed, and has found that this kind of brand new class sequiterpene has anti-HCV activity for the first time.External activity data shows that such is changed
The invasion and transcription duplicate stage of HCV virus infection can be acted on simultaneously by closing object, had multiple target point antiviral efficacy, be a kind of pole
Has the drug model molecule of the new object research and development potentiality of HCV-Ab IgG.
The first aspect of the present invention provides II compound represented of formula I and formula:
The second aspect of the present invention provides the preparation method of above compound, includes the following steps:
1) it using marine filamentous fungus Trichoderma harzianum (Trichoderma harzianum) as engineering bacteria, is trained through everfermentation
It supports, obtains fermentation material；
2) fermentation material is extracted and is concentrated, by chromatographic isolation and purifying, preparation formula I and formula II from strain fermentation object medicinal extract
Compound.
Specifically, above-mentioned steps 1) Trichoderma harzianum (Trichoderma harzianum) is inoculated on solid medium
It is cultivated, preferably on rice solid medium, fermented and cultured 30~40 days at room temperature.
Above-mentioned steps 2) it collects mycelium and after culture medium smashs to pieces, by ethyl acetate ultrasonic extraction, stands overnight, filter
It is concentrated after removing filter residue, is repeatedly extracted to obtain fermentation material medicinal extract；Then fermentation material medicinal extract is passed sequentially through into silica gel column chromatography, anti-
Phase pillar layer separation and HPLC purifying, prepare II compound of formula I and formula from fermentation material medicinal extract.
Wherein the silica gel column chromatography is vacuum liquid phase chromatography (VLC), using 160~200 mesh silica gel particles, petroleum ether/
The system of acetone volume ratio 50:1~1:1 carries out gradient elution as eluting solvent.The reversed-phase column chromatography separation uses C-
18ODS reversed-phase column, 20%~100% methanol/water gradient elution.The HPLC purifying is using half preparation HPLC, 35% acetonitrile/water
Isocratic elution.
The third aspect of the present invention, provides Formulas I and Formula II compound or its pharmaceutically acceptable salt is used in preparation
Purposes in the drug of prevention or treatment hepatitis.
The present invention is by inhibiting poisoning intrusion outside construct and replicates the experimental model in two stages, have rated above-mentioned formula I,
The anti-HCV activity of II compound of formula.Pass through the evaluation of external pseudovirion model active, SPR experiment and small molecule and target egg
White binding molecule docking analysis, it was demonstrated that above compound can be (extracellular big by acting on cell host factor CD81 albumen LEL
Ring region) on HCV memebrane protein E2 binding site, hinder HCV and host cell combination, thus inhibit HCV invade host cell.
In addition, demonstrating anti-hcv activity of the above compound in the Huh7.5 cell of HCV acute infection by experiment in vitro.And lead to
Cross molecular docking analysis, it was demonstrated that above compound acts on Ith area Palm on HCV virus NS5B, inhibits the transcription of HCV and answers
System.Final confirmation formula I and II compound of formula are a kind of multiple target point HCV inhibitor of brand new type.
Detailed description of the invention
The inhibition of Fig. 1 pseudovirion model inspection type I compound (A), II compound of formula (B) to the poisoning intrusion stage
Effect, wherein left side figure is VSV pseudovirion test result, and the right figure is VSV pseudovirion test result.
The SPR experimental data figure of Fig. 2 type I compound (A), II compound of formula (B) in conjunction with CD81.
(II (B) compound of A) ﹑ formula hinders CD81 and the protein bound SPR experimental data figure of E2 to Fig. 3 formula I.
Molecular docking analysis chart of Fig. 4 type I compound in conjunction with CD81, in which: A is that type I compound and CD81 are whole
Molecular docking analysis chart, B are the molecular docking analysis chart of type I compound and CD81 binding site.
Molecular docking analysis chart of Fig. 5 type I compound in conjunction with NS5B, in which: A shows three medicines of NS5B albumen
Object active binding site, B show the combination situation in type I compound and site 1, and C shows the knot of type I compound Yu site 2
Situation is closed, D shows the combination situation in type I compound and site 3.
Specific embodiment
Disclosed technology contents, those skilled in the art will be better understood when essence of the invention according to the present invention, under
It states embodiment and only makees example.
Embodiment 1: the preparation of compound and Structural Identification
(1) the extraction separation of compound
Marine fungi Trichoderma harzianum (Trichoderma harzianum) is inoculated in 100 bottles of 500mL sterilizing rice solids
On culture medium, stationary culture 30 days at 25 DEG C are collected after mycelium covers with culture medium.
Smashing growth to pieces has mycelial rice medium, appropriate ethyl acetate (not having culture medium) is added, ultrasound mentions
Take 30min, after stand overnight.It is filtered to remove filter residue, pressurization concentration ethyl acetate obtains extract coarse extract.It extracts 3 times altogether,
Total medicinal extract 15.8g is obtained after merging.
Total medicinal extract, 160~200 mesh silica gel mixed samples are separated using VLC silica gel column chromatography, petroleum ether/acetone system is used as and washes
Desolventizing carries out gradient elution (50:1~1:1, v/v), merges and obtains 8 fractions.The 5th part fraction (3.4g) is taken to carry out C-
The separation of 18ODS reversed-phase column chromatography, methanol/water 20%~100% (percent by volume) gradient elution obtain 5 fractions altogether.3rd
Fraction (202.3mg) carries out half preparation HPLC purifying, and 35% acetonitrile/water isocratic elution prepares type I compound (5.2mg)
With II compound of formula (2.1mg).
(2) Structural Identification of compound
Drying sample uses 0.55mL DMSO-d6It is dissolved, is fitted into nuclear magnetic tube and carries out 1D and 2D NMR test.Afterwards
It is parsed according to planar structure of the NMR data to compound, and correlation is coupled according to NOE, above-mentioned two compound has been determined
Relative configuration.On this basis, it is calculated by ECD, determines the absolute configuration of compound.Physical and chemical parameter is as follows:
Type I compound: colourless powder, [α]25 D-5.3(c 0.05,MeOH)；IR(KBr)νmax 3420,2925,2854,
1739,1679,1460,1376,1248,1123,1042cm-1；HRESIMS m/z 267.1234[M-H]?(calcd for
C14H19O5,267.1232)；Nuclear magnetic data is shown in Table 1.
II compound of formula: colourless powder, [α]25 D10.0(c 0.05,MeOH)；IR(KBr)νmax 3366,2922,
2851,1714,1681,1451,1374,1205,1138,1023cm-1；HRESIMS m/z 313.1289[M-H]?(calcd
for C15H21O7,313.1287)；Nuclear magnetic data is shown in Table 1.
1. formula I of table and II compound of formula1H and13C NMR data ownership
Embodiment 2: the external HCV-Ab IgG transcription replication activity evaluation of compound
(1) cell line
Huh7.5 cell is people's hepatic cell line, is given by Vertex drugmaker, the U.S. that culture solution used is addition 10%
The fetal calf serum (Fetal bovine serum, FBS) and every milliliter of 100 units of Penicillin/streptomysin of inactivation
Height sugar Dulbecco ' the s Modified Eagle Medium of (Penicillin-Streptomycin, Pen-Strep)
(DMEM) culture solution.Cell is containing 5%CO2And it is cultivated in 37 DEG C of cell incubators of saturated humidity.
(2) viral
Infectious Hepatitis C Virus (HCV) Strain is J6/JFH-1/JC.It will contain recombinant full-lenght HCV cDNA's
PFL-J6/JFH/JC1 plasmid (U.S. Vertex Pharmaceuticals Inc. give) digestion purifying, obtains HCV cDNA,
HCV RNA is obtained by being transcribed in vitro, transfects normal Huh7.5 cell, obtaining has infective virus liquid.
(3) control drug
VX-950: general entitled Telaprevir, it is a kind of HCV NS3/4A serpin.
PSI-7977: general entitled Sofosbuvir, it is HCV NS5B polymerase inhibitors.
Two kinds of drugs are purchased from MedChemExpress company.
(4) test method
The design of compound solution concentration and preparation:
Formula I and II compound of formula are made into the mother liquor of 10mM with DMSO, and Telaprevir, Sofosbuvir are made into DMSO
The mother liquor of 20mM is diluted to required concentration with DMEM complete medium when use.Compound concentration design is formulated as follows:
Cytotoxicity experiment and compound are in the HCV-Ab IgG effect experiment in the Huh7.5 cell of HCV acute infection, chemical combination
Object final concentration range is 0~100 μM, is diluted by 3 times；The final concentration range of Telaprevir, Sofosbuvir are 0~200 μM,
It is diluted by 5 times.
Anti-hcv activity of the compound in the Huh7.5 cell of HCV acute infection:
1) Huh7.5 cell is with 3 × 104A/cm2Density kind enter 96 orifice plates；
2) after culture for 24 hours, old culture solution is discarded, the compound or equivalent solvent control of respective concentration is added, carries out simultaneously
HCV infection (MOI=0.1)；
3) after cultivating 72h, intracellular total serum IgE is extracted with Qiagen RNeasy Mini Kit, and examine using qRT-PCR method
Intracellular HCV rna level is surveyed, calculates medium effective concentration using Reed&Muench method.
Cytotoxicity experiment:
1) Huh7.5 cell is with 3 × 104A/cm2Density kind enter 96 orifice plates；
2) after culture for 24 hours, old culture solution, the compound solution processing of 100 μ L various concentrations of cell are discarded；
3) after drug-treated 72h, every hole continues to cultivate after 10 μ L MTT solution (concentration is 5 μ g/mL) is added；
4) after cultivating 4h, culture solution is carefully discarded, every hole adds 150 μ L DMSO, shakes 15min sufficiently to dissolve first a ceremonial jade-ladle, used in libation knot
It is brilliant；Then using 630nm as reference wavelength, the light absorption value at 570nm is measured, and calculate half cell using Reed&Muench method
Toxic concentration.
Real-time qRT-PCR:
TaqMan probe method real-time fluorescence quantitative PCR uses kit AgPath-ID TM One-Step RT-PCR
Kit to house-keeping gene glyceraldehyde-3-phosphate dehydrogenase (glyceraldehyde-3-phosphate dehydrogenase,
GAPDH it) is quantified with the RNA of HCV.
Primer and probe sequence used in table 2.Real time qRT-PCR
2) result processing method:
Using GAPDH as internal reference, the CT value of target gene is normalized, using 2-△△CTMethod calculates purpose
The differential expression of gene.
Test result shows: formula I and II compound of formula and positive control Telaprevir, Sofosbuvir are thin in Huh7.5
Anti-HCV activity on born of the same parents is as shown in the table:
3. compound of table anti-HCV activity on Huh7.5 cell
SI: selection index is CC50With EC50Ratio.CC50With EC50Indicated with average value ± standard deviation.
Embodiment 3: compound inhibits the activity rating of HCV invasion cell
(1) pseudovirion is tested
Pseudovirus packaging
The packaging of HCV pseudovirus: the 293T cell per well in six orifice plates transfects pCMV-HCV GP, 0.7 μ g；HIV-Luc1μ
g；pAdvantage 0.3μg.8 μ L of transfection reagent Megatrans1.0.4-6h changes liquid after transfection, changes 3%FBS into, contains TPCK-
The DMEM of Trypsin and neuraminidase.After cultivating 72h, harvest supernatant crosses 0.45 μm of filter, freezes after packing in -80 DEG C
Refrigerator is spare.VSV pseudovirus packing method is same as above, and difference is to replace pCMV-HCV GP with the plasmid of expression VSVG albumen.
Pseudovirus infection experiment
The pseudovirus model of foundation can be used for the screening for the antiviral drugs that " cell entry cell " is target.It is specific real
Test that steps are as follows:
1) shift to an earlier date 1 day, 293T cell or A549 cell are passaged to 96 orifice plates, every hole 5 × 103A cell, in 37 DEG C
Culture；
2) it after mixing certain density compound with virus, is added in cell, is cultivated 72 hours in 37 DEG C；
3) it surveys luciferase activity: utilizing the activity of Bright-Glo detection kit detection luciferase, operation
Method is shown in product description.According to the signal value measured, the inhibiting rate and IC of compound are calculated50.Inhibiting rate %=(blank control
Fluorescence reading-addition compound fluorescence reading)/blank control fluorescence reading.
Experimental result (see Fig. 1) shows that formula I and II compound of formula can inhibit HCV to invade host cell.
SPR (surface plasma resonance) experiment
The action target spot for inhibiting HCV invasion host cell in order to further determine formula I and II compound of formula, using SPR reality
Test the binding ability for testing above-mentioned small molecule compound Yu HCV memebrane protein E2 receptor and host factor CD81.
Experimental result is as shown in Figures 2 and 3, shows that formula I and II compound of formula can be with host factor CD81 albumen LEL
E2 binding site phase separation in (extracellular big ring region), and then the combination of HCV memebrane protein E2 receptor and host factor CD81 is hindered,
And then play antiviral invasion effect.
Embodiment 4: the action target spot of molecular docking experimental verification compound
It is tested using molecular docking, compound HCV-Ab IgG target spot is confirmed.According to the two dimension of type I compound to be measured
Then conformation is converted to mol2 format simultaneously using Open Babel software using ChemOffice Software on Drawing LIG molecular structure
It is spare after progress structure optimization.
By small molecule compound with HCV key target protein NS3/4A, NS5A, NS5B, E2 and host factor CD81 into
Simulation docking of having gone is analyzed.As a result as shown in Figure 4 and Figure 5, type I compound can be good with the drug target of CD81 and NS5B
Good to combine, external activity actual test data is coincide in docking analysis result and embodiment 2 and 3, the analysis knot of Formula II compound
Seemingly, further confirmation formula I and II compound of formula are that one kind can act on host factor CD81 and virus NS 5 B simultaneously to fruit
Multiple target point anti-HCV activity molecule.
SEQUENCE LISTING
<110>Peking University, Chinese ocean mineral resources research and develop association
<120>a kind of sesquiterpenoids and its anti-hepatitis purposes
<130> WX2018-BY-013
<160> 6
<170> PatentIn version 3.3
<210> 1
<211> 23
<212> DNA
<213>artificial sequence
<400> 1
cgggagagcc atagtggtct gcg 23
<210> 2
<211> 25
<212> DNA
<213>artificial sequence
<400> 2
ctcgcaagca ccctatcagg cagta 25
<210> 3
<211> 19
<212> DNA
<213>artificial sequence
<400> 3
aggccttgtg gtactgcct 19
<210> 4
<211> 24
<212> DNA
<213>artificial sequence
<400> 4
cggactcaac ggatttggtc gtat 24
<210> 5
<211> 24
<212> DNA
<213>artificial sequence
<400> 5
agccttctcc atggtggtga agac 24
<210> 6
<211> 19
<212> DNA
<213>artificial sequence
<400> 6
ccgtcaaggc tgagaacgg 19
Claims (9)
1. II compound represented of formula I and formula:
2. the preparation method of compound described in claim 1, comprising the following steps:
1) using Trichoderma harzianum (Trichoderma harzianum) as engineering bacteria, by fermented and cultured, fermentation material is obtained；
2) fermentation material is extracted and is concentrated, by chromatographic isolation and purifying, II compound of preparation formula I and formula from fermentation material medicinal extract.
3. preparation method as claimed in claim 2, which is characterized in that step 1) is by Trichoderma harzianum (Trichoderma
Harzianum it) is inoculated on solid medium and is cultivated.
4. preparation method as claimed in claim 3, which is characterized in that the solid medium is rice solid medium, is connect
Fermented and cultured 30~40 days at room temperature after kind.
5. preparation method as claimed in claim 2, which is characterized in that after step 2) collects mycelium and culture medium smashs to pieces, lead to
Peracetic acid ethyl ester ultrasonic extraction, stands overnight, and is concentrated after being filtered to remove filter residue, is repeatedly extracted to obtain fermentation material medicinal extract；Then
Fermentation material medicinal extract is passed sequentially through into silica gel column chromatography, reversed-phase column chromatography separation and HPLC purifying, prepares and obtains from fermentation material medicinal extract
Obtain II compound of formula I and formula.
6. preparation method as claimed in claim 5, which is characterized in that the silica gel column chromatography is vacuum liquid phase chromatography, is used
160~200 mesh silica gel particles, petroleum ether/acetone volume ratio 50:1~1:1 system carry out gradient elution as eluting solvent.
7. preparation method as claimed in claim 5, which is characterized in that the reversed-phase column chromatography separation uses C-18ODS reverse phase
Column,
20%~100% methanol/water gradient elution.
8. preparation method as claimed in claim 5, which is characterized in that the HPLC purifying is using half preparation HPLC, 35% second
Nitrile/water isocratic elution.
9. compound described in claim 1 or its pharmaceutically acceptable salt are in preparing the drug for preventing or treating hepatitis
Purposes.
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| CN201811588057.2A CN109574828B (en) | 2018-12-25 | 2018-12-25 | Sesquiterpene compound and anti-hepatitis C application thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101041840A (en) * | 2007-01-25 | 2007-09-26 | 中国计量学院 | Preparation method of sesquiterpenoids Trichothec-9-en-4-o1,12,13-epoxy-,acetate,(4beta)-(8CI,9CI) |
| CN105602994A (en) * | 2016-04-08 | 2016-05-25 | 广东海洋大学 | Fermentation extract of marine fungus Trichoderma harzianum DLEN2008005 and preparation method and application of fermentation extract |
-
2018
- 2018-12-25 CN CN201811588057.2A patent/CN109574828B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101041840A (en) * | 2007-01-25 | 2007-09-26 | 中国计量学院 | Preparation method of sesquiterpenoids Trichothec-9-en-4-o1,12,13-epoxy-,acetate,(4beta)-(8CI,9CI) |
| CN105602994A (en) * | 2016-04-08 | 2016-05-25 | 广东海洋大学 | Fermentation extract of marine fungus Trichoderma harzianum DLEN2008005 and preparation method and application of fermentation extract |
Non-Patent Citations (1)
| Title |
|---|
| BO LI等: "Harzianoic acids A and B, new natural scaffolds with inhibitory effects", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
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