CN104876945A - Alkaloid dimer, preparation method thereof and application of alkaloid dimer as antiviral agent - Google Patents
Alkaloid dimer, preparation method thereof and application of alkaloid dimer as antiviral agent Download PDFInfo
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Abstract
The invention discloses an alkaloid dimer, a preparation method thereof and application of the alkaloid dimer as an antiviral agent. The method comprises the following steps: firstly, carrying out strain culture on fungus Pestalotiopsis sp.(ZJ-2009-7-6) during preparation, and carrying out fermental cultivation on the fungus; leaching the obtained mycelium with a chloroform-methanol mixed liquid (1 to 1) for three times, carrying out vacuum concentration, and extracting with ethyl acetate for three times, so as to obtain crude extractum; and sequentially carrying out positive slica column chromatography, Sephadex LH-20 gel column chromatography and HPLC (high-performance liquid chromatography) on ethyl acetate-phase crude extractum to obtain a compound shown in a formula I. The antiviral agent provided by the method has the characteristics that the compound shown in the formula I or a pharmaceutically acceptable salt is taken as an effective component for preventing and/or treating diseases caused by herpes simplex virus I (HSV-1) and/or enterovirus 71 (EV71).
Description
Technical field
The present invention relates to a kind of alkaloid dimer (alkaloid dimer) compound and preparation method thereof and application, particularly relate to one, to herpes simplex virus type 1 (HSV-1) and Enterovirus 71 (EV71), there is extremely strong inhibiting alkaloid dimer and preparation method thereof and application.
Background technology
Herpes simplex virus type 1 is a kind of DNA virus be wrapped in, there is high incidence, latent period is long, neurotropic feature, hides in peripheral nervous system, main infection children, immunocompromised person and organ transplantation person, will large-scale outbreak once be subject to extraneous suitably stimulation, cause encephalitis and keratitis, severe patient energy causing death.Current antiviral mainly nucleoside antibiotics clinically, as acyclovir, but resistant infections crowd increases sharply in recent years.Enterovirus 71 is a kind of little single positive chain RNA virus, is cause hand foot and mouth disease main pathogens, can causes serious neurological complication, causes the irreversible injury of brain function of immunoenzyme technics even dead.At present not to the effective vaccine of EV71 and medicine, clinical treatment to suit the medicine to the illness, supportive treatment.They cause serious impact to the health of the health of the mankind especially children.Therefore, the antiviral finding new antiviral especially novel structure has become problem urgently to be resolved hurrily.The living environment (high pressure, high salt, anoxic, lucifuge etc.) of marine microorganism uniqueness, impelling marine microorganism to produce a large amount of novel structure, has the compound of antiviral activity, providing important sources for finding potential antiviral.But also quite few about the report with the compound of anti-HSV-1 and EV71 activity of ocean microorganism, especially there is the report that potential exploitation becomes the marine-derived compound of chiral drug.
Summary of the invention
The object of the present invention is to provide a kind of alkaloid dimer compound deriving from thalassiomycetes and preparation method thereof and the application as antiviral agent, it can meet the demand of prior art.Culture presevation information: depositary institution's title: China Committee for Culture Collection of Microorganisms's common micro-organisms center; Depositary institution address: No. 3, Yard 1, BeiChen xi Road, Chaoyang District, Beijing City Institute of Microorganism, Academia Sinica; Preservation date: on December 17th, 2012; Deposit number: CGMCC No. 6960; Classification And Nomenclature: Pestalotiopsis sp..
The invention provides formula I or its pharmacy acceptable salt:
or its pharmacy acceptable salt.
Formula I is selected from following compounds:
The invention provides the preparation method of formula I, it is characterized in that first in bacterium culture medium, carrying out spawn culture to fungi Pestalotiopsis sp. (ZJ-2009-7-6), in the fermentation medium fermentation culture is carried out to this fungi again, by gained mycelium with after chloroform-methanol mixed solution (1: 1) lixiviate 3 concentrating under reduced pressure, be extracted with ethyl acetate 3 times to obtain crude extract; After ethyl acetate phase crude extract carries out purification on normal-phase silica gel column chromatography, Sephadex LH-20 gel filtration chromatography respectively, then through HPLC high performance liquid preparative chromatography, gained elutriant is concentrated, be formula I.
In above-mentioned preparation method, bacterium culture medium is preferably containing glucose 0.1%-5.0% (weight percent, down together), yeast extract paste 0.01%-1%, peptone 0.01%-1%, agar 0.1%-3.0%, sodium-chlor 0.05%-5%, all the other are water, culture temperature is preferably 0-30 DEG C, and incubation time is preferably 3-15 days; Fermention medium is preferably containing rice 1.0%-80.0% (weight percent, lower same), sodium-chlor 0.05%-5%, calcium chloride 0.01%-5%, Potassium Bromide 0.01%-5%, all the other are water, and culture temperature is preferably 0-30 DEG C, and incubation time is preferably 20-100 days; The stationary phase preferred 200-300 order silica gel that described purification on normal-phase silica gel column chromatography adopts, moving phase preferred volume ratio is the ethyl acetate-light petrol mixed solvent of 50%-100%; The moving phase preferred volume ratio that described Sephadex LH-20 gel filtration chromatography adopts is chloroform: methyl alcohol=1: the mixed solvent of 1; The chromatographic column adopted in described HPLC high performance liquid preparative chromatography: conventional ODS C18 post, be preferably Kromasil 10 × 250mm, 5 μm, flow velocity is preferably 1.0-5.0mL/min, and moving phase preferred volume ratio is the Methanol+Water of 20%-70%; Chiral column, preferred Kromasil Series of Chiral post, Kromasil 10 × 250mm, 5 μm, flow velocity is preferably 1.0-5.0mL/min, and moving phase preferred volume ratio is the dehydrated alcohol-normal hexane mixed solvent of 40%-95%.
Another embodiment of the present invention provides the crystal of formula I, crystal data: spacer is P-1, and unit cell parameters is
α=106.75 (3) °, β=97.22 (3) °, γ=95.45 (3) °,
z=2, Dc=1.358g/cm
3, F (000)=532, μ=0.106mm
-1.
Another embodiment of the present invention provides the preparation method of above-mentioned formula I crystal, it is characterized in that formula I being dissolved in any one or several in methyl alcohol, ethanol, water, tetrahydrofuran (THF) or acetone, leave standstill the crystal that slow crystallization can obtain formula I.
Leave standstill the condition optimization of slow crystallization in the preparation method of above-mentioned crystal at 0-30 DEG C, leave standstill 1-30 days.
The present invention obtains alkaloid dimer compound and has strong inhibit activities to herpes simplex virus type 1 (HSV-1) and Enterovirus 71 (EV71) virus from thalassiomycetes, can be used as antiviral, has a extensive future.
A kind of antiviral agent is provided in another embodiment of the present invention, it is characterized in that comprising formula I or its pharmacy acceptable salt as effective constituent.
In the present invention, term " pharmacy acceptable salt " refers to the additive salt of atoxic inorganic or organic acid and/or alkali.Can see " Salt selection for basic drugs ", Int.J.Pharm. (1986), 33,201-217.
Accompanying drawing explanation
Figure of description is the XRD figure of formula I.
Above-mentioned alkaloid dimer compound is preparing the application in antiviral agent.
Embodiment
For the ease of a further understanding of the present invention, the embodiment provided below has done more detailed description to it.But these embodiments are only not used for limiting scope of the present invention or implementation principle for understanding invention better, and embodiments of the present invention are not limited to following content.
Embodiment 1
(1) spawn culture of soft coral endogenetic fungus Pestalotiopsis sp. (ZJ-2009-7-6)
Spawn culture substratum used contains glucose 1.0% (weight percent, down together), yeast extract paste 0.2%, peptone 0.2%, agar 1.0%, sodium-chlor 3.0%, all the other are water, make test tube slant during use, and fungal bacterial strain is cultivated 3 days at 30 DEG C.
(2) fermentation of soft coral endogenetic fungus Pestalotiopsis sp. (ZJ-2009-7-6)
Fermentation culture substratum used contains rice 40.0% (weight percent, lower with), sodium-chlor 3.0%, 0.2% calcium chloride, 2% Potassium Bromide, and all the other are water; Fungal bacterial strain is cultivated 90 days in 28 DEG C.
(3) extraction and isolation of formula I
Get the mycelium that 60 bottles of steps (2) obtain, after chloroform-methanol mixed solution (1: 1) lixiviate 3 concentrating under reduced pressure, be extracted with ethyl acetate 3 times to obtain crude extract, ethyl acetate phase crude extract carries out purification on normal-phase silica gel column chromatography respectively, and (stationary phase is 200-300 order silica gel, moving phase is 100% ethyl acetate solvent), Sephadex LH-20 gel filtration chromatography (chloroform: methyl alcohol=1: the mixed solvent of 1, volume ratio) after, through the separation of HPLC high performance liquid preparative chromatography, (chromatographic column is Kromasil 10 × 250mm again, 5 μm, flow velocity is 2.0mL/min, moving phase is the Methanol+Water of 35%, volume ratio), gained elutriant is concentrated, obtain colourless crystallization, be formula I, with Kromasil chiral analysis preparation fractionation, (chromatographic column is Kromasil250 × 10mm, 5 μm, flow velocity is 2.0mL/min, moving phase is the normal hexane-dehydrated alcohol mixed solvent of 90%, volume ratio), obtain compound 1 and 2.
The structural identification data of formula I:
Compound 1: clear crystal; [α]
20 d+ 1.09 ° of (c 0.1, CH
3oH); IR (KBr) v
max3750,3419,1702,1599,1455cm
-1;
1h NMR (CH
3oH, 500MHz) δ: 6.42 (1H, s, H-7), 3.89 (1H, m, Ha-5), 3.78 (1H, m, Hb-5), 3.64 (2H, t, J=6.9Hz, H-10), 2.57 (1H, m, Ha-3), 2.31 (2H, t, J=6.9Hz, H-9), 2.16 (1H, m, Ha-4), 2.09 (3H, s, H-11), 1.93 (1H, m, Hb-4), 1.79 (1H, m, Hb-3).
13c NMR (CD
3oD, 150MHz) δ: 166.2 (C, C-1), 87.3 (C, C-2), 30.9 (CH
2, C-3), 19.0 (CH
2, C-4), 42.6 (CH
2, C-5), 168.3 (C, C-6), 117.6 (CH, C-7), 155.4 (C, C-8), 44.9 (CH
2, C-9), 61.3 (CH
2, C-10), 19.3 (CH
3, C-11) and .ESIMS m/z 481.3 [M+H]
+, 503.3 [M+Na]
+; [983.6 2M+Na]
+; [999.6 2M+K]
+hRESIMS m/z 481.2304 [M+H]
+(calcd for C
22h
33n
4o
8, 481.2298).
Compound 2: clear crystal; [α]
20 d-3.22 ° of (c 0.1, CH
3oH); IR (KBr) v
max3750,3419,1702,1599,1455cm
-1;
1h NMR (CH
3oH, 500MHz) δ: 6.42 (1H, s, H-7), 3.89 (1H, m, Ha-5), 3.78 (1H, m, Hb-5), 3.64 (2H, t, J=6.9Hz, H-10), 2.57 (1H, m, Ha-3), 2.31 (2H, t, J=6.9Hz, H-9), 2.16 (1H, m, Ha-4), 2.09 (3H, s, H-11), 1.93 (1H, m, Hb-4), 1.79 (1H, m, Hb-3).
13c NMR (CD
3oD, 150MHz) δ: 166.2 (C, C-1), 87.3 (C, C-2), 30.9 (CH
2, C-3), 19.0 (CH
2, C-4), 42.6 (CH
2, C-5), 168.3 (C, C-6), 117.6 (CH, C-7), 155.4 (C, C-8), 44.9 (CH
2, C-9), 61.3 (CH
2, C-10), 19.3 (CH
3, C-11) and .ESIMS m/z 481.3 [M+H]
+, 503.3 [M+Na]
+; [983.6 2M+Na]
+; [999.6 2M+K]
+hRESIMS m/z 481.2304 [M+H]
+(calcd for C
22h
33n
4o
8, 481.2298).
Embodiment 2
(1) spawn culture of soft coral endogenetic fungus Pestalotiopsis sp. (ZJ-2009-7-6)
Spawn culture substratum used contains glucose 0.1%-5.0% (weight percent, down together), yeast extract paste 0.01%-1%, peptone 0.01%-1%, agar 0.1%-3.0%, sodium-chlor 0.05%-5%, all the other are water, make test tube slant during use, fungal bacterial strain cultivates 3-15 days at 0-30 DEG C.
(2) fermentation of soft coral endogenetic fungus Pestalotiopsis sp. (ZJ-2009-7-6)
Fermentation culture substratum used contains rice 1.0%-80.0% (weight percent, lower with), sodium-chlor 0.05%-5%, calcium chloride 0.01%-5%, Potassium Bromide 0.01%-5%, and all the other be water, and fungal bacterial strain is in 0-30 DEG C of cultivation 20-100 days.
(3) extraction and isolation of formula I
Get 10-60 bottle step (2) gained by after gained mycelium chloroform-methanol mixed solution (1: 1) lixiviate 3 concentrating under reduced pressure, be extracted with ethyl acetate 3 times crude extract, (stationary phase is the conventional purification on normal-phase silica gel in this area to carry out purification on normal-phase silica gel column chromatography after ethyl acetate phase crude extract is concentrated respectively, moving phase is the ethyl acetate-light petrol mixed solvent of 50%-100%, volume ratio), (moving phase is chloroform to Sephadex LH-20 gel filtration chromatography: methyl alcohol=1: the mixed solvent of 1, volume ratio) after, through HPLC high performance liquid preparative chromatography, (chromatographic column is this area conventional ODS C18 post again, flow velocity is 1.0-5.0mL/min, moving phase is the Methanol+Water of 20%-70%, volume ratio), gained elutriant is concentrated, obtain colourless crystallization, be formula I.Split (chromatographic column is Kromasil250 × 10mm, 5 μm, and flow velocity is 1.0-5.0mL/min, and moving phase is the normal hexane-dehydrated alcohol mixed solvent of 40%-95%, volume ratio) with the preparation of Kromasil chiral analysis, obtain compound 1 and 2.
The structural identification data of its compounds of formula I are consistent with corresponding data in embodiment 1.
Other spawn culture, the fermentation condition that specifically do not indicate in embodiment 1-2, and other experimental operating conditions such as normal phase silica gel column chromatography separation, the separation of Sephadex LH-20 gel filtration chromatography, high performance liquid chromatography separation are the experimental operating conditions of this area routine, those skilled in the art can according to actual needs, reasonably select.
Embodiment 3
Modus ponens I 1.5mg is dissolved in the bottle that any one is housed in 500 μ L methyl alcohol, ethanol, water, tetrahydrofuran (THF) or acetone, and leave standstill after 30 days at 0 DEG C, namely slow crystallization obtains the crystal of formula I.
Embodiment 4
Modus ponens I 3mg is dissolved in the bottle that any one or several are housed in 1000 μ L methyl alcohol, ethanol, tetrahydrofuran (THF) or acetone, and leave standstill after 1 day at 30 DEG C, namely slow crystallization obtains the crystal of formula I.
The crystal data of above-mentioned crystal: spacer is P-1, and unit cell parameters is
α=106.75 (3) °, β=97.22 (3) °, γ=95.45 (3) °,
z=2, Dc=1.358g/cm
3, F (000)=532, μ=0.106mm
-1.
Embodiment 5
In bacterium culture medium, spawn culture is carried out to thalassiomycetes Pestalotiopsis sp. (ZJ-2009-7-6), in the fermentation medium fermentation culture is carried out to this fungi again, by gained filtering fermentation liquor, removing thalline, after filtrate is concentrated, be extracted with ethyl acetate; After carrying out purification on normal-phase silica gel column chromatography, Sephadex LH-20 gel filtration chromatography respectively after extraction liquid is concentrated, again through HPLC high performance liquid preparative chromatography, gained elutriant is concentrated, obtains clear crystal, be formula I, its structural identification data are consistent with corresponding data in embodiment 1.Containing glucose, yeast extract paste, peptone, agar, thick sea salt, water in wherein said bacterium culture medium, containing rice, thick sea salt, peptone, water in described fermention medium, calcium chloride, Potassium Bromide; Described chromatographic separation is that normal phase silica gel column chromatography is separated, Sephadex LH-20 gel filtration chromatography is separated with high performance liquid chromatography.
In order to explore the method being applicable to widely prepare formula I, the interpolation of each composition in bacterium culture medium, fermention medium in the present embodiment, all add in ratio conventional in this area or add in any proportion, the specification of the specification of used silica gel, Sephadex LH-20 gel, the model of chromatographic column and the selection of eluting solvent during chromatographic separation, the routine being this area is selected.Experimental result shows, the preparation method that above-mentioned routine is selected, and all can obtain the clear crystal invented, i.e. formula I, its structural identification data are consistent with corresponding data in embodiment 1, only there is the fine difference of individual compound in purity and yield.
The result of embodiment 1-3 shows, according to spawn culture, the fermentation condition of this area routine, the condition that conventional normal phase silica gel column chromatography is separated, Sephadex LH-20 gel column chromatography is separated, high performance liquid chromatography is separated carries out spawn culture, fermentation, separation and purification to thalassiomycetes Pestalotiopsis sp. (ZJ-2009-7-6), all can obtain the compound of formula I structure.The preparation method of formula I, the method recorded in preferred embodiment 1-2.
Embodiment 6
The antiviral activity of formula I
(1) antiviral activity test
Cytopathic effect inhibition effect (CPE) Anti-viral activity in vitro to herpes simplex virus type 1 (HSV-1) and anti-Enterovirus 71 (EV71) is adopted to test.
(2) activity test method
After the Hep-2 cell that is trained individual layer or the trysinization of Vero cell, be inoculated in 96 orifice plates, grow up to individual layer for subsequent use.HSV-1 and EV71 virus is inoculated on Hep-2 and Vero cell respectively, adds rearmounted 37 DEG C of 2% serum RPMI-1640,5%CO
2cultivate under condition, after there is the pathology of more than 90%, blow and beat centrifugal after multigelation 3 times, quantitative separating ,-80 DEG C of refrigerators are frozen for subsequent use.Given the test agent often pipe, with after 10 μ L DMSO dissolvings, adds 2%1640 nutrient solutions of 200 μ L, and continuous 10 2 doubling dilutions, totally 10 extent of dilution, then be laterally inoculated on the monolayer cell in 96 plate holes, 11 are classified as virus control, 12 is classified as cell controls, 37 DEG C, 5%CO
2cultivate, observation pathology per hour, Continuous Observation 24h (HSV-1 and EV71).After the pathology of more than 90% appears in virus control, liquid in plate hole is inhaled and abandons, add 1% neutral red staining, measure OD value at 540nm wavelength, calculate medicine median toxic concentration (TC by Reed-Muench method
50), medium effective concentration (IC
50), observe medicine and press down viricidal effect.By half cytotoxic concentration divided by medium effective concentration TC
50/ IC
50for selectivity index (SI).
(3) active testing result
Test-results shows, and formula I prepared by the present invention infects HSV-1 and EV71 and has very strong restraining effect, IC
50value is respectively 14.2 μMs and 16.2 μMs, is better than positive drug ribavirin (IC far away
50) 128 μMs and 256 μMs, list the Activity Results of the compounds of this invention in table 1.
The Anti-viral activity in vitro of compound prepared by table 1 the present invention
Experiment shows, the alkaloid dimer compound of novel structure uniqueness of the present invention infects HSV-1 and EV71 and has very strong inhibit activities, antiviral can be made into, and soft coral endogenetic fungus Pestalotiopsis sp. (ZJ-2009-7-6) can carry out large scale fermentation production, ensure that the natural origin of formula I, have broad application prospects.
Claims (12)
1. an alkaloid dimer for formula I structure, it is characterized in that the structural formula with formula I is
2. the preparation method of formula I according to claim 1, it is characterized in that first in bacterium culture medium, carrying out spawn culture to fungi Pestalotiopsis sp. (ZJ-2009-7-6), in the fermentation medium fermentation culture is carried out to this fungi again, by gained mycelium with after chloroform-methanol mixed solution (1: 1) lixiviate 3 concentrating under reduced pressure, be extracted with ethyl acetate 3 times to obtain crude extract; After ethyl acetate phase crude extract carries out purification on normal-phase silica gel column chromatography, Sephadex LH-20 gel filtration chromatography respectively, then through HPLC high performance liquid preparative chromatography, gained elutriant is concentrated, obtain formula I; Containing glucose, yeast extract paste, peptone, agar, thick sea salt, water in wherein said bacterium culture medium; Containing rice, thick sea salt, water, Potassium Bromide, calcium chloride in described fermention medium; Described chromatographic separation is that normal phase silica gel column chromatography is separated, gel filtration chromatography is separated and is separated with high performance liquid chromatography.
3. preparation method as claimed in claim 2, it is characterized in that described bacterium culture medium preferably containing glucose 0.1%-5.0%, yeast extract paste 0.01%-1%, peptone 0.01%-1%, agar 0.1%-3.0%, sodium-chlor 0.05%-5%, all the other are water, above-mentioned percentage composition is all weight percentage, culture temperature is preferably 0-30 DEG C, and incubation time is preferably 3-15 days.
4. preparation method as claimed in claim 2, it is characterized in that described fermention medium preferably containing rice 1.0%-80.0% (weight percent, down together), sodium-chlor 0.05%-5%, calcium chloride 0.01%-5%, Potassium Bromide 0.01%-5%, all the other are water, and culture temperature is preferably 0-30 DEG C, and incubation time is preferably 20-100 days.
5. the preparation method as described in any one of claim 2-4, is characterized in that the stationary phase that described purification on normal-phase silica gel column chromatography adopts is 200-300 order silica gel, the ethyl acetate-light petrol mixed solvent of moving phase to be volume ratio be 50%-100%; The moving phase that described Sephadex LH-20 gel filtration chromatography adopts is volume ratio is chloroform: methyl alcohol=1: the mixed solvent of 1; The chromatographic column adopted in described HPLC high performance liquid preparative chromatography is Kromasil 10 × 250mm, 5 μm, and flow velocity is 1.0-5.0mL/min, and moving phase is the Methanol+Water of volume ratio 20%-70%.Chiral separation, preferred Kromasil Series of Chiral post, Kromasil 10 × 250mm, 5 μm, flow velocity is preferably 1.0-5.0mL/min, and moving phase preferred volume ratio is the dehydrated alcohol-normal hexane mixed solvent of 40%-95%.
6. formula I according to claim 1 is crystal, and it is characterized in that the spacer of this crystal is P-1, unit cell parameters is
α=106.75 (3) °, β=97.22 (3) °, γ=95.45 (3) °,
z=2, Dc=1.358g/cm
3, F (000)=532, μ=0.106mm
-1.
7. the preparation method of crystal described in claim 6, is characterized in that formula I being dissolved in any one or several in methyl alcohol, ethanol, water, tetrahydrofuran (THF) or acetone, leaves standstill the crystal that slow crystallization can obtain formula I.
8. preparation method as claimed in claim 7, is characterized in that the condition of standing slow crystallization is at 0-30 DEG C, leaves standstill 1-30 days.
9. an antiviral agent, is characterized in that it contains formula I according to claim 1 or its pharmacy acceptable salt as effective constituent.
10. an antiviral agent, is characterized in that it contains crystal according to claim 6 as effective constituent.
11. formula I according to claim 1 or its pharmacy acceptable salt are preparing the application in antiviral agent.
12. crystal according to claim 7 are preparing the application in antiviral agent.
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Cited By (5)
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| WO2017025031A1 (en) * | 2015-08-10 | 2017-02-16 | 于跃 | Diazaoxa heterocyclic spiro-dione piperazine alkaloid derivative having antiviral activity and preparation method thereof |
| CN107459526A (en) * | 2016-06-03 | 2017-12-12 | 于跃 | A kind of method by pentahomoserine synthesis of natural product (±) Pestaloxazine A |
| CN107459524A (en) * | 2016-06-03 | 2017-12-12 | 于跃 | A kind of dinitrogen oxa- ring spiral shell diketopiperazine skeleton class compound and its construction method |
| CN107459525A (en) * | 2016-06-03 | 2017-12-12 | 于跃 | A kind of method by ornithine synthesis of natural product (±) Pestaloxazine A |
| CN116102578A (en) * | 2023-01-28 | 2023-05-12 | 青岛职业技术学院 | Synthetic method of natural product (+/-) -pestaloxazine A |
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| WO2017025031A1 (en) * | 2015-08-10 | 2017-02-16 | 于跃 | Diazaoxa heterocyclic spiro-dione piperazine alkaloid derivative having antiviral activity and preparation method thereof |
| CN106795174A (en) * | 2015-08-10 | 2017-05-31 | 于跃 | A kind of antiviral activity dinitrogen oxa- ring spiral shell diketopiperazine alcaloid-derivatives and preparation method thereof |
| CN106795174B (en) * | 2015-08-10 | 2020-04-28 | 扬州蓝色生物医药科技有限公司 | Antiviral active diazacyclospirodiketopiperazine alkaloid derivative and preparation method thereof |
| CN107459526A (en) * | 2016-06-03 | 2017-12-12 | 于跃 | A kind of method by pentahomoserine synthesis of natural product (±) Pestaloxazine A |
| CN107459524A (en) * | 2016-06-03 | 2017-12-12 | 于跃 | A kind of dinitrogen oxa- ring spiral shell diketopiperazine skeleton class compound and its construction method |
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| CN109438474A (en) * | 2016-06-03 | 2019-03-08 | 扬州蓝色生物医药科技有限公司 | A kind of intermediate of synthesis of natural product (±)-Pestaloxazine A |
| CN107459525B (en) * | 2016-06-03 | 2019-09-27 | 扬州蓝色生物医药科技有限公司 | A method of by ornithine synthesis of natural product (±)-Pestaloxazine A |
| CN107459526B (en) * | 2016-06-03 | 2019-09-27 | 扬州蓝色生物医药科技有限公司 | A method of by pentahomoserine synthesis of natural product (±)-Pestaloxazine A |
| CN116102578A (en) * | 2023-01-28 | 2023-05-12 | 青岛职业技术学院 | Synthetic method of natural product (+/-) -pestaloxazine A |
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