CN100469364C - Antiviral medicine, prepn. method and application thereof - Google Patents
Antiviral medicine, prepn. method and application thereof Download PDFInfo
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- CN100469364C CN100469364C CNB2005100109363A CN200510010936A CN100469364C CN 100469364 C CN100469364 C CN 100469364C CN B2005100109363 A CNB2005100109363 A CN B2005100109363A CN 200510010936 A CN200510010936 A CN 200510010936A CN 100469364 C CN100469364 C CN 100469364C
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Abstract
An antiviral medicine is prepare from C-21 steroid and medicinal carrier. It can selectively suppress the alphavirus-like viruses and prevent and treating their associated diseases. Its preparing process is also disclosed.
Description
Technical field: the present invention relates to a kind of antiviral drugs, particularly, relate to a class C-21 steroid compound, its preparation method, with and as the purposes of anti-plant or animal virus medicine.
Background technology: do not have the report of C-21 steroid compound in the prior art as antiviral drugs.
Summary of the invention: the present invention is based on the purpose of finding and studying the natural anti-virus active substance of newtype, screening and antiviral activity Study on Mechanism thereof by antiviral activity, find that the natural C-21 steroid compound that exists in the plant has anti-TMV activity, and the action target spot of this compounds is the subgenomic RNA of RNA viruses TMV CP, may the broad-spectrum antiviral activity be arranged to the RNA disease of the similar genome structure of TMV, can be used as novel anti-plant and animal virus drugs.
The present invention is by having separated five C-21 steroid compounds in plant Rhizoma Et Radix Baphicacanthis Cusiae (Strobilanthes cusia) and the Radix Cynanchi Paniculati (Cynanchumpaniculatum kitag): (1) glaucogenin C (glaucogenin C), (2) glaucogenin C 3-O-β-D-Folium seu Cortex Nerii pyranoside (cynatratoside A), (3) glaucogenin C 3-O-β-D-glucopyanosyl base-(1 → 4)-B-D-glucopyanosyl base-(1 → 4)-O-D-Folium seu Cortex Nerii pyrans glycosyl-(1 → 4) → β-D-digoxigenin pyrans glycosyl-(1 → 4)-β-D-Folium seu Cortex Nerii pyranoside (paniculatumoside), (4) glaucogenin C 3-O-β-D-glucopyanosyl base-(1 → 4)-β-D-glucopyanosyl base-(1 → 4)-O-L-2-deoxidation digitalis pyrans glycosyl-(1 → 4)-β-D-magnetic pyrans glycosyl-(1 → 4)-β-D-bamboo peach pyranoside (paniculatumosideD), (5) glaucogenin C 3-O-β-D-glucopyanosyl base-(1 → 4)-β-D-glucopyanosyl base-(1 → 4)-α-L-magnetic pyrans glycosyl-(1 → 4)-β-D-digoxigenin pyrans glycosyl-(1 → 4)-β-D-Folium seu Cortex Nerii pyranoside (paniculatumoside E), find that they are to the propagation of RNA viruses with infect the inhibitory action with height, prove that such compound selective ground suppresses mRNA synthetic of the coat protein CP of tobacco mosaic virus (TMV) (TMV), thereby make virus can not be assembled into complete virion and suppress the propagation of virus.This compounds does not have toxicity to host cell in the time can suppressing the concentration (50nM) of virus multiplication fully, can be used for preventing and treating the RNA viruses that has the plant and animal of similar genome structure with TMV.
The concrete technical scheme of the present invention is:
Antiviral drugs wherein contains formula (I) chemical compound and/or pharmaceutically acceptable carrier
(1)R＝H
The present invention provides the medicine of the RNA viruses of the anti-and tobacco mosaic virus (TMV) structural similarity that contains formula (I) chemical compound and pharmaceutically acceptable carrier simultaneously.
In addition, the present invention also further provides the application of formula (I) chemical compound in the preparation antiviral drugs.
The application of formula (I) chemical compound in the RNA viruses medicine of and tobacco mosaic virus (TMV) structural similarity anti-in preparation.
The specific embodiment:
Further specify essentiality content of the present invention with embodiments of the invention below, but content of the present invention is not limited thereto.
Embodiment 1: the preparation of formula of the present invention (I) chemical compound:
1, the preparation of chemical compound (1) and (2):
Get Rhizoma Et Radix Baphicacanthis Cusiae Herb (20kg), chemical compound (1) and (2) Herb from Rhizoma Et Radix Baphicacanthis Cusiae obtain, and extracting method is as follows:
Rhizoma Et Radix Baphicacanthis Cusiae Herb 20kg is with 90% methanol extraction, and extractum is dispersed in water and the chloroformic solution, and chloroform extractum 70g crosses silicagel column CHCl
3/ CH
3OH (9:1) carries out eluting, and active part obtains mixture (1) and (2) with silicagel column, Sephadex LH-20 and RP-18 chromatography, obtains 11mg chemical compound (1) and 17mg chemical compound (2) with the HPLC purification.
2, the preparation of chemical compound (3), (4) and (5):
Get paniculate swallowwort root 70kg, ethanol extraction with 95%, extractum is assigned to petroleum ether and aqueous phase defat, ethyl acetate extraction three times of part after the defat, get ethyl ester part extract after reclaiming solvent, this part goes up silicagel column 9:1 repeatedly, the 8:2 chloroform: methanol, 7:3,6:4 dichloromethane: acetone eluant eluting, last reversed-phase column is used 8:2,7:3,6:4,5:5 methanol: water and 7:3,6:4 acetone: water elution agent eluting, carry out purification with HPLC at last and obtain 535mg chemical compound 3,1120mg chemical compound 4 and 310mg chemical compound 5 respectively.
Embodiment 2:
Formula of the present invention (I) chemical compound is tested the inhibitory action of TMV:
1, knot born of the same parents' experiments (inhibitory action that the C-21 steroidal compounds duplicates in protoplast TMV):
(1) viral material: TMV (2mg/ml): cell material: the protoplast of tobacco cell BY-2.
(2) method:
A. the fluid suspension culture of tobacco cell BY-2: suspension cell culture is in containing 20-25ml culture medium 50ml triangular flask, and 28 ℃, 140/min changes lucifuge and cultivates.Every 7 days subcultures once.
B. the solid culture of Nicotiana tabacum L. BY-2 cell: for the strain of long term maintenance BY-2 cell, in the solid culture ware, 28 ℃, lucifuge cultured cell group, every month, subculture one was inferior in the fresh culture.
C. the preparation of the protoplast of Nicotiana tabacum L. BY-2 cell: 160 * g, 3-5 days BY-2 cell of 15 minutes centrifugal collection successive transfer culture is also washed one time with the mannitol solution of 0.4M, cell is resuspended in the mannitol solution of the 0.4M that contains 1% cellulase RS and 0.1% pectase Y-23,30 ℃ of water enzyme digestions three hours were jiggled once every 15 minutes and with microscopy enzymolysis situation.After treating that cell is by abundant enzymolysis, the enzymolysis cell solution is crossed the screen cloth of 100 μ m and 60 μ m respectively and collected protoplast in centrifugal 15 minutes.Reuse W5 solution (NaCl 154mM/CaCl
2.2H
2O 125mM/kCl 5mM/Surcrose 5 mM PH 5.9) be resuspended in protoplast in the 2-5ml W5 solution after giving a baby a bath on the third day after its birth time and place 4 ℃ stand-by.
The d.C-21 steroidal compounds suppresses virus duplicating in protoplast: the protoplast virus inoculation adopts the poly ornithine inocalation method: will contain 3 * 10
6The suspension low-speed centrifugal of/ml protoplast is standby, placed 30 minutes at 37 ℃ after the medicament mixed with the 10ul TMV (2mg/ml) of purification and variable concentrations, be suspended in then in the 0.02M potassium citrate buffer of mannitol that 10ml contains 0.7M (PH 5.2), include the poly ornithine (molecular weight 130000) of 2 μ g/ml.Protoplast being resuspended to making its concentration in the mannitol of 10ml 0.7M is 3 * 10
6/ ml.Immediately viral suspension is mixed with protoplast suspension liquid, this moment, the ultimate density of each composition was: TMV 1 μ g/ml, poly ornithine 1 μ g/ml, protoplast 1.5 * 10
6/ ml, 25 ℃ of down insulations after 10 minutes, (35 * g) collected protoplasts, included 0.1mMCaCl with the mannitol of 0.7M/L in centrifugal 3 minutes
2It is inferior to give a baby a bath on the third day after its birth, and to remove the virion that is not adsorbed, puts into protoplast culture medium then and cultivates.The different time sampling is with the viral down propagation of withered speckle host method detection variable concentrations of TMV.
(3) experimental result:
Chemical compound shown in the formula (I) propagation to TMV when concentration reaches 10nM all has significant inhibitory effect, and along with the increase of concentration, suppression ratio raises gradually, and when concentration reached 50nM, the propagation of TMV was suppressed (table 1) fully.
Table 1 antiviral compound is to TMV inhibition of proliferation (12 hours sampling and measuring effects of viral infection)
| Chemical compound | Concentration (nM) | Withered spot number a | Withered spot diameter (mm) b | Suppression ratio (%) |
| glaucogenin?C(1) | 0 10 20 30 40 50 | 52±2.64 43±4.58 21±1.00 11±2.64 8±3.00 0 | 2.6±0.10 2.1±0.20 1.9±0.37 1.5±0.10 1.3±0.10 0 | 0 17 60 79 85 100 |
| cynatratoside?A (2) | 0 10 20 30 40 50 | 54±2.00 43±1.52 34±2.64 7±1.52 4±1.0 0 | 2.5±0.20 2.33±0.25 1.76±0.208 1.46±0.305 1.2±0.2 0 | 0 20 37 87 93 100 |
| paniculatumoside C(3) | 0 10 20 30 40 50 | 55.6±1.52 45.0±2.00 33.6±2.08 15.6±2.08 4.0±2.00 0 | 2.53±0.152 2.43±0.152 1.63±0.208 1.1±0.1 1.0±0.6 0 | 0 19 40 72 93 100 |
| paniculatumoside D(4) | 0 10 20 30 40 50 | 52±2.64 49±1.0 、36±2.08 11±4.35 6.33±1.52 0 | 2.6±0.1 1.7±0.1 1.6±0.3 1.4±0.208 1.2±0.204 0 | 0 6 31 79 88 100 |
| paniculatumoside E(5) | 0 10 20 30 40 50 | 51.3±2.51 43.0±2.0 32±2.0 14±3.05 6.6±1.52 0 | 2.6±0.528 1.56±0.153 1.33±0.152 1.2±0.1 1.1±0.152 0 | 0 16 38 73 87 100 |
2, whole plant experimental (the C-21 steroidal compounds is to the inhibitory action that infect of TMV virus to the Nicotiana tabacum L. that grows in the greenhouse):
(1) viral material: TMV (2mg/ml); Vegetable material: the Nicotiana tabacum L. K326 plant in 5 weeks of greenhouse growth,
(2) method: the C-21 steroidal compounds is made solution in different concentration, mix with the TMV (2mg/ml) of 5ul, 37 ℃ of temperature are bathed after 15 minutes frictional inoculation to Nicotiana tabacum L. K326.After the inoculation,, calculate diseased plant rate (RDP/%), disease index (ID/%) and prevention effect every 5～10 days its sick progression of observed and recorded. diseased plant rate (the RDP/%)=total strain number of diseased plant number/investigation * 100
Disease index (ID)=∑ [(the sick numbers of sheets at different levels * relative level numerical value)]/investigate total number of sheets * highest number
Prevention effect (Ce/%)=check plot disease index-trial zone disease index/check plot disease index * 100
(3) experimental result
The test of pesticide effectiveness result of whole Nicotiana tabacum L. shows that C-21 steroidal prevention effect to TMV when 50nM is 84.9%～92.4%, and these five chemical compounds do not influence the normal growth (table 2) of cigarette Seedling.
Table 2 antiviral compound is to the prevention effect of TMV
2, the exploration of C-21 steroidal compounds antivirus action mechanism
(1) the C-21 steroidal compounds is to the influence of TMV systemic infection in Nicotiana tabacum L.:
For ease of observing the influence that medicine moves TMV, the present invention has made up the plant expression vector p35S-30B of TMV, and the protein gene gfp of green fluorescence inserted be built into the p35S-30B:GFP plasmid among the TMV and change in the Agrobacterium, use simple Agrobacterium injection inoculation method (agroinoculation) inoculation Nicotiana tabacum L. (N.benthamiana) then.P35S-30B:GFP expresses the virus that generation has the green fluorescence labelling after entering plant cell in cell, and can on host plant, infect by generation systems, make non-inoculation leaf under ultraviolet lighting, send green fluorescence, with the C-21 steroidal compounds handle contain the Agrobacterium of p35S-30B:GFP plasmid after, the blade of injection inoculation N.benthamiana again compares with the Agrobacterium that contains the p35S-30B:GFP plasmid of treated with medicaments not.Inject the situation of movement of observing virus after 5 days, the result shows that the p35S-30B:GFP that handles with antiviral compound is only at injection site green-emitting fluorescence, and contrast virus can infect along the vein generation systems, illustrates that this compounds can suppress the long distance transportation of virus and not influence virus genomic duplicating.This compounds only suppresses the long distance transportation of virus and does not influence duplicating of virus.
(2) the C-21 steroidal compounds of variable concentrations is to TMV coat protein and TMV genome and the synthetic influence of subgenomic RNA:
A. method:
(1) Western blotting and ELISA experiment detects the C-21 steroidal compounds to the synthetic influence of TMV coat protein
BY-2 protoplast virus inoculation and different pharmaceutical concentration are handled as stated above, extract total protein from the protoplast with the viral infection of compound treatment 3 hours and 12 hours, and the mensuration of coat protein accumulation is with Western and ELISA detection.Anti-as one with the anti-TMV serum of rabbit, Iga is anti-as two with the link coupled goat-anti rabbit of alkali phosphatase.Stain is used o-phenylenediamine (ELISA) and NBT/BCIP (Northern) respectively.
(2) the Northern hybrid experiment detects the influence of C-21 steroidal compounds to viral RNA s
Extract total RNA of 3 hours protoplast of viral infection with TRIZOL reagent, get 5 μ g RNA electrophoresis on the agaropectin of 1.2% denaturing formaldehyde, change film then.CDNA with coat protein does the synthetic of the viral RNAs of probe observation.
B. experimental result:
The genome encoding viral RNA of TMV duplicates the non-structural protein of necessary 130KD and 180KD, and it is then coded by its subgenomic RNA to determine viral short distance to move and grow floating preteins and coat protein that distance moves.It is necessary that these two albumen are not that viral RNA duplicates.By above-mentioned experiment as can be known this compounds only influenced viral long distance and move and do not influence duplicating of virus, so we whether observe the accumulation of virus capsid protein influenced.The Western Blot experiment shows, along with the accumulation of the increase coat protein of compound concentration reduces gradually, when concentration reached 50nM, the accumulation of coat protein had been subjected to inhibition fully.
Synthetic and the translation of the mRNA of coat protein is depended in the accumulation of virus capsid protein, therefore the present invention utilizes the cDNA of coat protein to make probe, observe the synthetic of viral RNA s, experimental result shows, the synthetic of virus capsid protein mRNA reduces gradually along with the increase of C-21 sterides compound substrate concentration, when concentration reached 50nM, the synthetic quilt of the coat protein mRNA of virus suppressed fully, but virus genomic synthetic unaffected.And the accumulation of the accumulation of virus capsid protein and its mRNA is synchronous.This conclusion shows that this compounds has optionally suppressed the synthetic of virus capsid protein mRNA and do not influenced its translation.The synthetic promoter that depends on RNA polymerase and subgenomic RNA of coat protein mRNA, because chemical compound does not influence duplicating of geneome RNA, therefore RNA polymerase should not be subjected to the influence of this compounds, have only the promoter possibility of subgenomic RNA influenced, so the action target spot of this compounds is the promoter of the subgenomic RNA of RNA viruses.The virus similar to its genome structure owing to TMV is very strong in the sequence and the conservative aspect the secondary structure of subgenomic RNA promoter, therefore this compounds may also can suppress the RNA viruses with the TMV structural similarity, comprise plant virus and animal virus, have the broad-spectrum antiviral activity.
Embodiment 3: The compounds of this invention C-21 steroidal compounds is as the pharmaceutical preparation of effective ingredient:
When chemical compound of the present invention is used as on the medicine, can directly use, perhaps use with the form of pharmaceutical composition, this pharmaceutical composition contains 0.1-99%, preferred 0.5-90%'s, all the other be acceptable on the materia medica, to nontoxic and inert pharmaceutically suitable carrier of humans and animals and/or excipient.
Described pharmaceutical carrier or excipient are that one or more are selected from solid, semisolid and liquid diluent, extra-fill material and pharmaceutical preparation adjuvant.Described effective site is used with the form of per weight dose.But medicine oral administration of the present invention administration.
Oral available its solid or liquid preparation are as tablet, powder, sugar-coat agent, capsule, solution, Emulsion, syrup, drop pill etc.
The example of several preparations only is provided below, and preparation of the present invention is not limited thereto.
(1) makes 5 chemical compounds of formula (I) by embodiment 1: (1) glaucogenin C (glaucogeninC), (2) glaucogenin C 3-O-β-D-Folium seu Cortex Nerii pyranoside (cynatratoside A), (3) glaucogenin C 3-O-β-D-glucopyanosyl base-(1 → 4)-B-D-glucopyanosyl base-(1 → 4)-O-D-Folium seu Cortex Nerii pyrans glycosyl-(1 → 4) → β-D-digoxigenin pyrans glycosyl-(1 → 4)-β-D-Folium seu Cortex Nerii pyranoside (paniculatumoside), (4) glaucogenin C 3-O-β-D-glucopyanosyl base-(1 → 4)-β-D-glucopyanosyl base-(1 → 4)-O-L-2-deoxidation digitalis pyrans glycosyl-(1 → 4)-β-D-magnetic pyrans glycosyl-(1 → 4)-β-D-bamboo peach pyranoside (paniculatumoside D), (5) glaucogenin C 3-O-β-D-glucopyanosyl base-(1 → 4)-β-D-glucopyanosyl base-(1 → 4)-α-L-magnetic pyrans glycosyl-(1 → 4)-β-D-digoxigenin pyrans glycosyl-(1 → 4)-β-D-Folium seu Cortex Nerii pyranoside (paniculatumoside E), in chemical compound 12 or 34 or 5 and the ratio of excipient weight ratio 1:2 add excipient, pelletizing press sheet.
(2) in chemical compound 12 or 34 or 5 and the ratio of excipient weight ratio 1:1 add excipient, pelletizing press sheet.
(3) tablet:
Chemical compound 1 or 2 or 3 or 4 or 5 100mg
Starch 100mg
Semen Maydis pulp is an amount of
Magnesium stearate is an amount of
(4) the capsule preparations method is made capsule routinely.
Capsule:
Chemical compound 1 or 2 or 3 or 4 or 5 100mg
Starch 100mg
Glucose 200mg
Magnesium stearate is an amount of
Preparation method: chemical compound ground well with auxiliary agent mix, sieve, uniform mixing in suitable containers is the mixture that the obtains hard gelatin capsule of packing into.
(5) powder:
Chemical compound 1 or 2 or 3 or 4 or 5 100mg
Starch 100mg
Sucrose 200mg
Preparation method: with chemical compound 1 or 2 or 3 or 4 or 5, starch, sucrose porphyrize, mix homogeneously sieves, and subpackage promptly.
Claims (1)
1, the application of formula (I) chemical compound in preparation resisting tobacco mosaic virus medicine
(1) R=H or
(2)
Or
(3)
Or
(4)
Or
(5)
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| CNB2005100109363A CN100469364C (en) | 2005-07-26 | 2005-07-26 | Antiviral medicine, prepn. method and application thereof |
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| CN100469364C true CN100469364C (en) | 2009-03-18 |
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Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102329358A (en) * | 2011-05-31 | 2012-01-25 | 苏州派腾生物医药科技有限公司 | Preparation method of cynatratoside A |
| CN102824351B (en) * | 2011-10-11 | 2013-09-04 | 泸州医学院 | Application of disaccharide compound in preparation of antiviral drug |
| CN102584845B (en) * | 2011-12-30 | 2014-09-24 | 云南烟草科学研究院 | Furan flavonoid compound in nicotiana tobacum and application thereof |
| CN102812969B (en) * | 2012-08-29 | 2014-07-09 | 陕西上格之路生物科学有限公司 | Botanical antiviral agent, and preparation method and application thereof |
| CN104370874B (en) * | 2014-08-06 | 2016-05-25 | 云南中烟工业有限责任公司 | A kind of parallel heptatomic ring biphenyl compound and its preparation method and application |
| CN104758333B (en) * | 2015-04-08 | 2018-01-26 | 青岛大学 | Paniculate swallowwort C21 steroidal extracts and its production and use |
| CN111418595A (en) * | 2020-04-27 | 2020-07-17 | 中国科学院昆明植物研究所 | Application of C21 steroid compounds 1-8 in paniculate swallowwort root in preparing anti-TSWV active product |
| CN115716835B (en) * | 2022-10-17 | 2024-05-07 | 广西中医药大学 | 13/14, 14/15-Two-split ring pregnenolone type C21Steroid compound and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1041527A (en) * | 1989-11-21 | 1990-04-25 | 中国人民解放军军事医学科学院毒物药物研究所 | The preparation method of ftibamzone compound liniment |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1041527A (en) * | 1989-11-21 | 1990-04-25 | 中国人民解放军军事医学科学院毒物药物研究所 | The preparation method of ftibamzone compound liniment |
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| 博士论文"三种萝藦植物中C21甾类成分的研究". 张援虎.. 2005 * |
| 博士论文"三种萝藦植物中C21甾类成分的研究". 张援虎. 2005 * |
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