CN1245408C - Use of Maituolaicin - Google Patents
Use of Maituolaicin Download PDFInfo
- Publication number
- CN1245408C CN1245408C CN 200410019544 CN200410019544A CN1245408C CN 1245408 C CN1245408 C CN 1245408C CN 200410019544 CN200410019544 CN 200410019544 CN 200410019544 A CN200410019544 A CN 200410019544A CN 1245408 C CN1245408 C CN 1245408C
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- Prior art keywords
- maituolaimycin
- virus
- coxsackie
- viruses
- hiv
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- Expired - Lifetime
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- 241000700605 Viruses Species 0.000 claims abstract description 33
- 241000725303 Human immunodeficiency virus Species 0.000 claims abstract description 13
- 230000000840 anti-viral effect Effects 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 241000209140 Triticum Species 0.000 claims 1
- 235000021307 Triticum Nutrition 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 11
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 9
- 229940100050 virazole Drugs 0.000 abstract description 8
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- 238000000034 method Methods 0.000 description 7
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- 208000030507 AIDS Diseases 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
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- 238000006243 chemical reaction Methods 0.000 description 4
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- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 4
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- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 206010057190 Respiratory tract infections Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- 206010047470 viral myocarditis Diseases 0.000 description 2
- 229940124321 AIDS medicine Drugs 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
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- 206010014612 Encephalitis viral Diseases 0.000 description 1
- 241000709661 Enterovirus Species 0.000 description 1
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- 241000598860 Garcinia hanburyi Species 0.000 description 1
- 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 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 1
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- CKMXBZGNNVIXHC-UHFFFAOYSA-L ammonium magnesium phosphate hexahydrate Chemical compound [NH4+].O.O.O.O.O.O.[Mg+2].[O-]P([O-])([O-])=O CKMXBZGNNVIXHC-UHFFFAOYSA-L 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention discloses the application of maituolaimycin, particularly the application on preparing a medicament for resisting viruses containing Coxsackie B6 viruses or human immunodeficiency viruses. Experimental results of the application show that the maituolaimycin has the good inhibiting function on the Coxsackie B6 viruses, the inhibiting effect of the maituolaimycin is superior to that of virazole frequently used in current clinics, and safe indexes of the maituolaimycin are also higher than that of the virazole. Thus, Coxsackie virus resistance is one important application of the maituolaimycin, and the maituolaimycin also has certain activity on the function for resisting proteinase of the human immunodeficiency viruses. The maituolaimycin is possible to become one of medicaments for resisting the human immunodeficiency viruses.
Description
Technical field
The invention belongs to field of medicaments, specifically, relate to the purposes of a kind of macrolide antibiotics in the preparation antiviral.
Background technology
Macrolide antibiotics be clinical in a normal class microbiotic that uses, they are applied to prepare antibacterial medicine at large, and with its has a broad antifungal spectrum, antibacterial effect is obvious, curative effect is determined and is widely used, Chinese patent publication number 1488633 discloses " a kind of macrolide antibiotics and preparation method thereof ", in this patent application, the structure and the preparation method of a kind of Macrocyclic lactone compounds that is named as maituolaimycin are disclosed, and prove that by experiment various bacteria is had stronger restraining effect, the golden Portugal bacterium of erythromycin-resistant also there is effect.
Virus is the microorganism that causes the multiple disease of human body, because morphological structure is different from bacterium, therefore, as the preparation antiviral drug, report is arranged seldom with microbiotic.
Coxsackie virus Coxsackievirus belongs to enterovirus, and the people is the unique natural host of Coxsackie virus, and by respiratory tract and alimentary infection, contact is its main mode of infection.After virus enters people's oral cavity, at first in pars oralis pharyngis or gastrointestinal tract cell, breed, enter regional nodes or circulation of blood then, enter its hetero-organization again and cause corresponding disease.After this virus enters central nervous system, cause struvite infringement, vascular lesion at meninx and/or cerebral tissue.This virus also can suppress humoral immunization and cellular immunization, and is obvious with the latter.The Coxsackie virus back clinical manifestation weight that causes a disease differs, and this is relevant with viral virulence and different body's immunological function.The lighter's symptom is slight, similar flu, and as heating, upper respiratory tract infection etc., weight person shows as many organ injuries such as meningitis, Bornholm disease, fatigue syndrome, dizziness, respiratory tract infection, pneumonia and diarrhoea, case fatality rate height.All febris acuta patients all should doubtful Coxsackie virus infection during with many organ injuries.Some patient infects for the first time to have again after the recovery from illness for the second time and infects, and illustrates that this virus is not semelincident immunization, can intersect other type to infect, and the means of treatment are then based on antiviral.
Can cause this viewpoint of myocarditis about virus infection.Experimentation on animals is confirmed, particularly the Coxsackie B virus papova is the important pathogenic agent that causes viral myocarditis, bibliographical information is arranged: it is to be caused by change of coxsackie b virus that area, China Changchun viral myocarditis has more than half, and great mass of data has confirmed this point.
Because understanding is not enough, change of coxsackie b virus causes that viral encephalitis or myelitis, meningoencephalitis report are less, often will have a headache, dizzy, weak, visual deterioration is used as symptom that other cause of disease causes and mistaken diagnosis or ignore, do not recognize that more Coxsackie virus infection is a kind of systemic disease, its symptom complexity can show as the multisystem infringement, is not simple cardiac damage, make a definite diagnosis out and treat as untimely, some patient may lose the sight of both eyes or disable.
Acquired immune deficiency syndrome (AIDS) full name is acquired immune deficiency syndrome (AIDS) (Acquired Immune Deficiency Syndrome, be called for short AIDS), be by human immunodeficiency virus (Human immunodeficiency Virus, be called for short HIV) invade self-replication behind the human body and breed, main invasion and attack helper T lymphocyte, destroy immunity system, the patient immune function is died of exhaustion die.Therefore in the past in more than 20 year, be subjected to the countries in the world scientists, it studied obtained breakthrough than the closer concern of other any infection medium.People also get clear substantially to HIV replication cycle process, simultaneously, recognize also how HIV infects normal cell and duplicate the detailed process that itself produces new infectious virus particle.The reproduction process of discovering HIV is a process by interaction and altitude mixture control between cell and the encoding viral protein.Many processes that these protein are regulated may be unique to HIV.Because global HIV number of the infected is nearly 6,000 ten thousand more than, so that world's antiviral demand presents is unprecedented strong.The annual growth in world's antiviral market surpasses 1% in recent years, and wherein the overwhelming majority is anti-HIV/AIDS medicine.
With the required specific enzymes of viral proliferation process as target spot, by changing the structure of substrate, selectivity suppresses these specific enzymess or mixes the genome of virus replication as the substrate of specific enzymes, makes the viral RNA chain termination extend purpose in the time of can reaching antiviral.
Summary of the invention
The purposes that the purpose of this invention is to provide maituolaimycin.
Technical scheme of the present invention is summarized as follows:
Maituolaimycin
Purposes, described purposes is in the purposes of preparation in the antiviral.
Described virus is coxsackie B 6 viruses.
Described virus is human immunodeficiency virus.
Because the virus type disease is lacked medicine targetedly, in order to suppress duplicating of virus, usually strengthen the dosage of broad-spectrum antiviral class medicine in clinical, the mutation that this causes virus again is difficult to effective control more.In addition.Along with further investigation to hiv virus route of transmission and treatment, find that hiv protease is a critical step during hiv virus is propagated, therefore have the compound of anti-hiv protease, just can effectively suppress hiv virus and duplicate, thereby reach the effect of treatment.Experimental result of the present invention shows, maituolaimycin has the good restraining effect to coxsackie B 6 viruses, its suppress effect be better than modern clinical in virazole commonly used, safety index also is higher than virazole, therefore, anti-Coxsackie virus is one of important use of having of maituolaimycin.The effect of its anti-hiv protease also has certain activity, promises to be one of anti HIV-1 virus class medicine.
Embodiment
The present invention is further illustrated below in conjunction with specific embodiment.
Embodiment 1
The preparation of compound (I)
(1) spawn culture fermentation:
1. the preparation of substratum (g/l): get glucose 5.0g, Zulkovsky starch 40.0g, peptone 4.0g, corn steep liquor 2.0ml g, K
2HPO
10.5g, MgSO
47H
2O 0.5g, NaCl 0.5g, add water to 1000ml at 6.0,121 ℃ of pH sterilization 15min; 2. fermentation: the gamboge ash streptomycete bacterial strain (streptomyces luteogriseus via.099) that the prompt development in science and technology of Tianjin English company limited is sold adds in the culture medium after sterilization, adding bacterial classification weight is 10% of fermention medium weight, shake flask fermentation, 160 rev/mins, 28 ℃, fermented 4 days;
(2) fermentation liquor treatment: 1. fermented liquid is through 4800 rev/mins, and is centrifugal, 20 minutes; 2. with equal-volume ethyl acetate extraction 5 times, the ethyl acetate part is removed pigment impurity through the water back extraction of 2: 1 volumes; 3. reclaim ethyl acetate, obtain having the brown oil of reactive site; 4. carry out silica gel column chromatography, with methylene dichloride: 1: 0 to 0: 1 gradient elution of methyl alcohol, collect methylene dichloride: methyl alcohol is 11: 1 active ingredient, reclaims solvent, obtains a kind of macrolide antibiotics of crude product; 5. with a kind of macrolide antibiotics process of crude product preparation high performance liquid phase purifying, collect active crest segment, lyophilize obtains the pure product of a kind of macrolide antibiotics.
Per 2 liters fermented liquid can obtain the purpose product of 0.05g.
The as above The compounds of this invention of gained has following physics and chemistry and biological property:
1. proterties: faint yellow crystallization or off-white powder.
2. fusing point: 123 ± 1 ℃ (second eyeball water body be dry before solvent).
3. molecular weight: molecular weight is 600.3047.
4. molecular formula: molecular formula is C
32H
44N
2O
9
5. ultimate analysis: C 63.98%, H 7.38%, N 4.66%, O 23.97%.
6. ultra-violet absorption spectrum: UV λ mRx:252,337 (alcohol solvents) prove that α is arranged in the molecular structure, β is unsaturated conjugated, the diene system.
7. infrared absorption spectrum: (KBr) IR (3590,3421,2990,2932,1704,1622,1568,1444,1398,1297,1239,1206,982,933,750cm
-1Wavelength)
In the proof molecular structure hydroxyl is arranged, carbonyl, amide group, cis-double bonds, trans double bond, the oxa-triatomic ring, and the oxa-six-ring etc.
1The H spectrum,
13C spectrum, HSQC (the single quantum of heteronuclear is relevant), HMBC (the heteronuclear multikey is relevant), NOESY difference spectrum, H-H COSY (with the relevant spectrum of nuclear displacement), fast atom bombardment(FAB) high resolution mass spectrum are analyzed (HRFAB-MS) M
+Na=623.2930.Confirm that molecular weight is 600.3047; Molecular formula is C
32H
44N
2O
9
Identify that this compound is a macrolide antibiotics, this microbiotic can with multiple sour salify, example hydrochloric acid salt, vitriol, phosphoric acid salt etc.
Embodiment 2
The anti-Coxsackie virus of maituolaimycin (maimolaimycin) (Coxsackievirus) B6 virus (COXB6) active testing
With Vero (African green monkey kidney) cell is virus host, and anti-coxsackie B 6 viruses of working sample cause Veto cytopathy degree.(lot number: (960501) positive control drug, sample faces with before being dissolved in dimethyl sulfoxide (DMSO) virazole, is made into proper concn, makes 3 times of dilutions, totally 8 extent of dilution with nutrient solution for RBV, the abundant pharmaceutcal corporation, Ltd of Zhejiang health.COXB6 cell kind 96 well culture plates, infecting coxsackie B 6 viruses after 24 hours is respectively provided 1/210-4 (233TCID by ATCC
50) infective dose, adsorbed 2 hours, abandon viral liquid, add the sample maituolaimycin by above extent of dilution, establish cell control well and virus control hole simultaneously, 36 hours observation of cell lesion degrees (CPE) calculate the half-inhibition concentration (IC of maituolaimycin to coxsackie B 6 viruses respectively with the Reed-Muench method
50).The result shows that maituolaimycin (maituolaimycin) has very strong antivirus action, IC
50Be 231.1gg/ml, antiviral activity is apparently higher than positive control drug virazole, IC
50Be 569.3.And its safety index SI is 2.88, also is higher than the control drug virazole, and the SI of virazole is 1.75 (seeing Table 1).(test of Shanghai The National Center for Drug Screening)
Table 1: the anti-Coxsackievirus B6 of maituolaimycin virus (COXB6) screening active ingredients
| Sample number into spectrum | TC 50(μg/ml) | Experiment starting point concentration (μ g/ml) | IC 50(μg/ml) | SI |
| maituolaimycin RBV | 666.7 ＞1000 | 1000 1000 | 231.1 569.3 | 2.88 ＞1.75 |
TC
50: the poisonous concentration of half; IC
50: to viral half-inhibition concentration; SI=TC
50/ IC
50
Embodiment 3
Anti-HIV-1 proteolytic enzyme effect test result
HIV-1 proteolytic enzyme can cut the fluorescent mark substrate in optimum reaction condition and reaction system, and fluorescence intensity reflects the activity of enzyme in the measurement of enzymatic reaction products.In reaction system, add the inhibitor that the maituolaimycin sample can be used for screening this enzyme.Choose the positive contrast medicine of indinavir (indinavir) (GlaxoSmithKline PLC company provides).The maituolaimycin sample faces with before being dissolved in DMSO, is made into proper concn, 2 times of dilutions, each 5 extent of dilution.Add behind the diluted sample and contain in the reaction buffer of fluorescent mark substrate, and add genetically engineered target enzyme (the HIV-1 PR of 85 ℃ of preservations), under optimum reaction condition, hatch, measure fluorescent value with FLUO star Galaxy luminoscope.(seeing Table 2) (test of Shanghai The National Center for Drug Screening)
The external anti-HIV-1 PR screening active ingredients of table 2 maituolaimycin
| Contrast | 250μg/ml | 50μg/ml | 10μg/ml | 0.4μg/ml | IC 50 |
| maituolaimycin | 75.8 | -1.7 | 0.1 | 12.4 | 39.8μg/ml |
A: positive control: Indinavir (indinavir) 95.1 (nM) is selected from GSK (GlaxoSmithKline PLC company)
Claims (3)
1. maituolaimycin
Purposes, it is characterized in that described purposes is in the purposes of preparation in the antiviral.
2. wheat according to claim 1 is opened up the purposes of dish mycin, it is characterized in that described virus is coxsackie B 6 viruses.
3. the purposes of maituolaimycin according to claim 1 is characterized in that described virus is human immunodeficiency virus.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410019544 CN1245408C (en) | 2004-06-11 | 2004-06-11 | Use of Maituolaicin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410019544 CN1245408C (en) | 2004-06-11 | 2004-06-11 | Use of Maituolaicin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1583758A CN1583758A (en) | 2005-02-23 |
| CN1245408C true CN1245408C (en) | 2006-03-15 |
Family
ID=34600532
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410019544 Expired - Lifetime CN1245408C (en) | 2004-06-11 | 2004-06-11 | Use of Maituolaicin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1245408C (en) |
-
2004
- 2004-06-11 CN CN 200410019544 patent/CN1245408C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CN1583758A (en) | 2005-02-23 |
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