CN101991583B - Anti-hepatitis C composition and method for preparing drugs for inhibiting hepatitis C virus or treating hepatitis C - Google Patents
Anti-hepatitis C composition and method for preparing drugs for inhibiting hepatitis C virus or treating hepatitis C Download PDFInfo
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- CN101991583B CN101991583B CN 200910169270 CN200910169270A CN101991583B CN 101991583 B CN101991583 B CN 101991583B CN 200910169270 CN200910169270 CN 200910169270 CN 200910169270 A CN200910169270 A CN 200910169270A CN 101991583 B CN101991583 B CN 101991583B
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Abstract
The invention provides an anti-hepatitis C composition which comprises therapeutically effective dose of limonoid compound or pharmaceutical salts thereof, the molecular formula of the limonoid compound is shown as formula (I), wherein R1 is H or OAc, and R2 is H or COCH(CH3)2; the composition further comprises a pharmaceutical carrier; and the anti-hepatitis C composition is used for inhibiting hepatitis C virus or treating hepatitis C. The invention further comprises a method for preparing drugs for inhibiting the hepatitis C virus or treating the hepatitis C. (Formula I).
Description
Technical field
The present invention relates to a kind of compositions of anti-hepatitis C, and be particularly related to a kind of compositions that comprises class citrin chemical compound, it can be used for suppressing hepatitis C virus or treatment hepatitis C.
Background technology
The whole world has 2-3% (about 300,000,000 people) population to infect hepatitis C, and spread with the speed that increases 300-400 ten thousand routine patients newly every year.Unique anti hepatitis C virus drug that is proved and checks and approves is that (α-Interferon), ribavirin (ribavirin) then is proved and checks and approves the anti-hepatitis c virus curative effect that can strengthen interferon-alpha to first type (A Erfa) interferon at present.Yet the two all can produce serious side effect, and the phenomenon that develops immunity to drugs is arranged more.
The basic structure of class citrin chemical compound is that three hexatomic rings add a five-membered ring, links to each other with furan nucleus (furan ring) with singly-bound again.They mainly are present in mandarin orange, Rutaceae (Rutaceae) and Meliaceae (Meliaceae) plant.Toosendanin (toosendanin) in the class citrin chemical compound can be separated from Fructus Toosendan (Meliatoosendan Sieb.Et Zucc.), and Toosendanin is mainly as natural insecticide, but and the present also apoptosis (apoptosis) of known Toosendanin inducing leukemia cell.In addition, also can extract Toosendanin from Fructus Toosendan, and Fructus Toosendan is the dry mature fruit of Fructus Toosendan, it can be used as the Chinese herbal medicine of driving away ascarid and pinworm.
Yet do not learn clearly yet at present whether class citrin chemical compound can the establishment hepatitis C.
Summary of the invention
The invention provides a kind of compositions of anti-hepatitis C, it comprises the class citrin compound or pharmaceutically acceptable salt thereof for the treatment of effective dose, and the molecular formula of such citrin chemical compound is suc as formula shown in (I):
Formula (I)
Wherein R1 is H or OAc, and R2 is H or COCH (CH
3)
2And pharmaceutically acceptable salt or carrier; Wherein the compositions of this anti-hepatitis C is used for suppressing hepatitis C virus.
The present invention also provides a kind of method for preparing the medicine that suppresses hepatitis C virus or treatment hepatitis C, and it uses the class citrin compound or pharmaceutically acceptable salt thereof for the treatment of effective dose, and the molecular formula of such citrin chemical compound is suc as formula shown in (I):
Formula (I)
Wherein R1 is H or OAc, and R2 is H or COCH (CH
3)
2
The invention provides class citrin compound or pharmaceutically acceptable salt thereof for the preparation of the purposes in the medicine that suppresses hepatitis C virus or treatment hepatitis C, the molecular formula of such citrin chemical compound is suc as formula shown in (I):
Formula (I)
Wherein R1 is H or OAc, and R2 is H or COCH (CH
3)
2
For above and other objects of the present invention, feature and advantage can be become apparent, hereinafter to enumerate preferred embodiment and be equipped with accompanying drawing, it is described in detail as follows:
The specific embodiment
The present invention is with the compositions that the contains class citrin chemical compound medicine as anti-hepatitis C, and it can be used for suppressing hepatitis C virus or treatment hepatitis C.In one embodiment, above-mentioned composition can comprise class citrin compound or pharmaceutically acceptable salt thereof and the pharmaceutically suitable carrier for the treatment of effective dose, and wherein the molecular formula of such citrin chemical compound is suc as formula shown in (I):
Formula (I)
Wherein R1 can be H or OAc, and R2 can be H or COCH (CH
3)
2
In addition, above-mentioned class citrin chemical compound can extract from vegetable material, and this vegetable material can comprise Fructus Toosendan (Melia toosendan Sied.Et Zucc.) or Melia azedarach L. (Melia azedarach Linn.).
And above-mentioned class citrin chemical compound can comprise Toosendanin or Trichilin H (Trichilin H).The molecular formula of Toosendanin and Trichilin H respectively suc as formula (II) and formula (III) with shown in:
Formula (II)
Formula (III).
This hepatitis C virus cellular replication system is as the method for new medicament screen research, for the hepatitis C research field generally acknowledge accept and current the use in method (V.Lohmann et al., 1999, Replication of subgenomic hepatitis C virus RNAs in hepatoma cell line, Science.Vol.285,110-113; R.Bartenschlager, 2002, Hepatitis C virus replicons:potential role for drug development, Nature Reviews/Drug Discovery.Vol.1,911-916; J.M.Vorlijk et al., 2003, A replicon-based bioassay for themeasurement of interferons in patients with chronic hepatitis C, Journal ofVirological Methods.110:201-209).The Huh-luc/neo-ET cell is the hepatitis C virus cellular replication system with I389luc-ubi-NS3-3 '/ET gene structure (gene construct).This hepatitis C virus cellular replication system can be to internal ribosome entry site (the internal ribosome entry site by hepatitis C virus, IRES) firefly luciferase of translating (fireflyluciferase)-ubiquitin (ubiquitin)-neomycin phosphotransferase (neomycin phosphotransferase) fused protein is expressed, and can (comprise protease (protease) to the hepatitis c virus non structural protein (NS3-5B) of translating by the internal ribosome entry site of encephalomyocarditis virus (Encephalomyocarditisvirus, EMCV), unwindase (helicase) and polymerase (polymerase)) express.When the replication complex (replication complex) that forms when internal ribosome entry site or the hepatitis c virus non structural protein of hepatitis C virus was subject to affecting of test compounds, the firefly luciferase activity also can change.Therefore, the effect of class citrin chemical compound inhibition hepatitis C virus can be measured by the intensity of the expressed firefly luciferase activity of Huh-luc/neo-ET cell in the presence of class citrin chemical compound.
Above-mentioned class citrin chemical compound in the Huh-luc/neo-ET cell to the inhibition concentration (IC of 50% hepatitis c viral replication
50) at least less than about 0.5 μ g/ml, preferred about 0.045 μ g/ml.In addition, class citrin chemical compound is to the lethasl concentration (CC of 50% cell
50) with to the inhibition concentration (IC of 50% hepatitis c viral replication
50) ratio at least greater than about 100, be preferably greater than about 2500.
In one embodiment, above-mentioned class citrin chemical compound can comprise Toosendanin, and its molecular formula is suc as formula shown in (II):
Formula (II).
And Toosendanin can extract from vegetable material, and this vegetable material can comprise Fructus Toosendan or Melia azedarach L..And Toosendanin in the Huh-luc/neo-ET cell to the inhibition concentration (IC of 50% hepatitis c viral replication
50) at least less than about 0.05 μ g/ml, Toosendanin is to the lethasl concentration (CC of 50% cell in addition
50) with to the inhibition concentration (IC of 50% hepatitis c viral replication
50) ratio at least greater than about 2500.
In another embodiment, above-mentioned class citrin chemical compound can comprise Trichilin H (TrichilinH), and its molecular formula is suc as formula shown in (III):
Formula (III).
And Trichilin H can extract from vegetable material, and this vegetable material can comprise Fructus Toosendan or Melia azedarach L..And Trichilin H in the Huh-luc/neo-ET cell to the inhibition concentration (IC of 50% hepatitis c viral replication
50) at least less than about 0.5 μ g/ml, Trichilin H is to the lethasl concentration (CC of 50% cell in addition
50) with to the inhibition concentration (IC of 50% hepatitis c viral replication
50) ratio at least greater than about 100.
And aforementioned pharmaceutically suitable carrier can include but not limited to the pharmaceutically suitable carrier compatible with administration such as solvent, disperse medium (dispersion medium), coating (coating), antibacterial, antifungal, isotonic agent, absorption delay agent.For different administering modes, can utilize conventional method that pharmaceutical composition is configured to dosage form (dosage form).
Aforementioned pharmaceutically acceptable salt can include but not limited to following salt, and described salt comprises the salt of inorganic cation, for example alkali metal salt such as sodium salt, potassium salt, the salt of ammonium salt, alkali salt such as magnesium salt, calcium salt, bivalence or quadrivalent cation such as zinc salt, aluminum salt or zirconates.In addition, described salt also can be organic salt, such as hexanamine salt, methyl-D-glucamine salt, amino acid salts such as arginine salt, leucine salt, histidine salt, glutamy amine salt.
The administering mode of compositions can be oral, non-oral, suck spraying (inhalation spray) or implant medicine storage device (implanted reservoir).Non-oral comprise (intrathecal), intralesional (intraleaional) injection and infusion techniques in (intrasynovial) in subcutaneous (subcutaneous), Intradermal (intracutaneous), intravenous (intravenous), intramuscular (intramuscular), intraarticular (intraarticular), intra-arterial (intraarterial), the synovial membrane, breastbone interior (intrasternal), the sheath.
The form of oral composition can include but not limited to lozenge, capsule, emulsion (emulsion), waterborne suspension (aqueous suspension), dispersion liquid (dispersion) and solution.
In yet another aspect, the present invention also provides a kind of method for preparing the medicine that suppresses hepatitis C virus or treatment hepatitis C.
And in the method, use the class citrin chemical compound for the treatment of effective dose as active constituents of medicine.The molecular formula of class citrin chemical compound is suc as formula shown in (I):
Formula (I)
Wherein R1 can be H or OAc, and R2 can be H or COCH (CH
3)
2
Above-mentioned class citrin chemical compound can extract from vegetable material, and this vegetable material can comprise Fructus Toosendan or Melia azedarach L..
In addition, above-mentioned class citrin chemical compound can comprise Toosendanin or Trichilin H (Trichilin H).The molecular formula of Toosendanin and Trichilin H respectively suc as formula (II) and formula (III) with shown in:
Formula (II)
Formula (III).
In yet another aspect, the present invention also provides class citrin chemical compound for the preparation of the purposes in the medicine that suppresses hepatitis C virus or treatment hepatitis C, and the molecular formula of such citrin chemical compound is suc as formula shown in (I):
Formula (I)
Wherein R1 is H or OAc, and R2 is H or COCH (CH
3)
2
Above-mentioned class citrin chemical compound can extract from vegetable material, and this vegetable material can comprise Fructus Toosendan or Melia azedarach L..
In addition, above-mentioned class citrin chemical compound can comprise Toosendanin or Trichilin H (Trichilin H).The molecular formula of Toosendanin and Trichilin H respectively suc as formula (II) and formula (III) with shown in:
Formula (II)
Formula (III).
Embodiment
Embodiment 1
Effective ingredient from vegetable material retrieval inhibition hepatitis C virus
5.96g Fructus Toosendan alcoholic extract is dissolved in 20 milliliters of mixed solvents of methanol and water, and respectively with each 15 milliliters extractions of normal hexane, ether, dichloromethane and ethyl acetate 2-3 time, obtain respectively normal hexane layer extract, ether layer extract, dichloromethane layer extract and ethyl acetate layer extract.Each layer extract obtained respectively normal hexane layer extract, ether layer extract, dichloromethane layer extract and ethyl acetate layer extract behind the concentrate drying respectively, and these extracts use respectively Huh-luc/neo-ET cell (hepatitis C virus cellular replication system) to test the activity that these extracts suppress hepatitis C virus.
The result shows that gained ether layer extract (1.113g) has the activity that suppresses hepatitis c viral replication, and it is to the inhibition concentration (IC of 50% hepatitis c viral replication
50) be 0.68 ± 0.11 μ g/ml.
(filling 33 restrains silica gel 1.1g the ether layer extract is with open chromatographic columns, 2.2 * 25.3cm) and with the normal hexane of different mixing proportion separate as mobile phase with acetone, be a plurality of fraction with the ether layer rough segmentation, select the fraction that contains active component via active testing, isolate two chemical compounds with anti-phase partly preparation property chromatographic column and with water and acetonitrile as mobile phase again.Then these two chemical compounds are carried out spectrum and mass spectral analysis.
The spectrum analysis result of the first chemical compound shows:
1H NMR(500MHz，CD
3OD)：7.39(s，1H)；7.19(s，1H)；6.16(s，1H)；5.34(s，1H)；5.20(s，1H)；4.71-4.24(m，5H)；3.80(s，1H)；3.58-3.31(m，1H)；2.90-2.54(m，4H)；2.19-1.89(m，8H)；1.37-1.33(3H)；1.14-1.11(3H)；0.84(s，3H)。
The mass spectrometry results of the first chemical compound shows:
LC-MS/MS：621[M+2×Na]
+；598[M+Na]
+；558[M-O]
+，498[M-O-OAc]
+；438[M-O-2×OAc]
+。
Therefore confirm that the first chemical compound is Toosendanin.
And the spectrum analysis result of the second chemical compound shows:
1H NMR(500MHz，CD
3OD)：7.40(s，1H)；7.20(s，1H)；6.16(s，1H)；5.77(s，1H)；5.47(s，1H)；5.37(s，1H)；5.34(s，1H)；4.52(s，1H)；4.53-4.31(m，2H)；3.82(s，1H)；3.578(m，1H)；2.96-2.87(m，2H)；2.48-2.50(m，1H)；2.20(m，2H)；；2.08(sm，2H)；1.99(s，3H)；1.93(s，3H)；1.90(s，3H)；1.34-1.29(3H)；1.17-1.13(m，3H)；0.95-0.88(m，6H)；0.83(s，3H)。
The mass spectrometry results of the second chemical compound shows:
LC-MS/MS：749[M+2×Na]
+；726[M+Na]
+；635[M-furan]
+；616[635-COCH(CH
3)
2]
+；558[616-OAc]
+。
Therefore confirm that the second chemical compound is Trichilin H (Trichilin H).
Embodiment 2
1. Toosendanin is to the toxotest of Huh-luc/neo-ET cell
With the Huh-luc/neo-ET cell with 2.5 * 10
4The density in individual cell/100 μ l/ holes is inoculated in the 96 porocyte culture plates (Corning Incorporation COSTAR, 3599), places cell culture incubator (NUAIR nu-5510) to cultivate.
Every other day the Toosendanin sample being diluted to respectively concentration with the DMEM culture fluid is 28.73 μ g/ml, 9.57 μ g/ml, 3.19 μ g/ml, 1.06 μ g/ml, 0.35 μ g/ml, 0.11 μ g/ml, 0.039 μ g/ml and 0.013 μ g/ml, or be diluted to 114.92 μ g/ml, 38.33 μ g/ml, 12.77 μ g/ml, 4.25 μ g/ml, 1.42 μ g/ml, 0.46 μ g/ml, 0.16 the Toosendanin culture fluid of μ g/ml and the different diluted concentrations such as 0.057 μ g/ml, and the original culture in 96 orifice plates is absorbed by vacuum pump (DOAT-704AA), must note being drawn onto cell in this process.Again the Toosendanin culture fluid of above-mentioned concentration is added to respectively in the above-mentioned 96 porocyte culture plates that contain cell as experimental group with the amount in 100 μ l/ holes, and matched group is the culture fluid that cell adds to be had without any processing.
Cultivate and after two days culture fluid is removed, again with 100 μ l, 1 * PBS (1mM KH
2PO
4, 10mMNa
2HPO
4, 137mM NaCl, 2.7mM KCl) clean twice, observe whether sample precipitation and record are arranged.Remove afterwards PBS, every hole adds the culture fluid that 50 μ l contain 0.5mg/ml MTT (Sigma, M2128), places carbon dioxide cell incubator, cultivates after 1 hour, adds 150 μ lDMSO (Riedel-de
60153), with waving after oscillator (KS shaker Type 670) shakes up violet precipitate, with continuous wavelength microwell plate analytical system (Molecular Devices, SPECTRAMAX 190) by measuring cell concentration at the light absorption value at 560nm wavelength place.
Represent the cell survival rate (%) that 100% cell survival rate (%) calculates the experimental group that adds various variable concentrations samples with the average light absorption value of matched group.The computing formula of cell survival rate is: (experimental group light absorption value/matched group light absorption value) * 100%.Sample concentration with each experimental group is made the xy scatter diagram to cell survival rate, can try to achieve R
2Value surpasses 0.9 Trendline formula.
The resulting x of this formula of y=50 substitution is the sample concentration (CC that causes 50% cell death
50)), or the resulting x of this formula of y=85 substitution is the sample concentration (CC that causes 15% cell death
15).Because of sample characteristics of for example, only utilizing from sample concentration is that the Trendline formula that the experimental group of 3.19 μ g/ml, 1.06 μ g/ml, 0.35 μ g/ml, 0.11 μ g/ml and 0.039 μ g/ml obtains calculates CC
15Value.The result is as shown in table 1.Toosendanin is to the lethasl concentration (CC of 50% cell
50) greater than 114.8 μ g/ml, to the lethasl concentration (CC of 15% cell
15) be 0.34 μ g/ml.
When reaching 85%, cell survival rate is considered as this sample (CC under this concentration when above
15The concentration that value is following) to the cell avirulence.Select avirulent concentration to carry out the Lampyridea fluorescence activity test (details are as follows) of Huh-luc/neo-ET cell.
2. test Lampyridea fluorescence activity suppresses the effect Huh-luc/neo-ET cell of hepatitis c viral replication with 2.5 * 10 with the assessment Toosendanin
4The density in individual cell/100 μ l/ holes is inoculated in 96 porocyte culture plates (Corning Incorporation COSTAR, 3599) in, be that the Toosendanin of 0.15 μ g/ml, 0.075 μ g/ml, 0.038 μ g/ml, 0.019 μ g/ml and 0.0085 μ g/ml was cultivated two days altogether with concentration respectively.Use afterwards 100 μ l, 1 * PBS (1mM KH
2PO
4, 10mM Na
2HPO
4, 137mM NaCl, 2.7mMKCl) clean twice, then absorb PBS.After adding 35 μ l 1 * passive cytolysis buffer (passivelysis buffer) (Promega, E1941), with waving oscillator (KS shaker Type 670) concussion 10 minutes, then cell is evenly broken up.
Draw 30 μ l Cell saps to the 96 holes white plates (NUNC, 236108) that are used for test Lampyridea fluorescence, add respectively successively again 40 μ l fluorescence analysis buffer (21.5mM MgCl
2, 3.7mM ATP, 0.1MKH
2PO
4) and 20 μ l fluorogenic substrates (1mM D-Luciferin), and after adding substrate, use immediately microplate luminoscope (Berthold, MPL4) to measure its fluorescence activity (Rlu/s).
Calculate each sample experimental group take the fluorescence activity of matched group as standard to the suppression ratio (inhibition rate) of hepatitis C virus (%).Suppression ratio (inhibition rate) computing formula (%) is: { [(matched group fluorescence activity)-(experimental group fluorescence activity)]/(matched group fluorescence activity) } * 100%.Behind the suppression ratio to hepatitis c viral replication when sample passes through serial dilution and measures it at variable concentrations, with the sample concentration (IC of grafit5 software (Erithacus Software) when sample is suppressed 50% virus replication
50) calculate.
When each experiment, except using 0.5ng/ml and 0.1ng/ml PEG IFN α-2a as IC
50Positive controls (positive control) outside, also use the Ciclosporin A (cyclosporin A, CsA) of 1 μ g/ml) as IC
50Positive controls (positive control).
The results are shown in the table 1.Toosendanin is to the inhibition concentration (IC of 50% hepatitis c viral replication
50) be 0.045 ± 0.004 μ g/ml, also calculate in addition Toosendanin to the inhibition concentration (IC of 90% hepatitis c viral replication
90) be 0.35 μ g/ml.
Embodiment 3
1. Trichilin H (Trichilin H) is to the toxotest of Huh-luc/neo-ET cell
Experimental procedure is with embodiment 2, and specimen replaces with Trichilin H.Wherein the Trichilin H sample is diluted to respectively the Trichilin H culture fluid that concentration is 50 μ g/ml, 25 μ g/ml, 8.33 μ g/ml, 2.78 μ g/ml, 0.93 μ g/ml, 0.31 μ g/ml, 0.1 μ g/ml and 0.03 μ g/ml with the DMEM culture fluid.
The result is as shown in table 1.Trichilin H is to 50% lethasl concentration (CC of cell
50) greater than 50 μ g/ml, 15% lethasl concentration (CC
15) be 0.7 μ g/ml.
2. test Lampyridea fluorescence activity suppresses the effect of hepatitis c viral replication with assessment Trichilin H (Trichilin H)
Experimental procedure is with embodiment 2, and specimen replaces with Trichilin H.The Huh-luc/neo-ET cell is that the Trichilin H of 0.75 μ g/ml, 0.5 μ g/ml, 0.25 μ g/ml and 0.125 μ g/ml is cultivated altogether with concentration respectively.
The results are shown in the table 1.Trichilin H is to the inhibition concentration (IC of 50% hepatitis c viral replication
50) be 0.48 ± 0.10 μ g/ml, to the inhibition concentration (IC of 90% hepatitis c viral replication
90) be 0.9 μ g/ml.
The cytotoxicity of table 1. specimen with to the suppression ratio of hepatitis c viral replication
| Sample | CC 50 (μg/ml) | CC 15 (μg/ml) | IC 50 (μg/ml) | IC 90 (μg/ml) | EW (CC 50/IC 50) |
| Toosendanin | ＞114 | 0.34 | 0.045±0.004 | 0.35 | ＞2531.6 |
| Trichilin H | ＞50 | 0.7 | 0.48±0.10 | 0.9 | ＞104.2 |
CC
50: the drug level during 50% cell death
CC
15: the drug level during 15% cell death
IC
50: suppress the drug level when hepatitis C copies in 50% cell
IC
90: suppress the drug level when hepatitis C copies in 90% cell
Coefficient of efficiency (EW): the drug level when hepatitis C copies in the drug level during 50% cell death/inhibition 50% cell
Although the present invention discloses as above with preferred embodiment; but these embodiment are not for restriction the present invention; those skilled in the art can carry out various modifications and variations in the situation that does not break away from the spirit and scope of the invention, so protection scope of the present invention limits by appended claims.
Claims (9)
1. class citrin compound or pharmaceutically acceptable salt thereof is for the preparation of the purposes in the medicine that suppresses hepatitis C virus or treatment hepatitis C,
The molecular formula of such citrin chemical compound is suc as formula shown in (I):
Wherein R1 is H, and R2 is H, and such citrin chemical compound is Toosendanin, or R1 is OAc, and R2 is COCH (CH
3)
2, and such citrin chemical compound is Trichilin H,
Again, the molecular formula of this Toosendanin and this four triterpene falls and molecular formula respectively suc as formula (II) with shown in the formula (III):
Formula (III).
2. purposes as claimed in claim 1, wherein such citrin chemical compound extracts from vegetable material.
3. purposes as claimed in claim 2, wherein this vegetable material comprises Fructus Toosendan or Melia azedarach L..
4. purposes as claimed in claim 1, wherein such citrin chemical compound is Toosendanin, and this Toosendanin molecular formula is suc as formula shown in (II):
5. purposes as claimed in claim 4, wherein this Toosendanin extracts from vegetable material.
6. purposes as claimed in claim 5, wherein this vegetable material comprises Fructus Toosendan or Melia azedarach L..
7. purposes as claimed in claim 1, wherein such citrin chemical compound is Trichilin H, and the molecular formula of this Trichilin H is suc as formula shown in (III):
8. purposes as claimed in claim 7, wherein this Trichilin H extracts from vegetable material.
9. purposes as claimed in claim 8, wherein this vegetable material comprises Fructus Toosendan or Melia azedarach L..
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Non-Patent Citations (3)
| Title |
|---|
| Takeya, Koichi 等..Cytotoxic trichilin-type limonoids from Melia azedarach..《Bioorg. Med. Chem.》.1996,第4卷(第8期),1355-1359. * |
| Zhou, Jian-Bo 等..Limonoid antifeedants from Melia toosendan..《Phytochemistry》.1996,第41卷(第1期),117-20. * |
| 王云玲 等..川楝素静脉注射剂的研究.《中草药》.1982,第13卷(第1期),13-15. * |
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