CN105330629A - Anti-liver fibrosis penicilfuranone A compound, and pharmaceutical composition and applications thereof - Google Patents

Anti-liver fibrosis penicilfuranone A compound, and pharmaceutical composition and applications thereof Download PDF

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Publication number
CN105330629A
CN105330629A CN201510672179.XA CN201510672179A CN105330629A CN 105330629 A CN105330629 A CN 105330629A CN 201510672179 A CN201510672179 A CN 201510672179A CN 105330629 A CN105330629 A CN 105330629A
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furanone
mould
compound
acid
acceptable salt
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CN105330629B (en
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普建新
汪伟光
李傲
杜雪
孙汉董
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Kunming Institute of Botany of CAS
Chongqing University of Technology
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Chongqing University of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms
    • C12P17/04—Oxygen as only ring hetero atoms containing a five-membered hetero ring, e.g. griseofulvin, vitamin C

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  • Engineering & Computer Science (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
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Abstract

The invention discloses penicilfuranone A represented by structural formula (I), or pharmaceutical salt thereof, a pharmaceutical composition composed of penicilfuranone A and at least one pharmaceutically acceptably carrier, a preparation method of penicilfuranone A, and applications of penicilfuranone A in preparing drugs used for preventing or treating liver fibrosis, wherein in the pharmaceutical composition, penicilfuranone A is taken as the active ingredient. Penicilfuranone A is a furanone compound with a novel chemical structure, possesses excellent in vitro anti-liver fibrosis activity, the novel chemical structure, high activity, and advantages as a drug used for resisting liver fibrosis.

Description

Anti-hepatic fibrosis mould furanone A compound and pharmaceutical composition thereof and application
Technical field:
The invention belongs to technical field of pharmaceuticals, specifically, relate to furanone polyketone class active compound PenicilfuranoneA with anti-hepatic fibrosis activity and preparation method thereof, with the pharmaceutical composition that this compound is activeconstituents, and it treats the application in the medicine of hepatic fibrosis disease in preparation.
Background technology:
Furanones polyketides is that a class has mycetogenetic secondary metabolite, sees at present and is reported in fungi Aspergillusrugulosus, Cephalosporiumgregatum, and in the secondary metabolite of Penicilliumdaleae.Up to now, the furans polyketides of bibliographical information is less than 20 compounds, and its molecular weight is all about 300.It is antibacterial that forefathers' research shows that this compounds has, and causes plant and wither, and suppresses the effects such as Mammals Y race DNA enzymatic.The compounds of this invention novel structure, molecular weight is 486, and with this compounds reported before, structure is completely different.Up to now, the furanone polyketides that there is not yet novel structure of the present invention in prior art is in the news, and also has no the research that such Furanones compound of any bibliographical information has anti-hepatic fibrosis activity simultaneously.
Summary of the invention:
The object of the invention is to provide the furans polyketides A being separated from endogenetic fungus Penicilliumdaleae and obtaining, its preparation method, the application in medicine particularly in anti-hepatic fibrosis medicines.
In order to realize this bright above-mentioned purpose, the invention provides following technical scheme:
Mould furanone A compound shown in following structural formula (I) or its pharmacy acceptable salt,
Pharmaceutical composition, it comprises described mould furanone A compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of at least one and/or thinner.
According to described mould furanone A compound or its pharmacy acceptable salt, wherein said pharmacy acceptable salt is hydrochloride, hydrobromate, nitrate, vitriol, phosphoric acid salt, tartrate, Citrate trianion, formate, acetate, oxalate.
Invention also provides the preparation method of mould furanone A compound or its pharmacy acceptable salt, get mould furanone APenicilliumdaleae fermented product, with organic solvent extraction, concentrate to obtain medicinal extract, be extracted with ethyl acetate respectively, silica gel column chromatography, the methods such as preparative high performance liquid chromatography obtain structural formula (I) compound.
Preparation method is as follows more specifically: get Penicilliumdaleae mycelium and be inoculated in PDA in sterilizing potato dextrose broth, shake five days in shaking table with 170 rpms under room temperature, make seed liquor, seed liquor is transferred in the rice medium of sterilizing, sterile culture 40 days under 28 DEG C of conditions, the mycelium after 40 days is cultivated with ethyl acetate extraction and application rice medium, extract four times altogether, obtain ethyl acetate extract, utilize silica gel column chromatography, high performance liquid chromatography mass spectrometry, preparative high performance liquid chromatography process ethyl acetate extract, finally obtain mould furanone A, its preparative liquid chromatography condition is: 12mL/min, UV λ max230nm, MeCN-H 2o45:55, retention time 15.0min.
In above-mentioned preparation method, mould furanone A compound can further with suitable sour salify, suitable acid be selected from hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid, tartrate, citric acid, formic acid, acetic acid, oxalic acid or other be applicable to organic acid or mineral acid.
Present invention also offers described mould furanone A compound or the application of pharmaceutical composition in the medicine preparing anti-hepatic fibrosis.
Pharmaceutical composition of the present invention, can as the dosage form of suitable for oral administration or drug administration by injection.
The dosage form of wherein said oral administration is tablet, slow releasing tablet, controlled release tablet, lozenge, hard or soft capsule, dripping pill, micropill, water-based or oil suspension, emulsion, dispersible powder or granule, oral liquid, syrup or elixir, and the dosage form of described drug administration by injection is water-based or oily solution, sterilized powder, liposome, emulsion, microemulsion, nano-emulsion or the micro-capsule of sterilizing.
The compounds of this invention mould furanone A novel structure, molecular weight is 486, completely different with such compound structure reported before, and it is active to have obvious anti-hepatic fibrosis, its mechanism stimulates the Forming ability of the excessive activation of hepatic stellate cell and extracellular matrix relevant with blocking-up TGF-β 1, lower than under the concentration of 32 μMs, PenicilfuranoneA has no obvious hepatotoxicity.
Accompanying drawing illustrates:
Fig. 1 is the structural representation of PenicilfuranoneA of the present invention;
Fig. 2 is the X-single crystal diffraction structural representation of PenicilfuranoneA of the present invention;
Fig. 3 is the impact (mtt assay of PenicilfuranoneA of the present invention on normal people's liver cell growth vigor; Process 48h);
Fig. 4 is that under PenicilfuranoneA of the present invention suppresses TGF-β 1 to induce, hepatic stellate cell fibrosis forms expression (the westernblot method of associated protein; A is rat T6 hepatic stellate cell strain, and B is people LX-2 hepatic stellate cell strain).
Embodiment:
Below in conjunction with accompanying drawing, further illustrate essentiality content of the present invention with embodiments of the invention, but do not limit the present invention with this.
Embodiment 1:
The preparation of compound PenicilfuranoneA:
Separation process: the Penicilliumdaleae mycelium that takes a morsel is inoculated in 1000ml sterilizing potato dextrose broth (PDA), shakes five days with 170 rpms, makes seed liquor under room temperature in shaking table.Seed liquor is transferred in the rice medium of 2.0 kilograms of sterilizings, under 25 degree of conditions, sterile culture 35 days.Cultivate the mycelium after 35 days with ethyl acetate 5L extraction and application rice medium, extract five times altogether, each 5L, obtains ethyl acetate extract 18g.Utilize silica gel column chromatography, high performance liquid chromatography mass spectrometry, the ethyl acetate extract of preparative high performance liquid chromatography process 18g, finally obtains PenicilfuranoneA12mg, and its preparative liquid chromatography condition is: 12mL/min, UV λ max230nm, MeCN-H 2o45:55, retention time 15.0min.
Embodiment 2:
PenicilfuranoneA structure elucidation:
Compound PenicilfuranoneA, golden needle-like crystal, [α] 22d – 6 (c0.2, MeOH).It is m/z509 [M+Na] that ESI-MS spectrum provides quasi-molecular ion peak +, in conjunction with high resolution positive ion HR-ESI-MS (m/z [M+Na] +509.1792 calculated value is C 26h 30o 9na, 509.1782) and 13cNMR, DEPT compose the information provided, and determine that its molecular formula is C 26h 30o 9, degree of unsaturation is 12.UV spectrum has absorption at 196 (4.5), 222 (4.6), 359 (4.0), 495 (2.6) nm places, illustrates in molecule to there is large conjugation group.Analyze 1h and 13cNMR composes (table 1), then in conjunction with HSQC, HMBC, 1h- 1hCOSY, and the bright structure obtaining compound PenicilfuranoneA of ROESY stave.Finally, further demonstrate that above analysis by the analysis of X-single crystal diffraction, and determine its steric configuration (Fig. 2).The X-single crystal diffraction data of PenicilfuranoneA have uploaded to should Cambridge University's single crystal data storehouse www.ccdc.cam.ac.uk, its registration number is: CCDC1042018.
The NMR spectral data (δ inppm, JinHz) of table 1.PenicilfuranoneA
atest in 600MHz instrument, solvent is DMSO-d 6. btest in 600MHz instrument, solvent is acetone-d 6.
Embodiment 3:
PenicilfuranoneA is to the hepatocellular toxicity detection of normal people:
Normal Human Liver cell (L-02 cell strain) is purchased from Shanghai Inst. of Life Science, CAS cellular resources center; RPMI1640 substratum is Hyclone Products; Foetal calf serum is Gibco Products; Dimethyl sulfoxide (DMSO) (DMSO) and tetrazolium bromide (MTT) are sigma Products; Full-automatic microplate reader (U.S., Thermo company); Constant temperature CO 2incubator (U.S., Thermo company); Normal liver cell L-02 cell strain with RPMI1640 substratum (containing 10% inactivated fetal bovine serum, 100U/mL penicillin and 100 μ g/mL Streptomycin sulphates) in 37 DEG C, saturated air humidity, containing 5%CO 2incubator in routine passage cultivate.Get L-02 cell strain exponential phase of growth, the centrifugal 5min of 1000 × g, abandoning supernatant, beats with corresponding substratum, makes cell suspension, and being diluted to concentration after counting is 3 × 10 4the cell suspension of individual cell/mL, be inoculated in 96 orifice plates, every hole 200 μ L, be placed in administration after cell culture incubator 24h, the PenicilfuranoneA sample sets (0.125 of cell controls group and 11 concentration is set respectively, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64, 128 μMs), each concentration arranges 3 multiple holes, after dosing, 96 orifice plates to be incubated at respectively in cell culture incubator after 48h, every hole adds 20uLMTT solution (with PBS, MTT powder being made into the storage liquid of 5mg/mL), centrifugal abandoning supernatant continue to hatch 4h in cell culture incubator after, every hole adds 100uLDMSO, slight oscillatory makes purple crystals dissolve completely, every hole absorbancy (OD value) is measured in 570nm place by microplate reader, calculate 3 multiple hole OD value mean values, and calculate cell survival rate: cell survival rate (%)=(administration group cell OD average-background OD average)/(cellular control unit OD average-background OD average) × 100%.
Hepatocellular injury is often considered to the incitant that hepatic fibrosis occurs, and therefore, medicine can stop hepatic fibrosis process by protecting hepatocellular mode, and at least itself should not have hepatotoxicity.MTT detected result finds, after PenicilfuranoneA each concentration process 48h, under very high concentration (32 μMs), people's normal liver cell does not occur that obvious vigor suppresses phenomenon yet, this means, lower than under the concentration of 32 μMs, PenicilfuranoneA has no obvious hepatotoxicity, the results are shown in Figure 3.
Embodiment 4:
Adopt the impact that westernblot method detection PenicilfuranoneA stimulates hepatic stellate cell activator and extracellular matrix components to express on TGF-β 1
Human liver microsome proteins LX-2 cell strain draws from China typical culture collection center; Cultured rat hepatic stellate cells T6 cell strain is for drawing from Shanghai Inst. of Life Science, CAS cellular resources center; Use DMEM substratum and RPMI1640 substratum (containing 10% inactivated fetal bovine serum, 100U/mL penicillin and 100 μ g/mL Streptomycin sulphates) respectively, in 37 DEG C, containing 5%CO 2incubator in routine passage cultivate.Hepatic stellate cell strain LX-2 and T6 taken the logarithm vegetative period, at 6 well culture plates with 5 × 10 4individual cells/well is inoculated, after cell cultures is spent the night, respectively with corresponding serum free medium synchronizing culture 24h, after this, liquid is changed in grouping, add the recombinant human TGF-β 1 (Peprotech company of the U.S.) of final concentration 10ng/ml and the PenicilfuranoneA (1 of different concns respectively, 2 and 4 μMs), set solvent control group (0.5%DMSO) and concentration as SB431542 (TGF-β 1 I receptor kinase inhibitor, Cayman company of the U.S.) positive controls of 10 μMs respectively simultaneously.Collecting cell after drug effect 48h, protein lysate lysing cell, 4 DEG C, 12000 × g low-temperature centrifugation 30min, collect supernatant.Supernatant measures its protein concentration through BCA method.Add equal-volume 2 × SDS sample loading buffer (125mmol/LTris-HCl, 20% glycerine, 0.01% tetrabromophenol sulfonphthalein, 4%SDS, 200mmol/LDTT), adjust each group of loading protein concentration consistent after, 5min is heated in boiling water bath, SDS-polyacrylamide gel electrophoresis, transferring film, after closing 1h containing the TBST of 5% skim-milk, add α-smooth muscle actin (α-SMA) respectively, vimentin (vimentin), type i collagen (typeIcollagen), Connective Tissue Growth Factor (CTGF) and internal reference β-actin antibody, 4 DEG C of overnight incubation.TBST washs 3 times, adds horseradish enzyme labelling goat anti-rabbit igg two and resists, wash film 3 times, carry out chemoluminescence by ECL test kit specification sheets, analyze the expression of associated protein at 37 DEG C with film reaction 1h, TBST.
A large amount of extracellular matrix components can be produced after hepatic stellate cell activator, therefore play a key effect in the generation, evolution of hepatic fibrosis.TGF-β 1 is the strongest factor of current known induction hepatic stellate cell activator, it not only induces hepatic stellate cell activator, raise the expression level of cell sign thing α-SMA and vimentin, also improve typeIcollagen in liver is main extracellular matrix synthesis simultaneously.Westernblot result shows, after PenicilfuranoneA process hepatic stellate cell 48h, obviously can reduce TGF-β 1 induces the marker protein α-SMA of lower cell-stimulating and vimentin to express, significantly reduce the ability of hepatic stellate cell synthesis typeIcollagen simultaneously, the ability that its falling tone vimentin expresses, is even better than positive control drug SB431542.In addition, CTGF, as the most important modulin in TGF-β 1 downstream, can work in coordination with TGF-β 1, promotes a large amount of founder cell epimatrix in hepatic tissue.The result of Westernblot finds simultaneously, and after the process of PenicilfuranoneA each dosage group, compare with TGF-β 1 induction group, in hepatic stellate cell, CTGF protein expression level significantly reduces.The above results is pointed out, and PenicilfuranoneA has obvious anti hepatic fibrosis, and its mechanism stimulates the Forming ability of the excessive activation of hepatic stellate cell and extracellular matrix relevant with blocking-up TGF-β 1, the results are shown in Figure 4.
Embodiment 5:
Obtain PenicilfuranoneA by embodiment 1, add vehicle in itself and excipient weight than the ratio of 1:1, pelletizing press sheet.
Embodiment 6:
Obtain PenicilfuranoneA by embodiment 1, add vehicle in itself and excipient weight than the ratio of 1:2, pelletizing press sheet.
Embodiment 7:
Obtain PenicilfuranoneA by embodiment 1, capsule preparations method makes capsule routinely.
Embodiment 8:
Obtain PenicilfuranoneA by embodiment 1, then make tablet as follows:
Embodiment 9:
Capsule: PenicilfuranoneA, 100mg
Starch is appropriate
Magnesium Stearate proper quantity
Preparation method: by PenicilfuranoneA, mixes with auxiliary agent, sieves, Homogeneous phase mixing in suitable container, and the mixture obtained is loaded hard gelatin capsule.
Embodiment 10:
Preparation method: at every turn add a kind of composition under stirring in the double distilled water of proper volume, separates until completely dark, and then adds another kind of composition.After adding water to 2ml, this solution is filtered on sterilizing filter, to load in bottle and to separate according to suitable dosage.
Embodiment 11:
Dripping pill: PenicilfuranoneA1g
Polyethylene glycol 6000 9g
The preparation of method for making: PenicilfuranoneA and polyethylene glycol 6000 fused solution: take PenicilfuranoneA by above-mentioned recipe quantity, add appropriate dehydrated alcohol, after low-grade fever is dissolved, add (60 DEG C of water bath heat preservations) in the polyoxyethylene glycol fused solution of recipe quantity, be uniformly mixed, till ethanol is waved to the greatest extent, be statically placed in 60 DEG C of water-baths and be incubated 30 minutes, treat that bubble eliminates, then the above-mentioned mixing fused solution eliminating bubble is proceeded in liquid storage cylinder, under the condition of insulation 80-85 DEG C, control to drip speed, instill dropwise in phlegma, complete Deng condensation, incline phlegma, collect dripping pill, drop is clean and remove the phlegma on ball with filter paper, place in silica gel drier or seasoning.

Claims (9)

1. the mould furanone A compound shown in following structural formula (I) or its pharmacy acceptable salt,
2. pharmaceutical composition, it comprises mould furanone A compound according to claim 1 or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of at least one and/or thinner.
3. mould furanone A compound as claimed in claim 1 or its pharmacy acceptable salt, wherein said pharmacy acceptable salt is hydrochloride, hydrobromate, nitrate, vitriol, phosphoric acid salt, tartrate, Citrate trianion, formate, acetate, oxalate.
4. the preparation method of mould furanone A compound according to claim 1 or its pharmacy acceptable salt, get mould furanone APenicilliumdaleae fermented product, with organic solvent extraction, concentrate to obtain medicinal extract, be extracted with ethyl acetate respectively, silica gel column chromatography, preparative high performance liquid chromatography method obtains mould furanone A compound.
5. the preparation method of mould furanone A compound as claimed in claim 4 or its pharmacy acceptable salt, it is characterized in that getting Penicilliumdaleae mycelium is inoculated in PDA in sterilizing potato dextrose broth, shake five days in shaking table with 170 rpms under room temperature, make seed liquor, seed liquor is transferred in the rice medium of sterilizing, sterile culture 40 days under 28 DEG C of conditions, the mycelium after 40 days is cultivated with ethyl acetate extraction and application rice medium, extract four times altogether, obtain ethyl acetate extract, utilize silica gel column chromatography, high performance liquid chromatography mass spectrometry, preparative high performance liquid chromatography process ethyl acetate extract, finally obtain mould furanone A, its preparative liquid chromatography condition is: 12mL/min, UV λ max230nm, MeCN-H 2o45:55, retention time 15.0min.
6. the mould furanone A compound as described in claim 4 or 5 or the preparation method of its pharmacy acceptable salt, it is characterized in that mould furanone A compound further with suitable sour salify, suitable acid be selected from hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid, tartrate, citric acid, formic acid, acetic acid, oxalic acid or other be applicable to organic acid or mineral acid.
7. mould furanone A compound according to claim 1 or the application of pharmaceutical composition according to claim 2 in the medicine preparing anti-hepatic fibrosis.
8. pharmaceutical composition according to claim 2, is characterized in that its dosage form as suitable for oral administration or drug administration by injection.
9. pharmaceutical composition according to claim 8, the dosage form of wherein said oral administration is tablet, slow releasing tablet, controlled release tablet, lozenge, hard or soft capsule, dripping pill, micropill, water-based or oil suspension, emulsion, dispersible powder or granule, oral liquid, syrup or elixir, and the dosage form of described drug administration by injection is water-based or oily solution, sterilized powder, liposome, emulsion, microemulsion, nano-emulsion or the micro-capsule of sterilizing.
CN201510672179.XA 2015-10-16 2015-10-16 Anti-hepatic fibrosis mould furanone A compounds and its pharmaceutical composition and application Active CN105330629B (en)

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Publication number Priority date Publication date Assignee Title
CN105399708A (en) * 2015-10-16 2016-03-16 中国科学院昆明植物研究所 Anti-liver fibrosis Penicilfuranone A compound as well as pharmaceutical composition and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2189453A1 (en) * 2008-11-25 2010-05-26 Université Louis Pasteur Rocaglaol derivatives as cardioprotectant agents
WO2015075165A1 (en) * 2013-11-22 2015-05-28 Deutsches Krebsforschungszentrum Translation inhibitors in high-dose chemo- and/or high-dose radiotherapy
CN105399708A (en) * 2015-10-16 2016-03-16 中国科学院昆明植物研究所 Anti-liver fibrosis Penicilfuranone A compound as well as pharmaceutical composition and application thereof

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Publication number Priority date Publication date Assignee Title
EP2189453A1 (en) * 2008-11-25 2010-05-26 Université Louis Pasteur Rocaglaol derivatives as cardioprotectant agents
WO2015075165A1 (en) * 2013-11-22 2015-05-28 Deutsches Krebsforschungszentrum Translation inhibitors in high-dose chemo- and/or high-dose radiotherapy
CN105399708A (en) * 2015-10-16 2016-03-16 中国科学院昆明植物研究所 Anti-liver fibrosis Penicilfuranone A compound as well as pharmaceutical composition and application thereof

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