CN104059040B - Sesquiterpenoids with anti-tumor activity and preparation method thereof - Google Patents
Sesquiterpenoids with anti-tumor activity and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a kind of sesquiterpenoids with anti-tumor activity and preparation method thereof, belong to biomedicine field.Described sesquiterpenoids structural formula:
Description
Technical field
The present invention relates to a kind of sesquiterpenoids with anti-tumor activity and preparation method thereof, belong to biomedicine field.
Background technology
Sesquiterpene (sesquiterpenes) refers to the natural terpenoids containing 15 carbon atoms in molecule.Sesquiterpenoids is distributed more widely, the abundantest in Magnoliales (magnoliales), rue order (rutales), Cornales (cornales) and chrysanthemum order (asterales) plant.Often being present in volatile oil with alcohol, ketone, lactone etc. form in plant materials, is the chief component of high-boiling fration in volatile oil.Have stronger fragrance and biological activity, be the important source material of medicine, food, cosmetic industry more.
The present inventor's research is learnt, wild Pleurotus abalonus (
pleurotus cystidiosus) ZYB2013(is preserved in China typical culture collection center on June 15th, 2014, deposit number is CCTCC M 2014256), solid culture mycelia in early stage is pure white, and late stage of culture mycelia can produce black point secretion.Then the activeconstituents of tunning is studied.Shown in research finds, sesquiterpenoids has anti-tumor activity, has not yet to see the report of shown sesquiterpenoids to the proliferation inhibition activity of tumour cell, therefore market also there is not yet medicine related to this.
Summary of the invention
The object of the present invention is to provide a kind of sesquiterpenoids produced by fungi fermentation and preparation method thereof.
Another object of the present invention is to this sesquiterpenoids as antitumor drug or Cytostatic to tumor cell medicine.
Fungi involved in the present invention be wild Pleurotus abalonus (
pleurotus cystidiosus) ZYB2013, this bacterial strain is preserved in China typical culture collection center, and the deposit number of registering on the books is CCTCC M 2014256, and the culture title of preservation and dated diagnostic characteristics are wild Pleurotus abalonus
pleurotus cystidiosus, preservation day is on June 15th, 2014.
The chemical structural formula of sesquiterpenoid of the present invention is as follows:
。
The preparation method of sesquiterpenoid of the present invention, by the wild Pleurotus abalonus of fermentation culture (
pleurotus cystidiosus) ZYB2013, obtain fermented product, then from fermented product, separation and purification goes out this compound, described wild Pleurotus abalonus (
pleurotus cystidiosus) ZYB2013, be preserved in China typical culture collection center on June 15th, 2014, deposit number is CCTCC M 2014256.
Concrete steps are:
1) fungus solids cultivate: by deposit number be CCTCC M 2014256 wild Pleurotus abalonus (
pleurotus cystidiosus) ZYB2013 slant strains activation after carry out solid culture fermentation, the culture medium prescription of solid fermentation is by weight: potato 10-30%, glucose 1-3%, agar powder 0.5-2%, surplus is water, pH nature, 0.1 Mpa, 121 DEG C of sterilizing 30 min, be placed in 25-30 DEG C of constant incubator and cultivate 20-50 days;
2) tunning process: after fermentation ends, mycelium and fermented substrate are cut into small pieces, with several mixing in the acetic acid of 1 ~ 3 times of volume, methyl alcohol, acetone, ethyl acetate, wherein acetic acid volume accounts for 1-5%, lixiviate more than 1 ~ 5 time, the organic vat liquor of collecting by filtration, paste is evaporated at 40 ~ 50 DEG C, paste pure water and ethyl acetate (volume of pure water and ethyl acetate is 1:1) extract 1 ~ 8 time, ethyl acetate is evaporated to paste at 40 ~ 50 DEG C, obtains ethyl acetate extract medicinal extract;
3) by 2) described in ethyl acetate extract medicinal extract dissolve with methanol, (reverse phase silica gel adopts RP18 to carry out reversed-phase silica gel column chromatography, consumption is 40 ~ 400 times of sample quality), first use pure water wash-out 5 ~ 10 column volumes, then with methanol-water gradient, be in charge of collection, each pipe is in 40 ~ 50 DEG C of difference concentrating under reduced pressure, according to thin-layer chromatography (with chloroform: methyl alcohol=10:1 is developping agent, with 10% sulfuric acid ethanol for developer) result, the collection tube containing target compound is merged into component Fr.1;
4) Fr.1 is carried out reversed-phase silica gel column chromatography, take methanol-water as eluent, be in charge of collection, thin-layer chromatography is carried out in every test tube sampling, merges similar compositions and obtains Fr.C1 and Fr.C2.Fr.C1 through Sephadex LH-20 dextrane gel column chromatography, acetone wash-out, then through reversed-phase silica gel column chromatography, 40% methanol-eluted fractions, then through purification on normal-phase silica gel column chromatography, chloroform: methyl alcohol (200:1) wash-out obtains compound
1.By Fr.C2 through Sephadex LH-20 dextrane gel column chromatography, acetone wash-out, purification on normal-phase silica gel column chromatography, chloroform: methyl alcohol (200:1) wash-out, then through Sephadex LH-20 dextrane gel column chromatography, acetone wash-out, be in charge of collection, thin-layer chromatography detects and obtains compound
2.
The present invention also protects described sesquiterpenoids and is preparing the purposes in Cytostatic to tumor cell medicine, and is preparing the purposes in antitumor drug.Described tumour cell is prostate cancer cell DU-145, C42B and LNCaP.
According to mass spectrum (ESI), high resolution mass spectrum (HRMS-EI), circular dichroism spectrum (CD), optically-active ([
a]), UV spectrum (UV), infrared spectra (IR) and NMR (Nuclear Magnetic Resonance) spectrum (
1h-NMR,
13c-NMR, HSQC, HMBC,
1h,
1h-COSY and NOESY) data Structural Identification is carried out to compound, can deterministic laminate structures.Utilize cell toxicant MTT(tetrazolium bromide) and method (see document Mosmann T. Rapid colorimetric assay for cellular growth and survival:application to proliferation and cytotoxicity assays [J]. J. Immunol Methods, 1983,65(1-2): 55-63.) measure the anti-tumor activity of compound, find that it has stronger inhibition to prostate cancer cell DU-145, C42B and LNCaP.Result shows, described sesquiterpenoid has anti-tumor activity, can be applicable to prepare antitumor drug or the active primer of other biological.
Sesquiterpenoid novel structure of the present invention, has very strong anti-tumor activity.Utilize wild Pleurotus abalonus (
pleurotus cystidiosus) ZYB2013 fermentation obtains, fermentation raw material source low price, preparation method is simple, easily realizes suitability for industrialized production.
Embodiment
The chemical structure of the compound 1,2 of indication in following embodiment:
The invention will be further described for following examples.
embodiment 1
Preparation solid PDA medium (be sub-packed in 750 90 mm glass culture dishs containing 15 L in every premium on currency, eachly about fill 20 mL substratum, access after sterilizing activated wild Pleurotus abalonus (
pleurotus cystidiosus) ZYB2013(is preserved in China typical culture collection center on June 15th, 2014, deposit number is CCTCC M 2014256) mycelia block, carries out cultivation 43 days in 28 DEG C of constant incubators.After cultivation, wild Pleurotus abalonus mycelium is shredded together with substratum, be placed in tap bottle, add organic solvent (ethyl acetate: methyl alcohol: acetic acid volume ratio=80:15:5) lixiviate 6 times, collect extracting solution, be evaporated to paste at 40 DEG C, paste pure water and ethyl acetate 1:1 extract 6 times, after ethyl acetate anhydrous sodium sulfate dehydration, be evaporated to paste at 40 DEG C, (4.4057 g) to obtain ethyl acetate extract medicinal extract.
By 4.4057 g ethyl acetate extracts in previous step, fully dissolve by proper amount of methanol, carry out reverse phase silica gel (170 g) column chromatographies.Use methanol-water gradient: water, 30% methyl alcohol, 50% methyl alcohol, 70% methyl alcohol, methyl alcohol and water wash-out 1.5 L, 1.5 L, 1.5 L, 1.4 L, 1 L and 1 L respectively, flow velocity is about 20 mL/min, and often 200 mL collected by pipe, thin-layer chromatography is carried out in every test tube sampling, and (developping agent is chloroform: methyl alcohol=15:1, developer: 10% sulfuric acid ethanol; Lower same) analytical results, merge similar compositions, obtain Fr.A(195.5 mg), Fr.B(154.8 mg), Fr.C(495.7 mg), Fr.D(240.0 mg), Fr.E(1733.5 mg), Fr.F(693.0 mg) and Fr.G(318.8 mg) seven components.
The component Fr.C(495.7 mg that previous step is obtained) carry out reverse phase silica gel (30 g) column chromatographies, respectively with 35% methanol-water and 45% methanol-water for eluent, be in charge of collection, thin-layer chromatography is carried out in every test tube sampling, merges similar compositions and obtains Fr.C1(222.9 mg) and Fr.C2(134.1 mg).Fr.C1 is through Sephadex LH-20 dextrane gel (120 g) column chromatographies, acetone wash-out obtains Fr.C1.1(88.6 mg), then through reversed-phase silica gel column chromatography, (30 g), 300 mL 40% methanol-eluted fractions obtain Fr.C1.1.1(56.5mg), Fr.C1.1.1 is through purification on normal-phase silica gel (2 g) column chromatographies, 150 mL chloroforms: methyl alcohol (200:1) wash-out obtains compound
1(6.1 mg).By Fr.C2 through Sephadex LH-20 dextrane gel (120 g) column chromatography, acetone wash-out obtains Fr.C2.1(16.6 mg) and Fr.C2.2(49.0 mg).Fr.C2.1 purification on normal-phase silica gel (1 g) column chromatography, 150 mL chloroforms: methyl alcohol (200:1) wash-out obtains Fr.C2.1.1(7.3 mg), then through Sephadex LH-20 dextrane gel (30 g) column chromatographies, acetone wash-out, be in charge of collection, thin-layer chromatography detects and obtains compound
2(3.0 mg).
By the compound of previous step gained
1,
2, carry out mass spectrum (ESI), high resolution mass spectrum (HRMS-EI), circular dichroism spectrum (CD), optically-active ([
a]), UV spectrum (UV), infrared spectra (IR) and NMR (Nuclear Magnetic Resonance) spectrum (
1h-NMR,
13c-NMR, HSQC, HMBC,
1h,
1h-COSY and NOESY) measure, and deterministic laminate structures.
Compound
1, white-amorphous, is soluble in methyl alcohol, [
a]
+ 51.7 (
c=0.23, MeOH); UV-vis (MeOH),
λ/ nm:216; HRMS-EI,
m/z: 266.1521 (theoretical values 266.1518); IR (KBr) n
max: 3441,1749,1623 cm
-1; In conjunction with
1h and
13c NMR modal data (table 1) determines that molecular formula is C
15h
22o
4.In infrared spectra, compound
1at 3441,1749 and 1623 cm
-1have and absorb more by force, point out at compound respectively
1containing hydroxyl, carbonyl and double bond group.Analyze
1h and
13c NMR and DEPT composes, and shows compound
1containing 3 methyl, 3 methylene radical (one of them is the methylene radical on end alkene), 5 methynes (wherein 3 company's oxygen, 1 is alkene methyne), 4 quaternary carbons (wherein 1 company's oxygen, 2 is olefinic carbon, and 1 is carbonyl).In HMBC spectrum, two methyl proton H
3-12 and H
3-13 to C-11 and C-10 and existence each other obvious hydrocarbon long-range relevant, then according to the hydrocarbon long-range relevant and C-9(δ of H-10 and C-9, C-12 and C-13
cchemical displacement value 199.8s), shows compound
1isoprene segments containing the band carbonyl be made up of C-9, C-10, C-11, C-12 and C-13.According to observable following hydrocarbon long-range relevant in HMBC spectrum: the methylene radical H of end alkene
2-15 with C-6 and C-8, H-1 and C-2, C-7 and C-8, H-6 and C-7, H-8 and C-7, and
1h-
1the stronger hydrogen hydrogen of H-6 and the H-1 existed during H COSY composes is correlated with, and can set up the furan structure fragment of the end alkene replacement be made up of C-1, C-6, C-7, C-8 and C-15.
1h-
1during H COSY composes, H-1 and H-2 and H-6, and H
2-5 have stronger reference point with H-4 and H-6, then according to H
3-14 HMBCs stronger to C-2, C-3 and C-4 are hydrocarbon long-range relevant, can set up by C-1, C-2, C-3, C-4, C-5, C-6 and C-15 form by hydroxyl and methyl substituted cyclohexane structure fragment, and can by H
2-4 HMBCs stronger to C-2, C-5, C-6 and C-14 are hydrocarbon long-rangely relevantly to be confirmed further.Also H-8 and C-9 is found in HMBC spectrum, and H
2-5 relevant to C-7 and C-15, accordingly can by three fragments composition compounds
1basic structure.In NOESY spectrum, H-1 and H-6, H-6 and H-5a, H-5a and H-6 have and are significantly correlated with, show H-1, H-6, H-5a same towards, meanwhile, H-2 and H
3-14, H-2 and H-8 have obvious NOESY is correlated with, and shows H-2, H
3-14, H-8 is towards the opposite, therefore compound
1relative configuration set up, through retrieval compound
1for bisabolane type sesquiterpene, called after pleuroton A.
Table 1 compound
1nMR data (MeOD, 500M)
(note: alphabetical q, t, d, s represent the primary respectively, secondary, uncle, quaternary carbon, is determined by DEPT figure; DH:H chemical shift; DC:C chemical shift; J: coupling constant; Multiplicity: multiplely split peak, Hereinafter the same).
Compound
2, white-amorphous, is soluble in methyl alcohol, [
a]
+ 79.6 (
c=0.32, MeOH); UV-vis (MeOH),
λ/ nm:247; ESI,
m/z: 281.2 [M-H]
-; HRMS-EI,
m/z: 282.1461 (theoretical values 282.1467); IR (KBr) n
max: 3443,1758,1684,1622 cm
-1; In conjunction with
1h and
13c NMR modal data (table 2) determines that molecular formula is C
15h
22o
5.Analyze
1h and
13c NMR and DEPT composes, and shows compound
2containing 3 methyl, 3 methylene radical (one of them is the methylene radical on end alkene), 4 methynes (wherein 2 company's oxygen, 1 is alkene methyne), 5 quaternary carbons (wherein 2 company's oxygen, 2 is olefinic carbon, and 1 is carbonyl).Compared by NMR data, show compound
2with compound
1similar, only compound
1in C-8 position be connect the methyne of oxygen, and compound
2in C-8 position be dioxygen replace quaternary carbon.Compound
2structure also tested by HMBC in the hydrocarbon long-range relevant (H that observes
3-12 and H
3-13 with C-11 and C-10 and each other, H-10 and C-12, C-13 and C-9, H-1 and C-2, C-7 and C-8, H-4 and C-5, C-14, C-6, C-3 and C-2, H-5 and C-4, C-6, C-3 and C-7, H
3-14 with C-2, C-3 and C-4, H
2-15 with C-6, C-7 and C-8), and
1h-
1the stronger hydrogen hydrogen relevant (H-1 and H-6 and H-2, H-5 and H-4 and H-6) existed during H COSY composes adds their confirmation.In NOESY spectrum, H-1 and H-6, H-6 and H-5a, H-5a and H-6 have and are significantly correlated with, show H-1, H-6, H-5a same towards, meanwhile, H-2 and H
3-14, H-2 and H-4b have obvious NOESY is correlated with, and shows H-2, H
3-14, H-4b is towards the opposite, accordingly compound
2relative configuration also set up.Compound
2also be bisabolane type sesquiterpene, called after pleuroton B.
Table 2 compound
2nMR data (MeOD, 500M)
Embodiment 2
The inhibition of compound on prostate cancer cells DU-145, C42B and LNCaP is measured with mtt assay.Cultured prostate cancer cell DU-145, C42B and LNCaP are made single cell suspension, and counting with cell plate and being diluted to cell concn is 6 × 10
4individual/mL.Inoculating cell in 96 orifice plates, every hole 80 μ L.Separately establish 2 holes acellular, only have 80 μ L nutrient solutions [Dulbecco ' s modified Eagle ' s media(DMEM, Gibco, USA)+10% calf serum] for instrument zeroing blank control wells.Put 37 DEG C, 5%CO
2incubator in cultivate 24 h, then add the sample that 20 μ L nutrient solutions have diluted.Meanwhile, add 20 μ L cis-platinums toward Positive control wells, respectively add 20 μ L nutrient solutions toward negative control hole and blank control wells.Continue to cultivate 72h, every hole adds 10 μ L 5 mg/mL MTT.37 DEG C of reaction 3 h, every hole adds 100 μ L 10%SDS-0.01mol/L HCl dissolvings and spends the night.Microplate reader colorimetric estimation (measuring wavelength 570 nm, reference wavelength 655 nm).Be (negative control group OD value-experimental group OD value)/(negative control group OD Zhi – blank group OD value) × 100% to the inhibiting rate method of calculation of tumour cell.Adopt SPSS computed in software IC
50value.Experiment shows, compound
1to the IC of prostate cancer cell DU-145, C42B and LNCaP
50value is respectively 0.174,0.104 and 0.091 mM, compound
2to the IC of prostate cancer cell DU-145, C42B and LNCaP
50value is respectively 0.028,0.052 and 0.051 mM, and compound 1-2 shows the activity of stronger suppression prostate cancer cell.Visible, sesquiterpenoid of the present invention can be used as antitumor drug or the active primer of other biological.
Claims (1)
1. a preparation method for sesquiterpenoids, is characterized in that: described sesquiterpenoids, has as shown in the formula a kind of structural formula in 1-2:
; By the wild Pleurotus abalonus of fermentation culture (
pleurotus cystidiosus) ZYB2013, obtain fermented product, then from fermented product, separation and purification goes out this compound, described wild Pleurotus abalonus (
pleurotus cystidiosus) ZYB2013, be preserved in China typical culture collection center on June 15th, 2014, deposit number is CCTCC M 2014256; Concrete steps are:
1) fungus solids cultivate: by deposit number be CCTCC M 2014256 wild Pleurotus abalonus (
pleurotus cystidiosus) ZYB2013 slant strains activation after carry out solid culture fermentation, the culture medium prescription of solid fermentation is by weight: potato 10-30%, glucose 1-3%, agar powder 0.5-2%, surplus is water, pH nature, 0.1 Mpa, 121 DEG C of sterilizing 30 min, be placed in 25-30 DEG C of constant incubator and cultivate 20-50 days;
2) tunning process: after fermentation ends, mycelium and fermented substrate are cut into small pieces, with several mixing in the acetic acid of 1 ~ 3 times of volume, methyl alcohol, acetone, ethyl acetate, wherein acetic acid volume accounts for 1-5%, lixiviate 1 ~ 5 time, the organic vat liquor of collecting by filtration, paste is evaporated at 40 ~ 50 DEG C, paste pure water and extraction into ethyl acetate 1 ~ 8 time, the volume of pure water and ethyl acetate is 1:1, ethyl acetate is evaporated to paste at 40 ~ 50 DEG C, obtains ethyl acetate extract medicinal extract;
3) by 2) described in ethyl acetate extract medicinal extract dissolve with methanol, carry out reversed-phase silica gel column chromatography, reverse phase silica gel adopts RP18, and consumption is 40 ~ 400 times of sample quality, first use pure water wash-out 5 ~ 10 column volumes, again with methanol-water gradient, be in charge of collection, each pipe is in 40 ~ 50 DEG C of difference concentrating under reduced pressure, according to thin-layer chromatography result, with chloroform: methyl alcohol=10:1 is developping agent, with 10% sulfuric acid ethanol for developer, the collection tube containing target compound is merged into component Fr.1;
4) Fr.1 is carried out reversed-phase silica gel column chromatography, take methanol-water as eluent, be in charge of collection, thin-layer chromatography is carried out in every test tube sampling, merges similar compositions and obtains Fr.C1 and Fr.C2; Fr.C1 through Sephadex LH-20 dextrane gel column chromatography, acetone wash-out, then through reversed-phase silica gel column chromatography, 40% methanol-eluted fractions, then through purification on normal-phase silica gel column chromatography, chloroform: methyl alcohol 200:1 wash-out obtains compound
1; By Fr.C2 through Sephadex LH-20 dextrane gel column chromatography, acetone wash-out, purification on normal-phase silica gel column chromatography, chloroform: methyl alcohol 200:1 wash-out, then through Sephadex LH-20 dextrane gel column chromatography, acetone wash-out, is in charge of collection, thin-layer chromatography detects and obtains compound
2.
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Non-Patent Citations (3)
| Title |
|---|
| Ken-ichi Takao et al..Total synthesis of (+)-cheimonophyllon E, a bisabolane sesquiterpenoid.《Tetrahedron Letters》.2001,第42卷 * |
| Marc Stadler et al..New nematicidal and antimicrobial compounds from the basidiomycete Cheimonophyllum candidissimum.《Journal of Antibiotics》.1994,第47卷(第11期), * |
| Shao-juan Wang et al..Pleurospiroketals A-E, Perhydrobenzannulated 5,5-Spiroketal Sesquiterpenes from the Edible Mushroom Pleurotus cornucopiae.《Journal of Natural Products》.2013,第76卷 * |
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