CN102321133B - Antibiotic Lobophorin E and F, preparation methods and applications thereof in preparing antibacterial and antitumor drugs - Google Patents
Antibiotic Lobophorin E and F, preparation methods and applications thereof in preparing antibacterial and antitumor drugs Download PDFInfo
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- 229930195405 lobophorin Natural products 0.000 title claims abstract description 69
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 10
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 9
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 7
- 230000003115 biocidal effect Effects 0.000 title abstract description 7
- 229940124350 antibacterial drug Drugs 0.000 title 1
- 241001655322 Streptomycetales Species 0.000 claims abstract description 17
- 229940088710 antibiotic agent Drugs 0.000 claims abstract description 6
- 239000001963 growth medium Substances 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 239000007788 liquid Substances 0.000 claims description 19
- 239000000284 extract Substances 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 14
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 claims description 12
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- 235000010627 Phaseolus vulgaris Nutrition 0.000 claims description 3
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- RQSOZTMIRJDUQP-UHFFFAOYSA-N Kijanimicin Natural products COC1=C(C)CC23OC(=O)C(=C2)C(=O)C4(C)C(C=CC5C(O)C(C)CC(C)C45)C(=CCC(O)C(=CC3C1)C)C RQSOZTMIRJDUQP-UHFFFAOYSA-N 0.000 description 1
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- 241000387651 Sciscionella marina Species 0.000 description 1
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- 210000004556 brain Anatomy 0.000 description 1
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- WUXHQHDSSKBJFH-DELKKKATSA-N chlorothricin Chemical compound COC1=CC=C(Cl)C(C)=C1C(=O)O[C@H]1[C@H](O)[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3[C@@H]4[C@H]([C@@]5(C(=O)OC=6C(=O)O[C@@]7(C=6O)C[C@@H](C)C(=C[C@H]7/C=C/CCCC[C@@H]5C=C4)C(O)=O)C)CCC3)C[C@H]2O)C)C1 WUXHQHDSSKBJFH-DELKKKATSA-N 0.000 description 1
- 238000005100 correlation spectroscopy Methods 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- 230000001461 cytolytic effect Effects 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229930186446 decatromicin Natural products 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
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- PGBHMTALBVVCIT-VCIWKGPPSA-N framycetin Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CN)O2)N)O[C@@H]1CO PGBHMTALBVVCIT-VCIWKGPPSA-N 0.000 description 1
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- WXINYBSBDLMHLF-HYTSUKQWSA-N lobophorin A Natural products CO[C@H]1[C@H](C)O[C@@H](C[C@H]1O)O[C@H]2[C@H](C)O[C@H](C[C@H]2O)O[C@@H]3C[C@H](O[C@H]4[C@@H](C)C[C@H](C)[C@@H]5[C@@H]4C=C[C@H]6C(=CC[C@H](O[C@H]7C[C@](C)(N)[C@@H](NC(=O)OC)[C@@H](C)O7)C(=C[C@@H]8C=C(CO)[C@H](C)C[C@]89OC(=O)C(=C9O)C(=O)[C@@]56C)C)C)O[C@@H](C)[C@@H]3O WXINYBSBDLMHLF-HYTSUKQWSA-N 0.000 description 1
- BFIFMYVVBKSDFE-CDLXNPJNSA-N lobophorin D Natural products CO[C@H]1[C@H](C)O[C@@H](C[C@H]1O)O[C@@H]2[C@@H](C)O[C@@H](C[C@@H]2O)O[C@@H]3C[C@H](O[C@H]4[C@H](C)C[C@H](C)[C@@H]5[C@@H]4C=C[C@H]6C(=CC[C@H](O[C@H]7C[C@](C)(N)[C@@H](NC(=O)OC)[C@@H](C)O7)C(=C[C@@H]8C=C(CO)[C@H](C)C[C@]89OC(=O)C(=C(O)[C@@]56C)C9=O)C)C)O[C@@H](C)[C@@H]3O BFIFMYVVBKSDFE-CDLXNPJNSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000005142 microbroth dilution method Methods 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
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- 229930014626 natural product Natural products 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
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- 229920002223 polystyrene Polymers 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
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- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses antibiotic Lobophrin E and F and preparation method thereof and the application in preparation antibacterial, anti-tumor drug. Shown in the structure such as formula (I) of the Lobophorin E and F. Lobophorin E and F are isolated from the fermentation culture medium of streptomycete SCSIO 1127. Lobophorin E and F have bacteriostatic activity, can be used for preparing antibacterials, and Lobophorin F has anti-tumor activity, can be used for preparing anti-tumor drug.
Lobophorin E, wherein R are as follows:
Lobophorin F, wherein R=H.
Description
Technical field:
The invention belongs to the industrial microorganism field, be specifically related to two kinds of new microbiotic Lobophorin E and F and preparation method thereof, and the application in antibiotic, the antitumor drug of preparation.
Background technology:
Spirotetronate class microbiotic is that a class has antibiotic and natural product anti-tumor activity, such as antlermicin, chlorothricin, kijanimicin, decatromicins, saccharocarcins, tetrocarcins and versipelostatins.Lobophorin A and lobophorin B, forefathers separate and obtain from the actinomycetes with the marine alga symbiosis, and demonstrate anti-inflammatory activity, but anti-microbial activity (Jiang, Z.D., Jensen, P.R.& do not detected; Fenical, W.Lobophorins A and B, new antiinflammatory macrolides produced by a tropical marine bacterium.Bioorg.Med.Chem.Lett., 1999,9,2003-2006.).Recently, lobophorins C and lobophorin D obtain from growing nonparasitically upon another plant altogether streptomycete to separate with sponge, several different cell strains are demonstrated to selective inhibitory activity (Wei, R.-B.et al.Lobophorin C and D, New Kijanimicin derivatives from a marine sponge-associated actinomycetal strain AZS 17.Mar.Drugs, 2011,9,359-368.).
Summary of the invention:
The first purpose of the present invention is to provide two kinds of new Antibiotique compositions, i.e. microbiotic lobophorin E and lobophorin F, and its structure is suc as formula shown in (I).
Microbiotic lobophorin E of the present invention and lobophorin F, its structure is suc as formula shown in (I):
Lobophorin E, wherein R is:
Lobophorin F, wherein R=H.
Second purpose of the present invention has been to provide the preparation method of microbiotic lobophorin E and lobophorin F.
Microbiotic lobophorin E of the present invention is from the fermenting culture of streptomycete Streptomyces sp SCSIO 1127, to prepare to separate to obtain with lobophorin F.
The present invention preferably prepares microbiotic lobophorin E and lobophorin F by the following method from the fermenting culture of streptomycete Streptomyces sp SCSIO 1127, and concrete steps are as follows:
A) prepare the fermenting culture of streptomycete SCSIO 1127, the fermented liquid of this fermenting culture and mycelium are separated, fermented liquid extracts through butanone, and the butanone layer obtains extractum A after distillation and concentration; Mycelium is first used acetone extraction, and after leaching liquid reclaims acetone, remaining water mixed liquid is again with the butanone extraction, and the butanone layer obtains medicinal extract B after distillation and concentration;
B) extractum A and medicinal extract B are merged, through silica gel column chromatography, using the volume ratio chloroform-methanol of 100: 0～0: 100 as the eluent gradient wash-out, collect the cut Fr.1 that 100: 1 gradient elutions of chloroform-methanol volume ratio get off;
C) cut Fr.1 is through gel filtration chromatography, the chloroform-methanol that the volume ratio of usining is 1: 1 is as the moving phase wash-out, successively obtain two inferior cut Fr1-1 and Fr.1-2, the standby chromatogram of compacting in the Fr.1-1 warp, with methanol/water volume fraction 10%-90% linear gradient elution 160min, flow velocity is 15ml/min, collect the cut that methanol/water volume fraction 85-90% gradient elution gets off, through HPLC, prepare again, moving phase: A is that volume fraction 10% acetonitrile solution is volume fraction 90% acetonitrile solution with B mutually mutually, 0-11min, the B phase content is changed to 100% by 40%, 11-16min, the 100%B phase, 16-17min, the B phase content is changed to 40% by 100%, 17-23min 40%B phase, flow velocity 2.5ml/min, detect wavelength 263nm, and the cut that the collection retention time is 22.0min, obtain compound 1, Fr.1-2 is through the Preparative TLC chromatography, and developping agent is the chloroform-methanol that volume ratio is 30: 1, collects the cut that the Rf value is 0.5, through HPLC, prepare again, moving phase: A is volume fraction 10% acetonitrile solution mutually, and B is volume fraction 90% acetonitrile solution mutually, 0-9min, the B phase content is changed to 100% by 40%, 9-17min, 100%B phase, 17-18min, the B phase content is changed to 40%, 18-26min 40%B phase by 100%, flow velocity 2.5ml/min, the detection wavelength is 263nm, the cut that the collection retention time is 21.3min, obtain compound 2.
The fermenting culture of the preparation streptomycete SCSIO 1127 of described a) step is preparation by the following method preferably: by the streptomycete SCSIO of activation 1127 access seed culture mediums, 28 ℃, 200rpm, cultivate 48h and make seed liquor, seed liquor is linked in fermention medium with 10% inoculum size, 28 ℃, 200rpm, shaking culture 144h, and make fermenting culture, the formula of described seed culture medium and fermention medium is all to contain in every liter of substratum: bean powder 3g, yeast extract powder 3g, trehalose 10g, proline(Pro) 1g, beef extract 3g, glycerine 6ml, K
2hPO
40.3g, MgSO
47H
2o 0.5g, FeSO
47H
2o 0.1g, CaCO
32g, thick sea salt 30g, surplus is water, pH 7.4.In the fermenting culture of the streptomycete SCSIO1127 prepared through present method, the content of lobophorin E and lobophorin F is higher.
Fermented liquid in described a) step extracts through butanone, and it is preferably butanone extraction 4 times for fermented liquid, 2 times of volumes that the amount of institute's solubilizing agent is fermented liquid.
By structural analysis, as follows to the qualification result of 2 compound-compounds 1 that prepare from the fermenting culture of streptomycete SCSIO 1127 of the present invention and compound 2:
Compound 1: white solid, ESI-MS data (m/z 1194.1[M+Na]
+and m/z 1170.2[M-H]
-), [a]
20 d-20.0 (c=0.38, methyl alcohol), IR (KBr) 3522,3439,2932,1734,1627,1545,1454cm
-1.The hydrogen spectrum of this compound and carbon spectrum nuclear magnetic data (as shown in table 1), compare (Jiang, Z.D., Jensen, P.R.& with known compound lobophorin B; Fenical, W.Lobophorins A and B, new antiinflammatory macrolides produced by a tropical marine bacterium.Bioorg.Med.Chem.Lett., 1999,9,2003-2006.), lacked 1 even methylene radical of oxygen, many 1 unimodal methyl [δ
h(1.80 s, Me-32); δ
c21.8 (q, Me-32)], simultaneously C-22 to high field displacement 3.6 chemical shift units, in conjunction with H-32 and C-21 in the HMBC Correlated Spectroscopy, C-22, C-23 is relevant, but the structure of deterministic compound 1 is 32-dehydroxyl-lobophorin B, its structure is suc as formula shown in (I), and wherein its R is:
Compound 2: white solid, FABMS data (m/z 1065.4902[M+Na]
+), [a]
20 d-60.0 (c=0.76, methyl alcohol), IR (KBr) 3440,2934,1737,1629,1545,1454cm
-1.The hydrogen spectrum of this compound and carbon spectrum nuclear magnetic data (as shown in table 1), compare with compound 1,3 sugar-tablet break signal [Sugar-A: δ only occurred
h4.97 (d, J=4.5Hz, H-A
1, 1.58 (m, H-A
2), 2.25 (m, H-A
2), 4.02 (m, H-A
3), 3.30 (d, J=6.5Hz, H-A
4), 4.04 (1H, m, H-A
5), 1.29 (3H, d, J=5.0Hz, Me-A
6); δ
c99.1 (d, C-A
1), 31.2 (t, C-A
2), 74.1 (d, C-A
3), 72.4 (d, C-A
4), 65.0 (d, C-A
5), 17.7 (q, Me-A
6); Sugar-B: δ
h5.07 (d, J=2.5Hz, H-A
1, 1.85 (m, H-A
2), 2.25 (m, H-A
2), 3.99 (m, H-A
3), 3.18 (dt, J=2.5,9.5Hz, H-A
4), 3.94 (1H, m, H-A
5), 1.32 (3H, d, J=6.0Hz, Me-A
6); δ
c96.5 (d, C-A
1), 33.4 (t, C-A
2), 66.9 (d, C-A
3), 72.5 (d, C-A
4), 65.6 (d, C-A
5), 17.7 (q, Me-A
6); Sugar-C: δ
h4.44 (d, J=9.5Hz, H-A
1, 1.62 (2H, m, H-A
2), 4.37 (d, J=10.0Hz, H-A
4), 3.50 (1H, m, H-A
5), 1.15 (3H, d, J=6.0Hz, Me-A
6), 1.58 (3H, s, Me-A
6), 3.75 (3H, s, H-A
9; δ
c97.4 (d, C-A
1), 35.8 (t, C-A
2), 90.9 (s, C-A
3), 53.9 (d, C-A
4), 68.9 (d, C-A
5), 17.0 (q, Me-A
6), 25.3 (q, Me-A
7), 157.4 (s, C-A
8), 52.7 (q, MeO-A
9)], the carbon of B-4 has been composed to high field displacement 9.7 chemical shift units simultaneously.Illustrate that the C sugar in compound 1 lacks in compound 2.Therefore, the structure of compound 2 is suc as formula shown in (I), its R=H, called after lobophorin F.
Table 1: compound 1 and 2 nuclear magnetic data (500MHz in CDCl
3) (δ
ppm, J
hz)
The present invention found through experiments, microbiotic lobophorin E of the present invention and lobophorin F have bacteriostatic activity preferably to streptococcus aureus, bacillus thuringiensis, excrement enterobacteria, so the present invention also provides microbiotic lobophorin E and the application of lobophorin F in the preparation antibacterials.
The present invention found through experiments, microbiotic lobophorin F of the present invention has anti-tumor activity preferably to human breast cancer cell strain, National People's Congress's sclc cell line, human glioma cells strain, so the present invention also provides the application of microbiotic lobophorin F in preparing antitumor drug.
Streptomycete Streptomyces sp.SCSIO 1127 of the present invention separates and obtains from the marine bottom sediment of 1350 meters of China's Northern Part of South China Sea (111 ° 54.693 of E ', N08 ° 56.003 ') depth of waters.By the 16S rDNA of this bacterium of ordinary method pcr amplification, and order-checking, its sequence, as shown in SEQ ID NO.1, is submitted in GenBank, obtains sequence number JF794566.16S rDNA gene sequencing result shows this bacterial strain and streptomycete Streptomyces sp.A00108, Streptomyces pactum strain173827, Streptomyces sp.A2Ydz-XD, Streptomycespactum strain 173848 similarities reach 100%.As shown in Figure 1, clearly disclose the Phylogenetic of this bacterial strain and one group of streptomyces species by adjacent method, shown a kind of in streptomyces of this Pseudomonas.By this bacterium called after: streptomycete Streptomyces sp.SCSIO 1127, this bacterium is preserved in Chinese Typical Representative culture collection center (CCTCC) on May 19th, 2011, address: Wuhan, China city Wuhan University, its deposit number is CCTCC NO:M 2011178.
The present invention has prepared two kinds of new compounds from the fermenting culture of the streptomycete SCSIO 1127 of marine source, microbiotic lobophorin E and lobophorin F, these two kinds of new compounds have anti-microbial activity, and lobophorin F also has anti-tumor activity, therefore for developing antibiotic new drug and anti-cancer agent, provide candidate compound.
Streptomycete Streptomyces sp.SCSIO 1127 of the present invention, be preserved in Chinese Typical Representative culture collection center (CCTCC), address on May 19th, 2011: Wuhan, China city Wuhan University, its deposit number is CCTCC NO:M 2011178.
The accompanying drawing explanation:
Fig. 1 is the systematic evolution tree of relation between the nearest kind of the sibship with it of the adjacent method reconstruction of streptomycete SCSIO 1127 of the present invention based on 16S rDNA sequence;
Fig. 2 is the extract-extractum A of supernatant liquor and the high-efficient liquid phase chromatogram of mycelial extract-medicinal extract B.
Embodiment:
Below to further illustrate of the present invention, rather than limitation of the present invention.
Embodiment 1:
One, the separation of streptomycete Streptomyces sp.SCSIO 1127 and evaluation
The separation of the genomic dna related to during streptomycete Streptomyces sp.SCSIO 1127 identifies, the pcr amplification of 16S rDNA, the establishment method of sequence alignment and systematic evolution tree etc. are reference [Tian all, X.P., Zhi, X.Y., Qiu, Y.Q., Zhang, Y.Q., Tang, S.K., Xu, L.H., Zhang, S., Li, W.J.Sciscionella marina gen.nov., sp.nov., a marine actinomycete isolated from a sediment in the northern South China Sea.Int J Syst Evol Microbiol, 2009, 59 (Pt 2): 222-228].
Bacterium source: streptomycete Streptomyces sp.SCSIO 1127 separates and obtains from the marine bottom sediment of 1350 meters of China's Northern Part of South China Sea (111 ° 54.693 of E ', N08 ° 56.003 ') depth of waters.
Strain identification: with reference to the method in above-mentioned document, the 16S rDNA of conventional pcr amplification streptomycete SCSIO 1127 order-checking, its sequence, as shown in SEQ ID NO.1, then is submitted in GenBank, obtains sequence number JF794566.16S rDNA gene sequencing result shows, this bacterial strain and streptomycete Streptomyces sp.A00108, Streptomycespactum strain173827, Streptomyces sp.A2Ydz-XD, Streptomycespactum strain 173848 similarities reach 100%.As shown in Figure 1, clearly disclose the Phylogenetic of this bacterial strain and one group of streptomyces species by adjacent method, shown a kind of in streptomyces of this Pseudomonas.By this bacterium called after: streptomycete Streptomyces sp.SCSIO 1127, this bacterium is preserved in Chinese Typical Representative culture collection center (CCTCC) on May 19th, 2011, address: Wuhan, China city Wuhan University, its deposit number is CCTCC NO:M 2011178.
Two, the scale of streptomycete SCSIO 1127 fermentation
A) fermentative medium formula:
In every liter of fermention medium, contain: bean powder 3g, yeast extract powder 3g, trehalose 10g, proline(Pro) 1g, beef extract 3g, glycerine 6ml, K
2hPO
40.3g, MgSO
47H
2o 0.5g, FeSO
47H
2o 0.1g, CaCO
32g, thick sea salt 30g, surplus is water, 7.4,121 ℃ of pH, sterilizing 30min, standby.
B) fermentation:
Seed culture: in the streptomycete SCSIO 1127 access fermention mediums (450mL) that will activate on flat board, 28 ℃, 200rpm, cultivate 48h and make seed liquor;
The scale fermentation culture: seed liquor is linked into to (4.5L) in fermention medium with 10% inoculum size, and 28 ℃, 200rpm, cultivate 144h, and make the fermenting culture of streptomycete SCSIO 1127.
Three, Lobophorin class microbiotic lobophorin E and lobophorin F's separates
A) extraction of fermented liquid
Fermenting culture by the streptomycete SCSIO 1127 of above-mentioned scale fermentation, separate with mycelium through the centrifugal fermented liquid that makes, and fermented liquid extracts 4 times with the butanone of two volumes, combining extraction liquid, and underpressure distillation obtains fermentation broth extract, is extractum A; The acetone extraction of 3 times of volumes 3 times for mycelium, merge vat liquor, after acetone is reclaimed in underpressure distillation, and its two volumes butanone extraction 4 times for remaining water mixed liquid, concentrated acquisition mycelium extract, be medicinal extract B.Through HPLC, detect, extractum A identical with medicinal extract B ingredient (seeing Fig. 2), therefore obtain crude extract 5.3g by extractum A and medicinal extract B merging.
B) Lobophorin class microbiotic lobophorin E and lobophorin F's separates
Through silica gel column chromatography, (the 300-400 order, 50g), using the volume ratio chloroform-methanol of 100: 0～0: 100 as the eluent gradient wash-out to crude extract, collects the cut Fr.1 that 100: 1 gradient elutions of chloroform-methanol volume ratio get off.
Cut Fr.1 is through the LH-20 gel filtration chromatography, and the chloroform-methanol that the volume ratio of usining is 1: 1, as the moving phase wash-out, successively obtains two inferior cuts (Fr1-1, Fr.1-2).Standby chromatogram (the YMC*GEL ODS-A ball-shaped filling material of compacting in the Fr.1-1 warp, the 120A aperture, 50 μ m particle diameters, 20 * 2.5cm), with methanol/water volume fraction 10%-90% linear gradient elution 160min, flow velocity is 15ml/min, collect the cut that methanol/water volume fraction 85-90% gradient elution gets off, again through HPLC preparation (YMC-PackODS-A chromatographic column particle diameter 5 μ m aperture 120A size 250 * 10mm), moving phase: A is volume fraction 10% acetonitrile solution mutually, B is volume fraction 90% acetonitrile solution mutually, 0-11min, the volume content of B phase is changed to 100% by 40%, 11-16min, the 100%B phase, 16-17min, the volume content of B phase is changed to 40% by 100%, 17-23min 40%B phase, flow velocity 2.5ml/min, detect wavelength 263nm, and the cut that the collection retention time is 22.0min, obtain compound 1 (2.5mg), and through the Structural Identification analysis, its structure is suc as formula shown in (I), and wherein R is:
Fr.1-2 is through Preparative TLC chromatography (20*20cm), developping agent is the chloroform-methanol that volume ratio is 30: 1, collect the cut that the Rf value is 0.5, again through HPLC preparation (YMC-Pack ODS-A chromatographic column particle diameter 5 μ m aperture 120A size 250 * 10mm), moving phase: A is volume fraction 10% acetonitrile solution mutually, B is volume fraction 90% acetonitrile solution mutually, 0-9min, B phase volume content is changed to 100% by 40%, 9-17min, 100%B phase, 17-18min, B is changed to 40%, 18-26min 40%B phase by 100%; Flow velocity 2.5ml/min, the detection wavelength is 263nm, and the cut that to collect retention time be 21.3min, obtain compound 2 (11.5mg), and through the Structural Identification analysis, its structure is suc as formula shown in (I), R=H wherein, called after lobophorinF.
Four, compound 1 and 2 Determination of Antibacterial Activity
Adopt streptococcus aureus (Staphylococcus aureus ATCC 29213), bacillus thuringiensis (Bacillus thuringensis), three kinds of bacteriums of enterococcus faecalis (Enterococcus faecalis ATCC 29212), as indicator, carry out the MIC pH-value determination pH.
Streptococcus aureus and bacillus thuringiensis are used Mueller-Hinton (MH) broth culture to cultivate, and the enterococcus faecalis heart leach liquor substratum (Brain heart infusion broth) that makes to require mental skill is cultivated.The mensuration of MIC, with reference to the National Committee for Clinical Laboratory Standards method, is used micro-broth dilution method (broth microdilution method) to measure the MIC value of compound to each indicator.
The preparation of antibacterials stock solution: precision takes each sample, uses the DMSO through 0.22 μ m filtering with microporous membrane to make solvent, is configured to 5.12mg/ml.The antibacterials stock solution prepared is stored in 4 ℃ of refrigerators.
The preparation of MIC plate: aseptic technique, the compound solution of different concns after 2 doubling dilutions is added to respectively in 96 aseptic hole transparent polystyrene microwell plates, the 1st to the 11st hole adds compound, and the 12nd hole adds 10 μ l DMSO as growth control.Every processing arranges 3 repetitions.
Indicator preparation: prepare concentration with growth method and be equivalent to 5 * 10
8the bacteria suspension of CFU/ml, after meat soup dilution in 1: 1000, making every hole make final volume is 100 μ l, and the final concentration of the 1st hole to the 11 hole compounds (compound 1 or 2) is respectively 128,64,32,16,8,4,2,1,0.5,0.25,0.125 μ g/ml.In the rearmounted 37 ℃ of incubators of sealing, hatch the 16-20h observations.
The result judgement: with visual inspection, in aperture, the lowest concentration of drug of bacteria growing inhibiting is MIC fully, the results are shown in Table 2.Result shows that lobophorin E and lobophorin F have antibacterial activity to Bacillus subtillis, and the MIC value is between 2-8 μ g/ml.Lobophorin F also has better inhibition activity to streptococcus aureus and enterococcus faecalis in addition, and the MIC value is 8 μ g/ml.Lobophorin E and lobophorin F have bacteriostatic activity as can be seen here, can be applicable to prepare antibacterials, for developing antibiotic new drug, provide candidate compound.
Five, the antitumor cytolytic activity of lobophorin F
Using human breast cancer cell strain (MCF-7Cells), National People's Congress's sclc cell line (NCI-H460), human glioma cells strain (SF-268) as the subject cell strain, lobophorin F is carried out to the cytotoxic activity test, experimental technique reference [Wu, Z.C.; Li, D.L.; Chen, Y.C.; Zhang, W.M., A new isofuranonaphthalenone and benzopyrans from the endophytic fungus Nodulisporium sp.A4 from Aquilaria sinensis.Helv.Chim.Acta 2010,93, (5), 920-924.]
Result is as shown in table 2, as can be seen from Table 2, and the IC of lobophorin F to three kinds of subject cell strains
50value, between 2.93-6.82 μ M, illustrates that lobophorin F has anti-tumor activity, for the exploitation anti-cancer agent provides candidate compound.
Bacteriostatic activity and the anti-tumor activity of table 2:lobophorin E and lobophorin F
anon-activity;
bdo not survey active
Claims (5)
1. microbiotic lobophorin E and lobophorin F, its structure is as shown in formula I:
Formula I
Lobophorin E, wherein R is:
Lobophorin F, wherein R=H.
2. the preparation method of a microbiotic lobophorin E claimed in claim 1 and lobophorin F, is characterized in that, is that preparation separates and obtains from the fermenting culture of streptomycete Streptomyces sp.SCSIO1127, and concrete steps are as follows:
A) prepare the fermenting culture of streptomycete SCSIO1127, the fermented liquid of this fermenting culture and mycelium are separated, fermented liquid extracts through butanone, and the butanone layer obtains extractum A after distillation and concentration; Mycelium is first used acetone extraction, and after leaching liquid reclaims acetone, remaining water mixed liquid is again with the butanone extraction, and the butanone layer obtains medicinal extract B after distillation and concentration;
B) extractum A and medicinal extract B are merged, through silica gel column chromatography, using the chloroform-methanol of volume ratio 100:0～0:100 as the eluent gradient wash-out, collect the cut Fr.1 that chloroform-methanol volume ratio 100:1 gradient elution gets off;
C) cut Fr.1 is through gel filtration chromatography, the chloroform-methanol that the volume ratio of usining is 1:1 is as the moving phase wash-out, successively obtain two inferior cut Fr1-1 and Fr.1-2, the standby chromatogram of compacting in the Fr.1-1 warp, with methanol/water volume fraction 10%-90% linear gradient elution 160min, flow velocity is 15ml/min, collect the cut that methanol/water volume fraction 85-90% gradient elution gets off, through HPLC, prepare again, moving phase: A is that volume fraction 10% acetonitrile solution is volume fraction 90% acetonitrile solution with B mutually mutually, 0-11min, the B phase content is changed to 100% by 40%, 11-16min, the 100%B phase, 16-17min, the B phase content is changed to 40% by 100%, the 17-23min40%B phase, flow velocity 2.5ml/min, detect wavelength 263nm, and the cut that the collection retention time is 22.0min, obtain lobophorin E, Fr.1-2 is through the Preparative TLC chromatography, and developping agent is the chloroform-methanol that volume ratio is 30:1, collects the cut that the Rf value is 0.5, through HPLC, prepare again, moving phase: A is volume fraction 10% acetonitrile solution mutually, and B is volume fraction 90% acetonitrile solution mutually, 0-9min, the B phase content is changed to 100% by 40%, 9-17min, 100%B phase, 17-18min, the B phase content is changed to 40%, 18-26min40%B phase by 100%, flow velocity 2.5ml/min, the detection wavelength is 263nm, the cut that the collection retention time is 21.3min, obtain lobophorin F,
The fermenting culture of the preparation streptomycete SCSIO1127 of described a) step is to prepare by the following method: by the streptomycete SCSIO1127 of activation access seed culture medium, 28 ° of C, 200rpm, cultivate 48h and make seed liquor, seed liquor is linked in fermention medium with 10% inoculum size, 28 ° of C, 200rpm, shaking culture 144h, and make fermenting culture, the formula of described seed culture medium and fermention medium is all to contain in every liter of substratum: bean powder 3g, yeast extract powder 3g, trehalose 10g, proline(Pro) 1g, beef extract 3g, glycerine 6ml, K
2hPO
40.3g, MgSO
47H
2o0.5g, FeSO
47H
2o0.1g, CaCO
32g, thick sea salt 30g, surplus is water, pH7.4.
3. preparation method according to claim 2, is characterized in that, the fermented liquid in described a) step extracts through butanone,
It is butanone extraction 4 times for fermented liquid, 2 times of volumes that the amount of institute's solubilizing agent is fermented liquid.
4.lobophorin E and the lobophorin F application in the preparation antibacterials.
5.lobophorin the application of F in preparing antitumor drug.
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