CN110106214A - A kind of extracting method and application of macrolides compound - Google Patents
A kind of extracting method and application of macrolides compound Download PDFInfo
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- CN110106214A CN110106214A CN201910454779.7A CN201910454779A CN110106214A CN 110106214 A CN110106214 A CN 110106214A CN 201910454779 A CN201910454779 A CN 201910454779A CN 110106214 A CN110106214 A CN 110106214A
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- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
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Abstract
The present invention relates to organic extractive technique fields, provide a kind of extracting method of macrolides compound: carrying out fermented and cultured to streptomycete, obtain tunning；Silica gel column chromatography is carried out to the tunning, the 2nd fraction is collected after elution；2nd fraction is subjected to reversed-phase silica gel column chromatography, the 2.3rd fraction is collected after elution；2.3rd fraction is subjected to gel chromatography separation, obtains 2.3.1 fraction；The 2.3.1 fraction is subjected to silica gel column chromatography, obtains macrolides compound after elution.The present invention also provides the macrolides compounds that the method described in above-mentioned technical proposal is extracted to prepare the application in the drug for inhibiting PTP 1B, and the macrolides compound is to PTP1B with certain inhibitory activity, IC50It is 140 μM.
Description
Technical field
The present invention relates to organic extractive technique field more particularly to a kind of extracting method of macrolides compound and answer
With.
Background technique
As the improvement of people's living standards, the quantity of global diabetes patient rises year by year, the year two thousand thirty is expected to reach
5.52 hundred million.The pathogenic factor of diabetes is complicated, is typically due to h and E factor (such as obesity, age, modern way of life
Deng) interaction caused by.Diabetes are generally divided into two kinds of I type and II type, the morbidity of type II diabetes mainly due to
Body insulin sensitivity reduces or defect of insulin secretion, and thus early period mainly passes through the treatment of diabetes and directly adjusts
Save insulin.Although drug acarbose and Miglitol of some treatment diabetes etc. are in the clinical application of diabetes at present
There is good therapeutic effect.But these drugs can largely cause the adverse reactions such as abdominal pain, abdominal distension, diarrhea, Nausea and vomiting
(Chen Z,Hao J,Wang L,Wang Y,Kong F,Zhu W.Newα-glucosidase inhibitors from
marine algae-derived Streptomyces sp.OUCMDZ-3434.Sci.Rep.2016,6,20004).With right
The understanding of the pathogenesis of diabetes, signal path is ripe day by day, and sight is gathered in signal and led to by more and more researchers
Target treatment in road.In numerous signal paths, PTP 1B (PTP1B) is most widely used, most classic
One of target spot, PTP1B be insulin transduction signal negative growth factor (S, Curchod M L, Gobert R P,
Arkinstall S,Huijstuijnen R H et al.Identification of tyrosine
phosphatasesthat dephosphorylate inseulin receptor.A brute force approach
Based on " substratetrapping " mutants.J.Biol.Chem.2000,275 (13): 9792-9796), it is treatment
New target spot (the Cicirelli M F.Microinjection of a proteintyrosine of type II diabetes
phosphatase inhibits insulin action in Xenopus oocytes.P.Nati.Acad.Sci.USA,
1990,87(14):5514-5517).But at present for the therapeutic substance of such novel target spot, there has been no correlative studys.
Summary of the invention
The purpose of the present invention is to provide a kind of extracting method of macrolides compound and applications.
The present invention provides a kind of extracting methods of macrolides compound, comprise the following steps:
(1.1) fermented and cultured is carried out to streptomycete, obtains tunning；
(2.1) silica gel column chromatography is carried out to the tunning, the 2nd fraction is collected after elution；
(2.2) the 2nd fraction is subjected to reversed-phase silica gel column chromatography, the 2.3rd fraction is collected after elution；
(2.3) the 2.3rd fraction is subjected to gel chromatography separation, obtains 2.3.1 fraction；
(2.4) the 2.3.1 fraction is subjected to silica gel column chromatography, obtains macrolides compound after elution；
Shown in the structural formula of the macrolides compound such as formula (1):
Preferably, eluant, eluent system used in the step 2.1 is petroleum ether-ethyl acetate.
Preferably, in the step 2.1, by petroleum ether: in terms of ethyl acetate, the volume gradient of the eluant, eluent is 10:1,
8:1,6:1,4:1,2:1,1:1,1:2.
Preferably, eluant, eluent system used in the step 2.2 is methanol-water.
Preferably, the volume gradient of methanol is 30~100% in the step 2.2 eluant, eluent system.
Preferably, gel chromatography is methanol gel chromatography in the step 2.3.
Preferably, eluant, eluent system used in the step 2.4 is petroleum ether-ethyl acetate.
Preferably, in the step 2.4, by petroleum ether: in terms of ethyl acetate, the volume gradient of the eluant, eluent is 3:1,2:
1,1:1.
The present invention also provides the macrolides compounds that the method described in above-mentioned technical proposal is extracted to prepare
Inhibit the application in the drug of PTP 1B.
The present invention provides a kind of extracting methods of macrolides compound, comprise the following steps: (1.1) are to streptomycete
Fermented and cultured is carried out, tunning is obtained；(2.1) silica gel column chromatography is carried out to the tunning, the 2nd is collected after elution and is evaporated
Point；(2.2) the 2nd fraction is subjected to reversed-phase silica gel column chromatography, the 2.3rd fraction is collected after elution；(2.3) by the described 2.3rd
Fraction carries out gel chromatography separation, obtains 2.3.1 fraction；(2.4) the 2.3.1 fraction is subjected to silica gel column chromatography, washed
Macrolides compound is obtained after de-.Extracting method of the present invention is easy to operate, easy to implement.
The present invention also provides the macrolides compounds that the method described in above-mentioned technical proposal is extracted to prepare
Inhibit the application in the drug of PTP 1B.By embodiment result it is found that in the big ring that the present invention extracts
Ester type compound has certain inhibitory activity, inhibiting rate 45.05%, IC to PTP1B50It is 140 μM, positive control drug bear
The IC of tartaric acid50It is 8 μM.
Detailed description of the invention
Fig. 1 is the half-inhibitory concentration of macrolides compound；
Fig. 2 is the combination of macrolides compound and PTP1B；
Fig. 3 is the combination of macrolides compound and PKC.
Specific embodiment
Below in conjunction with the embodiment in the present invention, the technical solution in the present invention is clearly and completely described.It is aobvious
So, described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based on the reality in the present invention
Example is applied, every other embodiment obtained by those of ordinary skill in the art without making creative efforts all belongs to
In the scope of protection of the invention.
The present invention provides a kind of extracting methods of macrolides compound, comprise the following steps:
(1.1) fermented and cultured is carried out to streptomycete, obtains tunning；
(2.1) silica gel column chromatography is carried out to the tunning, the 2nd fraction is collected after elution；
(2.2) the 2nd fraction is subjected to reversed-phase silica gel column chromatography, the 2.3rd fraction is collected after elution；
(2.3) the 2.3rd fraction is subjected to gel chromatography separation, obtains 2.3.1 fraction；
(2.4) the 2.3.1 fraction is subjected to silica gel column chromatography, obtains macrolides compound after elution；
Shown in the structural formula of the macrolides compound such as formula (1):
The present invention carries out fermented and cultured to streptomycete, obtains tunning.
The present invention is not particularly limited the source of the streptomycete, using conventional streptomycete.In the present invention, institute
The morphological feature for stating streptomycete preferably includes: the bacterium colony of the streptomycete is dry, quality is fine and close, combines closely with culture medium；
The aerial hyphae of the streptomycete is fractured into spore, and spore is smooth.
In the present invention, the 16S rRNA gene order of the streptomycete is as shown in SEQ ID No.1, specifically:
TGGCTCAGGACGAACGCTGGCGGCGTGCTTAACACATGCAAGTCGAACGATGAACCGGTTTCGGCCGG
GGATTAGTGGCGAACGGGTGAGTAACACGTGGGCAATCTGCCCTGCACTCTGGGACAAGCCCTGGAAACGGGGTCT
AATACCGGATACGACGCGTTCCCGCATGGGATACGTGTGGAAAGCTCCGGCGGTGCAGGATGAGCCCGCGGCCTAT
CAGCTTGTTGGTGGGGTGATGGCCTACCAAGGCGACGACGGGTAGCCGGCCTGAGAGGGCGACCGGCCACACTGGG
ACTGAGACACGGCCCAGACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACAATGGGCGCAAGCCTGATGCAGCG
ACGCCGCGTGAGGGATGACGGCCTTCGGGTTGTAAACCTCTTTCAGCAGGGAAGAAGCGTGAGTGACGGTACCTGC
AGAAGAAGCGCCGGCTAACTACGTGCCAGCAGCCGCGGTAATACGTAGGGCGCAAGCGTTGTCCGGAATTATTGGG
CGTAAAGAGCTCGTAGGCGGCTTGTCGCGTCGGATGTGAAAGCCCGGGGCTTAACTCCGGGTCTGCATTCGATACG
GGCAGGCTAGAGTTCGGTAGGGGAGATCGGAATTCCTGGTGTAGCGGTGAAATGCGCAGATATCAGGAGGAACACC
GGTGGCGAAGGCGGATCTCTGGGCCGATACTGACGCTGAGGAGCGAAAGCGTGGGGAGCGAACAGGATTAGATACC
CTGGTAGTCCACGCCGTAAACGTTGGGAACTAGGTGTGGGCGACATTCCACGTTGTCCGTGCCGCAGCTAACGCAT
TAAGTTCCCCGCCTGGGGAGTACGGCCGCAAGGCTAAAACTCAAAGGAATTGACGGGGGCCCGCACAAGCGGCGGA
GCATGTGGCTTAATTCGACGCAACGCGAAGAACCTTACCAAGGCTTGACATACACCGGAAACATCCAGAGATGGGT
GCCCCCTTGTGGTCGGTGTACAGGTGGTGCATGGCTGTCGTCAGCTCGTGTCGTGAGATGTTGGGTTAAGTCCCGC
AACGAGCGCAACCCTTGTCCTGTGTTGCCAGCGGGTTATGCCGGGGACTCACAGGAGACTGCCGGGGTCAACTCGG
AGGAAGGTGGGGACGACGTCAAGTCATCATGCCCCTTATGTCTTGGGCTGCACACGTGCTACAATGGCCGGTACAA
TGAGCTGCGAAGCCGTGAGGTGGAGCGAATCTCAAAAAGCCGGTCTCAGTTCGGATTGGGGTCTGCAACTCGACCC
CATGAAGTCGGAGTCGCTAGTAATCGCAGATCAGCATTGCTGCGGTGAATACGTTCCCGGGCCTTGTACACACCGC
CCGTCACGTCACGAAAGTCGGTAACACCCGAAGCCGGTGGCCCAACCCTTGTGGAGGGAGCCGTCGAAGGTGGGAC
TGGCGATTGGGACGAAGTCGTAACA。
In the present invention, the streptomycete fermentation culture preferably includes following steps: streptomycete is inoculated in PDA and cultivated by a
In base, 3d is cultivated at 28 DEG C, obtains culture；
The obtained culture of the step a is inoculated in culture solution by b to ferment, and obtains tunning.
The present invention is inoculated in the inoculum concentration in culture solution to the culture and is not particularly limited, using traditional vaccination strepto-
The inoculum concentration of bacterium,
In the present invention, the culture solution preferably takes water as a solvent, and every liter includes: mannitol 20g, yeast extract 3g, corn
Starch 1g, glucose 10g, monosodium glutamate 10g, MgSO4·7H2O 0.3g、KH2PO40.5g and NaCl 33g.The present invention is to mentioned reagent
Source be not particularly limited, using routine.In the present invention, the culture solution after sterilizing preferably through reusing.This
Invention is not particularly limited the sterilising conditions of the culture solution, using the condition of conventional sterilant.In the present invention, described
The pH value of culture solution is natural ph.
In the present invention, the time of the fermentation is preferably 8d, and the temperature of the fermentation is preferably 28 DEG C.
Culture is preferably inoculated in the conical flask of 500mL by the present invention to ferment, and is preferably equipped in the conical flask
The culture solution of 150mL.Conical flask is preferably placed on shaking table and carries out shaker fermentation by the present invention.The present invention is to the shaker fermentation
Revolving speed is not particularly limited, using the revolving speed of conventional shaker fermentation streptomycete.
After obtaining tunning, the present invention carries out silica gel column chromatography to the tunning, and the 2nd fraction is collected after elution.
In the present invention, the silica gel column chromatography in the step 2.1 preferably depressurizes silica gel column chromatography, the reduced pressure combination ability
The routine techniques knowledge in domain is configured；Eluant, eluent system used in the step 2.1 is preferably petroleum ether-acetic acid second
Ester；By petroleum ether: in terms of ethyl acetate, the volume gradient of the eluant, eluent is preferably 10:1,8:1,6:1,4:1,2:1,1:1,1:
2。
In the present invention, the 2nd fraction, for the 2nd kind of fraction according to chronological order, being precipitated from silicagel column.
2nd fraction is carried out reversed-phase silica gel column chromatography by the present invention, and the 2.3rd fraction is collected after elution.In the present invention,
Eluant, eluent system used in the step 2.2 is preferably methanol-water；The volume of methanol in the step 2.2 eluant, eluent system
Gradient is preferably 30~100%, specifically can be 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, may be used also
Think 30%, 50%, 70%, 90%, 100%.
In the present invention, the 2.3rd fraction, according to chronological order, to be precipitated from silicagel column during this
3rd kind of fraction.
2.3rd fraction is carried out gel chromatography separation by the present invention, obtains 2.3.1 fraction.In the present invention, described
Gel chromatography is preferably methanol gel chromatography in step 2.3.
In the present invention, the 2.3.1 fraction, according to chronological order, to be precipitated from silicagel column during this
The 1st kind of fraction.
The 2.3.1 fraction is carried out silica gel column chromatography by the present invention, obtains macrolides compound after elution.At this
In invention, eluant, eluent system used in the step 2.4 is preferably petroleum ether-ethyl acetate；In the step 2.4, with stone
Oily ether: ethyl acetate meter, the volume gradient of the eluant, eluent are preferably 3:1,2:1,1:1.
The present invention also provides the macrolides compounds that the method described in above-mentioned technical proposal is extracted to prepare
Inhibit the application in the drug of PTP 1B.
The present invention is not particularly limited the dosage form of the drug, can medically be connect using macrolides compound
The dosage form received.The present invention is not particularly limited content of the macrolides compound in drug, using routine
Content.
In the following embodiments, raw material is commercial goods.
Embodiment 1
1 fermenting and producing
Streptomycete bacterial strain is seeded in PDA culture medium, cultivates 3d in the incubator at 28 DEG C, by cultured culture
It is inoculated in the conical flask (500mL) equipped with the 150mL culture solution after sterilizing, the shaker fermentation 8d at 28 DEG C, obtains fermentation and produce
Object.
Culture solution takes water as a solvent, and every liter includes: mannitol 20g, yeast extract 3g, corn pulp 1g, glucose 10g, monosodium glutamate
10g、MgSO4·7H2O 0.3g、KH2PO4 0.5g、NaCl 33g。
2 separation and purifications
Tunning is adopted, (volume ratio of tunning and ethyl acetate is 1:1) is extracted with ethyl acetate, filtered, decompression
Medicinal extract 8.3g is obtained after concentration.Gained medicinal extract is subjected to decompression silica gel column chromatography, with petroleum ether-ethyl acetate (volume fraction 10:
1,8:1,6:1,4:1,2:1,1:1,1:2) gradient elution, it collects, concentration (being evaporated solvent) is obtained by TLC combining data detection
To 5 fractions (Fr.1-Fr.5).Fr.2 (1.1g) by reversed-phase silica gel column chromatography (methanol/water system, 30%~100%, body
Fraction) after gradient elution, collects, through TLC combining data detection obtains 4 fraction Fr.2.1-2.4 after concentration.Fr.2.3(84mg)
Fr.2.3.1 is obtained by methanol gel chromatography.Fr.2.3.1 is through silica gel column chromatography with petroleum ether-ethyl acetate (3:1~1:1)
Gradient elution purifies to obtain compound 1 (7.4mg).Compound 1, faint yellow oily, [α]25 D-75(c 0.2,CHCl3), ESI-
MS:597.3 [M+H]+；1H and13C NMR data is shown in Table 1.
1. compound 1 of table1H and13C NMR data (600and 150MHz in CD3OD)
Embodiment 2
Embodiment 1 extracts the obtained 1 active test of anti-PTP1B of compound
1 laboratory sample and experimental method
The fusion protein of the label containing His is made using laboratory E. coli expression system, using optical absorption method in 96 holes
With para-nitro-pheneye phosphate (pNPP) for substrate in flat bottom clear plate, PTP1B enzyme activity is detected, substrate pNPP can be by PTP1B water
Solution, obtained product p-nitrophenol (PNP) have strong light absorption at 405nm, with microplate reader measurement hydrolysate in 405nm
The optical absorption intensity at place according to the activity change of the Assessment of Changes enzyme of hydrolysate optical absorption intensity and then assesses compound to it
Inhibitory effect.It is positive reference substance that ursolic acid is used in experimentation, and sample to be tested is dissolved with distilled water, saved at 4 DEG C.?
In the preliminary screening stage, concentration is 200 μ g/mL when 1 sample activity of compound is tested, and calculates the inhibiting rate of sample to be tested, right
In the apparent sample of active testing inhibitory effect, the relationship between its activity and dosage is further measured, determines that its half inhibits
Concentration (IC50), as a result as shown in Figure 1.Sample inhibiting rate calculation formula is as follows:
Wherein A0For blank group absorbance, A1For the absorbance of sample to be tested.
2 experimental results
Compound 1 has certain inhibitory activity, inhibiting rate 45.05%, IC to PTP1B50It is 140 μM, it is positive right
According to the IC of medicine ursolic acid50It is 8 μM.
Embodiment 3
Compound and PTP1B, PKC, transactional analysis
It carries out target spot fishing from this laboratory albumen database using the method that target spot is fished first to take, discovery compound can
And PTP1B, PKC, HMGCoA reductase, COX2 exist specificity combination, further using Autodock vina 1.1.2 into
Row molecular Docking Study.The structure for drawing small molecule with 14.0 software of ChemBioDraw Ultra first, is then used
14.0 software of ChemBio3D Ultra is translated into three-dimensional structure, and energy-optimised using the progress of the field of force MMFF94, then
PDBQT format is converted into AutodockTools 1.5.6.To the combination mould of albumen and small molecule in Autodock vina
Formula carries out simulation and forecast.Mapping and interpretation of result are carried out with PyMoL 1.7.6 finally, choosing the highest conformation of marking value.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Sequence table
<110>Guangxi National Univ.
Chinese Marine University
<120>extracting method and application of a kind of macrolides compound
<141> 2019-05-28
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 1461
<212> DNA
<213>artificial sequence (2 Ambystoma laterale x Ambystoma jeffersonianum)
<400> 1
tggctcagga cgaacgctgg cggcgtgctt aacacatgca agtcgaacga tgaaccggtt 60
tcggccgggg attagtggcg aacgggtgag taacacgtgg gcaatctgcc ctgcactctg 120
ggacaagccc tggaaacggg gtctaatacc ggatacgacg cgttcccgca tgggatacgt 180
gtggaaagct ccggcggtgc aggatgagcc cgcggcctat cagcttgttg gtggggtgat 240
ggcctaccaa ggcgacgacg ggtagccggc ctgagagggc gaccggccac actgggactg 300
agacacggcc cagactccta cgggaggcag cagtggggaa tattgcacaa tgggcgcaag 360
cctgatgcag cgacgccgcg tgagggatga cggccttcgg gttgtaaacc tctttcagca 420
gggaagaagc gtgagtgacg gtacctgcag aagaagcgcc ggctaactac gtgccagcag 480
ccgcggtaat acgtagggcg caagcgttgt ccggaattat tgggcgtaaa gagctcgtag 540
gcggcttgtc gcgtcggatg tgaaagcccg gggcttaact ccgggtctgc attcgatacg 600
ggcaggctag agttcggtag gggagatcgg aattcctggt gtagcggtga aatgcgcaga 660
tatcaggagg aacaccggtg gcgaaggcgg atctctgggc cgatactgac gctgaggagc 720
gaaagcgtgg ggagcgaaca ggattagata ccctggtagt ccacgccgta aacgttggga 780
actaggtgtg ggcgacattc cacgttgtcc gtgccgcagc taacgcatta agttccccgc 840
ctggggagta cggccgcaag gctaaaactc aaaggaattg acgggggccc gcacaagcgg 900
cggagcatgt ggcttaattc gacgcaacgc gaagaacctt accaaggctt gacatacacc 960
ggaaacatcc agagatgggt gcccccttgt ggtcggtgta caggtggtgc atggctgtcg 1020
tcagctcgtg tcgtgagatg ttgggttaag tcccgcaacg agcgcaaccc ttgtcctgtg 1080
ttgccagcgg gttatgccgg ggactcacag gagactgccg gggtcaactc ggaggaaggt 1140
ggggacgacg tcaagtcatc atgcccctta tgtcttgggc tgcacacgtg ctacaatggc 1200
cggtacaatg agctgcgaag ccgtgaggtg gagcgaatct caaaaagccg gtctcagttc 1260
ggattggggt ctgcaactcg accccatgaa gtcggagtcg ctagtaatcg cagatcagca 1320
ttgctgcggt gaatacgttc ccgggccttg tacacaccgc ccgtcacgtc acgaaagtcg 1380
gtaacacccg aagccggtgg cccaaccctt gtggagggag ccgtcgaagg tgggactggc 1440
gattgggacg aagtcgtaac a 1461
Claims (10)
1. a kind of extracting method of macrolides compound, which is characterized in that comprise the following steps:
(1.1) fermented and cultured is carried out to streptomycete, obtains tunning；
(2.1) silica gel column chromatography is carried out to the tunning, the 2nd fraction is collected after elution；
(2.2) the 2nd fraction is subjected to reversed-phase silica gel column chromatography, the 2.3rd fraction is collected after elution；
(2.3) the 2.3rd fraction is subjected to gel chromatography separation, obtains 2.3.1 fraction；
(2.4) the 2.3.1 fraction is subjected to silica gel column chromatography, obtains macrolides compound after elution；
Shown in the structural formula of the macrolides compound such as formula (1):
2. the method according to claim 1, wherein eluant, eluent system used in the step 2.1 is petroleum
Ether-ethyl acetate.
3. according to the method described in claim 2, it is characterized in that, in the step 2.1, by petroleum ether: in terms of ethyl acetate, institute
The volume gradient for stating eluant, eluent is 10:1,8:1,6:1,4:1,2:1,1:1,1:2.
4. the method according to claim 1, wherein eluant, eluent system used in the step 2.2 is methanol-
Water.
5. according to the method described in claim 4, it is characterized in that, the volume of methanol is terraced in the step 2.2 eluant, eluent system
Degree is 30~100%.
6. the method according to claim 1, wherein gel chromatography is methanol gel chromatography in the step 2.3.
7. the method according to claim 1, wherein eluant, eluent system used in the step 2.4 is petroleum
Ether-ethyl acetate.
8. the method according to the description of claim 7 is characterized in that in the step 2.4, by petroleum ether: in terms of ethyl acetate, institute
The volume gradient for stating eluant, eluent is 3:1,2:1,1:1.
9. the macrolides compound that method according to any one of claims 1 to 8 is extracted inhibits albumen junket in preparation
Application in the drug of propylhomoserin phosphatase 1 B.
10. the macrolides compound that method according to any one of claims 1 to 8 is extracted is preparing protein kinase C
Application in inhibitor.
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