CN103694127A - Compound produced by Streptomyces labedae, as well as preparation method and application of compound - Google Patents
Compound produced by Streptomyces labedae, as well as preparation method and application of compound Download PDFInfo
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Abstract
The invention provides two new compounds with anti-tumor activity, as well as a preparation method and application of the new compounds. The invention further provides Streptomyces labedae for producing the two new compounds, wherein the preservation number is CGMCC No.8025; the Streptomyces labedae was preserved in China General Microbiological Culture Collection Center on August 14, 2013. The corresponding structural formulas of the two new compounds are obtained through authentication, and the two new compounds have anti-tumor activity through detection.
Description
Technical field
What the present invention relates to is a kind of medical technical field, particularly relates to compound that a kind of streptomyces bacterial classification produces and the preparation method and application of this compound.
Background technology
Streptomyces (streptomyces), the most high actinomycetes, there is well-developed branch mycelia, mycelia is without tabula, and that has reported has an over thousands of kind, is distributed widely in that organism is abundant, in acidity and the moderate soil of water content, battalion's aerobic saprogenesis, complicated organic mineralising in soil is played a significant role, and is most important production of antibiotics bacterium, such as Streptomycin sulphate, tsiklomitsin, erythromycin, Liu Suanyan NEOMYCIN SULPHATE, kantlex and jingganmycin etc.What have produces industrial proteolytic enzyme, glucose isomerase or vitamin B12 etc.
Cancer or tumour are animals and humans main causes of death, suffer from the antineoplastic agent of cancer patient in order to obtain effective and safe being applied to, and people have paid and paid huge effort.Finding anti-tumor active substance is one of microbial metabolites study hotspot.Less about the research report of gram positive bacterium Streptomyces labedae meta-bolites at present.
Summary of the invention
The present invention is directed to prior art above shortcomings, propose compound that a kind of streptomyces bacterial classification produces and the preparation method and application of this compound, by can be used in and prepare antitumor drug after fermentation.
The present invention is achieved by the following technical solutions:
The present invention's separation from physical environment has obtained streptomyces (Streptomyces labedae) HCCB11431 bacterial strain, this bacterial strain is deposited in the China Committee for Culture Collection of Microorganisms's common micro-organisms center (CGMCC) in Institute of Microorganism, Academia Sinica on August 14th, 2013, preservation date is on August 14th, 2013, first deposit number CGMCC No.8025 the present invention provide two kinds of compounds with anti-tumor activity, next provides produces this two kinds of streptomyces bacterial strains with the compound of anti-tumor activity, the present invention also provides the preparation method and application of above-mentioned two kinds of compounds.
First the present invention provides the compound shown in a kind of formula (A) with anti-tumor activity,
Wherein R be H Huo ?CH
3.
Compound shown in above-mentioned formula (A) comprises as shown in the formula the compound shown in the compound shown in (I) and formula (II).
Compound shown in the formula (I) that streptomyces CGMCC No.8025 bacterial strain of the present invention (Streptomyces labedae) produces, its structural formula is as follows:
（I）
Compound shown in above-mentioned formula (I), chemical name is: 3 ?(3 ?Yi Suan Ji ?4 ?Jia Yang Ji ?5 ?phenmethyl) ?2 ?alanine; 3 ?(3 ?acetoxy ?4 ?methoxy ?5 ?methylphenyl) ?2 ?aminopropanoic acid, the compound shown in this formula (I) has anti-tumor activity after testing.
Compound shown in above-mentioned formula (I), through positive ion electrospray spraying mass spectrometric detection, shows that its quasi-molecular ion peak is: m/z268.1166[M+H]+, molecular formula is C
13h
17nO
5through infrared spectra, BrukerAvance II ?after hydrogen spectrum, carbon spectrum and the two-dimensional spectrum of being correlated with (HMQC spectrum, H ?H COSY spectrum, HMBC spectrum) of 400 type NMR spectrometer with superconducting magnet working samples detect, by resolving, the ownership of having determined all carbon atoms of this compound and hydrogen atom, has obtained the structure of this compound as shown in the formula (I).
The present invention also provides the compound shown in the another kind of formula (II) that streptomyces CGMCC No.8025 bacterial strain (Streptomyces labedae) produces, and its structural formula is as follows:
（II）
Compound shown in above-mentioned formula (II), chemical name is: 3 ?(3 ?Yi Suan Ji ?4 ?Qiang Ji ?5 ?phenmethyl) ?2 ?alanine; 3 ?(3 ?acetoxy ?4 ?hydroxy ?5 ?methylphenyll ?2 ?aminopropanoic acid, the compound shown in this formula (II) has anti-tumor activity after testing.
Compound shown in above-mentioned formula (II), through positive ion electrospray spraying mass spectrometric detection, shows that its quasi-molecular ion peak is: m/z254.1022[M+H]+, molecular formula is C
12h
15nO
5, adopt BrukerAvance II ?400 type NMR spectrometer with superconducting magnet measured hydrogen spectrum and the Infrared spectroscopy of sample, and relatively find with the H spectrum of the compound shown in formula (I), except oxygen methyl (δ
h3.73), outside disappearing in the compound shown in formula (II), other H spectrum data are basically identical, show this compound than the compound shown in formula (I) few oxygen methyl, identical with shown in formula (I) of other structure, is a kind of new compound.By resolving, determined the ownership of this compound hydrogen atom, obtained the structure of the compound shown in formula (II).
The present invention also provides the streptomyces bacterial strain (Streptomyces labedae) of producing above-mentioned two kinds of compounds, this bacterial strain is deposited in the China Committee for Culture Collection of Microorganisms's common micro-organisms center (CGMCC) in Institute of Microorganism, Academia Sinica on August 14th, 2013, preservation date is on August 14th, 2013, deposit number CGMCC No.8025.
The cultural method of streptomyces CGMCC No.8025 bacterial strain of the present invention is as follows:
Seed culture medium: glucose 20g, glycerine 20g, Zulkovsky starch 20g, soyabean cake 30g, KH
2pO
40.2g, MgSO
47H
2o0.2g and water 1L;
Fermention medium: glucose 8g, soybean cake powder 22g, W-Gum 40g, MgSO
47H
2o1g, KH
2pO
40.2g, NaCl2g and water 1L.
Fermenting process: first by streptomyces HCCB11431 inoculation in seed culture medium, shaking table is cultivated 2 days (condition is 28 ℃, 220r/min), as, again cultured seed is inoculated in to the fermention medium in 5L fermentor tank with 8% inoculum size, cultivate 5 ?7 days, the temperature of described fermentation be 26 ?28 ℃.
The preparation method of the compound shown in the compound shown in formula of the present invention (I) and formula (II), comprises the steps:
(a), adopt solution culture fermentation streptomyces HCCB11431 bacterial strain, acquisition tunning;
(b), the tunning that adopts organic solvent extraction to obtain, underpressure distillation obtains extract;
(c), adopt organic solvent to extract the extract of acquisition, obtain extraction phase;
(d), the extraction phase of acquisition carried out to underpressure distillation obtain extract, then adopt and wear peace P680 chromatographic instrument and carry out separation;
(e), half preparative liquid chromatography makes the compound shown in the compound shown in described formula (I) and formula (II).
The extract that above-mentioned solution culture fermentation obtains is 5g altogether, with wearing peace P680 chromatographic instrument, carries out post separation, and adopting methanol/water is that eluting solvent carries out gradient elution, and preparation condition and the elution requirement thereof of two compounds are as follows:
According to the present invention, described in step (a) fermentation temperature be 26 ?28 ℃, the time be 5 ?7 days.The organic solvent that extracts tunning in step (b) is methyl alcohol; Described in step (c), the organic solvent of extraction is propyl carbinol, is extracted phase after n-butanol extraction.In step (d), described wearing pacified the separation of P680 chromatographic instrument, chromatography column be YMC ?ODS C ?18(5 μ m, 200250mm), adopt methanol/water to be that eluting solvent carries out gradient elution separation, 0～30min with 10% ?100% acetonitrile/water wash-out, flow velocity 8ml/min, collect 5.1 ?the cut of 6.3min, obtain study 50mg after concentrated; The study of 50mg is further carried out to half preparation with Agilent chromatographic instrument, and semipreparative column is Agilent ZORBAX SB-C18(5 μ m, 9.4mm*250mm), obtain the compound (1.8mg shown in formula (I); t
r=28.9min; 30% methanol/water isocratic elution for 0～30min, flow velocity 2ml/min) and the compound (1.9mg shown in formula (II); t
r22.0min).
The present invention also further provides a kind of pharmaceutical composition, contains the compound shown in the compound shown in formula (I) and/or formula (II); This pharmaceutical composition also further comprises pharmaceutically acceptable carrier or vehicle.
The present invention also provides a kind of antitumor drug, contains the compound shown in the compound shown in formula (I) and/or formula (II).
The present invention also provides the application of the compound shown in the compound shown in formula (I) and/or formula (II) in preparing antitumor drug.
Technique effect
Compared with prior art, streptomyces CGMCC No.8025 bacterial strain of the present invention, two kinds of compounds of its generation have anti-tumor activity after testing.Compound of the present invention (I) and/or compound (II) can be applicable to prepare in antitumor drug.
Accompanying drawing explanation
Fig. 1 is the mass spectrometric detection figure of the compounds of this invention 1.
Fig. 2 is the infrared spectrogram of the compounds of this invention 1.
Fig. 3 is the H spectrogram of the compounds of this invention 1.
Fig. 4 is the C spectrogram of the compounds of this invention 1.
Fig. 5 is the hsqc spectrum figure of the compounds of this invention 1.
Fig. 6 is the COSY spectrogram of the compounds of this invention 1.
Fig. 7 is the HMBC spectrogram of the compounds of this invention 1.
Fig. 8 is the mass spectrometric detection figure of the compounds of this invention 2.
Fig. 9 is the infrared spectrogram of the compounds of this invention 2.
Figure 10 is the H spectrogram of the compounds of this invention 2.
Embodiment
Below embodiments of the invention are elaborated, the present embodiment is implemented take technical solution of the present invention under prerequisite, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
The present embodiment comprises the following steps:
The cultural method of step 1, streptomyces CGMCC No.8025 bacterial strain is as follows:
Seed culture medium: glucose 20g, glycerine 20g, Zulkovsky starch 20g, soyabean cake 30g, KH
2pO
40.2g, MgSO
47H
2o0.2g and water 1L;
Fermention medium: glucose 8g, soybean cake powder 22g, W-Gum 40g, MgSO
47H
2o1g, KH
2pO
40.2g, NaCl2g and water 1L.
Fermenting process: first by streptomyces HCCB11431 inoculation in seed culture medium, shaking table is cultivated 2 days (condition is 28 ℃, 220r/min), again cultured seed is inoculated in to the fermention medium in 5L fermentor tank with 8% inoculum size, cultivate 5 ?7 days, the temperature of described fermentation be 26 ?28 ℃.
Above-mentioned streptomyces bacterial strain belongs to Streptomyces labedae, deposit number CGMCC No.8025, and preservation date is on August 14th, 2013.This bacterial strain is deposited in the China Committee for Culture Collection of Microorganisms's common micro-organisms center (CGMCC) in Institute of Microorganism, Academia Sinica on August 14th, 2013.
Step 2, compound preparation, comprise the steps:
2.1) adopt solution culture fermentation streptomyces CGMCC No.8025 bacterial strain, its method and each amount of substance are identical with the cultural method of above-mentioned streptomyces CGMCC No.8025 bacterial strain, acquisition tunning;
2.2) tunning that adopts organic solvent extraction to obtain, underpressure distillation obtains extract;
2.3) adopt organic solvent to extract the extract of acquisition, obtain extraction phase;
2.4) extraction phase of acquisition is carried out to underpressure distillation and obtain extract 5g, then adopt and wear peace P680 chromatographic instrument and carry out separation;
2.5) half preparative liquid chromatography makes
shown compound and
shown compound.
The extract that above-mentioned solution culture fermentation obtains is 5g altogether, with wearing peace P680 chromatographic instrument, carries out post separation, and adopting methanol/water is that eluting solvent carries out gradient elution, and preparation condition and the elution requirement thereof of two compounds are as follows:
Step 2.1) described in fermentation temperature be 26 ?28 ℃, the time be 5 ?7 days.
Step 2.2) organic solvent that extracts tunning in is methyl alcohol;
Step 2.3) described in, the organic solvent of extraction is propyl carbinol, is extracted phase after n-butanol extraction.
Step 2.4) in, described wearing pacified the separation of P680 chromatographic instrument, chromatography column be YMC ?ODS C ?18(5 μ m, 200250mm), adopt first alcohol and water to be that eluting solvent carries out gradient elution separation, the acetonitrile/water wash-out of 10% ?100% for 0～30min, flow velocity 8mL/min, collect 5.1 ?the cut of 6.3min, obtain study 50mg after concentrated; The study of 50mg is further carried out to half preparation with Agilent chromatographic instrument, and semipreparative column is Agilent ZORBAX SB-C18(5 μ m, 9.4mm*250mm), obtain compound (I) 1(1.8mg; t
r28.9min; 30% methanol/water isocratic elution for 0～30min, flow velocity 2mL/min) and compound (II) 2(1.9mg; t
r22.0min).Wherein the separation method of compound 1 is with compound 2.
The evaluation of step 3, compound:
3.1) evaluation of compound 1: the compound 1 that above-mentioned steps 2 is obtained is through positive ion electrospray spraying mass spectrometric detection, and its collection of illustrative plates as shown in Figure 1, shows that its quasi-molecular ion peak is: m/z268.1166[M+H]+, molecular formula is C
13h
17nO
5, through infrared spectra, detect its infrared spectra (IR:3440,3423cm as shown in Figure 2
?1on have and absorb the existence show to have amino or hydroxyl, 1630cm
?1on absorption show to have the existence of carbonyl, 1385,1122cm
?1the absorption at place shows to have the existence of aromatic nucleus), adopt BrukerAvance II ?400 type NMR spectrometer with superconducting magnet measured hydrogen spectrum, carbon spectrum and the two-dimensional spectrum of being correlated with (HMQC spectrum, H ?H COSY spectrum, HMBC spectrum) (this HMQC spectrum and H ?the H COSY position of composing auxiliary positioning H and C) of compound 1 sample, its nuclear magnetic data is as shown in table 1.
The NMR data sheet (MeOD, 400MHz) of table 1 compound 1
By above-mentioned detection, resolve, determined all carbon atoms of this compound 1 and the ownership of hydrogen atom, obtained the structure of this compound 1 as shown in the formula (I):
Above-claimed cpd (I) is a kind of new compound, its chemical name is: 3 ?(3 ?Yi Suan Ji ?4 ?Jia Yang Ji ?5 ?phenmethyl) ?2 ?alanine, 3 ?(3 ?acetoxy ?4 ?methoxy ?5 ?methylphenyll ?2 ?aminopropanoic acid.
3.2) evaluation of compound 2: the compound 2 that above-mentioned steps 2 is obtained is through positive ion electrospray spraying mass spectrometric detection, and its collection of illustrative plates as shown in Figure 8, shows that its quasi-molecular ion peak is: m/z254.1022[M+H]+, molecular formula is C
12h
15nO
5, adopt BrukerAvance II ?400 type NMR spectrometer with superconducting magnet measured the hydrogen spectrum of sample, its nuclear magnetic data is as shown in table 2.
The NMR data sheet of table 2 compound 2 (MeOD,, 400MHzz
| position | δ H(J?in?Hz) |
| 1 | ? |
| 2 | 4.57(dd,8.5,5.3) |
| 3α | 3.00(dd,13.9,5.1) |
| 3β | 2.78(dd,13.9,8.7) |
| 4 | ? |
| 5 | 6.53(s) |
| 6 | ? |
| 7 | ? |
| 8 | ? |
| 9 | 6.47(s) |
| 10 | ? |
| 11 | 1.94(s) |
| 12 | 2.17(s) |
As shown in Figure 9, the infrared spectra of compound 2 is almost close with compound 1 for the infrared spectra of compound 2, relatively finds, except oxygen methyl (δ by the H spectrum with compound 1
h3.73), outside disappearing in compound 2, other H spectrum data are basically identical, show this compound 2 than compound 1 few oxygen methyl, other structure is identical with compound 1, is new compound.Be tested and appraised parsing, determined the ownership of these compound 2 hydrogen atoms, obtained the structure of compound (II):
Above-mentioned compound (II) is a kind of new compound, and chemical name is: 3 ?(3 ?Yi Suan Ji ?4 ?Qiang Ji ?5 ?phenmethyl) ?2 ?alanine; 3 ?(3 ?acetoxy ?4 ?hydroxy ?5 ?methylphenyl) ?2 ?aminopropanoic acid.
Embodiment 2
Biological activity assay:
Tumor cell proliferation inhibition activity---mtt assay:
By logarithmic phase tumour cell, with micropipet, draw and remove supernatant, by appropriate PBS buffer solution for cleaning, remove the cell of top layer aging, with trypsin digestion and cell, the centrifugal 5min of 1000rpm, removes supernatant liquor.Add nutritive medium (containing 10% calf serum, 100U/ml penicillin and 100U/ml Streptomycin sulphate), make single-cell suspension liquid, with after blood counting chamber counting, according to 50,000/ml inoculation, get 100 μ l/ holes in 96 orifice plates, 96 orifice plates are placed in to the 5%CO of 37 ℃
2in incubator, cultivate 24h.The certain density compound (final concentration of DMSO is 1%) that DMSO is dissolved joins in cultured 96 orifice plate cells, is placed in the 5%CO of 37 ℃
2in incubator, cultivate 48h.Adopt MTT dyestuff to dye to viable cell, inferior daily Bio ?Rad680 microplate reader is measured OD value under wavelength 570nm, studies compound to inhibiting tumour cells ability.Negative control is 1% DMSO, positive control be 5 ?Fluracil; Each experiment repeats 3 times, calculating mean value.
Cell: MCF ?7(human breast cancer cell), PANC ?1 (human pancreatic cancer cell), Du ?145(prostate cancer cell).
By visible compound (I) formula of table 3, there is anti-tumor activity with the compound (II).
Table 3 compound is active to the inhibition of tumour cell
Claims (9)
1. there is the new compound shown in the formula (A) of anti-tumor activity,
wherein R be H Huo ?CH3.
2. the new compound shown in formula according to claim 1 (A), is characterized in that, the new compound shown in described formula (A) is produced by a kind of streptomyces (Streptomyces labedae) bacterial strain; The deposit number CGMCC No.8025 of described streptomyces bacterial strain.
3. a method of preparing the new compound shown in the formula (A) described in claim 1 or 2, comprises the steps:
(a), adopt solution culture fermentation streptomyces CGMCC No.8025 bacterial strain, acquisition tunning;
(b), the tunning that adopts organic solvent extraction to obtain, underpressure distillation obtains extract;
(c), adopt organic solvent to extract the extract of acquisition, be extracted phase;
(d), the extraction phase of acquisition carried out to underpressure distillation obtain extract, then adopt and wear peace P680 chromatographic instrument and carry out separation;
(e), adopt half preparative liquid chromatography to make the new compound shown in described formula (A);
Wherein, the new compound shown in described formula (A) comprises as shown in the formula the new compound shown in (I) with as shown in the formula the new compound shown in (II):
4. method according to claim 3, is characterized in that, in step (a), the process of described fermentation is as follows:
First by streptomyces CGMCC No.8025 inoculation in seed culture medium, shaking table is cultivated 2 days, the condition that wherein shaking table is cultivated is 28 ℃, 220r/min, again cultured seed is inoculated in to the fermention medium in 5L fermentor tank with 8% inoculum size, cultivate 5 ?7 days, the temperature of described fermentation be 26 ?28 ℃.
5. method according to claim 4, is characterized in that, the component of described seed culture medium and content are: glucose 20g, glycerine 20g, Zulkovsky starch 20g, soyabean cake 30g, KH2PO40.2g, MgSO47H2O0.2g and water 1L; The component of described fermention medium and content are: glucose 8g, soybean cake powder 22g, W-Gum 40g, MgSO47H2O1g, KH2PO40.2g, NaCl2g and water 1L.
6. method according to claim 3, is characterized in that,
The organic solvent that extracts tunning in step (b) is methyl alcohol;
In step (c), the organic solvent of described extraction is propyl carbinol;
In step (d), it is separated that peace P680 chromatographic instrument is worn in described employing, chromatography column be YMC ?ODS C ?18, adopt first alcohol and water to be that eluting solvent carries out gradient elution separation, 0～30min adopt 10% ?100% acetonitrile wash-out, flow velocity 8ml/min, collect 5.1 ?the cut of 6.3min, obtain study after concentrated;
In step (e), the study that step (d) is obtained further carries out half preparation, and semipreparative column is Agilent ZORBAX SB-C18, obtains the compound shown in the compound shown in described formula (I) and formula (II).
7. the application of the compound shown in formula according to claim 1 and 2 (A) in preparing antitumor drug.
8. the application of the compound shown in formula according to claim 7 (A) in preparing antitumor drug, it is characterized in that, the cell of described tumour be selected from human breast cancer cell MCF ?7, human pancreatic cancer cell PANC ?1 and prostate cancer cell Du ?one or more in 145.
9. pharmaceutical composition or an antitumor drug, described pharmaceutical composition or antitumor drug contain one or both in the compound shown in the formula (A) described in claim 1 or 2.
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| CN104974056A (en) * | 2015-07-20 | 2015-10-14 | 上海皓元生物医药科技有限公司 | Chiral resolution method for preparing high-purity intermediate of trabectedin |
| CN108102933A (en) * | 2018-02-28 | 2018-06-01 | 中国科学院微生物研究所 | One plant of white yellow black streptomycete bacterial strain and its application |
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| CN108102933A (en) * | 2018-02-28 | 2018-06-01 | 中国科学院微生物研究所 | One plant of white yellow black streptomycete bacterial strain and its application |
| CN108102933B (en) * | 2018-02-28 | 2020-01-07 | 中国科学院微生物研究所 | Streptomyces alboflavus strain and application thereof |
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