CN110483397A - Three lienomycin class compounds process for production thereof, three lienomycin class compounds and application - Google Patents
Three lienomycin class compounds process for production thereof, three lienomycin class compounds and application Download PDFInfo
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Abstract
The invention discloses three lienomycin class compounds process for production thereof, three lienomycin class compounds and applications, more particularly to Trienomycin A production medium and method for separating and preparing, production medium, chemical structural formula, physicochemical property and the corresponding nuclear magnetic data of Trienomycin A are disclosed.Above compound is isolated in the solid fermentation culture for the cocoa streptomycete A Su subspecies for being isolated from Qinling Mountains main peak Mount Taibai north slope Moss soil fauna from one plant, strain number is H2S5, GenBank number is KF620296, culture presevation is in Xibei Univ. of Agricultural & Forest Science & Technology's chemistry and pharmaceutical college's Natural Medicine Chemistry research center, number No.CA20151025.
Description
Technical field
The invention belongs to biomedicine fields, are related to three lienomycin class compound (Trienomycin A) preparation methods, three
Lienomycin class compound and the high-yield culture medium of application and preparation method thereof.
Background technique
Natural products refers to the internal constituent of animal in nature, plant and microorganism, or produces from its metabolism
Chemical component isolated in object, with biological activity or pharmacological activity, natural products be used to treat as drug
With existing thousands of years of the history of prevention disease.Microorganism is one of diversity species the most abundant in nature, is that we are existing
And the following huge treasure-house for needing to go to further investigate and excavate.The biology in 20,000 multiple-microorganism sources having found
In active material, about 45% is generated by actinomyces, and 17% is generated by slime bacteria, and 38% is generated by fungi[1].So actinomyces
It is very important medicament sources, especially streptomycete.Although the extensive use of antibiotic, infectious disease is still that population in the world is dead
One of the main reason for dying.In the case where no new treatment, to the year two thousand fifty, the death rate as caused by the infection that can not be treated
It is expected that 10 times or more will be increased.The natural products for being isolated from bacterium has become the main source of clinically useful antibiotic[2]。
Ansamycin is a kind of macrolactams antibiotic from plant or microorganism, has extensive biology living
Property, such as antiviral and antitumor and antibacterium[3].Although ansamycins antibiotic type is few, physiological activity extensively,
Druggability is high, is a kind of antibiotic of significant.TrienomycinA is a kind of typical benzene ansamycin, by Umezawa
It is isolated in streptomycete for the first time[4], relative to other ansamycins compounds, it shows more significant anti-
Tumor promotion[5].Trienomycin A belongs to ansamycin family C-17 class compound, has to HeLa-S3 cervical cancer cell poison
Remarkable activity.The compound has relevant chemical synthesis research report at present, but because synthesis process is cumbersome and not environmentally protective
Make its structure of modification, in terms of progress it is slow.
[1]Berdy,J.Bioactive microbial metabolites.J Antibiot(Tokyo),2005.58
(1):1-26.
[2]Hover,B.M.et al.Culture-independent discovery of the malacidins as
calcium-dependent antibiotics with activity against multidrug-resistant Gram-
positive pathogens.Nature Microbiology.2018,3(4):415-422.
[3]Ya-Nan Song,Wen-Jing Zhang,Shu-Feng Bi,Rui-Hua Jiao,Ren-Xiang Tan
and Hui-Ming Ge.New ansamycin analogues from the mutant strainof Streptomyces
seoulensis.The Journal of Antibiotics.2015,68,757–759.
[4]Shinji Funayama,Kenji Okada,Kazuyo Iwasaki,Kanki Komiyama,
IwaoUmezawa.Structure of trienomycin A,anovelcytocidalansamycin
antibiotic.The Journal of Antibiotics.1985,38(8):1107-1109.
[5]IwaoUmezawa,Shinji Funayama,Kenji Okada,Kazuyo Iwasaki,Junko
Satoh,Kazuaki Masuda,Kanki Komiyama.Studies on a novel cytocidal antibiotic,
trienomycin A.Taxonomy,fermentation,isolation,and physico-chemical and
Antibiotics.1985,38:699~705. biological characteristics.The Journal of
Summary of the invention
The present invention derives from the cocoa of Qinling Mountains main peak Mount Taibai north slope Moss soil fauna by a kind of solid medium from one plant
Separation can be obtained big in the tunning of streptomycete A Su subspecies Streptomyces cacaoi subsp.asoensis H2S5
TrienomycinA is measured, theoretical yield may be up to 8.5mg/L.
Culture medium prescription of the invention are as follows: starch: 20g；KNO3:1g；K2HPO4:0.5g；NaCl:0.5g；MgSO4·
7H2O:0.5g；FeSO4·7H2O:0.01g；Yeast extract: 5g；Agar: 20g；Water: 1L；PH:7.2.
Condition of culture of the invention are as follows: 28 DEG C of temperature, humidity 45%, the time: 14 days.
TrienomycinA structural formula of the invention are as follows:
The physicochemical property of three lienomycin A of the invention is[6,7]:
C36H50N2O7, white powder；
[α]D 20=+174 (c 0.1, MeOH)；
IR(KBr):νmax=3400,1730,1650,1540,1205,1000cm-1；
HRESIMS:m/z 645.3607[M+Na]+；
The TrienomycinA is generated by cocoa streptomycete A Su subspecies H2S5 solid fermentation, specifically,
TrienomycinA is isolated in the solid fermentation culture medium of cocoa streptomycete A Su subspecies.
The solid fermentation medium treatment method of the cocoa streptomycete A Su subspecies H2S5 are as follows: by solid fermentation culture
Base is cut into small pieces (about 1cm2), with ethyl acetate: methanol: the extract liquor ultrasonic extraction of acetic acid=80:15:5 (volume ratio) five times,
It is extracted after concentration with petroleum ether and methanol 1:1, it is to be separated after methanol is mutually concentrated.
Specific preparation method, including the methanol after the above concentration is mutually passed through column chromatography for separation
10 fractions are successively obtained, are fraction A, fraction B ... fraction J by fraction outflow serial number, fraction F is using column
Chromatography obtains 3 fractions, is fraction F1, fraction F2 by fraction outflow serial number, fraction F3, fraction F2 is through high-speed counter-current
Isolated 22 fractions of chromatography are fraction F2.1, fraction F2.2 ... fraction F2.22, fraction by fraction outflow serial number
F2.12 is TrienomycinA；
The TrienomycinA theoretical yield is up to 8.5mg/L, actual production 7.2mg/L.
A kind of three lienomycin class compounds, the three lienomycin class compounds are prepared into through method of the present invention
It arrives.
The three lienomycin class compounds that the present invention is prepared are used to prepare the application for the treatment of uterine neck cancer drug.
[6]Shinji Funayama,Kenji Okada,Kazuyo Iwasaki,Kanki Komiyama,
IwaoUmezawa.Structure of trienomycin A,anovelcytocidalansamycin
antibiotic.The Journal of Antibiotics.1985,38(8):1107-1109.
[7]Shinji Funayama,Kenji Okada,Kazuyo Iwasaki,Kanki Komiyama,
IwaoUmezawa.Structure of trienomycin A,B and C,novelcytocidalansamycin
antibiotics.The Journal of Antibiotics.1985,38(12):1677-1683.
Detailed description of the invention
Fig. 1 is Trienomycin A standard items HPLC figure；
Fig. 2 is Trienomycin A Specification Curve of Increasing figure；
Fig. 3 is the elution order schematic diagram of fraction A-J；
Fig. 4 is the hydrogen spectrogram of Trienomycin A；
Fig. 5 is the carbon spectrogram of Trienomycin A；
Wherein the arrow in Fig. 1-3 indicates the flow direction of mobile phase, and label represents the number of each fraction；
The present invention is illustrated below in conjunction with specification drawings and specific embodiments.
Specific embodiment
The compound of the present invention TrienomycinA is from one plant from Qinling Mountains main peak Mount Taibai north slope Moss soil fauna
The side that cocoa streptomycete A Su subspecies Streptomyces cacaoi subsp.asoensis H2S5 passes through solid fermentation culture
Method is isolated.Bacteria strain number is H2S5, and GenBank number is KF620296, and the bacterium is by Xibei Univ. of Agricultural & Forest Science & Technology
The separation identification of Xue Quanhong seminar, resource environment institute, culture presevation is in Xibei Univ. of Agricultural & Forest Science & Technology's chemistry and pharmaceutical college's crude drug
Object chemistry research center, number No.CA20151025.The bacterial strain is documented in " micro- in the 5 kinds of habitats of north slope of Qinling Mountains main peak Mount Taibai
Biota and Antagonistic Actinomycetes the Study on Resources "[8], Wang Dongsheng etc. in " Journal of Northwest Sci Tech University of Agriculture and Forestry " 2014, and applies
People promises to undertake in term of a patent, freely provides the bacterial strain for the public.
The preservation and activation culture condition of the cocoa streptomycete A Su subspecies are as follows: preservation of bacteria strain used medium is that TSB is oblique
Face culture medium.Activated spawn: strain is inoculated in TSB plate, is activated 3 days in 28 DEG C, until covering with bacterium colony on plate.TSB training
Feeding based formulas: tryptone, 1.5%；Soy peptone, 0.5%；Sodium chloride, 0.5%；pH7.2.
Bibliography:
[8] microbiota and Antagonistic Actinomycetes the Study on Resources in 5 kinds of habitats of the Qinling Mountains Wang Dongsheng main peak Mount Taibai north slope
[D] Xibei Univ. of Agricultural & Forest Science & Technology, 2014.
One, the processing method of culture medium of the invention, the assay and its method for separating and preparing of TrienomycinA:
1, experimental material
Culture medium: starch: 20g；KNO3:1g；K2HPO4:0.5g；NaCl:0.5g；MgSO4·7H2O:0.5g；FeSO4·
7H2O:0.01g；Yeast extract: 5g；Agar: 20g；Water: 1L；PH:7.2.
Reagent and instrument: common organic solvent: chloroform, methanol, ethyl acetate, petroleum ether, acetone etc. are industry
Reagent uses steam again after.Organic solvent: n-hexane, chromatography methanol, the views such as chromatography acetonitrile actually use situation using analyze it is pure or
Chromatography pure reagent.Below unless otherwise specified, reagent dosage is volume ratio.
Common instrument: III type of polarimeter Rudolph Autopol；High performance liquid chromatograph: Waters 1525；Ultraviolet light
Spectrometer: Thermo Evolution-300 type；Nuclear magnetic resonance: BrukerAvance III 500 (using TMS as internal standard)；Low resolution matter
Spectrometer: Thermo Fisher LTQ Fleet type.The semi-preparative high-speed counter-current chromatograph of enhanced edition 300mL (Jiangyin adverse current science and technology
Co., Ltd)；Rotary Evaporators: B ü chiRotavapor R-101, R-3HB type；Low-temperature cooling fluid circulating pump: DLSB-10/20
Type (Zhengzhou Greatwall Scientific Industrial & Trading Co., Ltd.)；Multiplex vavuum pump of circulating water type: III type of SHB- (the limited public affairs of Zhengzhou Great Wall science, industry and trade
Department)；Superclean bench: SW-OJ-2F type (SuZhou Antai Air Tech Co., Ltd., Su Jing group)；Vertical steam sterilizer (on
Medical Equipment Plant, Hai Boxun Industrial Co., Ltd.).Column chromatography silica gel (100-200 mesh, 200-300 mesh and 300-400 mesh) and thin
Layer chromatographic silica gel (silica gel H) is Haiyang Chemical Plant, Qingdao's production；Liquid-phase chromatographic column: 5 μm of C18 of Hypersil BDS (250 ×
4.6 and 250×10；Thermo)；The reversed silica gel of hydroxypropyl sephadex Sephadex LH-20 and RP-C18 is
The production of Merck company.
The fermented and cultured of 1.1 cocoa streptomycete A Su sp. strain H2S5 and its processing method of culture medium:
Cocoa streptomycete A Su sp. strain activation method: picking H2S5 mycelium lines TSB solid from glycerol tube
On plate, cultivated 3 days in 28 DEG C；H2S5 single bacterium on picking TSB plate is fallen in TSB fluid nutrient medium, and 28 DEG C, 130rpm training
It supports 3 days.TSB Liquid Culture based formulas: tryptone, 1.5%；Soy peptone, 0.5%；Sodium chloride, 0.5%；Water: 1L, pH
7.2。
Cocoa streptomycete A Su sp. strain fermentation culture conditions: the culture solution of activated H2S5 is pressed to 3% inoculation
In the culture dish for measuring the 150mm × 150mm for being inoculated in the culture medium of solid fermentation containing 100mL, with spreading rod even spread, two layers of guarantor
Fresh film seals culture dish, and culture 14 days is inverted in 28 DEG C, 45% humidified incubator.The formula of solid fermentation culture medium are as follows:
Starch: 20g；KNO3:1g；K2HPO4:0.5g；NaCl:0.5g；MgSO4·7H2O:0.5g；FeSO4·7H2O:0.01g；Yeast
Extract: 5g；Agar: 20g；Water: 1L；PH:7.2.It ferments respectively three times, fermentation volume is respectively as follows: 5L, 7L, 12L, has fermented
Solid fermentation culture medium is cut into small pieces (about 1cm by Cheng Hou2), with ethyl acetate: methanol: acetic acid=80:15:5 (volume ratio)
Extract liquor extracts five times, is extracted after concentration with petroleum ether and methanol 1:1, to be separated after methanol is mutually concentrated.
The extraction of 1.2TrienomycinA separates:
Methanol Xiang Jingzhu chromatographic grade elution to be separated obtained in 1.1 is successively obtained into 10 fractions and (is specifically shown in figure
It 3) is, fraction A, fraction B ... fraction J by fraction outflow serial number, chromatographic column RP-18, condition of gradient elution is methanol-water
(10%-100%)；Isolated 3 fractions after fraction F is eluted using gel column LH-20 (solvent is methanol), by distillate flow
Serial number is fraction F1, fraction F2, fraction F3 out, and fraction F2 is through isolated 22 fractions of high-speed countercurrent chromatography, by evaporating
It is TrienomycinA, fraction that serial number, which is distributed, as fraction F2.1, fraction F2.2 ... fraction F2.22, fraction F2.12
The acquisition amount of F2.12 is 52.5mg；The dicyandiamide solution of high-speed countercurrent chromatography is n-hexane: ethyl acetate: methanol: water 4:6:
4:6 (volume ratio).
The assay of Trienomycin A in 1.3 tunnings:
Trienomycin A standard items (standard items HPLC figure is shown in Fig. 1) 1.3mg is accurately weighed, is configured to methanol dissolution
The mother liquor of 1mg/mL, mother liquor is for diluting configuration standard gradient liquid (mg/mL): 0.0125,0.025,0.05,0.075,0.1,
0.2.In the identical situation of sampling volume (10 μ L), its absorption value is measured at 271nm, with concentration (mg/mL) for abscissa,
With the detection peak area (S) of each gradient mark product Trienomycin A for ordinate, standard curve is drawn, standard curve side is obtained
Journey y=31159x-98.837 (R2=0.9964) (see Fig. 2).By concentrate obtained in 1.1 it is dry after, accurately weigh its matter
Amount calculates Trienomycin A content according to the standard curve of drafting.By taking 7L tunning as an example, 5.3mg fermentation is accurately weighed
Product crude product, when sampling volume is 10 μ L, it is 2182 that Trienomycin A peak area is measured at 271nm absorption, according to mark
It is 8.5mg/L that directrix curve equation, which can obtain theoretical yield, actually obtains 7.2mg/L.
The comparison of 1.4 basal medium TSB progress Trienomycin A fermented and cultured
Cocoa streptomycete A Su sp. strain activation method: picking H2S5 mycelium lines TSB solid from glycerol tube
On plate, cultivated 3 days in 28 DEG C；H2S5 single bacterium on picking TSB plate is fallen in TSB fluid nutrient medium, and 28 DEG C, 130rpm training
It supports 3 days.TSB Liquid Culture based formulas: tryptone: 1.5%；Soy peptone: 0.5%；Sodium chloride: 0.5%；Water: 1L,
pH 7.2。
Cocoa streptomycete A Su sp. strain fermentation culture conditions: the culture solution of activated H2S5 is pressed to 5% inoculation
Amount is inoculated in the 250mL culture bottle of the fluid nutrient medium containing 100mLTSB, and 28 DEG C, 130rpm is cultivated 5 days.Do three in parallel,
It is 1L.After fermentation, isometric ethyl acetate is added, ultrasonic extraction is three times, 30 minutes every time, dense by ethyl acetate phase
It contracts to be determined.By taking wherein 1L as an example, 10mg tunning is accurately weighed, when sampling volume is 10 μ L, is surveyed at 271nm absorption
Obtaining Trienomycin A peak area is 2892, and can obtain theoretical yield according to calibration curve equation is 0.96mg/L, due to yield pole
It is low, later separation is not carried out.
After measured, the yield of basal medium TSB is only 0.96mg/L, (uses solid fermentation of the invention after optimization
Culture medium) output increased nearly 8 times.
Claims (9)
1. a kind of three lienomycin class compounds process for production thereof, the three lienomycin class compounds are Trienomycin A, special
Sign is that the Trienomycin A is isolated by the metabolin of cocoa streptomycete A Su subspecies H2S5.
2. three lienomycins class compounds process for production thereof according to claim 1, which is characterized in that described
Trienomycin A is isolated by the solid fermentation metabolin of cocoa streptomycete A Su subspecies H2S5.
3. three lienomycins class compounds process for production thereof as claimed in claim 2, which is characterized in that described cocoa streptomycete Ah
The culture medium prescription of the solid fermentation of Soviet Union subspecies H2S5 are as follows: starch 20g, KNO31g, K2HPO40.5g, NaCl0.5g,
MgSO40.5g, FeSO40.01g, yeast extract 5g, agar 20g, water 1L, pH=7.2.
4. three lienomycins class compounds process for production thereof as claimed in claim 2, which is characterized in that described cocoa streptomycete Ah
The cultivation temperature of the solid fermentation of Soviet Union subspecies H2S5 is 28 DEG C, and solid fermentation culture humidity is 45%.
5. three lienomycins class compounds process for production thereof as claimed in claim 2, which is characterized in that described cocoa streptomycete Ah
The incubation time of the solid fermentation of Soviet Union subspecies H2S5 is 14 days.
6. the three lienomycin class compounds process for production thereof as described in claim 2,3,4 or 5, which is characterized in that further including can
Can streptomycete A Su subspecies H2S5 solid fermentation product collect after, successively through organic solvent extraction and column chromatography for separation obtain 10
A fraction, by fraction outflow serial number be fraction A, fraction B ... fraction J, fraction F obtain 3 using column chromatography for separation and evaporate
Point, it is fraction F1, fraction F2 and fraction F3 by fraction outflow serial number, fraction F2 is through high-speed countercurrent chromatography isolated 22
A fraction is fraction F2.1, fraction F2.2 ... fraction F2.22 by fraction outflow serial number, and fraction F2.12 is described three
Lienomycin class compound.
7. three lienomycins class compounds process for production thereof as claimed in claim 6, which is characterized in that the organic solvent extraction
It include: volume ratio, ethyl acetate: methanol: acetic acid=80:15:5 extract liquor extracts solid fermentation product five times, it is concentrated
Be afterwards petroleum ether with volume ratio: methanol=1:1 extraction retains methanol phase；
Methanol mutually chromatographs to obtain 10 fractions, chromatographic column RP-18 through column, and condition of gradient elution is that methanol-water is 10%-
100%；
Fraction F affords 3 fractions using gel column LH-20, methanol；
The dicyandiamide solution of high-speed countercurrent chromatography is n-hexane: ethyl acetate: methanol: water=4:6:4:6, volume ratio.
8. a kind of three lienomycin class compounds, which is characterized in that the three lienomycin class compounds are any through claim 1-7
Method described in claim is prepared.
9. the application that three lienomycins class compound according to any one of claims 8 is used to prepare treatment uterine neck cancer drug.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0189330A2 (en) * | 1985-01-25 | 1986-07-30 | The Kitasato Institute | Antitumor antibiotics and their production |
| JPH08283156A (en) * | 1995-04-10 | 1996-10-29 | Nippon Steel Corp | Antiinflammatory agent |
| CN107382863A (en) * | 2017-06-30 | 2017-11-24 | 西北农林科技大学 | Three lienomycin class compounds, preparation method and the application for treating prostate cancer |
-
2018
- 2018-08-14 CN CN201810921531.2A patent/CN110483397A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0189330A2 (en) * | 1985-01-25 | 1986-07-30 | The Kitasato Institute | Antitumor antibiotics and their production |
| JPH08283156A (en) * | 1995-04-10 | 1996-10-29 | Nippon Steel Corp | Antiinflammatory agent |
| CN107382863A (en) * | 2017-06-30 | 2017-11-24 | 西北农林科技大学 | Three lienomycin class compounds, preparation method and the application for treating prostate cancer |
Non-Patent Citations (1)
| Title |
|---|
| 周杰 主编: "《动物医学实验教程 预防兽医学分册 第2版》", 31 August 2017 * |
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