CN104031954B - A kind of preparation method of monoterpene dihydro-quinolinone alkaloid compound and its crystal and the application as marine antifoulant - Google Patents
A kind of preparation method of monoterpene dihydro-quinolinone alkaloid compound and its crystal and the application as marine antifoulant Download PDFInfo
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Abstract
A kind of preparation method of monoterpene dihydro-quinolinone alkaloid compound and its crystal and the application as marine antifoulant, Spawn incubation first is carried out to fungi Scopulariopsis sp. (TA01 33) during preparation, fermented and cultured is carried out to the fungi again, it is filtered to remove thalline, after filtrate concentration, it is extracted with ethyl acetate；Normal-phase silica gel column chromatography, the gel filtration chromatographies of Sephadex LH 20, HPLC high performance liquid chromatography are carried out successively, produce compound of formula I.The present invention provides a kind of marine organisms anti-fouling agent, it is characterised in that with compound of formula I, its pharmaceutically acceptable salt or its crystal of the present invention, for preventing and treating marine biofouling caused by barnacle attachment.
Description
Technical field
Alkalized the present invention relates to a kind of monoterpene dihydro-quinolinone (monoterpenoid-dihydroquinolone) biology
The preparation method and application of compound and its crystal, it is more particularly to a kind of to marine fouling organism barnacle Balanus
Amphitrite larvas have monoterpene dihydro-quinolinone alkaloid compound and its preparation side of crystal of extremely strong inhibitory activity
Method and application.
Background technology
Marine biofouling is that subduction is set in ocean for organic molecule, microorganism, animal, plant and their accessory substance
Apply the harmfulness accumulation on surface.This harmfulness accumulation frequently occurs in the surface for the ocean subduction facility do not protected, including
Sea-freight and the ship of tourism, naval's warship, heat exchanger, sea sensor and aquaculture base etc..Biodeterioration causes
Huge economic loss, only by taking USN's warship as an example, every year economic loss in this respect 18 to 26 hundred million dollars it
Between, and USN's warship quantity only accounts for the 0.5% of global ships quantity, therefore marine biofouling is extremely serious nature
Harm.Barnacle is that representativeness very universal in fouling organism known today is biological because of its very strong Adhering capacity.From 2008
Year, the whole world was eliminated after the use of poisonous anti-fouling agent organotin, and the safe and efficient marine antifoulant of searching, which turns into, to be badly in need of solving in the world
Problem certainly.Marine natural products is considered as the important sources of novel sea anti-fouling agent.In fact, in the past few decades
From sponge, the compound for much having strong anti-fouling activity is found that in the marine organisms such as coral and marine alga.However, from above-mentioned
The reactive compound found in macro-organism is due to being leveraged its potential application by the limitation measured.Marine microorganism
Due in the lab can be with large scale fermentation, survivable natural environment, and as activity marine compound it is most important come
Source.However, in recent years there is not yet the monoterpene dihydro-quinolinone that important anti-fouling activity is obtained from marine microorganism is biological
Alkali cpd as anti-fouling agent use.(J.A.Callow, M.E.Callow, Nat.Commun.2011,2,244-253；
C.M. Kirschner, A.B.Brennan, Annu.Rev.Mater.Res.2012,42,1-19；M.Schultz, J.
Bendick, E.Holm, W.Hertel, Biofouling 2011,27,87-98；N.Fusetani, Nat.Prod.
Rep.2004,21,94-104；N.Fusetani, Nat.Prod.Rep.2011,28,400-410；P.-Y.Qian, Y.Xu,
N.Fusetani, Biofouling 2010,26,223-234.)
The content of the invention
It is an object of the invention to provide a kind of monoterpene dihydro-quinolinone alkaloid compound from marine fungi and
The preparation method of its crystal and the application as marine antifoulant, it can meet the demand of prior art.Culture presevation is believed
Breath：Depositary institution's title：China Committee for Culture Collection of Microorganisms's common micro-organisms center；Depositary institution address：Beijing
No. 3 Institute of Microorganism, Academia Sinica of institute of city Chaoyang District North Star West Road 1；Preservation date：On December 17th, 2012；Preservation is compiled
Number：CGMCC6959；Classification And Nomenclature： Scopulariopsis sp..
The present invention provides compound of formula I or its pharmaceutically acceptable salt：
The present invention provides the preparation method of compound of formula I, it is characterised in that first to being isolated from Liu Shan in bacterium culture medium
Coral Carijoa sp. endogenetic fungus Scopulariopsis sp. (TA01-33) carry out Spawn incubation, then in fermentation medium
In to the fungi carry out fermented and cultured, then by gained filtering fermentation liquor, remove thalline, after filtrate is concentrated, use ethyl acetate
Extraction；Carried out respectively after normal-phase silica gel column chromatography, Sephadex LH-20 gel filtration chromatographies after extract concentration, then through HPLC
High performance liquid preparative chromatography, gained eluent is concentrated, as compound of formula I.
Bacterium culture medium preferably comprises glucose 0.1%-5.0% (percentage by weight, similarly hereinafter), ferment in above-mentioned preparation method
Female cream 0.01%-1%, peptone 0.01%-1%, agar 0.1%-3.0%, sodium chloride 0.05%-5%, remaining is water, training
Foster temperature is preferably 0-30 DEG C, and incubation time is preferably 3-15 days；Fermentation medium preferably comprises glucose 0.1%-5.0%
(percentage by weight, similarly hereinafter), yeast extract 0.01%-1%, peptone 0.01%-1%, sodium chloride 0.05%-5%, remaining is
Water, cultivation temperature is preferably 0-30 DEG C, and incubation time is preferably 10-60 days；The fixation that described normal-phase silica gel column chromatography is used
Phase preferably 200-300 mesh silica gel, mobile phase preferred volume ratio is 15%-40% ethyl acetate-light petrol mixed solvent；It is described
The mobile phase preferred volume ratio that Sephadex LH-20 gel filtration chromatographies are used is petroleum ether: chloroform: methanol=2: 1: 1 mixing
Solvent；The chromatographic column used in the HPLC high performance liquid preparative chromatographies is this area routine ODS C18 post, preferably
Kromasil10 × 250mm, 7 μm, flow velocity is preferably 1.0-5.0mL/min, and mobile phase preferred volume ratio is 50%-80% first
Alcohol-water mixed solvent.
Another embodiment of the present invention provides the crystal of compound of formula I, its Cu target X-ray crystal diffraction data：Space
Group is P2 (1) 2 (1) 2 (1), and cell parameter is α
=90 °, β=90 °, γ=90 °,Z=4, Dc=1.243 g/cm3, F (000)=1852, μ
=0.697mm-1, Flack constants are 0.00 (16).
Another embodiment of the present invention provides the preparation method of above-mentioned compound of formula I crystal, it is characterised in that by Formulas I
Compound is dissolved in any of methanol, ethanol, water, tetrahydrofuran or acetone or several, stands slow crystallization and can obtain Formulas I
The crystal of compound.
The condition slowly crystallized is stood in the preparation method of above-mentioned crystal preferably at 0-30 DEG C, 1-30 days are stood.
The monoterpene dihydro-quinolinone alkaloid compound that the present invention is obtained from marine fungi is to marine fouling organism barnacle
Balanus amphitrite larvas have extremely strong inhibitory activity, available for exploitation marine antifoulant, have a extensive future.
Another embodiment of the present invention provides compound of formula I or its pharmaceutically acceptable salt is preparing marine antifoulant
In application.
Term " pharmaceutically acceptable salt " refers to the addition of atoxic inorganic or organic acid and/or alkali in the present invention
Salt.Reference can be made to " Salt selection for basic drugs ", Int.J.Pharm. (1986), 33,201-217.
Brief description of the drawings
Figure of description 1 is the XRD of compound of formula I.
Embodiment
For the ease of a further understanding of the present invention, examples provided below has done more detailed description to it.But
It is that these embodiments only are not used for limiting the scope of the present invention or implementation principle, reality of the invention for being better understood from invention
The mode of applying is not limited to herein below.
Embodiment 1
(1) gorgonian endogenetic fungus Scopulariopsis sp. (TA01-33) Spawn incubation
Culture medium used in Spawn incubation contains glucose 1.0% (percentage by weight, similarly hereinafter), yeast extract 0.2%, albumen
Peptone 0.2%, agar 1.0%, sodium chloride 3.0%, remaining is water, and test tube slant is made when using, and fungal bacterial strain is trained at 30 DEG C
Support 5 days.
(2) gorgonian endogenetic fungus Scopulariopsis sp. (TA01-33) fermentation
Culture medium used in fermented and cultured contains glucose 1.0% (percentage by weight, similarly hereinafter), yeast extract 0.2%, albumen
Peptone 0.2%, sodium chloride 3.0%, remaining is water；Fungal bacterial strain is cultivated 60 days in 28 DEG C.
(3) the extraction separation of compound of formula I
The filtering fermentation liquor for taking 10L steps (2) to obtain, removes thalline, after filtrate is concentrated, with isometric ethyl acetate
Extraction 5 times；Carrying out normal-phase silica gel column chromatography after extract concentration respectively, (stationary phase is 200-300 mesh silica gel；Mobile phase is
30% ethyl acetate/petroleum ether mixed solvent, volume ratio), Sephadex LH-20 gel filtration chromatographies (petroleum ether: chloroform: methanol
=2: 1: 1 mixed solvent, volume ratio) after, then through HPLC high performance liquid preparative chromatographies separation (chromatographic column be Kromasil10 ×
250mm, 7 μm, flow velocity is 2.0mL/min, and mobile phase is 75% Methanol+Water, volume ratio), by gained eluent
Concentration, obtains colourless crystallization, as compound of formula I.
The structural identification data of compound of formula I：
Aflaquinolone A：Clear crystal, specific rotation value [α]25 D=+
63.5 (c=0.051in MeOH)1H NMR (300MHz, acetone-d6, δ, ppm, J/Hz)：9.38 (s, 6-OH), 7.52
(d, 8.1, H-8), 7.34, (m, H-12-H-16), 6.82 (d, 17.1, H-17), 6.58 (d, 8.1, H-9), 6.43 (d,
16.5, H-18), 3.67 (s, H-3), 3.51 (s, H-27), 2.52 (m, H-21, Hax-23), 2.13 (overlaped, Heq-
24, Heq-20, Heq-23), 1.72 (t, 13.5, Hax-24), 1.45 (t, 13.2, Hax-20), 1.11 (s, H-25), 0.92
(d, 6.0, H-26)；EIMS m/z：435[M]·+.
Embodiment 2
(1) gorgonian endogenetic fungus Scopulariopsis sp. (TA01-33) Spawn incubation
Culture medium used in Spawn incubation contains glucose 0.1%-5.0% (percentage by weight, similarly hereinafter), yeast extract
0.01%-1%, peptone 0.01%-1%, agar 0.1%-3.0%, sodium chloride 0.05%-5%, remaining is water, when using
Test tube slant is made, fungal bacterial strain is cultivated 3-15 days at 0-30 DEG C.
(2) gorgonian endogenetic fungus Scopulariopsis sp. (TA01-33) fermentation
Culture medium used in fermented and cultured contains glucose 0.1%-5.0% (percentage by weight, similarly hereinafter), yeast extract
0.01%-1%, peptone 0.01%-1%, sodium chloride 0.05%-5%, remaining is water, and fungal bacterial strain is in 0-30 DEG C of culture
10-60 days.
(3) the extraction separation of compound of formula I
The filtering fermentation liquor obtained by 5-50L steps (2) is taken, thalline is removed, after filtrate is concentrated, with the second of 1-3 times of volume
Acetoacetic ester is extracted 2-5 times；Carrying out normal-phase silica gel column chromatography after extract concentration respectively, (stationary phase is the conventional positive silicon in this area
Glue, mobile phase is 15%-40% ethyl acetate-light petrol mixed solvent, volume ratio), Sephadex LH-20 gel columns layer
Analyse after (mobile phase is petroleum ether: chloroform: methanol=2: 1: 1 mixed solvent, volume ratio), then color is prepared through HPLC efficient liquid phases
Spectrum (chromatographic column is this area routine ODS C18 posts, and flow velocity is 1.0-5.0mL/min, the methanol that mobile phase is 50%-80%-
Water mixed solvent, volume ratio), gained eluent is concentrated, colourless crystallization, as compound of formula I is obtained.Its compounds of formula I
Structural identification data is consistent with corresponding data in embodiment 1.
Other Spawn incubations, the fermentation condition not particularly pointed out in embodiment 1-2, and normal phase silica gel column chromatography separation,
Other experimental operating conditions such as the separation of Sephadex LH-20 gel filtration chromatographies, high performance liquid chromatography separation are that this area is conventional
Experimental operating conditions, those skilled in the art can reasonably be selected according to actual needs.
Embodiment 3
Modus ponens I 5mg is dissolved in equipped with bottle any in 2mL methanol, ethanol, water, tetrahydrofuran or acetone
In, after standing 30 days at 0 DEG C, slow crystallization produces the crystal of compound of formula I.
Embodiment 4
Modus ponens I 10mg is dissolved in equipped with any one or several in 5mL methanol, ethanol, tetrahydrofuran or acetone
In bottle, after standing 1 day at 30 DEG C, slow crystallization produces the crystal of compound of formula I.
The Cu target X-ray crystal diffraction data of above-mentioned crystal：Space group is P2 (1) 2 (1) 2 (1), and cell parameter isA=90 °, β=90 °, γ=
90 °,Z=4, Dc=1.243g/cm3, F (000)=1852, μ=0.697mm-1, Flack is normal
Number is 0.00 (16).
Embodiment 5
To marine fungi Scopulariopsis sp. (TA01-33) progress Spawn incubations in bacterium culture medium, then
Fermented and cultured is carried out to the fungi in fermentation medium, by gained filtering fermentation liquor, thalline is removed, after filtrate is concentrated, uses second
Acetoacetic ester is extracted；Carry out after normal-phase silica gel column chromatography, Sephadex LH-20 gel filtration chromatographies, then pass through respectively after extract concentration
HPLC high performance liquid preparative chromatographies, gained eluent is concentrated, and obtains clear crystal, as compound of formula I, its structural identification data
It is consistent with corresponding data in embodiment 1.Contain glucose, yeast extract, peptone, agar, thick in wherein described bacterium culture medium
Contain rice, coarse sea salt, peptone, water in sea salt, water, the fermentation medium；Described chromatographic isolation is normal phase silicagel column
Chromatographic isolation, Sephadex LH-20 gel filtration chromatographies and high performance liquid chromatography separation.
In order to explore the method for being widely applied to prepare formula I, bacterium culture medium in the present embodiment,
The addition of each composition in fermentation medium, is added in conventional ratio in this area or added in any proportion, during chromatographic isolation
The specification of used silica gel, the specification of Sephadex LH-20 gels, the selection of the model of chromatographic column and eluting solvent, are ability
The conventional selection in domain.Test result indicates that, the preparation method of above-mentioned conventional selection, the clear crystal that can be invented, i.e. Formulas I
Compound, its structural identification data is consistent with corresponding data in embodiment 1, only exists individual compound in purity and yield side
The fine difference in face.
Embodiment 1-3 result shows, according to the conventional Spawn incubation in this area, fermentation condition, conventional purification on normal-phase silica gel
Pillar layer separation, the separation of Sephadex LH-20 gel column chromatographies, the condition of high performance liquid chromatography separation are to marine fungi
Scopulariopsis sp. (TA01-33) carry out Spawn incubation, ferment, isolate and purify, and can obtain formula I structures
Compound.The preparation method of formula I, the method described in preferred embodiment 1-2.
Embodiment 6
The compound of formula I of the present invention is tested according to following document barnacle Balanus amphitrite larvas attachment activity
Method is tested：Thiyagarajan, V.；Harder, T.；Qiu, J.W.；Qian, P.Y.Mar.Biol. (Berlin) 2003,
143,543-554.
The compound of formula I of the present invention and its attachment of crystal barnacle B.amphitrite larvas have extremely strong inhibitory activity,
Its EC50It is worth for 0.012 μ g/mL, and with very high security, its toxicity efficiency ratio LC50/EC50Value 208.Above-mentioned activity
Much it is better than potential natural anti-fouling compound EC as defined in USN50The μ g/mL of value 25 standard.Importantly, it
Toxicity efficiency ratio (LC50/EC50) much larger than 15, and LC50/EC50It is regarded as having more than 15 and develops into safety antifouling agent
Potentiality.This shows that compound of formula I, its pharmaceutically acceptable salt or its crystal can be used for the marine anti-pollution for preparing high-efficiency low-toxicity
Agent, and gorgonian endogenetic fungus Scopulariopsis sp. (TA01-33) can carry out large scale fermentation production, it is ensured that formula
The natural origin of I, it has broad application prospects.
Claims (2)
1. the monoterpene dihydro-quinolinone alkaloid compound and its pharmaceutically acceptable salt of a kind of Formulas I structure are prevented in preparation ocean
Application in terms of dirty agent
2. application of the crystal of the compound of formula I described in claim 1 in terms of marine antifoulant is prepared, it is characterised in that the crystalline substance
The space group of body is P2 (1) 2 (1) 2 (1), and cell parameter is
α=90 °, β=90 °, γ=90 °,Z=4, Dc=1.243g/cm3, F (000)=1852, μ=
0.697mm-1, Flack constants are 0.00 (16).
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| CN105218447B (en) * | 2015-06-24 | 2017-12-12 | 中国海洋大学 | Sclerotiorin derivatives and preparation method thereof and the application as anti-influenza A H 1 N 1 virus agent |
| CN106496115A (en) * | 2015-09-06 | 2017-03-15 | 中国海洋大学 | A kind of mixed source monoterpene alkaloid class compound and preparation method thereof and the application as marine antifoulant |
| CN106496202B (en) * | 2015-09-06 | 2019-08-06 | 中国海洋大学 | A kind of alkaloid compound and preparation method thereof and the application as I type viral agent of anti-herpes simplex |
| CN108658975A (en) * | 2017-03-28 | 2018-10-16 | 中国海洋大学 | A kind of nitrogenous compound and preparation method thereof and application as marine antifoulant |
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