CN103880809A - Macrolide compound and preparation method thereof and application as marine antifouling agent - Google Patents

Macrolide compound and preparation method thereof and application as marine antifouling agent Download PDF

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CN103880809A
CN103880809A CN201410103692.2A CN201410103692A CN103880809A CN 103880809 A CN103880809 A CN 103880809A CN 201410103692 A CN201410103692 A CN 201410103692A CN 103880809 A CN103880809 A CN 103880809A
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王长云
邵长伦
刘庆艾
王开玲
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Ocean University of China
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    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
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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 invention discloses a macrolide compound and a preparation method thereof and application as a marine antifouling agent. The macrolide compound is characterized in that a 14-dihydroxy-benzoic acid macrolide compound has a structure in a formula I shown in the specification, wherein R1 and R3 are OH; R2 and R4 are H; or R1 and R3 are H; R2 and R4 are OH; or R1 and R4 are OH; R2 and R3 are H. The compound in the formula I can be prepared from thalassiomycetes cochliobolus lunatus (TA26-46) by the means of cultivation, fermentation, chromatography separation and the like. The invention provides a natural marine antifouling agent which is high in efficiency and low in toxicity. The marine antifouling agent is characterized in that the compound in the formula I or the salt thereof is taken as an effective ingredient applied to prevention and treatment of fouling of marine organisms caused by barnacle.

Description

A kind of macrolides compound and preparation method thereof and application as marine antifoulant
Technical field
The present invention relates to a kind of ten quaternary dihydroxy-benzoic acid macrocyclic lactone compounds, particularly relate to a kind of the have preparation method of the ten quaternary dihydroxy-benzoic acid macrocyclic lactone compounds that suppress barnacle attachment activity and the application as natural marine organism stain control agent.
Background technology
Marine biofouling refers to that marine fouling organism is if the larva of barnacle, mussel, polyzoan etc. is in the growth of the maritime facilitieies such as hull, fish box, oil well or other marine organisms surface attachment and form group, thereby cause huge infringement to being attached thing, as accelerated metallic corrosion, reduce maritime facilities performance, affecting culture fishery output and quality etc.Only, take United States Navy's warship as example, annual financial loss is in this respect between 18 to 2,600,000,000 dollars, and United States Navy's warship quantity only accounts for 0.5% of global ships quantity, and therefore marine biofouling is extremely serious natural hazard.In marine fouling organism, barnacle is the class the widest, harm is maximum that distributes.Forbidden after the use of poisonous stain control agent organotin from the whole world in 2008, finding marine antifoulant safely and efficiently becomes the problem of being badly in need of in the world solution.The particular surroundingss such as the high salt in ocean, high pressure, low temperature, oligotrophic, low light shine make marine microorganism can produce a large amount of novel structures, active unique secondary metabolite, and wherein some compound has In Studies On Antifouling Activity; And marine microorganism can large scale fermentation, is not subject to resource limit, provides important sources for finding potential marine antifoulant.
Summary of the invention
The object of the present invention is to provide a kind of ten quaternary dihydroxy-benzoic acid macrocyclic lactone compounds of thalassiomycetes that derive from as the application of marine antifoulant, it can meet the demand of prior art.Culture presevation information: depositary institution's title: China Committee for Culture Collection of Microorganisms's common micro-organisms center; Depositary institution address: No. 3, Yard 1, BeiChen xi Road, Chaoyang District, Beijing City, Institute of Microorganism, Academia Sinica; Preservation date: on 01 09th, 2014; Deposit number: CGMCC8698; Classification And Nomenclature: Cochliobolus lunatus.
A kind of ten quaternary dihydroxy-benzoic acid macrocyclic lactone compounds or its salt of formula I structure:
Figure BSA0000102132970000021
Wherein R 1, R 3for OH, R 2, R 4for H; Or R 1, R 3for H, R 2, R 4for OH; Or R 1, R 4for OH, R 2, R 3for H.
Formula I compound is selected from following compounds:
Figure BSA0000102132970000022
The invention provides a kind of preparation method of above-mentioned formula I compound, it is characterized in that comprising the following steps: first in bacterium culture medium, fungi C.lunatus (TA26-46) is carried out to spawn culture, then in fermention medium, above-mentioned fungi is carried out to fermentation culture; Gained fermented product is soaked with methyl alcohol, after concentrating under reduced pressure, obtain methanol crude extract; Methanol crude extract is suspended in water, after ethyl acetate extraction concentrating under reduced pressure, obtain ethyl acetate phase medicinal extract; Ethyl acetate phase medicinal extract is carried out to chromatographic separation, obtain formula I compound.In wherein said bacterium culture medium, contain glucose, yeast extract paste, peptone, agar, thick sea salt, water, in fermention medium, contain rice, thick sea salt, peptone, water; Described chromatographic separation is that normal phase silica gel column chromatography separation separates with high performance liquid chromatography.
In above-mentioned preparation method, bacterium culture medium preferably contains glucose 0.1%-5.0% (weight percent, yeast extract paste 0.01%-2%, peptone 0.01%-2%, agar 0.1%-3.0%, thick sea salt 0.05%-5% down together),, all the other are water, culture temperature is preferably 5-45 ℃, and incubation time is preferably 3-15 days; Fermention medium preferably rice solid medium, in the Erlenmeyer flask of every 1000mL, adds rice 50-200g, thick sea salt 0.1-5g, peptone 0.1-2g, water 50-200mL, and culture temperature is preferably 5-45 ℃, and incubation time is preferably 7-40 days; The stationary phase adopting during described normal phase silica gel column chromatography separates is preferably 200-300 order silica gel, and moving phase is preferably ethyl acetate-sherwood oil of 0-100% (volume percent) and methyl alcohol-ethyl acetate mixed solvent of 0-100% (volume percent); The chromatographic column adopting during high performance liquid chromatography separates is preferably ODS C18 post (Kromasil, 7 μ m, 150 × 7.8mm), and moving phase is preferably the Methanol+Water of 45%-65% (volume percent).
The invention provides a kind of marine organisms stain control agent, it is characterized in that, using above-mentioned formula I ten quaternary dihydroxy-benzoic acid macrocyclic lactone compounds or its salt as effective constituent, adhering to for preventing and treating barnacle the marine biofouling causing.
Ten quaternary dihydroxy-benzoic acid macrocyclic lactone compounds of the present invention adhere to and have strong restraining effect kentrogon, and it is less to its toxicity, can be used for the friendly type natural marine organism of development environment stain control agent, and raw material can carry out scale operation by fungi fermentation, be not subject to resource limit, therefore have a extensive future.
Embodiment
For the ease of a further understanding of the present invention, the embodiment providing has below done more detailed description to it.But these embodiment are only not used for limiting scope of the present invention or implementation principle for better understanding invention, and embodiments of the present invention are not limited to following content.
Embodiment 1
(1) cultivation of thalassiomycetes C.lunatus (TA26-46) bacterial classification
The spawn culture substratum used of fungi C.lunatus (TA26-46) contains glucose 1.0% (weight percent, yeast extract paste 0.1%, peptone 0.2%, agar 1.0%, thick sea salt 3% down together),, all the other are water, when use, make test tube slant, fungal bacterial strain is cultivated 5 days at 28 ℃.
(2) fermentation of thalassiomycetes C.lunatus (TA26-46)
The fermentation culture fermention medium used of fungi C.lunatus (TA26-46) is rice solid medium, in the Erlenmeyer flask of every 1000mL, adds rice 100g, thick sea salt 3g, peptone 0.6g, water 100mL.Fungal bacterial strain is cultivated 28 days in 28 ℃.
(3) separation and Extraction of formula I compound of the present invention
Get step (2) gained fermented product and soak 3 times with methyl alcohol, obtain methanol extract after concentrating under reduced pressure, methanol extract is suspended in 500mL water, with ethyl acetate 1500mL extraction 3 times, concentrating under reduced pressure obtains ethyl acetate phase medicinal extract; First carry out normal phase silica gel column chromatography separation, stationary phase: 200-300 order silica gel, methyl alcohol-ethyl acetate mixed solvent of ethyl acetate-sherwood oil of moving phase: 0-100% (volume percent) and 0-100% (volume percent), then carry out high performance liquid chromatography separation, stationary phase: ODS C18 post (Kromasil, 7 μ m, 150 × 7.8mm), the Methanol+Water of moving phase: 45%-65% (volume percent), separation obtains 3 unformed powder of white (compound 1-3), is formula I compound.
The structural identification data of gained formula I compound:
Cochliomycin D (1)
Figure BSA0000102132970000041
the unformed powder of white, [α] 25 d-125 (c0.16, MeOH), UV (MeOH) λ max(log ε) 198 (3.27), 232 (4.30), 271 (3.88), 312 (3.62) nm, CD (1.38mM, MeOH) λ max(Δ ε) 219 (+8.07), 246 (+10.95), 273 (14.44), 310 (3.85), 351 (+0.31) nm, IR (KBr) v max3747,3648,1700,1650,1540,1510cm -1, 1h NMR (DMSO-d 6, 400MHz) δ 10.46 (1H, s, 2-OH), 6.82 (1H, ddd, J=15.9, 9.8, 5.2Hz, H-8 '), 6.48 (1H, d, J=2.4Hz, H-5), 6.42 (1H, d, J=15.9Hz, H-1 '), 6.35 (1H, d, J=2.4Hz, H-3), 6.21 (1H, d, J=15.9Hz, H-7 '), 6.18 (1H, ddd, J=15.9, 7.8, 6.7Hz, H-2 '), 5.33 (1H, m, H-10 '), 5.18 (1H, d, J=5.9Hz, 5 '-OH), 4.94 (1H, d, J=5.6Hz, 4 '-OH), 4.25 (1H, t, J=5.9Hz, H-5 '), 3.79 (1H, m, H-4 '), 3.75 (3H, s, 4-OCH 3), 2.67 (1H, ddd, J=14.4,5.2,2.1Hz, Ha-9 '), 2.40 (1H, ddd, J=14.4,9.8,7.0Hz, Hb-9 '), 2.31 (1H, m, Ha-3 '), 2.20 (1H, m, Hb-3 '), 1.32 (3H, d, J=6.3Hz, H-11 '), 13c NMR (DMSO-d 6, 100MHz) and δ 200.2 (C, C-6 '), 167.9 (C, C-12 '), 161.8 (C, C-4), 158.8 (C, C-2), 143.9 (CH, C-8 '), 138.9 (C, C-6), 131.0 (CH, C-7 '), 130.7 (CH, C-2 '), 129.2 (CH, C-1 '), 110.4 (C, C-1), 103.6 (CH, C-5), 100.3 (CH, C-3), 75.8 (CH, C-5 '), 72.7 (CH, C-4 '), 69.9 (CH, C-10 '), 55.3 (CH 3, 4-OCH 3), 37.5 (CH 2, C-9 '), 36.5 (CH 2, C-3 '), 19.7 (CH 3, C-11 '), ESIMSm/z385.1[M+Na] +, 747.2[2M+Na] +, HRESIMS m/z385.1266[M+Na] +(calculated value C 19h 22o 7na, 385.1258).
Cochliomycin E (2)
Figure BSA0000102132970000051
the unformed powder of white, [α] 25 d-73 (c0.10, MeOH), UV (MeOH) λ max(log ε) 198 (3.33), 223 (4.10), 271 (3.93), 312 (3.66) nm, CD (0.83mM, MeOH) λ max(Δ ε) 220 (+5.53), 245 (+3.86), 278 (1.99) nm, IR (KBr) v max3745,3646,1696,1647,1556,1518cm -1, 1h NMR (DMSO-d 6, 500MHz) δ 10.04 (1H, s, 2-OH), 6.71 (1H, dt, J=16.2, 7.8Hz, H-8 '), 6.55 (1H, brs, H-5), 6.33 (1H, m, H-2 '), 6.31 (1H, brs, H-3), 6.21 (1H, d, J=15.9Hz, H-1 '), 6.13 (1H, d, J=16.2Hz, H-7 '), 5.02 (1H, m, H-10 '), 5.02 (1H, d, J=5.6Hz, 5 '-OH), 4.91 (1H, d, J=6.1Hz, 4 '-OH), 4.27 (1H, t, J=5.6Hz, H-5 '), 3.86 (1H, m, H-4 '), 3.73 (3H, s, 4-OCH 3), 2.59 (1H, m, Ha-9 '), 2.45 (1H, m, Hb-9 '), 2.45 (1H, m, Ha-3 '), 2.13 (1H, m, Hb-3 '), 1.33 (3H, d, J=5.5Hz, H-11 '), 1c NMR (DMSO-d 6, 125MHz) and δ 199.9 (C, C-6 '), 167.6 (C, C-12 '), 160.7 (C, C-4), 155.8 (C, C-2), 143.9 (CH, C-8 '), 136.3 (C, C-6), 131.3 (CH, C-7 '), 131.3 (CH, C-2 '), 129.0 (CH, C-1 '), 114.3 (C, C-1), 100.9 (CH, C-5), 100.5 (CH, C-3), 73.6 (CH, C-5 '), 71.5 (CH, C-4 '), 70.5 (CH, C-10 '), 55.3 (CH 3, 4-OCH 3), 37.9 (CH 2, C-9 '), 35.7 (CH 2, C-3 '), 20.4 (CH 3, C-11 '), ESIMSm/z385.1[M+Na] +, HRESIMS m/z385.1269[M+Na] +(calculated value C 19h 22o 7na, 385.1258).
Cochliomycin F (3)
Figure BSA0000102132970000061
the unformed powder of white, [α] 25 d-23.3 (c0.10, MeOH), UV (MeOH) λ max(log ε) 198 (3.09), 231 (4.19), 271 (3.95), 312 (3.67) nm, CD (3.86mM, MeOH) λ max(Δ ε) 228 (+2.20), 248 (+2.62), 274 (1.77), 316 (+0.16) nm, IR (KBr) v max3747,3648,1700,1650,1556,1521cm -1, 1h NMR (DMSO-d 6, 500MHz) δ 10.08 (1H, s, 2-OH), 6.80 (1H, ddd, J=15.7, 7.9, 5.7Hz, H-8 '), 6.48 (1H, d, J=2.2Hz, H-5), 6.46 (1H, d, J=15.7Hz, H-7 '), 6.30 (1H, d, J=2.2Hz, H-3), 6.24 (1H, d, J=15.7Hz, H-1 '), 6.20 (1H, ddd, J=15.7, 9.0, 5.2Hz, H-2 '), 5.24 (1H, m, H-10 '), 5.24 (1H, d, J=5.3Hz, 5 '-OH), 5.00 (1H, d, J=5.6Hz, 4 '-OH), 4.30 (1H, dd, J=5.3, 2.6Hz, H-5 '), 3.89 (1H, m, H-4 '), 3.72 (3H, s, 4-OCH 3), 2.65 (1H, m, Ha-9 '), 2.42 (1H, m, Hb-9 '), 2.29 (1H, m, Ha-3 '), 2.12 (1H, m, Hb-3 '), 1.30 (3H, d, J=6.3Hz, H-11 '), 13c NMR (DMSO-d 6, 125MHz) and δ 200.1 (C, C-6 '), 167.6 (C, C-12 '), 161.0 (C, C-4), 156.7 (C, C-2), 142.7 (CH, C-8 '), 137.3 (C, C-6), 129.7 (CH, C-7 '), 130.5 (CH, C-2 '), 129.2 (CH, C-1 '), 112.9 (C, C-1), 101.9 (CH, C-5), 100.3 (CH, C-3), 78.8 (CH, C-5 '), 73.0 (CH, C-4 '), 69.8 (CH, C-10 '), 55.2 (CH 3, 4-OCH 3), 37.5 (CH 2, C-9 '), 36.0 (CH 2, C-3 '), 19.9 (CH 3, C-11 '), ESIMS m/z385.1[M+Na] +, 747.1[2M+Na] +, HRESIMS m/z385.1268[M+Na] +(calculated value C 19h 22o 7na, 385.1258).
Embodiment 2
(1) cultivation of thalassiomycetes C.lunatus (TA26-46) bacterial classification
Bacterium culture medium contains glucose 0.1%-5.0% (weight percent, yeast extract paste 0.01%-2%, peptone 0.01%-2%, agar 0.1%-3.0%, thick sea salt 0.05%-5% down together),, all the other are water, culture temperature is preferably 5-45 ℃, and incubation time is preferably 3-15 days.
(2) fermentation of thalassiomycetes C.lunatus (TA26-46)
Fermention medium is rice solid medium, in the Erlenmeyer flask of every 1000mL, adds rice 50-200g, thick sea salt 0.1-5g, peptone 0.1-2g, water 50-200mL, and culture temperature is preferably 5-45 ℃, and incubation time is preferably 7-40 days.
(3) separation and Extraction of formula I compound of the present invention
The fermented product of getting step (2) gained soaks 2-6 time with methyl alcohol, obtains methanol extract after concentrating under reduced pressure, and methanol extract is suspended in 200-1000mL water, and with ethyl acetate 600-3000mL extraction 2-6 time, concentrating under reduced pressure obtains ethyl acetate phase medicinal extract; First carry out normal phase silica gel column chromatography separation, stationary phase: 200-300 order silica gel, methyl alcohol-ethyl acetate mixed solvent of ethyl acetate-sherwood oil of moving phase: 0-100% (volume percent) and 0-100% (volume percent), then carry out high performance liquid chromatography separation, stationary phase: ODS C18 post (Kromasil, 7 μ m, 150 × 7.8mm), the Methanol+Water of moving phase: 45%-65% (volume percent), separation obtains 3 unformed powder of white (compound 1-3), is formula I compound.The structural identification data of its Chinese style I compound are consistent with corresponding data in embodiment 1.
Other spawn culture, the fermentation condition that in embodiment 1-2, specifically do not indicate, and other experimental implementation conditions such as normal phase silica gel column chromatography separation, high performance liquid chromatography separation are the experimental implementation condition of this area routine, those skilled in the art can according to actual needs, reasonably select.
Embodiment 3
In bacterium culture medium, thalassiomycetes C.lunatus (TA26-46) is carried out to spawn culture, in fermention medium, above-mentioned thalassiomycetes is carried out to fermentation culture again, gained fermented product is soaked with methyl alcohol, after concentrating under reduced pressure, obtain methanol extract, methanol extract is suspended in water, be extracted with ethyl acetate, concentrating under reduced pressure obtains ethyl acetate phase medicinal extract; Ethyl acetate phase medicinal extract is carried out obtaining 3 unformed powder of white (compound 1-3) after chromatographic separation, be formula I compound, its structural identification data are consistent with corresponding data in embodiment 1.In wherein said bacterium culture medium, contain glucose, yeast extract paste, peptone, agar, thick sea salt, water, in described fermention medium, contain rice, thick sea salt, peptone, water; Described chromatographic separation is that normal phase silica gel column chromatography separation separates with high performance liquid chromatography.
In order to explore the method that is applicable to widely prepare formula I compound of the present invention, the interpolation of each composition in bacterium culture medium, fermention medium in the present embodiment, all add or add in any proportion in conventional ratio in this area, the model of the specification of used silica gel, chromatographic column and the selection of eluting solvent when chromatographic separation, the routine that is this area is selected.Experimental result shows, the above-mentioned conventional preparation method who selects, all can obtain 3 the unformed powder of white, i.e. formula I compounds inventing, its structural identification data are consistent with corresponding data in embodiment 1, only have the fine difference of individual compound aspect purity and yield.
The result of embodiment 1-3 shows, according to the spawn culture of this area routine, fermentation condition, the condition that conventional normal phase silica gel column chromatography separates, high performance liquid chromatography separates is carried out spawn culture, fermentation, separation and purification to thalassiomycetes C.lunatus (TA26-46), all can obtain the compound of formula I structure of the present invention.The preparation method of formula I compound of the present invention, the method for recording in preferred embodiment 1-2.
Embodiment 4
Formula I compound of the present invention adheres to inhibition activity test to barnacle Balanus amphitrite larva to be tested according to following literature method: Thiyagarajan V.; Harder T.; Qiu J.W.; Qian P.Y.Mar Biol (Berl) 2003,143,543-554.By suppressing the test of barnacle B.amphitrite larva attachment activity, find that compound cochliomycin D of the present invention (1) and cochliomycin F (3) have stronger inhibition kentrogon attachment activity, and less to its toxicity.Wherein, medium effective concentration (EC 50) be respectively 17.3,6.67 μ g/mL, its median lethal concentration (LC 50) be all greater than 50 μ g/mL, show that the inhibition activity that kentrogon is adhered to is high, and low to the toxicity of kentrogon, there is the feature of high-efficiency low-toxicity.
Ten quaternary dihydroxy-benzoic acid macrocyclic lactone compounds of the present invention have stronger inhibition barnacle attachment activity, and it is lower to the toxicity of kentrogon, can be made into natural marine organism stain control agent efficient, low toxicity, and raw material can carry out scale operation by fungi fermentation, be not subject to resource limit, therefore have a extensive future.

Claims (8)

1. ten quaternary dihydroxy-benzoic acid macrocyclic lactone compounds or its salt of a formula I structure:
Figure FSA0000102132960000011
Wherein R 1, R 3for OH, R 2, R 4for H; Or R 1, R 3for H, R 2, R 4for OH; Or R 1, R 4for OH, R 2, R 3for H.
2. formula I compound as claimed in claim 1, is characterized in that being selected from following compound:
Figure FSA0000102132960000012
3. the preparation method of the formula I compound described in claim 1 or 2, it is characterized in that comprising the following steps: first in bacterium culture medium, fungi Cochliobolus lunatus (TA26-46) is carried out to spawn culture, then in fermention medium, above-mentioned fungi is carried out to fermentation culture; Gained fermented product is soaked with methyl alcohol, after concentrating under reduced pressure, obtain methanol crude extract; Methanol crude extract is suspended in water, after ethyl acetate extraction concentrating under reduced pressure, obtain ethyl acetate phase medicinal extract; Ethyl acetate phase medicinal extract is carried out to chromatographic separation, obtain formula I compound; In wherein said bacterium culture medium, contain glucose, yeast extract paste, peptone, agar, thick sea salt, water, in fermention medium, contain rice, thick sea salt, peptone, water; Described chromatographic separation is that normal phase silica gel column chromatography separation separates with high performance liquid chromatography.
4. preparation method claimed in claim 3, it is characterized in that described bacterium culture medium contains glucose 0.1%-5.0%, yeast extract paste 0.01%-2%, peptone 0.01%-2%, agar 0.1%-3.0%, thick sea salt 0.05%-5%, all the other are water, and above-mentioned percentage composition is all weight percentage; Culture temperature is 5-45 ℃, and incubation time is 3-15 days.
5. the preparation method described in claim 3-4 any one, it is characterized in that described fermention medium is rice solid medium, in the Erlenmeyer flask of every 1000mL, add rice 50-200g, thick sea salt 0.1-5g, peptone 0.1-2g, water 50-200mL, culture temperature is 5-45 ℃, and incubation time is 7-40 days.
6. the preparation method described in claim 3-5 any one, it is characterized in that the stationary phase adopting in described normal phase silica gel column chromatography separation is 200～300 order silica gel, methyl alcohol-ethyl acetate mixed solvent of ethyl acetate-sherwood oil that moving phase is 0-100% and 0-100%; The chromatographic column adopting during described high performance liquid chromatography separates is ODS C18 post Kromasil, 7 μ m, 150 × 7.8mm, the Methanol+Water that moving phase is 45%-65%; Above-mentioned mixed solvent per-cent is volume percent.
7. a marine organisms stain control agent, is characterized in that containing compound or its salt described in claim 1 or 2 as effective constituent.
8. the application in the marine biofouling that the formula I compound or its salt described in claim 1 or 2 causes at control barnacle.
CN201410103692.2A 2014-03-13 2014-03-13 Macrolide compound and preparation method thereof and application as marine antifouling agent Pending CN103880809A (en)

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CN111944858A (en) * 2019-05-14 2020-11-17 中国海洋大学 8' -hydroxy-tetradecyl macrolide compound, preparation method thereof and application thereof as marine antifouling agent

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Application publication date: 20140625