CN113817008A - Preparation method and application of novel succinyl sixteen-membered macrolide - Google Patents
Preparation method and application of novel succinyl sixteen-membered macrolide Download PDFInfo
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/44—Preparation of O-glycosides, e.g. glucosides
- C12P19/60—Preparation of O-glycosides, e.g. glucosides having an oxygen of the saccharide radical directly bound to a non-saccharide heterocyclic ring or a condensed ring system containing a non-saccharide heterocyclic ring, e.g. coumermycin, novobiocin
- C12P19/62—Preparation of O-glycosides, e.g. glucosides having an oxygen of the saccharide radical directly bound to a non-saccharide heterocyclic ring or a condensed ring system containing a non-saccharide heterocyclic ring, e.g. coumermycin, novobiocin the hetero ring having eight or more ring members and only oxygen as ring hetero atoms, e.g. erythromycin, spiramycin, nystatin
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to novel macrolide compounds 4 '-O- (6-O-succinyl-glucoside) -25-methyl ivermectin and 4' -O- (6-O-succinyl-glucoside) -25-ethyl ivermectin, a microbial transformation preparation method thereof and application thereof in preparing medicines for preventing and treating agricultural and forestry pests and mites.
Description
Technical Field
The invention belongs to the technical field of biology, and particularly relates to 4 '-O- (6-O-succinyl-glucosyl) -25-methyl vermectins and 4' -O- (6-O-succinyl-glucosyl) -25-ethyl vermectins, a microbial transformation preparation method thereof, and application thereof in preparation of medicines for preventing and treating agricultural and forestry pests and mites.
Background
The 25-methyl virtectin and the 25-ethyl virtectin are novel sixteen-membered macrolide antibiotics, have the characteristics of broad spectrum, high efficiency, low toxicity, small dosage, safer use and the like, and have the following chemical structural formulas:
through activity determination, compared with abamectin, ivermectin and milbemycin, the compound has a dispelling and killing effect on in-vivo and in-vitro parasitic diseases of nematodes, mites, ticks, lice, flies, maggots and the like of animals such as pigs, cows, sheep, horses, rabbits, poultry and the like, and various parasites, and is an antiparasitic lead compound with a very good prospect.
Microbial transformation is the structural modification of a complex substrate by microbial cells, namely, a certain enzyme or a series of enzymes generated in the metabolic process of a microorganism are used for carrying out catalytic reaction on a specific part (group) of the substrate, so that the molecular structure of the substrate is changed into another similar compound. The microbial transformation has the advantages of reaction orientation, single product, less side reaction, fast biomass accumulation, short transformation time, high invertase expression efficiency, mild reaction condition, safety, environmental protection and the like, and is a convenient means for carrying out structural modification on natural active compounds.
According to the invention, the Bacillus subtilis ATCC 6633 is used for transforming 25-methyl/25-ethyl virmectins to obtain a new 2-hexadecimal macrolide active compound with a novel structure, the activity of the compound is equivalent to that of a precursor compound of 25-methyl/25-ethyl virmectins, but the crystallinity of the compound is better than that of the precursor compound, so that the quality control of subsequent products is facilitated, and the production cost is reduced. In addition, the structure of the compound 1-2 has a carboxyl group compared with the parent compound, which shows that the water solubility is increased, and the development of the water-based pesticide is facilitated.
Disclosure of Invention
1. A compound having the formula:
wherein R is CH3Or CH2CH3。
Wherein R is1＝CH3Which is compound 1 of the following structural formula:
or
R1＝CH2CH3Which is compound 2 of the formula:
the invention provides a preparation method of a compound 1-2, which comprises the following steps:
1) preparing a penicillium griseofulvum seed solution: inoculating Bacillus subtilis strain with ATCC 6633 on PDA solid culture medium, culturing in constant temperature incubator at 20-28 deg.C for 5-7 days, inoculating activated strain to soybean meal liquid culture medium, culturing in horizontal shaker at 20-28 deg.C and 250rpm for 40 hr to obtain seed liquid;
2) preparation of Compounds 1-2: transferring the seed solution into a fresh soybean meal liquid culture medium by 1mL per bottle, culturing for 24h at the temperature of 28 ℃ at 180rpm/min, adding 1mL of 25-methyl/25-ethyl virmectins (the concentration is 10mg/mL) dissolved in an organic solvent into each bottle, and carrying out transformation culture for 96 h under the same conditions to obtain a fermentation liquid; extracting the fermentation liquor by using an extractant, recovering the extractant, and performing chromatographic separation to obtain a pure product of the compound 1-2.
As a preferred technical meansThe preparation method of the liquid culture medium in the step 1) comprises the following steps: taking 30g of glucose, 5g of yeast extract, 5g of NaCl and K2HPO45g, adding distilled water to a constant volume of 1000ml, adjusting pH to 7.0-7.2 with 1mol/l NaOH, subpackaging 50ml in 250ml triangular flask per bottle, weighing 0.25-0.30g of soybean meal, placing in the triangular flask, wrapping, and sterilizing at 121 ℃ and 0.15MPa for 20 min.
As a preferred technical scheme, the organic solvent in the step 2) comprises one or more of methanol, ethanol and DMSO.
As a preferable technical scheme, the extractant in the step 2) comprises one or more of ethyl acetate, n-butanol, isobutyl acetate, diethyl ether, petroleum ether, dichloromethane or trichloromethane.
As a preferred technical scheme, the purification of the step 2) comprises reversed-phase high performance liquid chromatography.
As a preferred technical scheme, the purification of the step 2) further comprises silica gel column chromatography.
The present invention further provides pesticidal compositions comprising compound 1 and/or compound 2 as described above, said compositions further comprising one or more conventional carriers and/or diluents. The pesticide composition can be in the dosage forms of water dispersible granules, missible oil, water suspending agents, oil suspending agents, micro-emulsions or tablets.
The invention further provides application of the compound 1-2 in preparing a medicament for preventing and treating crop diseases and insect pests. The crop pests comprise nematodes and red spiders.
Drawings
FIG. 1 high resolution Mass Spectrometry of Compound 1 obtained in example 1;
FIG. 2 hydrogen spectrum of Compound 1 obtained in example 1;
FIG. 3 carbon spectrum of Compound 1 obtained in example 1;
FIG. 4 DEPT135 spectrum of Compound 1 obtained in example 1;
FIG. 5 preparation of Compound 1 obtained in example 11H-1H COSY carbon spectrum;
FIG. 6 HMQC spectra of Compound 1 obtained in example 1;
FIG. 7 HMBC spectrum of Compound 1 obtained in example 1;
FIG. 8 high resolution Mass Spectrometry of Compound 2 obtained in example 2;
FIG. 9 hydrogen spectrum of Compound 2 obtained in example 2;
FIG. 10 carbon spectrum of Compound 2 obtained in example 2;
FIG. 11 DEPT135 spectrum of Compound 2 obtained in example 2;
FIG. 12 preparation of Compound 2 obtained in example 21H-1H COSY carbon spectrum;
FIG. 13 HMQC spectra of Compound 2 obtained in example 2;
FIG. 14 HMBC spectrum of compound 2 obtained in example 2.
Detailed Description
The present invention is described below by way of specific examples, it being understood that the examples are intended to illustrate the invention and are not intended to limit the invention, the scope and core content of which is defined by the claims.
Example 1
1) Inoculating Bacillus subtilis strain ATCC 6633 on PDA solid culture medium, culturing in constant temperature incubator at 20-28 deg.C for 5-7 days, inoculating activated strain to soybean meal liquid culture medium, culturing in horizontal shaker at 20-28 deg.C and 250rpm for 40 hr to obtain seed solution, inoculating 1mL of seed solution to 100mL of fresh soybean meal liquid culture medium, culturing at 180rpm and 28 deg.C for 24 hr, adding 1mL of 25-methyl virnectin (10 mg/mL) dissolved in organic solvent, and culturing under the same conditions for 96 hr to obtain fermentation liquid.
2) 2L of fermentation liquor is obtained by fermentation culture according to the method, the fermentation liquor is extracted for three times by using equal volume of ethyl acetate to obtain ethyl acetate extract liquor, and the extract liquor is concentrated to be dry under the condition of reduced pressure at 50 ℃ to obtain 4.5g of oily substance.
The obtained oily substance was subjected to column chromatography on a silica gel column (particle size 100-200 mesh), chloroform: gradient elution with methanol 100:0-60:40(V/V) was followed by thin layer identification (TLC) to give 3 fractions. Subjecting fraction 3 to gel (Sephadex LH-20) column chromatography to obtain fraction 3-1, and further purifying with semi-preparative column chromatography to obtain pure 4 "-O- (6-O-succinyl-glucoside) -25-methyl virectin (1).
The thin layer identification method comprises the following steps: the converted sample and the blank control are spotted on a silica gel G thin layer plate, developed under the developing agent condition of chloroform and methanol (8:2), taken out and dried after running, observed under an ultraviolet lamp at 254nm, developed by concentrated sulfuric acid, and the conversion result is observed.
Semi-preparative column chromatography conditions: mobile phase: methanol-water (containing one thousandth of acetic acid) (90: 10); column C18, 9.4 × 250 mm; detection wavelength: 244 nm; flow rate: 1.5 mL/min; column temperature: 30 ℃; the sample injection amount is as follows: 50 uL. The peak at a retention time of 14.35min was collected to give 4 "-O- (6-O-succinyl-glucosyl) -25-methyl virnectin (1, 14.5 mg).
3) And (3) identifying the structure of the compound 1.
The structure of compound 1 was determined by 1D and 2D NMR, MS, etc. spectroscopy as follows:
compound identification involves the following instruments:
the nuclear magnetic resonance spectrum is measured by a superconducting nuclear magnetic resonance instrument (Zhongke-400) of Oxford of Zhongke;
the mass spectrum and the high-resolution mass spectrum are measured by a Q-TOF Micro LC-MS-MS mass spectrometer of Waters company;
the UV spectrum was measured using a Varian Cary 300Bio spectrophotometer from Varian corporation;
specific data for the compounds are as follows:
structure of compound 1:
white crystalline powder;
the solubility is that the product is easily dissolved in chloroform, acetone, methanol and ethanol and is not dissolved in water;
molecular formula C55H82O22；
HRESI-MS m/z:1117.5198[M+Na]+(MeterCalculating the value: c55H82O22Na,1117.5195)；
UVλmax(EtOH)nm(logε):245(4.45)；
IR vmaxcm-1：3381,2963,1724,1680,1448,1384,1261,1091；
Hydrogen spectrum (1H NMR) and carbon Spectroscopy (13C NMR) data are shown in table 1.
Example 2
1) Inoculating Bacillus subtilis with a preservation number of ATCC 6633 on a PDA solid culture medium in a streak mode, culturing for 5-7 days in a constant-temperature incubator at 20-28 ℃, transferring the activated strain to a soybean meal liquid culture medium, culturing for 40 hours in a horizontal shaking table at 20-28 ℃ and 250rpm to obtain a seed solution, transferring the seed solution into 100mL of a fresh soybean meal liquid culture medium by 1mL of each bottle, culturing for 24 hours at 180rpm and 28 ℃, respectively adding 25-ethyl virnectin (the concentration is 10mg/mL) dissolved in 1mL of an organic solvent into each bottle, and performing transformation culture for 96 hours under the same conditions to obtain a fermentation liquid.
2) 2L of fermentation liquor is obtained by fermentation culture according to the method, the fermentation liquor is extracted for three times by using equal volume of ethyl acetate to obtain ethyl acetate extract liquor, and the extract liquor is concentrated to be dry under the condition of reduced pressure at 50 ℃ to obtain 5.3g of oily substance.
The obtained oily substance was subjected to column chromatography on a silica gel column (particle size 100-200 mesh), chloroform: gradient elution with methanol 100:0-60:40(V/V) was followed by thin layer identification (TLC) to give 3 fractions. Fraction 3 was subjected to gel (Sephadex LH-20) column chromatography to give fraction 3-1, which was further purified by semi-preparative column chromatography to give pure and 4 "-O- (6-O-succinyl-glucoside) -25-ethyl virnectin (2, 25.8 mg).
The thin layer identification method comprises the following steps: the converted sample and the blank control are spotted on a silica gel G thin layer plate, developed under the developing agent condition of chloroform and methanol (8:2), taken out and dried after running, observed under an ultraviolet lamp at 254nm, developed by concentrated sulfuric acid, and the conversion result is observed.
Semi-preparative column chromatography conditions: mobile phase: methanol-water (containing one thousandth of acetic acid) (90: 10); column C18, 9.4 × 250 mm; detection wavelength: 244 nm; flow rate: 1.5 mL/min; column temperature: 30 ℃; the sample injection amount is as follows: 50 uL. The peak with retention time of 14.63min was collected to obtain 4' -O- (6-O-succinyl-glucosyl) -25-ethyl virnectin (2).
3) And (5) identifying the structure of the compound 2.
Structure of compound 2:
white crystalline powder;
the solubility is that the product is easily dissolved in chloroform, acetone, methanol and ethanol and is not dissolved in water;
molecular formula C56H84O22；
HRESI-MS m/z:1131.5356 (calculated value: C)56H84O22Na,1131.5352)；
UVλmax(EtOH)nm(logε):245(4.06)；
IR vmaxcm-1：3466,2931,1719,1451,1380,1120,1066,993；
Hydrogen spectrum (1H NMR) and carbon Spectroscopy (13C NMR) data are shown in tables 1 and 2.
TABLE 1 Compounds 1-2 in CD3Hydrogen (400MHz) and carbon (100MHz) nuclear magnetic data in OD
Example 3
Biological activity of compound 1-2 on tetranychus cinnabarinus
The test organisms: tetranychus cinnabarinus (Tetranychus cinnabarinus): inoculating the seeds on broad bean seedlings for culture under the condition of artificial climate room [ (26 +/-1) DEG C, RH (70 +/-5)%, H/D14 ].
The experimental method comprises the following steps: adopting a leaf disc insect soaking method: selecting adult mites which are fed indoors and have consistent physiological state. Selecting broad bean leaves with consistent growth, making broad bean leaves with the diameter of 2cm into leaf dishes by using a puncher, placing the leaves with the back facing upwards on absorbent cotton in the center of a plastic dish, selecting and inoculating 3 leafbutterflies in each dish to the leaf dishes by using a small-size brush pen, inoculating mites on the leaf dishes, adding a proper amount of water to the leaf dishes at 30 heads of each leaf dish, and placing the leaf dishes in a culture room with the illumination intensity of (26 +/-1) ° C, the illumination intensity of 3000-4500 lx, the illumination intensity of 14h/d and the illumination intensity of RH of 50% -75%. After 2h, the number of the mites is checked under a stereoscopic microscope, and the number of the mites on each dish of the leafdisk is not less than 20. Dissolving a sample to be detected in a small amount of acetone, taking alkylphenol ethoxylates as an emulsifier, diluting with water, preparing medicaments with mass concentrations of 0.005, 0.01, 0.02, 0.04 and 0.08mg/L, putting the medicaments into a beaker, clamping leaves by using tweezers, sequentially soaking the medicaments from low concentration to high concentration for 5s, treating female adult mites with distilled water in contrast, wherein each mass concentration is one treatment, and repeating the treatment for 3 times. After the medicament on the leaves is dried, the treated leaf disks are placed in a climatic chamber with the photoperiod of 26 +/-1 ℃ for 24 hours, and a small amount of water is added into the culture dish for moisture preservation. The mites are very active after the drug is soaked, the activity is slowed down 5 to 8 hours after the treatment, and the worm bodies are static after 12 to 24 hours. Death judgment criteria: the mites were touched with a brush pen during examination, and the mites were judged to be dead. The test results are shown in Table 2
Table 2: activity of compound 1-2 against Tetranychus cinnabarinus
Example 4
Activity assay of Compound 1-2 against Bursaphelenchus xylophilus
The test organisms: pine wood nematode as test insect
The test method comprises the following steps: inoculating the prepared pine wood nematodes to a PDA culture medium full of tomato Botrytis cinerea (Botrytis cinerea), culturing for 7 days in a constant-temperature incubator at 25 ℃, picking out the culture medium containing the pine wood nematodes, soaking the pine wood nematodes in distilled water for 24 hours, filtering to separate the nematodes, and preparing the nematodes into a suspension of about 2500 heads/mL for later use.
A sample to be detected is dissolved in a small amount of acetone by adopting an immersion method, alkylphenol ethoxylates is used as an emulsifier and is diluted by water, and the 5 samples are respectively prepared into 5 samples with mass concentrations of 1, 2, 5, 10 and 20 mg/L. 10 mu L of test reagent and 90 mu L of pine wood nematode suspension are respectively put into a 96-hole culture plate and cultured in an incubator at 25 ℃ by taking missible oil without a sample to be tested as a contrast. Each mass concentration is 1 treatment, each treatment is repeated for 3 times, and after 24 hours, microscopic examination is carried out to count survival number and death number of the pine wood nematodes.
All nematodes with movement or "S" shape, wave shape, curl shape and spiral shape are considered as live worms, and all nematodes with immobility and "C" shape, "J" shape, stiffness and no opacity of body wall are considered as dead worms. Mortality and corrected mortality were calculated separately and the virulence regression equation, LC, were calculated using software SPSS 22.050Values, correlation coefficients, and 95% confidence limits. Wherein the mortality rate is (number of death nematode/number of test nematode) x 100%; corrected mortality-control mortality)/(1-control mortality) x 100%. The test results are shown in Table 3.
Table 3: activity of Compound 1-2 against Bursaphelenchus xylophilus
The invention utilizes Bacillus subtilis ATCC 6633 to transform 25-methyl/25-ethyl virmectins, and can prepare 2 novel hexadecimal macrolide compounds: 4 '-O- (6-O-succinyl-glucoside) -25-methyl verfectin (1) and 4' -O- (6-O-succinyl-glucoside) -25-ethyl verfectin (2). The 2 compounds have good effect on preventing and controlling agricultural and forestry pests or mites.
The use of the compounds 1-2 of the present invention has been described by way of specific examples, and those skilled in the art can take the contents of the present invention and appropriately modify the starting materials, the process conditions and the like to achieve other objects without departing from the scope of the present invention, and all such similar substitutes and modifications which are obvious to those skilled in the art are deemed to be within the scope of the present invention.
The above-described embodiments are merely preferred embodiments of the present invention, which is not intended to be limiting in any way, and other variations and modifications are possible without departing from the scope of the invention as set forth in the appended claims.
Claims (12)
1. The invention relates to a macrolide compound with the following general formula and application thereof in preparing pesticide compositions for preventing and controlling agricultural and forestry pests or mites:
wherein R is CH3Or CH2CH3。
2. The compound of claim 1, comprising 4 "-O- (6-O-succinyl-glucoside) -25-methyl virnectin, which has the following structure:
3. the compound of claim 1, comprising 4 "-O- (6-O-succinyl-glucoside) -25-ethyl virnectin, which has the following structure:
4. a process for the preparation of a compound according to claims 1-3, comprising the steps of:
1) preparing a penicillium griseofulvum seed solution: inoculating Bacillus subtilis strain with ATCC 6633 on PDA solid culture medium, culturing in constant temperature incubator at 20-28 deg.C for 5-7 days, inoculating activated strain to soybean meal liquid culture medium, culturing in horizontal shaker at 20-28 deg.C and 250rpm for 40 hr to obtain seed liquid;
2) preparation of the compound: transferring the seed solution into a fresh soybean meal liquid culture medium by 1mL per bottle, culturing for 24h at the temperature of 28 ℃ at 180rpm/min, adding 1mL of 25-methyl virtectin or 25-ethyl virtectin (the concentration is 10mg/mL) dissolved in an organic solvent into each bottle, and carrying out transformation culture for 96 h under the same conditions to obtain a fermentation liquid; extracting the fermentation liquor by using an extracting agent, recovering the extracting agent, and performing chromatographic separation to obtain the compound.
5. The method for preparing the compound according to claim 4, wherein the liquid medium in step 1) is prepared by: taking 30g of glucose, 5g of yeast extract, 5g of NaCl and K2HPO45g, adding distilled water to a constant volume of 1000ml, adjusting pH to 7.0-7.2 with 1mol/l NaOH, subpackaging 50ml in 250ml triangular flask per bottle, weighing 0.25-0.30g of soybean meal, placing in the triangular flask, wrapping, and sterilizing at 121 ℃ and 0.15MPa for 20 min.
6. The method for preparing the compound according to claim 4, wherein the organic solvent in step 2) comprises one or more of methanol, ethanol and DMSO.
7. The method for preparing the compound according to claim 4, wherein the extractant in step 2) comprises one or more of ethyl acetate, n-butanol, isobutyl acetate, diethyl ether, petroleum ether, dichloromethane and chloroform.
8. The method of claim 4, wherein the step 2) of purifying comprises reverse phase high performance liquid chromatography.
9. The method for preparing the compound according to claim 4, wherein the purification of step 2) further comprises silica gel column chromatography.
10. A pharmaceutical composition comprising one or more of the compounds of claims 1-3, together with one or more conventional carriers and/or diluents.
11. Use of the compounds of claims 1-3 and 10 and their pharmaceutical compositions for the preparation of a medicament for the control of crop pests.
12. The crop pest of claim 11 comprising nematodes and spider mites.
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| CN114931144A (en) * | 2022-06-21 | 2022-08-23 | 台州科技职业学院 | Macrolide compound and application thereof in prevention and treatment of agricultural and forestry pests and pest mites |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114931144A (en) * | 2022-06-21 | 2022-08-23 | 台州科技职业学院 | Macrolide compound and application thereof in prevention and treatment of agricultural and forestry pests and pest mites |
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