CN110590521A - Synthesis method and application of natural products Stipulin and Angusticornin B - Google Patents

Synthesis method and application of natural products Stipulin and Angusticornin B Download PDF

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Publication number
CN110590521A
CN110590521A CN201910919111.5A CN201910919111A CN110590521A CN 110590521 A CN110590521 A CN 110590521A CN 201910919111 A CN201910919111 A CN 201910919111A CN 110590521 A CN110590521 A CN 110590521A
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China
Prior art keywords
stipulin
angusticornin
natural products
product
application
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CN201910919111.5A
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Chinese (zh)
Inventor
桑锋
付林
李媛媛
翟佳黛
王新哲
赵甜甜
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Shandong University of Technology
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Shandong University of Technology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

The invention discloses a synthetic method and application of natural products Stipulin (I) and Angusticornin B (II), wherein the structural formula is as follows: wherein. The obtained natural products Stipulin and Angusticornin B have certain inhibitory activity to Bacillus subtilis. The preparation route of the invention has fewer process steps and easily obtained raw materials, and is suitable for industrial production.

Description

Synthesis method and application of natural products Stipulin and Angusticornin B
Technical Field
The invention relates to the field of compound synthesis, in particular to a method for synthesizing natural products Stipulin and Angusticornin B.
Background
(E) -1- (2, 4-dihydroxy-5- (2-hydroxy-3-methylbutyl-3-en-1-yl) phenyl) -3- (4-hydroxy-3- (2-hydroxy-3-methylbutyl-3-en-1-yl) phenyl) -propyl-2-en-1-one Angusticoat B is a natural product extracted from Dorstenia, and the compound reports the antibacterial effect on gram-negative bacteria, but does not report the chemical preparation method and the structure-activity relationship thereof, so that the research on chemical preparation and structure modification has important scientific significance.
Disclosure of Invention
The invention aims to provide a synthetic method and application of natural products Stipulin and Angusticornin B.
The invention further aims to provide application of the two compounds in inhibition of escherichia coli, pseudomonas aeruginosa, staphylococcus aureus and bacillus subtilis.
The natural products Stipulin (I) and Angusticornin B (II) have the following structural formulas:
the natural products Stipulin and Angusticornin B are synthesized by the following routes:
the preparation method of the natural products Stipulin and Angusticornin B comprises the following steps:
(1) reacting the intermediate 1 obtained by the known reaction with activated clay in dichloromethane in an ice water bath, and performing suction filtration, reduced pressure concentration and column chromatography to obtain a product 2;
(2) reacting the product 2 obtained in the step (1), the raw material 3 and 5M sodium hydroxide in ethanol at room temperature, and extracting, drying and carrying out column chromatography to obtain a product 4;
(3) adding the product 4 obtained in the step (2) and p-toluenesulfonic acid into methanol and tetrahydrofuran for reflux reaction, and obtaining a target product (I) through extraction, drying and column chromatography;
(4) and (3) adding the target product (I) obtained in the step (3) and tetraphenylporphyrin into dichloromethane, illuminating the dichloromethane with 500W halogen lamp until the raw materials react completely, adding triphenylphosphine, stirring overnight at room temperature, concentrating under reduced pressure, and performing column chromatography to obtain the target product (II).
Wherein:
in the step (1), the ratio of the amount of the intermediate obtained by a known reaction to the amount of activated clay and dichloromethane was 1 g: 1 g: 6 mL.
In the step (1), the temperature of the ice-water bath is controlled to be 0-5 DEGoAnd C, reacting for 1-2 h.
In the step (2), the dosage ratio of the product 2 in the step (3) to the raw material 3, 5M sodium hydroxide and ethanol is 1 mmol: 1.3 mmol: 30 mmol: 7.5 mL.
In the step (2), the room temperature is 20-30 DEGoAnd C, reacting for 30-35 h.
In the step (3), the dosage ratio of the product 3 in the step (4) to the p-toluenesulfonic acid, the methanol and the tetrahydrofuran is 1 mmol: 2 mmol: 10 mL: 10 mL.
In the step (3), the reflux temperature is 50-55 DEGoAnd C, the reaction time is 15-20 h.
In the step (4), the using amount ratio of the product (I) in the step (5) to tetraphenylporphyrin, triphenylphosphine and dichloromethane is 1 mmol: 0.2 mmol: 2.2 mmol: 100 mL.
In the step (4), the reaction temperature is controlled to be 5-10 ℃ under illuminationoC, the reaction time is 6-8 h
In the step (4), triphenylphosphine is added, and the reaction temperature is 20-30 DEGoAnd C, reacting for 10-15 h.
The natural products Stipulin and Angusticornin B are used for preparing antibacterial drugs.
The invention has the following beneficial effects:
the preparation route of the invention has fewer process steps and easily obtained raw materials, and is suitable for industrial production. The obtained natural products Stipulin and Angusticornin B have certain inhibitory activity on the growth of staphylococcus aureus and bacillus subtilis.
Detailed Description
In order that the objects and advantages of the invention will be more clearly understood, the invention is further described in detail below with reference to examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention
The embodiment of the invention provides a synthetic method of natural products Stipulin and Angusticornin B, and the synthetic route is as follows:
(1) putting an intermediate (1 g) obtained by a known reaction and activated clay (1 g) into a round-bottom flask, adding 6 mL of dichloromethane serving as a reaction solvent, stirring for 1.5 h in an ice-water bath state, performing suction filtration, reduced pressure concentration and column chromatography to obtain a product 1;
(2) placing the product 2 (1 mmol) obtained in the step (3) and the raw material 3 (1.3 mmol) in a round-bottom flask, adding ethanol (7.5 mL) as a reaction solvent, adding 5M NaOH (7.5 mL) at room temperature, continuing stirring for 30 h, extracting and separating by using water and ethyl acetate, reserving an organic layer, drying by using anhydrous sodium sulfate, and carrying out column chromatography by concentration under reduced pressure to obtain a product 3;
(3) dissolving the product 3 (1 mmol) obtained in the step (4) with methanol (10 mL) and tetrahydrofuran (10 mL), adding p-toluenesulfonic acid (2 mmol), and heating in oil bath to 50 DEGoAnd C, after reacting for 15 hours, extracting and separating the solution by using water and ethyl acetate, reserving an organic layer, drying, concentrating under reduced pressure, and carrying out column chromatography to obtain a natural product (I).
(4) Placing the product (I) (1 mmol) obtained in the step (5) and tetraphenylporphyrin (0.2 mmol) in a round-bottom flask, adding dichloromethane (100 mL) as a reaction solvent, cooling in an ice-water bath, irradiating under a 500w halogen lamp, stirring for 6 h, adding triphenylphosphine (2.2 mmol), naturally raising the temperature to room temperature, continuing stirring overnight, concentrating under reduced pressure, and carrying out column chromatography to obtain a natural product (II).
The natural product Angusticorn B product test results are as follows:
(E) -1- (2, 4-dihydroxy-5- (2-hydroxy-3-methylbutyl-3-en-1-yl) phenyl) -3- (4-hydroxy-3- (2-hydroxy-3-methylbutyl-3-en-1-yl) phenyl) -propyl-2-en-1-one
Yellow oil, yield 18 percent (the total yield of the reaction in the 6 steps), 1H NMR (400 MHz, Acetone-d6) δ 13.51 (s, 1H), 9.99 (brs, 1H), 9.48 (brs, 1H), 8.01 (s, 1H), 7.80 (s, 1H), 7.79 (s,1H), 7.60 (s, 1H) 7.59 (d, J = 8.6 Hz, 1H), 6.89 (d, J = 8.9 Hz, 1H), 6.35(s, 1H), 5.16 (s, 2H), 4.97 (s, 2H), 4.79 (s, 2H), 4.47 – 4.35 (m, 2H), 2.98– 2.81 (m, 4H), 1.81 (s, 3H) , 1.80 (s, 3H).
13C NMR (101 MHz, Acetone-d6) δ 192.78, 166.27, 164.48, 159.81, 148.35, 148.31, 145.24, 134.31, 133.87, 129.74, 127.57, 127.56, 119.09, 118.28,117.54, 114.37, 110.82, 104.39, 76.67, 76.57, 38.65, 38.09, 18.29.
the following bacteriostatic experimental studies were performed on the natural products Stipulin and Angusticornin B:
1. experimental Material
1.1 bacterial species
Bacillus subtilisBacillus subtilis (B. subtilis)[CMCC(B)63 501],
Staphylococcus aureusStaphylococcus aureus (S. aureus) [CMCC(B)260003],
1.2 reagents
LB (Luria Bertani) solid medium, LB agar, drug stock. The others are domestic pure chemical reagents.
2. Experimental methods
2.1 preparation of the culture Medium
Lb (luria bertani) solid medium: 10 g of peptone, 5 g of yeast extract powder and 10 g of sodium chloride (NaCl), wherein the volume is fixed to 1L by using distilled water, and agar powder is added according to the proportion of 1.0-1.5%. Adjusting the pH value to about 7.4 by 1 mol/L NaOH, and sterilizing for 20 min at 121 ℃ by high-pressure steam for later use.
2.2 preparation of drug stock solution
Accurately weighing 50mg of the sample to be detected respectively, adding into a sterilized 1.5mL centrifuge tube, adding 1mL DMSO to prepare 50mg/mL mother solution, and-40oAnd C, freezing and storing. Before use, the culture medium is added to be diluted to corresponding concentration for application after being thawed.
2.3 rejuvenation and purification of the Strain
(1) Taking out the glycerol tube containing the strain to be tested from a refrigerator at the temperature of-80 ℃;
(2) inoculating and culturing: after the bacterial liquid in the glycerin pipe is melted, sucking 200 uL of liquid in the superclean workbench by using a liquid-transferring gun
Putting the mixture into a sterilized PA bottle filled with 5mL of LB culture medium, and culturing for 12 h at 37 ℃ by a shaking table at 200 rpm;
(3) and (4) purity testing: dipping the cultured bacteria liquid on the poured LB solid plate by an inoculating loop in an ultra-clean workbench
Streaking, and culturing in a constant-temperature incubator at 37 ℃ for 12 h for purity test.
(4) Inoculation: picking a single colony from the purified plate in a clean bench to inoculate the colony containing 5mL of LB
Culturing in a liquid culture medium PA bottle at 37 deg.C with shaking table at 200 rpm for 12 h, storing at 4 deg.C as the bacterial liquid to be tested,
the product can be used within three days;
2.4 agar dilution method
Adding antibacterial drugs with different dosages into quantitative LB agar which is melted and cooled to about 50 ℃ to prepare flat plates containing the antibacterial drugs with different degressive concentrations, inoculating tested bacteria, and observing the growth condition of the bacteria after incubation so as to ensure that the minimum drug concentration contained in the agar plate for inhibiting the growth of the bacteria is MIC. The method has the advantages that the method can simultaneously measure the Minimum Inhibitory Concentration (MIC) of a plurality of strains on one flat plate, has reliable result and is easy to find the pollution bacteria.
(1) Preparing a drug-containing flat plate: taking the mother liquor 50μL，25μL，12.5μAdding L into 50 mL MH culture medium, pouring into flat plate in ultra-clean bench to obtain medicinal solution with thickness of 3 ~ 4 mmμg/mL，25μg/mL，12.5μg/mL of the drug-containing plate.
(2) Culturing two test bacteria (staphylococcus aureus and bacillus subtilis) and preparing a gradient diluent: the test bacteria were inoculated into a PA flask containing 5mL of LB medium and cultured at 37 ℃ for 12 hours with a shaker at 200 rpm. Diluting the cultured bacterial liquid to 10% with normal saline-1，10-2，10-3，10-4，10-5，10-6Six gradients of bacterial liquid.
(3) Sample application: in a clean bench, 1.5 percent of diluted bacteria liquid is suckedμL are dropped on the drug-containing flat plate in sequence,
there are 24 spots in a plate.
(4) Culturing: placing the plate with the spotted sample in a constant temperature incubator at 37 ℃ for culture, and observing bacterial colonies after the culture is finished
Growth conditions
And (3) bacteriostasis result:
the compound Stipulin only performs an antibacterial test on the bacillus subtilis, and has inhibitory activity on the bacillus subtilis when the concentration is 68.75 mug/mL; the compound Angusticornin B has bacteriostasis tests on staphylococcus aureus and bacillus subtilis, and has inhibitory activity on both of the staphylococcus aureus and the bacillus subtilis at the concentration of 56.25 mu g/mL.

Claims (3)

1. The synthesis method and the application of natural products Stipulin (I) and Angusticornin B (II), the structural formula of which is as follows:
。
2. the method for synthesizing natural products Stipulin (I) and Angusticornin B (II) and the use thereof as claimed in claim 1, wherein the synthetic route is as follows:
。
3. the natural products Stipulin and Angusticornin B are used for preparing antibacterial drugs.
CN201910919111.5A 2019-09-26 2019-09-26 Synthesis method and application of natural products Stipulin and Angusticornin B Pending CN110590521A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109053406A (en) * 2018-08-30 2018-12-21 中国农业科学院农产品加工研究所 Chalcone compound and its preparation method and application derived from alpha, beta-lonone

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109053406A (en) * 2018-08-30 2018-12-21 中国农业科学院农产品加工研究所 Chalcone compound and its preparation method and application derived from alpha, beta-lonone

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KAZUHIRO SUGAMOTO等: "Synthesis and antibacterial activity of chalcones bearing prenyl or geranyl groups from Angelica keiskei", 《TETRAHEDRON》 *
SUYU GAO等: "Growth inhibitory effect of paratocarpin E, a prenylated chalcone isolated from Euphorbia humifusa Wild., by induction of autophagy and apoptosis in human breast cancer cells", 《BIOORGANIC CHEMISTRY》 *
付林等: "5′位羟基异戊烯基查尔酮类天然产物的合成及其抗菌活性研究", 《有机化学》 *

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Application publication date: 20191220