CN116444473B - Compound and preparation method and application thereof - Google Patents
Compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN116444473B CN116444473B CN202211434909.9A CN202211434909A CN116444473B CN 116444473 B CN116444473 B CN 116444473B CN 202211434909 A CN202211434909 A CN 202211434909A CN 116444473 B CN116444473 B CN 116444473B
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- CN
- China
- Prior art keywords
- fraction
- compound
- salt
- pharmaceutically acceptable
- eluting
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 66
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 17
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 17
- 239000003208 petroleum Substances 0.000 claims abstract description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003480 eluent Substances 0.000 claims abstract description 12
- 238000009210 therapy by ultrasound Methods 0.000 claims abstract description 10
- 238000004440 column chromatography Methods 0.000 claims abstract description 9
- 238000001914 filtration Methods 0.000 claims abstract description 7
- -1 flavonoid compounds Chemical class 0.000 claims abstract description 6
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 6
- 238000001035 drying Methods 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 21
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- 239000002032 methanolic fraction Substances 0.000 claims description 9
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 claims description 8
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- 239000003814 drug Substances 0.000 claims description 7
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- 239000003795 chemical substances by application Substances 0.000 claims description 6
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- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 5
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- 239000007884 disintegrant Substances 0.000 claims description 3
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- 150000007529 inorganic bases Chemical class 0.000 claims description 3
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- 159000000003 magnesium salts Chemical class 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 3
- 239000003755 preservative agent Substances 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
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- 231100000002 MTT assay Toxicity 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical class C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 2
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- CNNRPFQICPFDPO-UHFFFAOYSA-N octacosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCO CNNRPFQICPFDPO-UHFFFAOYSA-N 0.000 description 2
- CJDAIJHZTKDLTJ-VABKMULXSA-N ohioensin f Chemical compound C([C@]1(O)C2=CC=CC=C2O2)C(=O)C3=C(O)C=C(O)C4=C3[C@H]1[C@@H]2C1=CC(O)=CC=C41 CJDAIJHZTKDLTJ-VABKMULXSA-N 0.000 description 2
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- HZYXFRGVBOPPNZ-UHFFFAOYSA-N UNPD88870 Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)=CCC(CC)C(C)C)C1(C)CC2 HZYXFRGVBOPPNZ-UHFFFAOYSA-N 0.000 description 1
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 1
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- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- SFKAGUQNIDQIQI-UHFFFAOYSA-N butyl octacosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)OCCCC SFKAGUQNIDQIQI-UHFFFAOYSA-N 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
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- VKOBVWXKNCXXDE-UHFFFAOYSA-N icosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCC(O)=O VKOBVWXKNCXXDE-UHFFFAOYSA-N 0.000 description 1
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- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 1
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- WCYLDNUDABIGOI-UHFFFAOYSA-N octadecyl octacosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCCCC WCYLDNUDABIGOI-UHFFFAOYSA-N 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
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- GBKSZCGTJFDPEG-UHFFFAOYSA-N pentyl octacosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)OCCCCC GBKSZCGTJFDPEG-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 235000017807 phytochemicals Nutrition 0.000 description 1
- 229930000223 plant secondary metabolite Natural products 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
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- SXJVFYZNUGGHRG-GDDJFQTCSA-N stigmast-5-ene-3beta,7alpha-diol Chemical compound C([C@H]1O)=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 SXJVFYZNUGGHRG-GDDJFQTCSA-N 0.000 description 1
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 description 1
- 229940032091 stigmasterol Drugs 0.000 description 1
- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- YECWTLGLNDDPGE-PIFXLSLCSA-N trichostatin C Chemical compound C(/[C@@H](C)C(=O)C=1C=CC(=CC=1)N(C)C)=C(/C)\C=C\C(=O)NO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O YECWTLGLNDDPGE-PIFXLSLCSA-N 0.000 description 1
- YECWTLGLNDDPGE-YPBJGXFISA-N trichostatin D Chemical compound C(/[C@@H](C)C(=O)C=1C=CC(=CC=1)N(C)C)=C(/C)\C=C\C(=O)NO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O YECWTLGLNDDPGE-YPBJGXFISA-N 0.000 description 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/40—Separation, e.g. from natural material; Purification
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- 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 discloses two flavonoid compounds in physcomitrella patens and a preparation method and application thereof, wherein the preparation method comprises the following steps: step one, taking mossPolytrichum commune) Crushing the L.ex Hedw, filtering the crushed L.ex Hedw by using acetone for at least three times under ultrasonic treatment, and carrying out ultrasonic treatment for at least 12 hours each time to obtain a concentrated solution; step two, performing silica gel column chromatography on the concentrated solution, eluting sequentially by using petroleum ether and ethyl acetate as an eluting system in a ratio of 20:1, 10:1,5:1,3:1 and 1:1, detecting and tracking according to TLC to obtain 6 fractions Fr 1-Fr 6, and taking a fraction Fr3 dry product; step three, 20%, 40% and 80% MeOH/H was used 2 O is used as eluent, and MCI column chromatography separation is carried out on the fraction Fr3 dry product. The compound obtained by the invention has good anti-breast cancer activity, and lays a foundation for the development and utilization of natural compounds in physcomitrella patens.
Description
Technical Field
The invention relates to a compound, a preparation method and application thereof, belonging to the technical field of natural medicines.
Background
Sphagnum macrophyllum (Tuma falcatum) Polytrichum commune L.ex Hedw. Belongs to the genus sphagnum of the family sphagnaceae of the class sphagnum. Plants are about 10-30 cm high and are often clustered into large colonies. Dark green at young and yellow brown at old. There is stem and leaf differentiation. The stem stands upright, and the lower part is provided with a plurality of pseudoroots. She Congsheng on the upper part of the stem, gradually thin and small, scaly, long needle-like, with teeth at the edge, protruding middle rib, composed of several layers of cells, leaf edge composed of one layer of cells, and leaf base sheath. The cervical ova apparatus and the sperm apparatus are respectively grown on the top of the stems of two plants (namely gametophytes). Mature sperm in the sperm cell moves in water in early spring, combines with egg cells in the neck egg cell to form a zygote, and germinates to form sporophytes, wherein the feet of the sporophytes extend into the neck egg cell to absorb nutrition. The capsule is long, the capsule is quadrangular, a large number of spores are formed in the capsule, the spores germinate into protonema, and the buds on the protonema grow into ligands (namely plant bodies). The plant is distributed nationwide and is used in mountain areas and plain areas. The whole herb is used as a medicine, and can clear heat and detoxify, cool blood and stop bleeding. Has effects of nourishing yin and tonifying deficiency. Can be used for treating cough, hematemesis, night sweat, etc.
Moss plants have a long history of use as medicinal plants in China. The bryophyte resources of China are very rich, so far, more than 50 bryophytes are applied in folk and clinic, and belong to the genus 39 of 25 families. The medicinal value of the physcomitrella patens is relatively early developed, and the physcomitrella patens is known as an effective anti-inflammatory medicinal plant. Studies on the phytochemicals of physcomitrella patens have also been reported, and Kunzler and Eichen-berger analyzed by TLC for betaine esters and phospholipids belonging to 8 species of 11 genus 12 moss plants (including physcomitrella patens) using dragndorff and molybdenum blue reagent, and found that these moss plants all contained betaine esters, PC and PE. Gametes of sphagnum megaterium identified several important chemical components in vivo including linoleic acid, linolenic acid and arachidonic acid. Chen Sheng et al reported that 13 compounds were isolated and identified from sphagnum calycarpa Polytrichum Commune L.ex Hedw from Guiyang City, guizhou: the composition comprises the following components of the composition, namely, the composition comprises the following components of reesei, methyl octacosanoate, butyl octacosanoate, amyl octacosanoate, beta-sitosterol, stearyl octacosanoate, nonadecanol eicosanoate, n-tetratriacontanol, n-octacosanol, stigmasterol, glycerol trioctanoate, 5, 7-dihydroxyl-4 '-methoxyl-3' -acetyl flavone and 3-oxo-30-carboxymethyl olean-12, 18-diene-28-carboxylic acid. Fu and the like, 11 compounds, which are 11-fold polymers of Communin A, communin B, ohioensin F, 6-acetyl indoline, 4-hydroxy-2-methoxybenzoic acid, 5-hydroxy-7-methoxy chromone, beta-D-furalactone, beta-sitosterol, 7alpha-hydroxysitosterol, ergosterol and ethylene glycol, p-hydroxybenzoic acid, 5, 7-dihydroxy-6-methoxycoumarin-7-O-beta-D-glucoside, sucrose, alpha-D-furalactone sugar, were isolated from Physcomitrella patens Polytrichum Commune L.ex Hedw of Tian Ping, natural protection area of Fengyang mountain, longquan, zhejiang province. Wherein Communoxin A and Communoxin B are two styryl dihydroflavonoids with novel structural skeletons, and Ohioensin F is a benzonaphthoxanthone derivative. However, no more styryl dihydroflavonoids, a process for preparing them and new applications are known.
Disclosure of Invention
In view of the above problems, an object of the present invention is to provide a compound isolated from sphagnum calycarpa or a pharmaceutically acceptable salt thereof, which is a styryl dihydroflavonoid compound.
Meanwhile, the invention provides a preparation method of the compound, and the preparation method can simultaneously obtain two compounds of the invention.
Meanwhile, the invention provides application of the compound or pharmaceutically acceptable salt thereof in preparation of an anti-breast cancer medicament.
In order to solve the technical problems, the invention adopts the following technical scheme:
a compound or a pharmaceutically acceptable salt thereof, having the structure of formula:
wherein R is selected from: -H or-OH.
The compound is selected from compounds of formula 1 or formula 2, and the specific structural formula is as follows:
the pharmaceutically acceptable salt is a salt of the compound of formula (I) with an organic or inorganic base.
The formed salt is sodium salt, potassium salt, calcium salt, ferric salt, magnesium salt, zinc salt, aluminum salt, barium salt or ammonium salt.
A process for the preparation of a compound comprising the steps of:
step one, taking dry moss (Polytrichum commune) L.ex Hedw, crushing, filtering at least three times by using acetone under ultrasonic treatment at room temperature, carrying out ultrasonic treatment for at least 12 hours each time, wherein the dosage of the acetone is 3-5 times of that of the moss each time, and concentrating an acetone extract to 1/400-1/300 of that of the acetone extract under reduced pressure at 40-45 ℃ to obtain a concentrated solution;
step two, performing silica gel column chromatography on the concentrated solution, sequentially eluting by using petroleum ether and ethyl acetate as elution systems in the proportions of 20:1, 10:1,5:1,3:1 and 1:1, wherein each gradient elution is 3-4 column volumes, the elution flow rate is 3-5mL/min, every 200-250 mL is connected with one bottle, 6 fractions Fr 1-Fr 6 are obtained according to TLC detection and tracking, and the fraction Fr3 is obtained, and after concentrating under reduced pressure at 40-45 ℃, the fraction Fr3 is dried to obtain a dry fraction Fr 3;
step three, 20%, 40% and 80% MeOH/H was used 2 O is used as eluent, each elution volume is 500mL, MCI column chromatography is carried out on the fraction Fr3 dry product, and 80% MeOH/H is collected 2 Concentrating and drying the O eluent to obtain 80% MeOH fraction;
step four, placing 80% MeOH fractions into a silica gel column, eluting with petroleum ether-acetone 8:1, 5:1,3:1 and 1:1 in sequence, eluting 4-5 column volumes per gradient, concentrating and merging each gradient to obtain 4 fractions Fr3.1-Fr3.4; collecting fraction Fr3.3, concentrating, and drying to obtain fraction Fr3.3;
dissolving the fraction Fr3.3 dry product with methanol, adopting a reversed phase chromatographic column method, taking 60% acetonitrile-water solution as a mobile phase, performing preparation liquid phase separation at a flow rate of 20mL/min, collecting chromatographic peaks with retention time of 19min, and drying to obtain a crude compound;
step six, purifying the crude product by a SephadexLH-20 column to obtain a compound 1;
step seven, collecting fraction Fr3.4, concentrating and drying to obtain fraction Fr3.4, subjecting the fraction Fr3.4 to preparative column chromatography, eluting with methanol-water 58:42, flowing at 10mL/min, and collecting chromatographic peak with retention time of 24min to obtain fraction Fr 3.4.2;
step eight, taking fraction Fr.3.4.2, drying and loading, eluting with semi-preparative column chromatography and acetonitrile-water 21:79 at a flow rate of 15mL/min, and collecting fraction with retention time of 30min to obtain compound 2.
In the second step, the silica gel is 200-300 meshes, the dosage is 850-1000 g, and the diameter-to-height ratio of the chromatographic column is: the height is 8-10 times of the diameter;
the thin layer plate for TLC detection is GF254, the developing agent is petroleum ether-acetone 10:1, and concentrated sulfuric acid ethanol solution is sprayed for developing color.
In the fourth step, the silica gel is 200-300 meshes, the dosage of the silica gel is 170-200 g, and the diameter-to-height ratio is 1:6-8.
The application of the compound or the pharmaceutically acceptable salt thereof in preparing the anti-breast cancer medicament.
An anti-breast cancer drug contains the above compound or pharmaceutically acceptable salt thereof.
An anti-breast cancer drug, further comprising a pharmaceutically acceptable carrier; the pharmaceutically acceptable carrier is selected from the group consisting of diluents, preservatives, fillers, flow control agents, permeation promoters, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, antibacterial agents, antifungal agents, lubricants and dispersing agents.
Compared with the prior art, the invention has the following advantages:
the invention separates two styryl dihydroflavonoid compounds from the physcomitrella patens, and the compound has good anti-breast cancer activity, and lays a foundation for the development and utilization of natural compounds in the physcomitrella patens.
Drawings
FIG. 1 is a schematic diagram of Compound 1 of the present invention 1 H-spectrum;
FIG. 2 is a diagram of Compound 1 of the present invention 13 C spectrum;
FIG. 3 is a diagram of Compound 2 of the present invention 1 H-spectrum;
FIG. 4 is a diagram of Compound 2 of the present invention 13 C spectrum.
Detailed Description
The invention will now be described in further detail with reference to the drawings and to specific examples. The following examples are only illustrative of the present invention and are not intended to limit the scope of the invention.
Moss source: the moss was collected in Duzhou city (latitude 26 ° 35'42.8 "N; longitude 107 ° 38' 32.1" E; altitude 1250 m) and identified as whole grass of physcomitrella patens (Polytrichum commune l.ex hedw.) by professor Zhao Jiancheng from the university of Hebei, hebei university of Hebei, national institute of university of Kong. The voucher specimen (HBZY 2019110402) was stored in the university student's life sciences laboratory system and evolution laboratory in river north.
Example 1
A compound or a pharmaceutically acceptable salt thereof, having the structure of formula:
wherein R is selected from: -H or-OH.
The compound is selected from compounds of formula 1 or formula 2, and the specific structural formula is as follows:
pharmaceutically acceptable salts are salts of the compounds of formula (I) with organic or inorganic bases.
The salt is sodium salt, potassium salt, calcium salt, ferric salt, magnesium salt, zinc salt, aluminum salt, barium salt or ammonium salt.
A process for the preparation of a compound comprising the steps of:
step one, taking Polytrichum commune L.ex Hedw 1.3kg of dry moss plant material, crushing, filtering with acetone at room temperature under ultrasonic treatment for three times, carrying out ultrasonic treatment for 12 hours each time, wherein the ultrasonic power is 100Hz, the dosage of acetone is 5L each time, and concentrating the acetone extract under reduced pressure at 45 ℃ to obtain 45g of concentrated solution;
step two, performing silica gel column chromatography on the concentrated solution, wherein the silica gel is 200-300 meshes, the dosage is 850g, and the diameter-to-height ratio of the chromatographic column is 1:8, 8; sequentially eluting with petroleum ether and ethyl acetate 20:1, 10:1,5:1,3:1 and 1:1 as elution systems, eluting 3 column volumes per gradient, wherein the elution flow rate is 3mL/min, sampling one bottle per 250mL, detecting and tracking according to TLC to obtain 6 fractions Fr 1-Fr 6, detecting a thin layer plate by TLC as GF254, developing with petroleum ether-acetone 10:1 as developing agent, spraying concentrated sulfuric acid ethanol solution, and mixing components with substantially identical thin layer behavior spots; concentrating fraction Fr3 under reduced pressure at 45deg.C, oven drying at 60deg.C to obtain fraction Fr3 dry product (6.8 g);
step three, 20%, 40% and 80% MeOH/H was used 2 O is an eluent, perThe elution volume is 500mL, the dry fraction Fr3 is subjected to MCI column chromatography separation, and the loading method comprises the following steps: after dissolving the dry fraction Fr3 with 50% methanol, loading, adsorbing for 3H, and sequentially using 20%, 40% and 80% MeOH/H 2 O elution, wherein the diameter-to-height ratio of the MCI column is 1:4, and the dosage of the MCI packing is 200g; collect 80% MeOH/H 2 O eluent, concentrating under reduced pressure at 45 ℃, oven drying at 50 ℃ to obtain 80% MeOH fraction (3.5 g);
dissolving 80% MeOH fraction with methanol, adding silica gel with the same weight as 80% MeOH fraction, stirring, drying in a 50 ℃ oven, placing in a silica gel column, wherein the silica gel is 200-300 meshes, the silica gel dosage is 170g, the diameter-to-height ratio is 1:6, eluting with petroleum ether-acetone 8:1, 5:1,3:1 and 1:1 in sequence, eluting 5 column volumes per gradient, concentrating and merging each gradient, and obtaining 4 fractions Fr3.1-Fr3.4; concentrating fraction Fr3.3 under reduced pressure at 45deg.C, oven drying at 50deg.C to obtain fraction Fr3.3 (550 mg);
dissolving the fraction Fr3.3 dry product with methanol, adopting a reversed phase chromatographic column method, adopting a reversed phase C18 column of Kromasil C18X 250mm, adopting a sample injection amount of 200mg, adopting an ultraviolet detection wavelength of 290nm, adopting a 60% acetonitrile-water solution as a mobile phase, adopting a flow rate of 20mL/min to prepare a liquid phase for separation, collecting chromatographic peaks with a retention time of 19min, concentrating under reduced pressure at 45 ℃, and drying at 50 ℃ to obtain a crude compound;
step six, purifying the crude product by a SephadexLH-20 column to obtain a compound 1 (8.1 mg); the diameter-height ratio of the SephadexLH-20 gel column is 1:10, the dosage of the SephadexLH-20 gel is 50g, the crude product is dissolved by chloroform-methanol=5:5, then the solution is filtered, the filtrate is loaded by a wet method, after loading, chloroform and chloroform-methanol=8:2 are respectively used for eluting 3 column volumes in sequence, and after chloroform-methanol=3: 7 elution 5 column volumes, chloroform-methanol=3 were collected: 7, concentrating the eluent under reduced pressure at 45 ℃ and drying in a 50 ℃ oven to obtain a compound 1 (8.1 mg);
the compound 1 is named as trichostatin C, and the English name is (2S, 7' Z) -2-phenyl-6-styryl chroman-4-one; compound 1 1 H spectrum 13 The C spectrum is shown in FIG. 1 and FIG. 2.
Step seven, taking a fraction Fr3.4, concentrating and drying to obtain a fraction Fr3.4 dry product, dissolving the fraction Fr3.4 dry product with methanol, filtering, reversely preparing a filtrate by using a column chromatography, wherein a reversed phase C18 column is Kromasil C1810 multiplied by 250mm, the sample injection amount is 100mg, the ultraviolet detection wavelength is 295nm, the methanol-water 58:42 is eluted, the flow rate is 10mL/min, and collecting chromatographic peaks with the retention time of 24min to obtain a fraction Fr 3.4.2;
step eight, taking fraction Fr.3.4.2, drying and loading, and carrying out semi-preparative column chromatography, wherein a reversed phase chromatographic column is SunfireTM C18 (10 multiplied by 250 mm), the sample injection amount is 50mg, the ultraviolet detection wavelength is 295nm, acetonitrile-water is 21:79, the flow rate is 15mL/min, and the fraction with the retention time of 30min is collected to obtain compound 2 (10.5 mg).
The compound 2 is named as trichostatin D, and the English name is (2S, 7 'E) -4' -hydroxy-2-phenyl-6-styryl chroman-4-one; compound 2 1 H spectrum 13 The C spectrum is shown in FIG. 3 and FIG. 4.
Compound 1 and compound 2 1 H spectrum 13 C spectrum (DMSO-d) 6 ) The data are shown in Table 1 below.
TABLE 1 Compounds 1 and 2 1 H NMR 13 C NMR data sheet
The application of the compound or the pharmaceutically acceptable salt thereof in preparing the breast cancer resisting medicine is provided.
An anti-breast cancer drug comprising the compound of this example or a pharmaceutically acceptable salt thereof.
An anti-breast cancer drug, further comprising a pharmaceutically acceptable carrier; the pharmaceutically acceptable carrier is selected from the group consisting of diluents, preservatives, fillers, flow control agents, permeation promoters, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, antibacterial agents, antifungal agents, lubricants and dispersing agents.
Pharmacological activity: the compounds have good anti-breast cancer activity.
Cell activity culture:
the human breast cancer cell lines MDA-MB-468, MDA-MB-231, BT-47 and MCF-7 are provided by cell libraries of Shanghai Biochemical and cell biology institute of China academy of sciences (Shanghai China). MCF-7 was cultured in MEM medium, and the remaining cell lines were cultured in L-15 medium. The medium was supplemented with penicillin/streptomycin (1:100, shandong deer harbor medicine Co., ltd., china) and 10% (V/V) fetal bovine serum (FBS; gibco, invitrogen Corp., USA). The cells were incubated at 37℃with 5% CO 2 Culturing in the environment.
MTT experiment:
preparation of 5×10 logarithmic growth phase cancer cells 4 /mL cell suspension. Cells were seeded into 96-well plates and 100 μl of cell suspension was added to each well. Compounds 1 and 2 were dissolved in fresh medium at eight concentrations of 0. Mu.M, 1.5625. Mu.M, 3.125. Mu.M, 6.25. Mu.M, 12.5. Mu.M, 25. Mu.M, 50. Mu.M and 100. Mu.M, respectively, and then sequentially added to 96-well plates, each concentration being repeated 3 times. After 48 hours of incubation in the incubator, each well of medium was aspirated and 100. Mu.L of 0.5mg/mL MTT solution was added. After 1 hour of incubation, the MTT solution was aspirated, and 200. Mu.L of DMSO was added to each well to dissolve the purple crystals of MTT. UV absorbance values were measured for each well using an enzyme-linked immunosorbent assay at a wavelength of 550 nm.
Experimental results:
the MTT assay results for Compound 1 are shown in Table 2 below.
Table 2 MTT experimental results table for compound 1
The experimental results above illustrate: compared with a blank control group, the compound 1 has stronger inhibition effect on breast cancer cell strains MDA-MB-468 and BT-47 than MDA-MB-231 and MCF-7, wherein the inhibition effect on the MDA-MB-468 cell strains is better.
The MTT assay results for Compound 2 are shown in Table 3 below.
Table 3 MTT experimental results table for compound 2
The experimental results above illustrate: the inhibitory effect of compound 2 on breast cancer cell lines was similar to that of compound 1. Compared with a blank control group, the compound 2 has stronger inhibition effect on breast cancer cell strains MDA-MB-468 and BT-47 than MDA-MB-231 and MCF-7, wherein the inhibition effect on the MDA-MB-468 cell strains is better.
Example 2
This embodiment differs from embodiment 1 only in that:
a process for the preparation of a compound comprising the steps of:
step one, taking 1kg of dry moss plant material (Polytrichum commune) L.ex Hedw, crushing into fragments, filtering four times with acetone under ultrasonic treatment at room temperature, performing ultrasonic power of 80Hz for 15 hours each time, using 3L of acetone each time, and concentrating the acetone extract under reduced pressure at 40 ℃ to obtain 40mL of concentrated solution;
step two, after dry sample mixing of the concentrated solution, silica gel column chromatography is carried out, the silica gel is 200-300 meshes, the dosage is 1000g, and the diameter-to-height ratio of the chromatographic column is 1:10, sequentially eluting by using petroleum ether and ethyl acetate as an eluting system of 20:1, 10:1,5:1,3:1 and 1:1, wherein each gradient elutes 4 column volumes, the eluting flow rate is 5mL/min, each 200mL is sampled and tracked according to TLC detection to obtain 6 fractions Fr 1-Fr 6, concentrating the fraction Fr3 at 40 ℃ under reduced pressure until the concentration, and drying the concentrated fraction Fr3 in a 50 ℃ oven to obtain a fraction Fr3 dry product;
step three, 20%, 40% and 80% MeOH/H was used 2 O is used as eluent, each elution volume is 500mL, MCI column chromatography is carried out on the fraction Fr3 dry product, and 80% MeOH/H is collected 2 Concentrating the O eluent under reduced pressure at 40deg.C, and oven drying at 50deg.C to obtain 80% meoh fraction;
step four, placing 80% MeOH fraction into a silica gel column, wherein the silica gel is 200-300 meshes, the silica gel dosage is 200g, the diameter-to-height ratio is 1:8, and petroleum ether-acetone is sequentially used for eluting with 8:1, 5:1,3:1 and 1:1, wherein each gradient is used for eluting for 4 column volumes, and each gradient is concentrated and combined to obtain 4 fractions Fr 3.1-Fr 3.4; concentrating the fraction Fr3.3 under reduced pressure at 40deg.C, and oven drying at 50deg.C to obtain fraction Fr3.3;
dissolving the fraction Fr3.3 dry product with methanol, adopting a reversed phase chromatographic column method, taking 60% acetonitrile-water solution as a mobile phase, performing preparation liquid phase separation at a flow rate of 20mL/min, collecting chromatographic peaks with retention time of 19min, concentrating under reduced pressure at 40 ℃, and drying in a 50 ℃ oven to obtain a crude compound;
step six, purifying the crude product by a SephadexLH-20 column to obtain a compound 1;
step seven, collecting fraction Fr3.4, concentrating under reduced pressure at 40 ℃ and drying in a 50 ℃ oven to obtain fraction Fr3.4 dry product, eluting the fraction Fr3.4 dry product by a preparation column chromatography, eluting with methanol-water 58:42 at a flow rate of 10mL/min, and collecting chromatographic peaks with retention time of 24min to obtain fraction Fr 3.4.2;
step eight, taking fraction Fr.3.4.2, drying and loading, eluting with semi-preparative column chromatography and acetonitrile-water 21:79 at a flow rate of 15mL/min, and collecting fraction with retention time of 30min to obtain compound 2.
Example 3
This embodiment differs from embodiment 1 only in that:
a process for the preparation of a compound comprising the steps of:
step one, taking 1kg of dry moss plant material (Polytrichum commune) L.ex Hedw, crushing into fragments, filtering with acetone at room temperature under ultrasonic treatment for five times, wherein the ultrasonic power is 50Hz, the ultrasonic power is 13h each time, the dosage of the acetone is 5L each time, and concentrating the acetone extract under reduced pressure at 40 ℃ to obtain 62.5mL of concentrated solution;
step two, after dry sample mixing of the concentrated solution, silica gel column chromatography is carried out, the silica gel is 200-300 meshes, the dosage is 900g, and the diameter-to-height ratio of the chromatographic column is 1:9, sequentially eluting by using petroleum ether and ethyl acetate as an eluting system of 20:1, 10:1,5:1,3:1 and 1:1, wherein each gradient elutes 4 column volumes, the eluting flow rate is 5mL/min, each 200mL is sampled and tracked according to TLC detection to obtain 6 fractions Fr 1-Fr 6, concentrating the fraction Fr3 at 40 ℃ under reduced pressure until the concentration is achieved, and drying the fraction Fr3 in a 50 ℃ oven to obtain a dry product;
step three, 20%, 40% and 80% MeOH/H was used 2 O is used as eluent, each elution volume is 500mL, MCI column chromatography is carried out on the fraction Fr3 dry product, and 80% MeOH/H is collected 2 Concentrating the O eluent under reduced pressure at 40 ℃, and drying in a baking oven at 50 ℃ to obtain 80% MeOH fraction;
step four, placing 80% MeOH fraction into a silica gel column, wherein the silica gel is 200-300 meshes, the silica gel dosage is 180g, the diameter-to-height ratio is 1:7, and sequentially eluting with petroleum ether-acetone 8:1, 5:1,3:1 and 1:1, wherein each gradient elutes 4 column volumes, and each gradient is concentrated and combined to obtain 4 fractions Fr 3.1-Fr 3.4; concentrating the fraction Fr3.3 under reduced pressure at 40deg.C, and oven drying at 50deg.C to obtain fraction Fr3.3;
dissolving the fraction Fr3.3 dry product with methanol, adopting a reversed phase chromatographic column method, taking 60% acetonitrile-water solution as a mobile phase, performing preparation liquid phase separation at a flow rate of 20mL/min, collecting chromatographic peaks with retention time of 19min, concentrating under reduced pressure at 40 ℃, and drying in a 50 ℃ oven to obtain a crude compound;
step six, purifying the crude product by a SephadexLH-20 column to obtain a compound 1;
step seven, collecting fraction Fr3.4, concentrating under reduced pressure at 40 ℃ and drying in a 50 ℃ oven to obtain fraction Fr3.4 dry product, eluting the fraction Fr3.4 dry product by a preparation column chromatography, eluting with methanol-water 58:42 at a flow rate of 10mL/min, and collecting chromatographic peaks with retention time of 24min to obtain fraction Fr 3.4.2;
step eight, taking fraction Fr.3.4.2, drying and loading, eluting with semi-preparative column chromatography and acetonitrile-water 21:79 at a flow rate of 15mL/min, and collecting fraction with retention time of 30min to obtain compound 2.
It should be appreciated that in the above description of exemplary embodiments of the invention, various features of the invention are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure and aiding in the understanding of one or more of the various inventive aspects. However, the disclosed method should not be construed as reflecting the intention that: i.e., the claimed invention requires more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive aspects lie in less than all features of a single foregoing disclosed embodiment. Thus, the claims following the detailed description are hereby expressly incorporated into this detailed description, with each claim standing on its own as a separate embodiment of this invention.
While the invention has been described with respect to a limited number of embodiments, those skilled in the art, having benefit of the above description, will appreciate that other embodiments are contemplated within the scope of the invention as described herein. Furthermore, it should be noted that the language used in the specification has been principally selected for readability and instructional purposes, and may not have been selected to delineate or circumscribe the inventive subject matter. Accordingly, many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the appended claims. The disclosure of the present invention is intended to be illustrative, but not limiting, of the scope of the invention, which is defined by the appended claims.
The foregoing is only a preferred embodiment of the invention, it being noted that: it will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the principles of the present invention, and such modifications and adaptations are intended to be comprehended within the scope of the invention.
Claims (9)
1. A compound or a pharmaceutically acceptable salt thereof, characterized by the following formula:
wherein R is selected from: -H or-OH.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a salt of a compound of formula (I) with an organic or inorganic base.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the salt formed is a sodium salt, potassium salt, calcium salt, iron salt, magnesium salt, zinc salt, aluminum salt, barium salt, or ammonium salt.
4. A process for the preparation of a compound according to claim 1, comprising the steps of:
taking dry moss Polytrichum commune L.ex Hedw, crushing, filtering at least three times by using acetone under ultrasonic treatment at room temperature, carrying out ultrasonic treatment for at least 12 hours each time, wherein the dosage of the acetone is 3-5 times of that of the moss each time, and concentrating the acetone extract to 1/400-1/300 of that of the acetone extract under reduced pressure at 40-45 ℃ to obtain concentrated solution;
step two, performing silica gel column chromatography on the concentrated solution, sequentially eluting by using petroleum ether and ethyl acetate as elution systems in the proportions of 20:1, 10:1,5:1,3:1 and 1:1, wherein each gradient elution is 3-4 column volumes, the elution flow rate is 3-5mL/min, every 200-250 mL is connected with one bottle, 6 fractions Fr 1-Fr 6 are obtained according to TLC detection and tracking, and the fraction Fr3 is obtained, and after concentrating under reduced pressure at 40-45 ℃, the fraction Fr3 is dried to obtain a dry fraction Fr 3;
step three, 20%, 40% and 80% MeOH/H was used 2 O is used as eluent, each elution volume is 500mL, MCI column chromatography is carried out on the fraction Fr3 dry product, and 80% MeOH/H is collected 2 Concentrating and drying the O eluent to obtain 80% MeOH fraction;
step four, placing 80% MeOH fractions into a silica gel column, eluting with petroleum ether-acetone 8:1, 5:1,3:1 and 1:1 in sequence, eluting 4-5 column volumes per gradient, concentrating and merging each gradient to obtain 4 fractions Fr3.1-Fr3.4; collecting fraction Fr3.3, concentrating, and drying to obtain fraction Fr3.3;
dissolving the fraction Fr3.3 dry product with methanol, adopting a reversed phase chromatographic column method, taking 60% acetonitrile-water solution as a mobile phase, performing preparation liquid phase separation at a flow rate of 20mL/min, collecting chromatographic peaks with retention time of 19min, and drying to obtain a crude compound;
step six, purifying the crude product by a SephadexLH-20 column to obtain a compound 1;
step seven, collecting fraction Fr3.4, concentrating and drying to obtain fraction Fr3.4, subjecting the fraction Fr3.4 to preparative column chromatography, eluting with methanol-water 58:42, flowing at 10mL/min, and collecting chromatographic peak with retention time of 24min to obtain fraction Fr 3.4.2;
step eight, taking fraction Fr.3.4.2, drying and loading, eluting with semi-preparative column chromatography and acetonitrile-water 21:79 at a flow rate of 15mL/min, and collecting fraction with retention time of 30min to obtain compound 2.
5. The method according to claim 4, wherein in the second step, silica gel is 200 to 300 mesh, the amount is 850 to 1000g, and the diameter-to-height ratio of the chromatographic column is: the height is 8-10 times of the diameter;
the thin layer plate for TLC detection is GF254, the developing agent is petroleum ether-acetone 10:1, and concentrated sulfuric acid ethanol solution is sprayed for developing color.
6. The preparation method according to claim 4, wherein in the fourth step, the silica gel is 200-300 meshes, the amount of the silica gel is 170-200 g, and the diameter-height ratio is 1:6-8.
7. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of an anti-breast cancer medicament.
8. An anti-breast cancer medicament comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
9. The anti-breast cancer drug of claim 8, further comprising a pharmaceutically acceptable carrier; the pharmaceutically acceptable carrier is selected from the group consisting of diluents, preservatives, fillers, flow control agents, permeation promoters, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, antibacterial agents, antifungal agents, lubricants and dispersing agents.
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| CN1784251A (en) * | 2003-02-26 | 2006-06-07 | 弗赖堡后期临床教学医学院 | Method for the production of flavonoid-containing compositions and use thereof |
| CN108524554A (en) * | 2018-07-16 | 2018-09-14 | 西安文理学院 | A kind of method of general flavone in ultrasonic wave assisted extraction common polytrichum herb |
| CN114671841A (en) * | 2022-04-28 | 2022-06-28 | 深圳大学 | Flavanone compound and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1784251A (en) * | 2003-02-26 | 2006-06-07 | 弗赖堡后期临床教学医学院 | Method for the production of flavonoid-containing compositions and use thereof |
| CN108524554A (en) * | 2018-07-16 | 2018-09-14 | 西安文理学院 | A kind of method of general flavone in ultrasonic wave assisted extraction common polytrichum herb |
| CN114671841A (en) * | 2022-04-28 | 2022-06-28 | 深圳大学 | Flavanone compound and preparation method and application thereof |
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