CN116063264A - Preparation method of compound for improving endothelial dysfunction - Google Patents
Preparation method of compound for improving endothelial dysfunction Download PDFInfo
- Publication number
- CN116063264A CN116063264A CN202310361478.6A CN202310361478A CN116063264A CN 116063264 A CN116063264 A CN 116063264A CN 202310361478 A CN202310361478 A CN 202310361478A CN 116063264 A CN116063264 A CN 116063264A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound shown
- silica gel
- column chromatography
- compound
- 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.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 206010048554 Endothelial dysfunction Diseases 0.000 title claims abstract description 8
- 230000008694 endothelial dysfunction Effects 0.000 title claims abstract description 8
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 claims abstract description 24
- 229930003944 flavone Natural products 0.000 claims abstract description 24
- 150000002212 flavone derivatives Chemical class 0.000 claims abstract description 24
- 235000011949 flavones Nutrition 0.000 claims abstract description 24
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000002023 wood Substances 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 11
- 239000011630 iodine Substances 0.000 claims abstract description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000000126 substance Substances 0.000 claims abstract description 10
- 230000009471 action Effects 0.000 claims abstract description 8
- 230000008569 process Effects 0.000 claims abstract description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 238000010898 silica gel chromatography Methods 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000003480 eluent Substances 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 3
- 239000002535 acidifier Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 16
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 66
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 48
- 239000002609 medium Substances 0.000 description 27
- 239000000243 solution Substances 0.000 description 26
- 239000012224 working solution Substances 0.000 description 17
- 239000006180 TBST buffer Substances 0.000 description 16
- 238000004113 cell culture Methods 0.000 description 14
- 238000005119 centrifugation Methods 0.000 description 14
- 239000008188 pellet Substances 0.000 description 14
- 229940079593 drug Drugs 0.000 description 13
- 238000005259 measurement Methods 0.000 description 12
- 230000004927 fusion Effects 0.000 description 10
- 229940045109 genistein Drugs 0.000 description 10
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Natural products C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 description 10
- 235000006539 genistein Nutrition 0.000 description 10
- ZCOLJUOHXJRHDI-CMWLGVBASA-N genistein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000011550 stock solution Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000001962 electrophoresis Methods 0.000 description 8
- 238000000751 protein extraction Methods 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- BEVHTVRRVVEMEF-UHFFFAOYSA-N [6'-acetyloxy-4-amino-2',7'-difluoro-5-(methylamino)-3-oxospiro[2-benzofuran-1,9'-xanthene]-3'-yl] acetate Chemical compound C12=CC(F)=C(OC(C)=O)C=C2OC2=CC(OC(C)=O)=C(F)C=C2C21OC(=O)C1=C(N)C(NC)=CC=C21 BEVHTVRRVVEMEF-UHFFFAOYSA-N 0.000 description 6
- 239000006143 cell culture medium Substances 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 6
- 230000037361 pathway Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 5
- 241000205585 Aquilegia canadensis Species 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 229940098773 bovine serum albumin Drugs 0.000 description 4
- 230000009089 cytolysis Effects 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 238000003384 imaging method Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical class FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 235000020183 skimmed milk Nutrition 0.000 description 4
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- 235000021314 Palmitic acid Nutrition 0.000 description 3
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 3
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 3
- 239000007850 fluorescent dye Substances 0.000 description 3
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FBUBVLUPUDBFME-UHFFFAOYSA-N Xanthoxylin Chemical compound COC1=CC(O)=C(C(C)=O)C(OC)=C1 FBUBVLUPUDBFME-UHFFFAOYSA-N 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 241000411851 herbal medicine Species 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- JVTZFYYHCGSXJV-UHFFFAOYSA-N isovanillin Chemical compound COC1=CC=C(C=O)C=C1O JVTZFYYHCGSXJV-UHFFFAOYSA-N 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 235000019624 protein content Nutrition 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 238000002073 fluorescence micrograph Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
Images
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
- C07D311/30—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 not hydrogenated in the hetero ring, e.g. flavones
-
- 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
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Abstract
The invention relates to the technical field of medicine synthesis, and particularly provides a preparation method of a compound for improving endothelial dysfunction, which is characterized in that a compound shown in a formula 1 and a compound shown in a formula 2 are reacted under the action of a catalyst to obtain a compound shown in a formula 3, then the compound shown in the formula 3 and the compound shown in a formula 4 are reacted under the action of a catalyst, acidized to obtain a compound shown in a formula 5, and then the compound shown in the formula 5 is reacted with iodine simple substance in the presence of pyridine to obtain 4' -methyl ether golden-wood flavone. The method has the advantages of reasonable process route, easily available raw materials, simple operation and reduced production cost, and is an economic method for preparing the 4' -methyl ether golden-wood flavone in a large scale.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a preparation method of a compound for improving endothelial dysfunction.
Background
China has rich Chinese herbal medicine resources, extracts and purifies natural micromolecular medicaments which are hundreds of thousands of, and provides a plurality of precious wealths for human beings. Flavonoid medicines are compounds extracted from traditional Chinese herbal medicines and have various biological and pharmacological characteristics, including anticancer, antioxidant, osteoporosis resisting, antiinflammatory, antiaging, etc. The 4' -methyl ether golden-wood flavone is a biflavanoid compound separated from honeysuckle, has been researched and found to have important treatment effect in the endothelial injury of diseases, and provides opportunities for application in the treatment fields of cardiovascular diseases, erection dysfunction and the like. The existing 4' -methyl ether golden-wood flavone is obtained from honeysuckle plants by a natural extraction method, and the yield is only 0.025 percent. If the honeysuckle is required to be obtained in large scale, the preparation is complex, the economic cost is high, and a large amount of honeysuckle raw materials (from the aspect of environmental protection) are required, so that the further commercial application is limited. Aiming at the problem of obtaining the intermediate 4 '-methyl ether golden-wood flavone, the method for synthesizing the 4' -methyl ether golden-wood flavone has the advantages of easily obtained raw materials, low cost, mild reaction conditions, simple and convenient operation and easy realization of industrial production.
Disclosure of Invention
Therefore, the invention aims to provide the preparation method of the 4' -methyl ether golden-wood flavone, which has the advantages of simple preparation process, higher product purity and yield, low cost and easy realization of industrial production.
Therefore, the invention provides the following technical scheme:
the invention provides a preparation method of 4' -methyl ether golden-wood flavone, which comprises the following steps:
(1) Reacting a compound shown in a formula 1 with a compound shown in a formula 2 under the action of a catalyst to obtain a compound shown in a formula 3;
(2) Reacting the compound shown in the formula 3 with the compound shown in the formula 4 under the action of a catalyst, and acidifying to obtain a compound shown in the formula 5;
(3) Reacting a compound shown in a formula 5 with an iodine simple substance in the presence of pyridine to obtain 4' -methyl ether golden-wood flavone;
further, in the step (1), the adopted catalyst is anhydrous potassium carbonate; and/or the molar ratio of the compound shown in the formula 1 to the compound shown in the formula 2 is 60-66:70-75.
Further, in the step (1), the temperature of the reaction is 75-85 ℃.
Further, in the step (1), the reaction is performed under a nitrogen atmosphere. The reaction solvent was Dimethylformamide (DMF).
Further, in the step (1), the reaction is followed by cooling the reaction product with water and chloroform (CHCl) 3 ) Extracting, drying the organic layer, and purifying by silica gel column chromatography to obtain pure product.
Preferably, in the step (1), the volume ratio of the eluent used in the silica gel column chromatography is 2:8-4:6 ethyl acetate and hexane.
Further, in the step (2), the catalyst is potassium hydroxide; and/or, the acidifying agent adopted in the acidifying process is 4-8M hydrochloric acid; and/or, carrying out the reaction in an ice bath; and/or the molar ratio of the compound shown in the formula 3 to the compound shown in the formula 4 is 1:2-4.
Further, in the step (2), the reaction solvent is ethanol (EtOH).
In the step (2), the reaction is further carried out by decompressing and filtering the reactant, and purifying by silica gel column chromatography to obtain a pure product.
Preferably, in the step (2), the volume ratio of the eluent used in the silica gel column chromatography is 2:8-4:6 ethyl acetate with hexane.
Further, in the step (3), the reaction temperature is 75-85 ℃ and the reaction time is 20-30h; and/or, in the step (3), the molar ratio of the compound shown in the formula 5 to the iodine simple substance is 1:1.5-2.5; and/or, in the step (3), adding a sodium thiosulfate solution into the reactant to remove the excessive iodine simple substance.
Further, in the step (3), the reaction further comprises adding a reactant into dichloromethane (CH) 2 Cl 2 ) Extracting, washing with water, drying the organic layer, and purifying by silica gel column chromatography to obtain pure product.
Preferably, in the step (3), the volume ratio of the eluent used in the silica gel column chromatography is 7:3-9: ethyl acetate and hexane of 1.
The technical scheme of the invention has the following advantages:
1. the preparation method of 4 '-methyl ether golden-wood flavone provided by the invention is characterized in that a compound shown in a formula 1 and a compound shown in a formula 2 are reacted under the action of a catalyst to obtain a compound shown in a formula 3, then the compound shown in the formula 3 and the compound shown in a formula 4 are reacted under the action of a catalyst, acidized to obtain a compound shown in a formula 5, and then the compound shown in the formula 5 reacts with iodine simple substance in the presence of pyridine (iodine substitution and then elimination reaction) to obtain the 4' -methyl ether golden-wood flavone.
2. In the preparation method of 4' -methyl ether golden-wood flavone, in the preferred embodiment, the reaction temperature is controlled to be 75-85 ℃ and the reaction time is controlled to be 20-30h in the step (3); or controlling the mole ratio of the compound shown in the formula 5 to the iodine simple substance to be 1:1.5-2.5 can further improve the yield of 4' -methyl ether golden-wood flavone.
3. According to the preparation method of 4' -methyl ether golden-wood flavone, the pure substances can be obtained through simple extraction and silica gel column purification in each step, and in the preferred embodiment, in the step (1) or the step (2), the eluent adopted by the silica gel column chromatography is in a volume ratio of 2:8-4:6 ethyl acetate and hexane; the eluent adopted by the silica gel column chromatography in the step (3) is 7 in volume ratio: 3-9:1 and hexane are beneficial to obtaining more pure matters with higher purity.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is a mass spectrum of the objective 4' -methyl ether golden-wood flavone obtained in example 1, wherein the upper graph shows negative ions (M-H), and the lower graph shows positive ions (M+H);
FIG. 2 is an H-spectrum nuclear magnetic resonance spectrum of the objective product 4' -methyl ether genistein prepared in example 1;
FIG. 3 is a C-spectrum nuclear magnetic resonance spectrum of the objective product 4' -methyl ether genistein prepared in example 1;
FIG. 4 is a fluorescence microscope image in Experimental example 1;
FIG. 5 shows the effect of 4' -methyl ether genistein on AKT-eNOS pathway in Experimental example 2;
FIG. 6 is a graph showing the effect of 4' -methyl ether genistein on EGFR-AKT pathway in Experimental example 2;
FIG. 7 shows the effect of 4' -methyl ether genistein on EGFR-AKT-eNOS pathway in Experimental example 3;
FIG. 8 is a graph showing the effect of 4' -methyl ether genistein on rapid phosphorylation in Experimental example 4;
FIG. 9 shows the effect of 4' -methyl ether genistein on endothelial dysfunction due to palmitic acid in Experimental example 5.
Detailed Description
The following examples are provided for a better understanding of the present invention and are not limited to the preferred embodiments described herein, but are not intended to limit the scope of the invention, any product which is the same or similar to the present invention, whether in light of the present teachings or in combination with other prior art features, falls within the scope of the present invention.
The specific experimental procedures or conditions are not noted in the examples and may be followed by the operations or conditions of conventional experimental procedures described in the literature in this field. The reagents or apparatus used were conventional reagent products commercially available without the manufacturer's knowledge.
Example 1
The embodiment provides a preparation method of 4' -methyl ether golden-wood flavone, which comprises the following reaction equation and preparation method:
(1) A mixture of isovanillin (10 g,65.8 mmol) and anhydrous potassium carbonate (13.62 g,98.6 mmol) was added to dry DMF under nitrogen, and 4-fluorobenzaldehyde (8.96 g,72.2 mmol) was added. The mixture was heated at 80 ℃ with stirring until all starting material was consumed (monitored by TLC). The reaction was then cooled at room temperature, 400℃ 400 mL cold water was added, and 3X 400 mL of CHCl was used 3 The mixture was extracted. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The resulting residue was purified by silica gel column chromatography (EtOAc/hexane, volume ratio 3:7) as an eluent to obtain 14.96g (89%) of a pale yellow solid (compound represented by formula 3).
(2) To 12.12g (47.4 mmol) of the compound represented by formula 3 in EtOH (1.5L) was added 18.6g (94.8 mmol) of 2' -hydroxy-4 ',6' -dimethoxyacetophenone (compound represented by formula 4). The solution was cooled in an ice bath and powdered potassium hydroxide (10.6 g,188.7 mmol) was then added. After stirring overnight, the reaction mixture was diluted with ice water (1L) and acidified with 6M HCl. The precipitate formed as a yellow solid which was filtered under reduced pressure and then rinsed with water. The crude product was obtained as a yellow solid. Purification by column chromatography on silica gel (EtOAc/hexane, 3:7 by volume) afforded 21g (75%) of a pale yellow solid (compound of formula 5).
(3) To a stirred solution of the compound of formula 5 (14.4 g,23.5 mmol) in 15mL of pyridine was added 12g (46.3 mmol) of iodine, and the mixture was heated to 80℃while stirring 24. 24 h. The reaction was cooled to room temperature and a cold solution of sodium thiosulfate was added to the reaction mixture until all the excess iodine was consumed. Using 3X 800 mL CH 2 Cl 2 The obtained organic layer was extracted, washed with 800. 800 mL water, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the crude reaction mixture was purified by silica gel column chromatography with 8:2 volume ratio EtOAc/hexanes to give the compound of formula 6 (10 g, 70%) as a yellow solid.
The target product is successfully synthesized through the reaction, and the structure identification of the target product is carried out through nuclear magnetism and mass spectrum detection, so that the natural structure of the 4' -methyl ether golden-wood flavone is met, and the natural structure is shown in figures 1-3.
The purity of the 4' -methyl ether golden-wood flavone is measured by an HPLC normalization method, and the content is 99 percent.
Experimental example 1
1. Reagent
PA solution: a 10% solution of fatty acid-free bovine serum albumin (Bovine serum albumin, BSA) was first prepared using deionized water as the solvent. 512.8. 512.8 mg of powdery PA is completely dissolved in 10.0 mL of absolute ethanol (concentration: 200 mM) by a vortex method, the PA solution and 10% BSA are mixed according to the volume ratio of 1:19 at 55 ℃ to prepare 10mM of PA working solution, the PA working solution is sterile filtered by a microporous filter membrane with 0.45 mu m and 0.22 mu m, and the PA working solution is packaged and stored at-20 ℃.
S-MF solution: 5.5248mg of 4 '-methylether golden-wood flavone (Synthesized 4' -O-methylchloroflavone, S-MF) Synthesized in example 1 was dissolved in 1mL of dimethyl sulfoxide (Dimethyl sulfoxide, DMSO) to prepare a drug stock solution of 10mM, and then different volumes of the drug stock solution were added to the complete medium according to the required working concentration, to obtain a complete medium containing different concentrations of S-MF.
MF solution: the naturally extracted 4' -methyl ether golden-wood flavone (MF, purchased from Beijing-Bettrey biomedical technology Co., ltd.) was weighed and dissolved in DMSO to prepare a 10mM drug stock solution, and then different volumes of drug stock solution were added to the medium according to the required working concentration to obtain a complete medium containing MF at different concentrations.
2. Cell culture and group administration
Human Umbilical Vein Endothelial Cells (HUVECs) were cultured at 37deg.C in 5% CO 2 Is a conventional humidity sterile environment. Changing the culture solution every 2 days, and when the cells grow to 80-90% of fusion degree, according to the following steps: 3 proportion passage. Cells (cell density 50%, medium volume 2 mL) were inoculated into 6-well cell culture plates before cell intervention, 24-h (fusion degree about 70-80%). Randomly divided into 3 groups of 3 wells each, 2mL of cell fluid per well (cell concentration 10 6 and/mL).
DMSO group: after centrifugation, a cell pellet was obtained and the cells were resuspended in 2mL of complete medium containing 0.1% DMSO and further cultured 24 h.
MF group: after centrifugation, a cell pellet was obtained and the cells were resuspended in 2mL of complete medium containing 1.0 μm MF and cultured further 24 h.
S-MF group: after centrifugation, a cell pellet was obtained and the cells were resuspended in 2mL of complete medium containing 1.0. Mu.M S-MF and cultured for 24 further h.
3. NO fluorescent probe detection
The NO fluorescent probe DAF-FM DA was configured 24 hours after treatment with the different drugs according to the disclosure of DAF-FM DA (NO fluorescent probe) kit (manufacturer: shanghai bi yun biotechnology limited). And (3) diluting the DAF-FM DA stock solution with the DAF-FM DA diluent to prepare a working solution, wherein the final concentration is 5 mu M. The cell culture medium is removed from each group of cells, and a suitable volume of diluted DAF-FM DA working solution is added to fully cover the cells. Incubate in cell incubator at 37℃for 20 min. The cells were washed three times with sterile phosphate buffer to remove substantially all DAF-FM DA that did not enter the cells. The intracellular fluorescence intensity was then observed using a fluorescence microscope.
4. Experimental results
As can be seen from the results of FIG. 4, 4 '-methyl ether genistein (S-MF, 1.0. Mu.M) synthesized in example 1 of the present invention was able to increase NO production compared with the control (DMSO) group, similarly to the naturally extracted 4' -methyl ether genistein (MF, 1.0. Mu.M).
Experimental example 2
1. Reagent: the same as in experimental example 1.
2. Cell culture and group administration
HUVECs are cultured at 37deg.C in 5% CO 2 Is a conventional humidity sterile environment. Changing the culture solution every 2 days, and when the cells grow to 80-90% of fusion degree, according to the following steps: 3 proportion passage. Cells (cell density 50%, medium volume 2 mL) were inoculated into 6-well cell culture plates before cell intervention, 24-h (fusion degree about 70-80%). Randomly divided into 5 groups of 3 wells each, 2mL of cell fluid per well (cell concentration 10 6 and/mL).
Experimental groups 1-4: after centrifugation, a cell pellet was obtained, and the cells were resuspended in 2mL of complete medium containing S-MF at different concentrations (0.04 μm, 0.2 μm, 1 μm, 5 μm) respectively, and continued to be cultivated 24 h.
DMSO group: after centrifugation, a cell pellet was obtained and the cells were resuspended in 2mL of complete medium containing 0.1% DMSO and further cultured 24 h.
3. Test method
After each group of cells is treated for 24 hours by different medicines, cell culture solution is removed, protein extraction and concentration measurement are carried out after lysis, and the protein extraction and concentration measurement are carried out according to the instruction of a kit (name: BCA protein concentration measurement kit, manufacturer: shanghai Biyun Tian biotechnology Co., ltd.). 10% SDS-PAGE separating gel was prepared. Electrophoresis conditions: 80 V constant pressure electrophoresis is carried out for 30 min, and then 120V constant pressure separation is carried out for 90 min. Electric conversion conditions: 300 mA constant current transfer film 1.5. 1.5 h. 5% skim milk was prepared with TBST and blocked at room temperature for 1 h. The target primary antibody working solution was prepared using TBST and incubated overnight at 4 ℃. The TBST buffer was washed 3 times. Preparing secondary antibody working solution corresponding to the species, and placing a shaking table at room temperature of 1-h. The TBST buffer was washed 3 times. Images were acquired by the imaging system after ECL chemiluminescence.
4. Test results
As can be seen from the results of FIG. 5, 4' -methyl ether jinlian flavone synthesized in example 1 of the present invention can activate AKT-eNOS pathway, and phosphorylated eNOS and AKT expression are increased, and concentration dependence is exhibited. Compared with the DMSO group, the protein contents after the S-MF treatment of 0.04 mu M and 0.2 mu M show significant differences,* Pvalue of<0.05。
From the results of fig. 6, it can be seen that 4' -methyl ether jinline synthesized in example 1 of the present invention can activate EGFR-AKT pathway, and phosphorylated EGFR and AKT expression are significantly increased, and concentration dependence is exhibited. The protein contents after S-MF treatment of 0.04 mu M-5 mu M show significant differences,* Pvalue of<0.05。
Experimental example 3
1. Reagent: the same as in experimental example 1.
2. Cell culture and group administration
HUVECs are cultured at 37deg.C in 5% CO 2 Is a conventional humidity sterile environment. Changing the culture solution every 2 days, and when the cells grow to 80-90% of fusion degree, according to the following steps: 3 proportion passage. Cells (cell density 50%, medium volume 2 mL) were inoculated into 6-well cell culture plates before cell intervention, 24-h (fusion degree about 70-80%). Randomly divided into 6 groups of 3 wells each, 2mL of cell fluid per well (cell concentration 10 6 and/mL).
Experimental groups 1-4: after centrifugation, cell pellets are obtained, 2mL of complete medium containing S-MF with different concentrations (0.04 [ mu ] M, 0.2 [ mu ] M, 1 [ mu ] M and 5 [ mu ] M) are used for resuspension of cells, pretreatment is carried out for 1h, and 50 [ mu ] L of PA working solution is added, so that the final concentration of PA in the cell culture medium is 250 [ mu ] M. Cultivation was continued 24 h.
Blank control (bsa+dmso): after centrifugation, a cell pellet was obtained, and the cells were resuspended in 2mL of complete medium containing 0.1% DMSO, pretreated for 1h, and then 50. Mu.L of 10% BSA solution was added. Cultivation was continued 24 h.
Model group (pa+dmso): after centrifugation, a cell pellet was obtained, cells were resuspended in 2mL of complete medium containing 0.1% DMSO, pretreated for 1h, and then 50. Mu.L of PA working solution was added to give a final cell culture medium PA concentration of 250. Mu.M. Cultivation was continued 24 h.
3. Test method
After each group of cells is treated for 24 hours by different medicines, cell culture solution is removed, protein extraction and concentration measurement are carried out after lysis, and the protein extraction and concentration measurement are carried out according to the instruction of a kit (name: BCA protein concentration measurement kit, manufacturer: shanghai Biyun Tian biotechnology Co., ltd.). 10% SDS-PAGE separating gel was prepared. Electrophoresis conditions: 80 V constant pressure electrophoresis is carried out for 30 min, and then 120V constant pressure separation is carried out for 90 min. Electric conversion conditions: 300 mA constant current transfer film 1.5. 1.5 h. 5% skim milk was prepared with TBST and blocked at room temperature for 1 h. The target primary antibody working solution was prepared using TBST and incubated overnight at 4 ℃. The TBST buffer was washed 3 times. Preparing secondary antibody working solution corresponding to the species, and placing a shaking table at room temperature of 1-h. The TBST buffer was washed 3 times. Images were acquired by the imaging system after ECL chemiluminescence.
4. Test results
As can be seen from the results of FIG. 7, EGFR, AKT and eNOS content in the model group were significantly reduced as compared with that in the blank groupp value<0.05) Compared with the model group, the EGFR, AKT and eNOS contents of the experimental groups 1-4 are obviously improvedp value<0.05) It was demonstrated that concentration-dependent S-MF could activate EGFR-AKT-eNOS pathway, saving endothelial dysfunction caused by palmitic acid.
Experimental example 4
1. Reagent: the same as in experimental example 1.
2. Cell culture and group administration
HUVECs are cultured at 37deg.C in 5% CO 2 Is a conventional humidity sterile environment. Changing the culture solution every 2 days, and when the cells grow to 80-90% of fusion degree, according to the following steps: 3 proportion passage. Cells (cell density 50%, medium volume 2 mL) were inoculated into 6-well cell culture plates before cell intervention, 24-h (fusion degree about 70-80%). Randomly divided into 6 groups of 3 wells,2mL per well (cell concentration 10) 6 and/mL).
Experimental groups 1-5: after centrifugation, a cell pellet was obtained, and the cells were resuspended in 2mL of complete medium containing 1.0. Mu.M S-MF, and treated for 1min, 3min, 5min, 10min, and 15min, respectively.
Control group (DMSO): after centrifugation, a cell pellet was obtained and the cells were resuspended in 2mL of complete medium containing 0.1% DMSO and treated for 15min.
3. Test method
After each group of cells is treated for 24 hours by different medicines, cell culture solution is removed, protein extraction and concentration measurement are carried out after lysis, and the protein extraction and concentration measurement are carried out according to the instruction of a kit (name: BCA protein concentration measurement kit, manufacturer: shanghai Biyun Tian biotechnology Co., ltd.). 10% SDS-PAGE separating gel was prepared. Electrophoresis conditions: 80 V constant pressure electrophoresis is carried out for 30 min, and then 120V constant pressure separation is carried out for 90 min. Electric conversion conditions: 300 mA constant current transfer film 1.5. 1.5 h. 5% skim milk was prepared with TBST and blocked at room temperature for 1 h. The target primary antibody working solution was prepared using TBST and incubated overnight at 4 ℃. The TBST buffer was washed 3 times. Preparing secondary antibody working solution corresponding to the species, and placing a shaking table at room temperature of 1-h. The TBST buffer was washed 3 times. Images were acquired by the imaging system after ECL chemiluminescence.
4. Test results
As can be seen from the results of FIG. 8, the p-EGFR and p-AKT contents of the experimental group were significantly improved after 3min of S-MF treatment as compared with the control groupp value<0.05) The S-MF treatment for 3min can play a role, and shows a significant difference. 4' -methyl ether golden-wood flavone can regulate EGFR and AKT rapid phosphorylation.
Experimental example 5
1. Reagent
PA solution: a 10% solution of fatty acid-free bovine serum albumin (Bovine serum albumin, BSA) was first prepared using deionized water as the solvent. Then, 512.8. 512.8 mg of powdery PA was completely dissolved in 10.0. 10.0 mL of absolute ethanol (concentration: 200 mM) by vortex method, and at 55℃PA solution and 10% BSA were mixed in a volume ratio of 1:19 to prepare 10mM of PA working solution, which was sterile-filtered with 0.45 μm and 0.22 μm microporous filter membrane, and sub-packaged and stored at-20 ℃.
S-MF solution: 5.5248mg of the 4' -methyl ether golden-wood flavone synthesized in example 1 was dissolved in 1mL of DMSO to prepare a 10mM stock solution of the drug, and then different volumes of stock solution of the drug were added to the complete medium according to the required working concentration to obtain a complete medium containing 5. Mu.M of S-MF.
S-mf+ag1478 solution: the 4' -methyl ether genistein synthesized in example 1 and AG1478 (purchased from MedChemExpress Corp. Shanghai) were weighed and dissolved in DMSO to prepare 10mM stock solution of S-MF and 2mM AG1478, and then different volumes of the stock solution of the drug were added to the complete medium according to the required working concentration to obtain the complete medium containing 5. Mu.M of S-MF and 1. Mu.M AG 1478.
2. Cell culture and group administration
HUVECs are cultured at 37deg.C in 5% CO 2 Is a conventional humidity sterile environment. Changing the culture solution every 2 days, and when the cells grow to 80-90% of fusion degree, according to the following steps: 3 proportion passage. Cells (cell density 50%, medium volume 2 mL) were inoculated into 6-well cell culture plates before cell intervention, 24-h (fusion degree about 70-80%). Randomly divided into 4 groups of 3 wells each, 2mL of cell fluid per well (cell concentration 10 6 and/mL).
Experimental group 1 (pa+s-MF): after centrifugation, a cell pellet was obtained, cells were resuspended in 2mL of complete medium containing 5 μm S-MF, pretreated 1h, and then 50 μlpa working fluid was added to give a final cell culture medium PA concentration of 250 μm. Cultivation was continued 24 h.
Experimental group 2 (pa+s-mf+ag 1478): after centrifugation, a cell pellet was obtained, cells were resuspended in 2mL of complete medium containing 5 μm S-MF and 1 μm AG1478, pretreated with 1h, and then 50 μlpa working fluid was added to give a final cell culture medium PA concentration of 250 μm. Cultivation was continued 24 h.
Blank control (bsa+dmso): after centrifugation, a cell pellet was obtained, cells were resuspended in 2mL of complete medium containing 0.1% DMSO, pretreated with 1h, and then 50. Mu.L of 10% BSA solution was added. Cultivation was continued 24 h.
Model group (pa+dmso): after centrifugation, a cell pellet was obtained, cells were resuspended in 2mL of complete medium containing 0.1% DMSO, pretreated with 1h, and then 50. Mu.L of PA working solution was added to give a final cell culture medium PA concentration of 250. Mu.M. Cultivation was continued 24 h.
3. Test method
After each group of cells is treated for 24 hours by different medicines, cell culture solution is removed, protein extraction and concentration measurement are carried out after lysis, and the protein extraction and concentration measurement are carried out according to the instruction of a kit (name: BCA protein concentration measurement kit, manufacturer: shanghai Biyun Tian biotechnology Co., ltd.). 10% SDS-PAGE separating gel was prepared. Electrophoresis conditions: 80 V constant pressure electrophoresis is carried out for 30 min, and then 120V constant pressure separation is carried out for 90 min. Electric conversion conditions: 300 mA constant current transfer film 1.5. 1.5 h. 5% skim milk was prepared with TBST and blocked at room temperature for 1 h. The target primary antibody working solution was prepared using TBST and incubated overnight at 4 ℃. The TBST buffer was washed 3 times. Preparing secondary antibody working solution corresponding to the species, and placing a shaking table at room temperature of 1-h. The TBST buffer was washed 3 times. Images were acquired by the imaging system after ECL chemiluminescence.
4. Test results
As can be seen from the results of FIG. 9, the AKT and eNOS contents in the model group were significantly reduced as compared with those in the blank groupp value< 0.05). Compared with the model group, the AKT and eNOS content of the experimental group 1 is obviously improvedp value<0.05). Compared with the experimental group 1, the AKT and eNOS content of the experimental group 2 is obviously reducedp value<0.05）。
It was demonstrated that S-MF could ameliorate palmitic acid induced endothelial dysfunction, while EGFR inhibitor AG1478 would reduce this effect.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. And obvious variations or modifications thereof are contemplated as falling within the scope of the present invention.
Claims (10)
1. A method for preparing a compound for improving endothelial dysfunction, comprising the steps of:
(1) Reacting a compound shown in a formula 1 with a compound shown in a formula 2 under the action of a catalyst to obtain a compound shown in a formula 3;
(2) Reacting the compound shown in the formula 3 with the compound shown in the formula 4 under the action of a catalyst, and acidifying to obtain a compound shown in the formula 5;
(3) Reacting a compound shown in a formula 5 with an iodine simple substance in the presence of pyridine to obtain 4' -methyl ether golden-wood flavone;
2. the process of claim 1, wherein in step (1), the catalyst used is anhydrous potassium carbonate; and/or the molar ratio of the compound shown in the formula 1 to the compound shown in the formula 2 is 60-66:70-75.
3. The preparation method of claim 1, wherein in the step (1), the reaction further comprises cooling the reactant, extracting with water and chloroform, drying the organic layer, and purifying by silica gel column chromatography to obtain the pure product.
4. The method according to claim 3, wherein in the step (1), the eluent used in the silica gel column chromatography is in a volume ratio of 2:8-4:6 ethyl acetate with hexane.
5. The process according to any one of claims 1 to 4, wherein in step (2), potassium hydroxide is used as the catalyst; and/or, the acidifying agent adopted in the acidifying process is 4-8M hydrochloric acid; and/or, carrying out the reaction in an ice bath; and/or the molar ratio of the compound represented by formula 3 to the compound represented by formula 4 is 1:2-4.
6. The method according to claim 1, wherein in the step (2), the reaction is followed by filtering the reaction mixture under reduced pressure, and purifying the reaction mixture by silica gel column chromatography to obtain a pure product.
7. The method according to claim 6, wherein in the step (2), the eluent used for silica gel column chromatography is in a volume ratio of 2:8-4:6 ethyl acetate with hexane.
8. The process according to any one of claims 1 to 4, wherein in step (3), the reaction temperature is 75 to 85 ℃ for 20 to 30 hours; and/or, in the step (3), the molar ratio of the compound shown in the formula 5 to the iodine simple substance is 1:1.5-2.5; and/or, in the step (3), adding a sodium thiosulfate solution into the reactant to remove the excessive iodine simple substance.
9. The preparation method of claim 1, wherein in the step (3), the reaction further comprises adding dichloromethane into the reactant for extraction, washing with water, drying the organic layer, and purifying by silica gel column chromatography to obtain a pure product.
10. The method according to claim 9, wherein in the step (3), the eluent used for silica gel column chromatography is in a volume ratio of 7:3-9: ethyl acetate and hexane of 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310361478.6A CN116063264A (en) | 2023-04-06 | 2023-04-06 | Preparation method of compound for improving endothelial dysfunction |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310361478.6A CN116063264A (en) | 2023-04-06 | 2023-04-06 | Preparation method of compound for improving endothelial dysfunction |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116063264A true CN116063264A (en) | 2023-05-05 |
Family
ID=86182323
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310361478.6A Pending CN116063264A (en) | 2023-04-06 | 2023-04-06 | Preparation method of compound for improving endothelial dysfunction |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116063264A (en) |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030181494A1 (en) * | 1999-04-06 | 2003-09-25 | Partha Neogi | Novel heterocyclic analogs of diphenylethylene compounds |
| CN101591230A (en) * | 2008-05-27 | 2009-12-02 | 天津药物研究院 | 2,4-dyhydroxyl chalcone derivative, Preparation Method And The Use |
| WO2017124949A1 (en) * | 2016-01-19 | 2017-07-27 | 首都医科大学宣武医院 | Flavanone derivatives and preparation method and use thereof |
| CN108299366A (en) * | 2018-03-09 | 2018-07-20 | 遵义医学院 | A kind of application of the preparation method and melanoma of hinokiflavone derivative |
| CN109651120A (en) * | 2019-01-25 | 2019-04-19 | 河北海力香料股份有限公司 | A kind of preparation method of 4- (4- formvlphenoxv) benzaldehyde |
| CN111961022A (en) * | 2020-08-28 | 2020-11-20 | 辽宁中医药大学 | Biflavonoid compound with neuroprotective effect and extraction and separation method thereof |
| CN112830917A (en) * | 2021-01-18 | 2021-05-25 | 五邑大学 | Hydroxylated polymethoxyflavone and preparation method thereof |
| CN113024501A (en) * | 2021-03-30 | 2021-06-25 | 沈阳药科大学 | Polymethoxyflavone derivative with anti-hepatitis A virus activity and preparation method and application thereof |
-
2023
- 2023-04-06 CN CN202310361478.6A patent/CN116063264A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030181494A1 (en) * | 1999-04-06 | 2003-09-25 | Partha Neogi | Novel heterocyclic analogs of diphenylethylene compounds |
| CN101591230A (en) * | 2008-05-27 | 2009-12-02 | 天津药物研究院 | 2,4-dyhydroxyl chalcone derivative, Preparation Method And The Use |
| WO2017124949A1 (en) * | 2016-01-19 | 2017-07-27 | 首都医科大学宣武医院 | Flavanone derivatives and preparation method and use thereof |
| CN108299366A (en) * | 2018-03-09 | 2018-07-20 | 遵义医学院 | A kind of application of the preparation method and melanoma of hinokiflavone derivative |
| CN109651120A (en) * | 2019-01-25 | 2019-04-19 | 河北海力香料股份有限公司 | A kind of preparation method of 4- (4- formvlphenoxv) benzaldehyde |
| CN111961022A (en) * | 2020-08-28 | 2020-11-20 | 辽宁中医药大学 | Biflavonoid compound with neuroprotective effect and extraction and separation method thereof |
| CN112830917A (en) * | 2021-01-18 | 2021-05-25 | 五邑大学 | Hydroxylated polymethoxyflavone and preparation method thereof |
| CN113024501A (en) * | 2021-03-30 | 2021-06-25 | 沈阳药科大学 | Polymethoxyflavone derivative with anti-hepatitis A virus activity and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| MONICA M. NDOILE等: "Total synthesis of ochnaflavone", BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY, vol. 9, pages 1346 - 1351 * |
| 孔保华: "降血压、血脂功能性食品", vol. 1, 化学工业出版社, pages: 286 - 290 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2020022507A (en) | Biosynthesis of cannabinoids | |
| CN110551169B (en) | Glycyrrhetinic acid derivative and preparation method and application thereof | |
| CN113173857B (en) | Cannabidiol derivative and preparation method and application thereof | |
| CN114436924A (en) | Synthesis method of hydroxy pinacolone retinoic acid ester | |
| CN110551072A (en) | quinoxaline-N 1, N 4 -dioxide derivative with DNA topoisomerase activity inhibition function, preparation method and application | |
| Raper et al. | SEXUAL HORMONES IN ACHLYA: IV. PROPERTIES OF HORMONE A OF ACHLYA BISEXUALIS | |
| CN113698416A (en) | Singlet oxygen carrier for inhibiting beta-amyloid protein aggregation and preparation method and application thereof | |
| CN116063264A (en) | Preparation method of compound for improving endothelial dysfunction | |
| CN113004220A (en) | Esterase detection fluorescent probe, preparation method and application | |
| CN109134331A (en) | The synthetic method of azithromycin genotoxicity impurity | |
| EP0300062A1 (en) | Novel androst-4-ene-3,17-dione derivatives and process for their preparation | |
| CN108079294B (en) | Ferrocene-lanthanide metal compound and preparation method and application thereof | |
| CN108329300B (en) | Nitrobenzo [ d ] aza-quinazoline compound and preparation method and application thereof | |
| CN107382944B (en) | Coumarin gossypol derivatives with anti-tumor activity and synthesis method thereof | |
| CN111018885B (en) | 1, 2-dioxycyclohexene [3,4-f ] nitrogen oxo cyclononane derivative and synthetic method and application thereof | |
| CN110172078A (en) | The preparation method of 19 hydroxylation cortodoxone derivatives and 19- hydroxyandrostenedione diketone | |
| CN104496900A (en) | Method for preparing 2-methoxy-6-one-5,7,8-trihydro-quinoline | |
| CN113004368B (en) | Ursolic acid pyrimidine amide derivatives, and preparation method and application thereof | |
| CN115028643B (en) | Pyranoquinoline derivative, preparation method and application thereof | |
| CN110746480B (en) | Dehydroabietic acid benzimidazole-2-benzamide derivative and preparation method and application thereof | |
| RU2774174C1 (en) | Method for obtaining fluorescein-5-isothiocyanate | |
| CN110872307B (en) | Thiazole medicine molecule used in hospital and gynecology and preparation method and application thereof | |
| CN109400666B (en) | Preparation method of diosgenin ether | |
| CN114539282B (en) | Compound with osteoporosis resisting effect and preparation method and application thereof | |
| HAYAKAWA et al. | MICROBIOLOGICAL DEGRADATION OF BILE ACIDS X. A NEW DEGRADATION PRODUCT OF CHOLIC ACID BY STREPTOMYCES GELATICUS 1164 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20230505 |
|
| RJ01 | Rejection of invention patent application after publication |