CN104610054A - Caffeoyl hydroquinone ester and preparation method and application of caffeoyl hydroquinone ester in preparation of tyrosinase inhibitor - Google Patents
Caffeoyl hydroquinone ester and preparation method and application of caffeoyl hydroquinone ester in preparation of tyrosinase inhibitor Download PDFInfo
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- CN104610054A CN104610054A CN201510058731.6A CN201510058731A CN104610054A CN 104610054 A CN104610054 A CN 104610054A CN 201510058731 A CN201510058731 A CN 201510058731A CN 104610054 A CN104610054 A CN 104610054A
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- caffeate
- hydroxyphenyl
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- -1 hydroquinone ester Chemical class 0.000 title claims abstract description 45
- 101710147108 Tyrosinase inhibitor Proteins 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N 1,4-Benzenediol Natural products OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 title abstract 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- QAIPRVGONGVQAS-DUXPYHPUSA-N trans-caffeic acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 claims abstract description 29
- 241000196324 Embryophyta Species 0.000 claims abstract description 13
- 239000002537 cosmetic Substances 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 13
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 11
- 239000005452 food preservative Substances 0.000 claims abstract description 11
- 235000019249 food preservative Nutrition 0.000 claims abstract description 11
- 241000521919 Sphagneticola trilobata Species 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 31
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 20
- 239000000284 extract Substances 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 208000012641 Pigmentation disease Diseases 0.000 claims description 11
- 230000019612 pigmentation Effects 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 206010040829 Skin discolouration Diseases 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 239000000287 crude extract Substances 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- 238000010828 elution Methods 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- 238000010898 silica gel chromatography Methods 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 238000003811 acetone extraction Methods 0.000 claims description 2
- 238000004587 chromatography analysis Methods 0.000 claims description 2
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 claims description 2
- 102000003425 Tyrosinase Human genes 0.000 abstract description 12
- 108060008724 Tyrosinase Proteins 0.000 abstract description 12
- WZNJWVWKTVETCG-UHFFFAOYSA-N kojic acid Natural products OC(=O)C(N)CN1C=CC(=O)C(O)=C1 WZNJWVWKTVETCG-UHFFFAOYSA-N 0.000 abstract description 11
- BEJNERDRQOWKJM-UHFFFAOYSA-N kojic acid Chemical compound OCC1=CC(=O)C(O)=CO1 BEJNERDRQOWKJM-UHFFFAOYSA-N 0.000 abstract description 11
- 229960004705 kojic acid Drugs 0.000 abstract description 11
- 241000238631 Hexapoda Species 0.000 abstract description 8
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- 238000002474 experimental method Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 230000002087 whitening effect Effects 0.000 abstract description 2
- 102000004316 Oxidoreductases Human genes 0.000 description 14
- 108090000854 Oxidoreductases Proteins 0.000 description 14
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 6
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 6
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- 239000000523 sample Substances 0.000 description 5
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 4
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 4
- 235000012055 fruits and vegetables Nutrition 0.000 description 4
- 229960004502 levodopa Drugs 0.000 description 4
- 229960003742 phenol Drugs 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
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- 239000013558 reference substance Substances 0.000 description 3
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- XKZQKPRCPNGNFR-UHFFFAOYSA-N 2-(3-hydroxyphenyl)phenol Chemical group OC1=CC=CC(C=2C(=CC=CC=2)O)=C1 XKZQKPRCPNGNFR-UHFFFAOYSA-N 0.000 description 2
- 208000037259 Amyloid Plaque Diseases 0.000 description 2
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 2
- 208000003351 Melanosis Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
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- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 2
- 238000005570 heteronuclear single quantum coherence Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
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- 108010031396 Catechol oxidase Proteins 0.000 description 1
- 206010008570 Chloasma Diseases 0.000 description 1
- 241001269238 Data Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 1
- 206010027146 Melanoderma Diseases 0.000 description 1
- ADGWXEICJNSVIO-KRXBUXKQSA-N OC1C=CC(/C=C/C(Oc(cc2)ccc2O)=O)=CC1O Chemical compound OC1C=CC(/C=C/C(Oc(cc2)ccc2O)=O)=CC1O ADGWXEICJNSVIO-KRXBUXKQSA-N 0.000 description 1
- VSEOJXOYHGLPRY-UHFFFAOYSA-N Oc(cc1)ccc1OC(CCc(cc1)cc(O)c1O)=O Chemical compound Oc(cc1)ccc1OC(CCc(cc1)cc(O)c1O)=O VSEOJXOYHGLPRY-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- UGAPHEBNTGUMBB-UHFFFAOYSA-N acetic acid;ethyl acetate Chemical compound CC(O)=O.CCOC(C)=O UGAPHEBNTGUMBB-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
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- 238000006911 enzymatic reaction Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
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- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
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- HVGQWHMSVYODLJ-GFCCVEGCSA-N melanochrome Natural products CC1(C)Oc2cc3OC(=CC(=O)c3c(O)c2C[C@H]1O)CO HVGQWHMSVYODLJ-GFCCVEGCSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
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- 239000000758 substrate Substances 0.000 description 1
- 229940118172 sucrets Drugs 0.000 description 1
- 239000012747 synergistic agent Substances 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000004563 wettable powder Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L3/00—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs
- A23L3/34—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals
- A23L3/3454—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals in the form of liquids or solids
- A23L3/3463—Organic compounds; Microorganisms; Enzymes
- A23L3/3481—Organic compounds containing oxygen
- A23L3/3508—Organic compounds containing oxygen containing carboxyl groups
- A23L3/3517—Carboxylic acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/37—Esters of carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/56—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Food Science & Technology (AREA)
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- General Chemical & Material Sciences (AREA)
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- Polymers & Plastics (AREA)
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Abstract
The invention discloses caffeoyl hydroquinone ester, a preparation method of caffeoyl hydroquinone ester and application of caffeoyl hydroquinone ester in preparation of a tyrosinase inhibitor. According to the preparation method, a strong tyrosinase inhibitor compound (p-hydroxyphenyl caffeate) is extracted and separated from sphagneticola trilobata; the plant raw material source is rich; the preparation method is high in economical benefit, and environmentally friendly; the pharmacology experiment shows that the compound p-hydroxyphenyl caffeate has the tyrosinase inhibiting activity superior to that of kojic acid and is expected to be further developed to be a novel synergist of whitening cosmetics, a medicine for treating chromatodermatosis, an insect control agent and even a food preservative, and has good prospect.
Description
Technical field:
The invention belongs to Natural Medicine Chemistry and relate to medicine and cosmetic field, be specifically related to a kind of new caffeoyl para hydroxybenzene phenolic ester natural compounds, i.e. p-hydroxyphenyl caffeate, and this new compound method that in the Herbia Wedeliae of plant South America prepared by extraction and isolation is preparing the application in tyrosinase inhibitor or related drugs with this compound or its pharmaceutically useful salt.
Background technology:
Tyrosine oxidase, also known as phenol oxidase, polyphenoloxidase, is extensively present in microorganism, plant and Mammals, is the key enzyme regulating B16 cell in organism.Tyrosine oxidase is by katalysis, and make single phenolic hydroxyl group be oxidized to adjacent diphenol, then adjacent diphenol is oxidized to adjacent diquines further under its catalysis, subsequently again through the non-enzyme reaction process of series of complex, final generation melanochrome, in the process, tyrosine oxidase plays a part key.The aging of tyrosine oxidase and people, the wound healing of insect and growth, the brown stain of fruits and vegetables etc. have substantial connection.
As the key enzyme of B16 cell, its abnormal overexpression can cause the pigmentation disease of human body, causes the problems such as serious health & beauty, as color spot, blackspot, senile plaque etc.; Concerning insect, tyrosine oxidase B16 cell, wound healing, ossified etc. in there is vital role, and turning into relevant with tanning in insect molting process, is a kind of important enzyme that insect relies in existence; In fruits and vegetables and food-processing, tyrosine oxidase is the main enzyme causing brown stain, its because of catalyzed reaction cause fresh fruit, vegetables and beverage produce brown stain, thus reduce its storage cycle, nutritive value and marketable value.
Tyrosinase inhibitor can the activity of restraint of tyrosinase, and then the generation of check melanin, thus reduces the disadvantageous effect of tyrosine oxidase.Tyrosinase inhibitor can treat pigmentation tetter common at present as freckle, chloasma, senile plaque etc.; Because tyrosine oxidase is worked as important to the developmental phase of insect, in the design of novel biotic pesticide, also there is directive function to the research of this enzyme inhibitors; In addition, tyrosinase inhibitor, by the activity of restraint of tyrosinase, can stop or slow down the brown stain in fruits and vegetables accumulating and food-processing, and thus tyrosinase inhibitor is being used as also have important potentiality in food preservative.
Be worth purposes widely based on tyrosinase inhibitor is potential, the research of tyrosinase inhibitor receives much concern always.But because being limited to the factors such as validity, security and cost, up to the present only have only a few tyrosinase inhibitor to be used to commercial, this includes the representative kojic acid (kojic acid) for skin whitener manufacture and the 4-Sucrets etc. for food fresh keeping.Thus in fields such as medical cosmetic, food and insect controls, at present all in the urgent need to developing new tyrosinase inhibitor, and being the tyrosinase inhibitor of originating with natural product, having broad application prospects.
Summary of the invention:
First object of the present invention is to provide a kind of caffeoyl para hydroxybenzene phenolic ester-p-hydroxyphenyl caffeate with tyrosinase inhibitory activity.
New compound p-hydroxyphenyl caffeate of the present invention, its structural formula is as shown in formula I:
Second object of the present invention is to provide the preparation method of a kind of compound p-hydroxyphenyl caffeate, it is characterized in that, compound p-hydroxyphenyl caffeate preparative separation from plant South America Herbia Wedeliae (Wedelia trilobata (L.) Hitchc (Synonym:Sphagneticola trilobata (L.) Pruski)) obtains.
Concrete material can be the dry product of dry product or fresh goods, preferred plant.
Concrete steps are preferably:
A, prepare total medicinal extract: by after the Herbia Wedeliae plant complete stool dry product material disintegrating of South America with aqueous ethanolic solution, ethanol, aqueous acetone solution or acetone extraction, extracting solution is concentrated removes ethanol or acetone, obtain total medicinal extract crude extract, total medicinal extract crude extract is suspended in water, first use petroleum ether extraction, be extracted with ethyl acetate, acetic acid ethyl ester extract obtains the total medicinal extract of ethyl acetate after concentrated again;
B, separation and purification: the total medicinal extract of ethyl acetate is through purification on normal-phase silica gel column chromatography, take chloroform/methanol as eluent, successively from volume ratio 98:2, 95:5, 90:10, 85:15, 7:3, 6:4, 0:100 gradient elution, collect the cut of chloroform/methanol 9:1v/v wash-out, reversed-phase silica gel column chromatography is pressed again in warp, take methanol/water as moving phase, successively from volume ratio be 3:7, 4:6, 5:5, 6:4, the gradient elution of 10:0, collect the cut of methanol/water 5:5v/v wash-out, again through Sephadex LH-20 chromatography, with chloroform/methanol 1:4v/v wash-out, eluate obtains p-hydroxyphenyl caffeate through recrystallization.
Described aqueous ethanolic solution or aqueous acetone solution are preferably aqueous ethanolic solution or the aqueous acetone solution that volume fraction is more than or equal to 70%.
3rd object of the present invention is to provide South America Herbia Wedeliae in the application preparing compound p-hydroxyphenyl caffeate.
New compound p-hydroxyphenyl caffeate of the present invention, confirm through external pharmacological evaluation, it has potent restraining effect to tyrosine oxidase, its inhibit activities (IC
50=2.00 ± 0.31 μM) be even significantly better than positive reference substance kojic acid and Kojic acid (IC
50=12.55 ± 8.22 μMs).Therefore this new compound, even can develop for the preparation of skin-lightening cosmetic, the dermopathic medicine for the treatment of pigmentation, insect-controlling agent food preservative etc., application potential quality is extensive.
4th object of the present invention is to provide p-hydroxyphenyl caffeate or the application in tyrosinase inhibitor prepared by its pharmaceutically useful salt.
5th object of the present invention is to provide a kind of tyrosinase inhibitor, and it is characterized in that, the compound p-hydroxyphenyl caffeate containing significant quantity or its pharmacologically acceptable salt are as activeconstituents.
Even the 6th object of the present invention is to provide p-hydroxyphenyl caffeate or its pharmaceutically useful salt is preparing the application in skin-lightening cosmetic, the dermopathic medicine for the treatment of pigmentation, insect-controlling agent food preservative as tyrosinase inhibitor.
Even the 7th object of the present invention is to provide a kind of skin-lightening cosmetic, the dermopathic medicine for the treatment of pigmentation, insect-controlling agent food preservative, it is characterized in that, it contains the compound p-hydroxyphenyl caffeate of significant quantity or its pharmacologically acceptable salt as activeconstituents.
New compound p-hydroxyphenyl caffeate of the present invention or its pharmaceutically useful salt can be combined with conventional auxiliary material or carrier, prepare and there is p-hydroxyphenyl caffeate restraint of tyrosinase activity, can be used for inhibitor or the composition of preparing skin-lightening cosmetic, the dermopathic medicine for the treatment of pigmentation, insect-controlling agent or food preservative.This inhibitor or composition can adopt the formulations such as wettable powder, paste, aerosol; Also can adopt modern cosmetics circle or the known controlled release of pharmaceutical industry or slow release formulation or nanometer formulation.
What the present invention's employing extensively distributed from south China has extraction and isolation potent tyrosinase inhibitor compound p-hydroxyphenyl caffeate the invasive plant South America Herbia Wedeliae of huge biomass, material source enriches, and adopt this plant be raw material extract time can also be conducive to controlling the further invasion of this plant, can also be environmentally friendly while obtaining economic benefit.The tyrosinase inhibitory activity of this compound p-hydroxyphenyl caffeate is significantly higher than reference substance kojic acid, even be thus further development of effectively new skin-lightening cosmetic whitening agent, the dermopathic medicine for the treatment of pigmentation, insect-controlling agent food preservative etc. most probably, there is important application and development potential quality.
Accompanying drawing illustrates:
Fig. 1 is compound p-hydroxyphenyl caffeate
1h NMR collection of illustrative plates;
Fig. 2 is compound p-hydroxyphenyl caffeate
13c NMR collection of illustrative plates;
Fig. 3 is the HSQC collection of illustrative plates of compound p-hydroxyphenyl caffeate.
Fig. 4 is the HMBC collection of illustrative plates of compound p-hydroxyphenyl caffeate.
Embodiment:
Following examples further illustrate of the present invention, instead of limitation of the present invention, and essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Embodiment 1: the preparation of caffeoyl para hydroxybenzene phenolic ester p-hydroxyphenyl caffeate in the Herbia Wedeliae of South America
1.1 instruments and reagent
Concentrating under reduced pressure adopts Tokyo physics and chemistry company N-1000 Rotary Evaporators, the circulating cooling tank of CCA-1110 and SB-1000 electric-heated thermostatic water bath; MPLC adopts innovation Tong Heng company CXTH P3000 type liquid chromatograph, UV 3000UV-Vis detector and C18 reverse-phase chromatographic column (particle diameter 50 μm, YMC Co.Ltd., Kyoto, Japan, 400mm × 25mm); Electrospray ionization mass spectrum (ESIMS) adopts Applied biosystems MDS SCIEX API 2000LC/MS/MS instrument, is that solvent direct injection measures with methyl alcohol;
1h NMR compose and
13c NMR composes and adopts Bruker AVANCE 600 nuclear magnetic resonance analyser, and is that interior mapping is fixed with tetramethylsilane.Coloration method adopts 10% ethanol solution of sulfuric acid process post-heating colour developing.
1.2 plant origins and qualification
Pick up from South China Botanical Garden for extraction plant South America Herbia Wedeliae (Wedelia trilobata (L.) Hitchc) in September, 2011, identified by South China Botanical Garden Chinese Academy of Sciences Xing Fuwu researcher.
1.3 Extraction and isolation
Sample (South America Herbia Wedeliae dry product, weighs 2.0 kilograms) extracts three times with under volume fraction 95% aqueous ethanolic solution room temperature after pulverizing, and united extraction liquid concentrating under reduced pressure removing organic solvent ethanol, obtains total medicinal extract crude extract.Be suspended in 500ml water by total medicinal extract crude extract, after with isopyknic Petroleum ether extraction, then extract three times by isopyknic ethyl acetate, acetic acid ethyl acetate extract obtains the total medicinal extract of ethyl acetate (35g) through concentrating under reduced pressure.The chloroform/methanol (150mL) of total for ethyl acetate medicinal extract volume ratio 1:1 is dissolved, adds purification on normal-phase silica gel (80-100 order) and mix sample with weight ratio 1:1.5 and volatilize, dry column-packing (200-300 order, 1000 grams) dry method loading, use chloroform/methanol=98:2,95:5,90:10 successively, 85:15,7:3,6:4,0:100v/v are eluent gradient wash-out, detect according to thin layer plate, each stream part collects 7 component F1 – F7 from small to large successively according to the difference of polarity; Cut F3 (1.3g) under chloroform/methanol 9:1v/v wash-out, then through anti-phase medium pressure column chromatography, with MeOH/H
2o (3:7,4:6,5:5,6:4,10:0, v/v) is moving phase wash-out, with the MeOH/H of 5:5v/v
2o elution fraction E
5-2(66mg) again through SephadexLH-20 column chromatography (1500mm × 25mm i.d) separation and purification, with chloroform/methanol=1:4v/v wash-out, eluting fraction recrystallization obtains the pure compound 1 (p-hydroxyphenyl caffeate) (3.5mg) as shown in formula I.
The Structural Identification of 1.4 compounds 1 (p-hydroxyphenyl caffeate)
Institute's compound that obtains 1 is Yellow amorphous powder, and molecular formula is C
15h
12o
5, its
1h NMR collection of illustrative plates,
13c NMR collection of illustrative plates, HSQC collection of illustrative plates and HMBC collection of illustrative plates respectively as Fig. 1,2, shown in 3 and Fig. 4, ESI-MS (pos.) m/z 273 [M+H]
+, 295 [M+Na]
+, 567 [2M+Na]
+; ESI-MS (neg.) m/z 271 [M-H]
-, 543 [2M-H]
-; HR-ESI-MS (pos.) m/z 295.0564 [M+Na]
+(calcd for C
15h
12naO
5, 295.0577);
1h (CD
3oD, 600MHz) and
13c NMR (CD
3oD, 150MHz) data are as shown in table 1:
The NMR data of table 1. new compound p-hydroxyphenyl caffeate
Data were measured at 600MHz for
1H and 150MHz for
13C in CD
3OD,δin ppm and J in Hz.
According to the comprehensive analysis of above mass spectrum and the wave spectrum such as one dimension, two-dimentional nuclear-magnetism related data, the chemical structure that analytic derivation goes out this new compound is p-hydroxyphenyl caffeate, and its structural formula is as shown in formula I.
Embodiment 2: the tyrosinase inhibitory activity of compound p-hydroxyphenyl caffeate detects
2.1 reagent and instrument
Reagent: tyrosine oxidase is purchased from Sigma Chemical Co. (Sigma-Aldrich, St.Louis, USA), and levodopa (L-DOPA), kojic acid are purchased from Aladdin Industrial Corporation (USA), Na
2hPO
4, NaH
2pO
4, testing compound is the preparation of plant analysis design mothod;
Laboratory apparatus: microplate reader (Genois microplate reader, Tecan GENios, Swizerland).
2.2 testing method
A) compounding pharmaceutical solution: testing compound p-hydroxyphenyl caffeate, kojic acid are prepared respectively the solution becoming 10mg/ml by dimethyl sulfoxide (DMSO) (DMSO), the phosphoric acid buffer (ultrapure water preparation) of 67mmol, 46U/ml tyrosinase solution (preparing with phosphoric acid buffer), 2.5mM L-DOPA (preparing with phosphoric acid buffer).
B) adopt colorimetry, complete the mensuration of testing compound to tyrosine oxidase half-inhibition concentration by 96 porocyte culture plates.First testing sample solution phosphoric acid buffer is diluted (amount of DMSO is less than 5%) by a certain percentage, every hole adds sample solution 120 μ L, the ultimate density of testing sample is made to be: 100 μ g/mL, 50 μ g/mL, 25 μ g/mL, 12.5 μ g/mL, 6.25 μ g/mL, 3.125 μ g/mL, 1.56 μ g/mL, 0.78 μ g/mL, then the tyrosine oxidase (46U/ml) of 40 μ L is joined in sample well, at 23 DEG C of reaction 10min, finally add 40 μ L substrates L-DOPA (2.5mM) again.After being placed on 23 DEG C of reaction 10min, finally measure in 475nm wavelength place microplate reader.Positive control is kojic acid, and negative control is the phosphoric acid buffer containing DMSO that sample dissolution solution ratio used is identical, and all blanks are that the phosphoric acid buffer of same volume replaces enzyme solution.Testing compound is to the calculation formula of tyrosinase inhibition rate following (Masuda et al., 2005): inhibiting rate (%)=(OD
negative control– OD
blank) – (OD
test– OD
test control)/(OD
negative blank– OD
blank) × 100%.Wherein testing compound is to the half-inhibition concentration (IC of tyrosine oxidase
50) obtained by dose effect curve.
2.3 experimental datas are see table 2:
The tyrosinase inhibitory activity of table 2.p-hydroxyphenyl caffeate
2.4 experiment conclusion:
Tyrosine oxidase is a key enzyme of B16 cell in organism, the aging of itself and people, the wound healing of insect and growth, the brown stain etc. of fruits and vegetables and food has substantial connection, even thus tyrosinase inhibitor has widespread use potential quality preparing in skin-lightening cosmetic, treatment pigmentation dermopathic medicine, insect-controlling agent food preservative etc.This experimental result shows, the new compound p-hydroxyphenyl caffeate that we excavate has the effect of potent restraint of tyrosinase, its inhibit activities is even stronger than the positive reference substance kojic acid (Kojic acid) of commercial applications, thus there is stronger application and development potential quality, even be expected to further develop become new skin-lightening cosmetic synergistic agent, be used for the treatment of the dermopathic medicine of pigmentation or insect-controlling agent food preservative etc., application potential quality is extensive.
Claims (9)
1. compound p-hydroxyphenyl caffeate or its pharmaceutically useful salt, its structural formula is as shown in formula I:
2. the preparation method of a compound p-hydroxyphenyl caffeate according to claim 1, it is characterized in that, compound p-hydroxyphenyl caffeate preparative separation from plant South America Herbia Wedeliae (Wedelia trilobata (L.) Hitchc) obtains.
3. preparation method according to claim 2, is characterized in that, concrete steps are:
A, prepare total medicinal extract: by after the Herbia Wedeliae plant complete stool dry product material disintegrating of South America with aqueous ethanolic solution, ethanol, aqueous acetone solution or acetone extraction, extracting solution is concentrated removes ethanol or acetone, obtain total medicinal extract crude extract, total medicinal extract crude extract is suspended in water, first use petroleum ether extraction, be extracted with ethyl acetate, acetic acid ethyl ester extract obtains the total medicinal extract of ethyl acetate after concentrated again;
B, separation and purification: the total medicinal extract of ethyl acetate is through purification on normal-phase silica gel column chromatography, take chloroform/methanol as eluent, successively from volume ratio 98:2, 95:5, 90:10, 85:15, 7:3, 6:4, 0:100 gradient elution, collect the cut of chloroform/methanol 9:1v/v wash-out, reversed-phase silica gel column chromatography is pressed again in warp, take methanol/water as moving phase, successively from volume ratio be 3:7, 4:6, 5:5, 6:4, the gradient elution of 10:0, collect the cut of methanol/water 5:5v/v wash-out, again through Sephadex LH-20 chromatography, with chloroform/methanol 1:4v/v wash-out, eluate obtains compound p-hydroxyphenyl caffeate through recrystallization.
4. preparation method according to claim 3, is characterized in that, described aqueous ethanolic solution or aqueous acetone solution are aqueous ethanolic solution or the aqueous acetone solution that volume fraction is more than or equal to 70%.
5. the application of South America Herbia Wedeliae in preparation compound p-hydroxyphenyl caffeate according to claim 1.
6. compound p-hydroxyphenyl caffeate according to claim 1 is preparing the application in tyrosinase inhibitor.
7. a tyrosinase inhibitor, is characterized in that, the compound p-hydroxyphenyl caffeate according to claim 1 containing significant quantity or its pharmacologically acceptable salt are as activeconstituents.
8. even compound p-hydroxyphenyl caffeate according to claim 1 or its pharmaceutically useful salt are preparing the application in skin-lightening cosmetic, the dermopathic medicine for the treatment of pigmentation, insect-controlling agent food preservative as tyrosinase inhibitor.
9., even skin-lightening cosmetic, treatment pigmentation dermopathic medicine, an insect-controlling agent food preservative, is characterized in that, it contains the compound p-hydroxyphenyl caffeate of significant quantity or its pharmacologically acceptable salt as activeconstituents.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105851070A (en) * | 2016-04-25 | 2016-08-17 | 江苏大学 | Application of invasive weed Wedelia trilobata to killing of prodenia litura larva |
| CN107753542A (en) * | 2017-12-05 | 2018-03-06 | 海南师范大学 | South America amphibious crab chrysanthemum antioxidant extract and its production and use |
| CN111135159A (en) * | 2019-12-27 | 2020-05-12 | 广东省林业科学研究院 | Application of diterpene compound in preparation of tyrosinase inhibitor |
| KR20210053622A (en) * | 2019-11-04 | 2021-05-12 | 단국대학교 천안캠퍼스 산학협력단 | Composition for preventing or treating atopic dermatitis comprising caffeic acid ester derivatives and synthesis method thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105851070A (en) * | 2016-04-25 | 2016-08-17 | 江苏大学 | Application of invasive weed Wedelia trilobata to killing of prodenia litura larva |
| CN107753542A (en) * | 2017-12-05 | 2018-03-06 | 海南师范大学 | South America amphibious crab chrysanthemum antioxidant extract and its production and use |
| CN107753542B (en) * | 2017-12-05 | 2021-05-07 | 海南师范大学 | South American wedelia chinensis antioxidant extract and preparation method and application thereof |
| KR20210053622A (en) * | 2019-11-04 | 2021-05-12 | 단국대학교 천안캠퍼스 산학협력단 | Composition for preventing or treating atopic dermatitis comprising caffeic acid ester derivatives and synthesis method thereof |
| KR102307045B1 (en) * | 2019-11-04 | 2021-09-30 | 단국대학교 천안캠퍼스 산학협력단 | Composition for preventing or treating atopic dermatitis comprising caffeic acid ester derivatives and synthesis method thereof |
| CN111135159A (en) * | 2019-12-27 | 2020-05-12 | 广东省林业科学研究院 | Application of diterpene compound in preparation of tyrosinase inhibitor |
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