CN106431928B - Caffeoylquinic acid derivative and application thereof as neuron repair and protection medicament - Google Patents
Caffeoylquinic acid derivative and application thereof as neuron repair and protection medicament Download PDFInfo
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Abstract
The invention discloses a caffeoylquinic acid derivative, a pharmaceutical composition containing the derivative and the effect of the series of derivatives as drugs for repairing and protecting neurons. The caffeoylquinic acid derivative is used for preparing medicine for treating neurodegenerative diseases, traumatic brain injury, and apoplexy. The dicaffeoylquinic acid derivative has obvious neuron repair and protection activity, can be developed to be used for treating neurodegenerative diseases, traumatic brain injury, stroke diseases and other diseases, and provides potential opportunities for treating the diseases.
Description
The technical field is as follows:
the invention belongs to the field of biological pharmacy, and particularly relates to a caffeoylquinic acid derivative which has the effects of repairing and protecting neurons.
Background art:
neurodegenerative diseases are a disease state in which the cellular neurons of the brain and spinal cord are lost. The brain and spinal cord are composed of neurons that have diverse functions, such as controlling movement, processing sensory information, and making decisions. Cells of the brain and spinal cord are generally not regenerative, so excessive damage can be devastating and irreversible. Neurodegenerative diseases are caused by the loss of neurons or their myelin sheaths, which worsen over time, leading to dysfunction. Initial treatment depends on the diagnosis of the particular disease. Currently, only a few drugs are available for some neurodegenerative diseases. Therefore, the search for safe and effective therapeutic drugs is urgent.
Burdock is a plant belonging to family Compositae, genus Arctium, family Araliaceae, and called "fructus Arctii", radix Ginseng alba or Burdock, etc. Burdock is widely planted in China as a special health-care vegetable and a commercial crop for resisting aging and reducing blood sugar. Burdock root is recorded in book notes such as the treatise on herb properties and the book of materia medica supplement, has the functions of resisting oxidation and aging, does not form Chinese herbal medicine commodities, and is mostly used as a byproduct of burdock without being discarded. In recent years, researchers at home and abroad discover that the burdock root has various pharmacological effects on a human body, including liver protection, anti-inflammation, antioxidation and the like, and the effects are related to the fact that the burdock root contains a large amount of caffeoylquinic acid compounds. However, the effect of caffeoylquinic acid derivatives with what structure in burdock root on neurons is not reported.
The invention content is as follows:
the purpose of the invention is as follows: the invention aims to provide caffeoylquinic acid derivatives which are novel compounds.
The invention also aims to provide a preparation method of the caffeoylquinic acid derivative.
The invention further aims to provide application of the caffeoylquinic acid derivative in preparing a medicament for repairing and protecting neurons.
The invention also aims to provide a pharmaceutical composition containing the caffeoylquinic acid derivative and more than one pharmaceutically acceptable carrier.
The technical scheme is as follows:
in order to achieve the purpose, the invention adopts the following technical scheme:
a caffeoylquinic acid derivative, which specifically comprises a compound with the following formula or a pharmaceutically acceptable salt thereof:
the pharmaceutically acceptable salts may be acid addition salts, base addition salts or zwitterions.
For example: acetates, hydrochlorides, sulfates, benzoates, and the like.
The invention relates to a pharmaceutical composition containing the caffeoylquinic acid derivatives and more than one pharmaceutically acceptable carrier.
The carrier comprises various pharmaceutic adjuvants, packing materials and the like. The selection is carried out according to the requirements of the preparation. For example, adjuvants including fillers, disintegrants, binders, lubricants, etc. may be suitable for oral, inhalation, parenteral, or topical administration; dosage forms include, but are not limited to, injections, solutions, tablets, capsules, granules, and the like.
The caffeoylquinic acid derivative can be used for preparing medicines for repairing and protecting neurons. The caffeoylquinic acid derivative can be used as a medicament for treating neurodegenerative diseases, traumatic brain injury and stroke diseases.
A method for preparing the caffeoylquinic acid derivative is characterized in that: soaking burdock root medicinal material in 8-20 times of 55% ethanol water solution by mass, heating and refluxing for extraction for 3 times, 2 hours for the first time and 1 hour for the second time; mixing the extractive solutions, and recovering solvent under reduced pressure to obtain concentrated extract; dispersing the extract in appropriate amount of water, and extracting with ethyl acetate; recovering the solvent under reduced pressure to obtain an ethyl acetate extract, and extracting and separating the ethyl acetate layer extract by using a chromatographic separation means to obtain the caffeoylquinic acid derivative; with rationalized properties and modern spectroscopic approaches, the structural formulae were identified as follows:
the advantages and effects are as follows: the dicaffeoylquinic acid derivative has obvious neuron repair and protection activity, can be developed to be used for treating neurodegenerative diseases, traumatic brain injury, stroke diseases and other diseases, and provides potential opportunities for treating the diseases.
Description of the drawings:
1. FIG. 1 is a structural diagram of two novel compounds of the present invention;
2. FIG. 2 is a schematic diagram showing the results of repairing hydrogen peroxide-mediated SH-SY5Y cell injury by caffeoylquinic acid derivatives measured by MTT [3- (4, 5) -dimethyl-2-thiazole- (2, 5) -phenyltetrazolium bromide ] method; note: cell viability on the ordinate, cell viability on the abscissa: the con group represents a blank group, and 400. mu.M hydrogen peroxide was added to the other groups, wherein 7.5, 15,30 and 15,30,60 represent administration groups at different concentrations, respectively. The same applies below.
3. FIG. 3 is a diagram showing the results of the LDH (lactate dehydrogenase) assay of caffeoylquinic acid derivatives on the repair of SH-SY5Y cell damage mediated by hydrogen peroxide.
The specific implementation mode is as follows:
the invention will be further described with reference to examples and figures, but the mode of carrying out the invention is not limited thereto.
The present invention is further illustrated by the following examples.
Example 1: preparation of caffeoylquinic acid derivatives A and B.
10.0kg of burdock root medicinal material, 8-20 times of 55% ethanol water solution by mass percent for soaking overnight, heating and refluxing for extraction for 3 times, the first time for 2 hours, and the second time for 1 hour. Mixing the extractive solutions, and recovering solvent under reduced pressure to obtain concentrated extract. Dispersing the extract in appropriate amount of water, and sequentially extracting with petroleum ether, dichloromethane, ethyl acetate and n-butanol. The solvent was recovered under reduced pressure to give a petroleum ether extract (15.6g), a methylene chloride extract (43.1g), an ethyl acetate extract (256.8g) and an n-butanol extract (843.2 g). The ethyl acetate layer has the best activity through detection. The ethyl acetate extract (256.8g) was passed through a silica gel column and eluted with methylene chloride-methanol (100: 1-1:100) to give 15 fractions. The fraction Fr.12(10g) was chromatographed on ODS column eluting with methanol-water (10:90-100:0) as a solvent to give 18 fractions. Fraction Fr.12-10 was chromatographed on ODS column eluting with methanol-water (10:90-100:0) as solvent to give 10 fractions. Fraction Fr.12-10-4(800mg) was prepared using a preparative liquid chromatography under conditions (JASCO preparative high performance liquid chromatograph, YMC-Pack Pro ODS-A C18, Φ 250X 10mm,10 μm, water: acetonitrile: trifluoroacetic acid ═ 77.5: 22.5: 1) to give A (18mg, rt ═ 65min) and B (80mg, rt ═ 48 min).
HR-MS data and NMR data for Compound A: HR-TOF-MS M/z (rel. int.) 645.1453[ M-H ]+]-(calcd.645.1456for C30H29O16)；1H-NMR(600MHz,CD3OD):δ:7.60，7.55(each 1H,d,J＝15.8Hz,H-7″,7″′),7.07,7.05(each 1H,d,J＝1.9Hz,H-2″,2″′),6.98,6.96(each 1H,dd,J＝1.9,8.1Hz,H-6″,6″′),6.79,6.77(each 1H,d,J＝8.1Hz,H-5″,5″′),6.32,6.23(each1H,d,J＝15.8Hz,H-8″,8″′),5.58(1H,m,H-5),5.10(1H,dd,J＝3.2,8.5Hz,H-4),4.54(1H,m,H-3′),4.44(1H,m,H-3),3.70(OCH3),2.78(1H,d,J＝5.2,16.0Hz,H-2′a),2.60(1H,d,J＝5.2,16.0Hz,H-2′b),2.60(1H,m,H-6a),2.50(1H,m,H-2a),2.50(1H,m,H-2b),2.16(1H,m,H-6b).13C-NMR(150MHz,CD3OD):δ:174.9(C-1′),171.2(C-7),169.9(C-4′),168.1(C-9″),168.0(C-9″′),149.7(C-4″),149.1(C-4″′),147.7(C-7″),147.7(C-7″′),146.8(C-3″),146.8(C-3″′),127.8(C-1″),127.7(C-1″′),123.1(C-6″),123.1(C-6″′),116.5(C-5″),116.5(C-5″′),115.3(C-2″),115.2(C-2″′),115.1(C-8″),114.7(C-8″′),80.5(C-1),75.5(C-4),68.4(C-2′),68.3(C-5),67.2(C-3),52.8(OCH3),40.2(C-3′),37.4(C-6),35.7(C-2).
HR-MS data and NMR data for Compound B: HR-TOF-MS M/z (rel. int.) 669.1439[ M + Na ]]+(calcd.669.1432for C30H30O16Na)；1H-NMR(600MHz,CD3OD):δ:7.62，7.61(each 1H,d,J＝15.8Hz,H-7″,7″′),7.10,7.07(each 1H,d,J＝1.9Hz,H-2″,2″′),7.00,6.96(each1H,dd,J＝1.9,8.3Hz,H-6″,6″),6.81,6.79(each 1H,d,J＝8.2Hz,H-5″,5″′),6.35,6.30(each1H,d,J＝15.8Hz,H-8″,8″′),5.47(1H,m,H-3),5.43(1H,m,H-5),4.47(1H,m,H-2')3.95(each 1H,dd,J＝3.7,9.4Hz,H-4),3.56(OCH3),2.77(1H,m,H-2a)2.71(2H,m,H-3'),2.62(1H,m,H-6a),2.45(1H,m,H-2b),2.00(1H,m,H-6b).13C-NMR(150MHz,CD3OD):δ:175.0(C-1′),174.0(C-7),171.3(C-4′),168.6(C-9″′),167.7(C-9″),149.8(C-4″),149.6(C-4″′),148.1(C-7″),147.4(C-7″′),146.8(C-3″),146.7(C-3″′),127.7(C-1″),127.6(C-1″′),123.3(C-6″),123.0(C-6″′),115.3(C-8″),115.3(C-2″),115.2(C-8″′),115.2(C-2″′),115.0(C-5″),114.9(C-5″′),80.5(C-1),73.2(C-3),71.6(C-4),71.0(C-5),68.2(C-2′),52.8(OCH3),40.3(C-3′),37.9(C-6),32.7(C-2).
Example 2: the repair and protection activity of the caffeoylquinic acid derivatives in vitro nerve cells is researched.
The invention adopts MTT and LDH activity test method to test the protection function of caffeoylquinic acid derivatives on SH-SY5Y cell injury mediated by hydrogen peroxide, and the result shows that the caffeoylquinic acid derivatives have obvious function of repairing nerve cells, so the caffeoylquinic acid derivatives can be used for researching and developing medicines for treating neurodegenerative diseases, apoplexy and traumatic brain injury.
(1) Instruments and reagents: DMEM medium was purchased from Hyclone, fetal bovine serum is Hyclone; CKX31 model inverted microscope (olympus, japan); a constant temperature CO2 incubator (Thermo corporation, USA); 5810R model table high speed cryogenic centrifuge (Eppendorf, Germany); fully automatic enzyme labeling machine (Biotek group, usa); hydrogen peroxide (national chemical group chemical Co., Ltd.); LDH kit (Nanjing build)
(2) Cell culture: the recovered cells were transferred to a culture flask and cultured in an incubator at 37 ℃ (5% CO)2Relative humidity 90%), the culture medium was changed every other day. When the cells grow over about 80-90% of the bottle wall, passage or next step test is carried out, and the cell density is controlled at 1 × 105About cells/mL.
(3) Determination of biological activity by MTT method: taking SH-SY5Y cells in exponential growth phase, inoculating the cells in a 96-well culture plate, wherein the cell number density is 1 multiplied by 105one/mL, 100. mu.L/well, 37 ℃ and 5% CO2Culturing in incubator for 12h, adding 100ul400umol/L hydrogen peroxide per well after cell adherence, damaging for 8h, discarding culture solution after damage, adding 200ul new compound culture solution with different concentrations (20ug/ml,40ug/ml,80ug/ml), setting 3 multiple wells per concentration, placing at 37 deg.C and 5% CO2Culturing in an incubator for 24 h. After 24h, 20. mu.l of MTT (5mg/mL) was added to each well and incubation in the incubator was continued for 4 h. The supernatant was discarded, 150. mu.l DMSO was added to each well, and the absorbance (OD value) was measured at 490 nm. The proportion of viable cells was calculated according to the following formula:
the proportion of viable cells (Cell Viability) — (addition drug OD value)/(control OD) value × 100%
The results are as follows: as shown in fig. 2, compared to the injured group, the cell survival rate of the drug-added group was significantly higher than that of the injured group, and the cell survival rates of compound a at concentrations of 7.5, 15 and 30 μ M were 52%, 64% and 78%; cell viability was 58%, 69% and 82% for compound B at concentrations of 15,30 and 60 μ M.
(4) Determination of activity by LDH method: taking SH-SY5Y cells in exponential growth phase, inoculating the cells in a 96-well culture plate, wherein the cell number density is 1 multiplied by 105one/mL, 100. mu.L/well, 37 ℃ and 5% CO2Culturing in incubator for 12h, adding 100ul400umol/L hydrogen peroxide per well after cell adherence, damaging for 6h, discarding culture solution after damage, adding 200ul culture solution of new compounds with different concentrations (20ug/ml,40ug/ml,80ug/ml), setting 3 multiple wells per concentration, placing at 37 deg.C and 5% CO2Culturing in an incubator for 24 h. After 24h, taking the supernatant, and carrying out reaction according to the instruction of the LDH kit. After the reaction, the OD value was measured at 450nm with a microplate reader.
The results for LDH release were expressed as a percentage of the blank.
The results show that: as shown in fig. 3, compared with the injured group, the LDH release amount of the drug-added group was significantly lower than that of the injured group, and the LDH release amount of compound a at concentrations of 7.5, 15 and 30 μ M was 230%, 130% and 110%; LDH release at 15,30 and 60 μ M concentrations for compound B was 294%, 231% and 139%.
The above results show that: the caffeoylquinic acid derivatives have good nerve cell repair activity and show good dose-dependent relationship in a certain dose range.
Example 3: preparation of pharmaceutical compositions
Compound A6.5 g
Dextrin 80g
The materials are evenly mixed according to a conventional method, and are respectively filled into common gelatin capsules in 1000 equal parts to obtain 1000 capsules.
Example 4: preparation of pharmaceutical compositions
Compound B6.5 g
Dextrin 80g
The materials are evenly mixed according to a conventional method, and are respectively filled into common gelatin capsules in 1000 equal parts to obtain 1000 capsules.
The carrier in the above embodiments 3 and 4 is dextrin, and the carrier may also include various pharmaceutical excipients, packaging materials, and the like. The auxiliary materials are selected according to the requirements of the preparation, such as fillers, disintegrants, binders, lubricants and the like, and can be suitable for oral administration, inhalation, parenteral administration or surface administration; dosage forms include, but are not limited to, injections, solutions, tablets, capsules, granules, and the like.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention and are intended to be equivalent substitutions are included in the framework of the present invention.
Claims (1)
1. A preparation method of caffeoylquinic acid derivatives is characterized in that: the derivative is a compound having the following structure:
the preparation method specifically comprises the following steps:
10.0kg of burdock root medicinal material, 8-20 times of 55% ethanol water solution by mass percent, soaking overnight, heating and refluxing for extraction for 3 times, 2 hours for the first time, and 1 hour for the later time; mixing the extractive solutions, and recovering solvent under reduced pressure to obtain concentrated extract; dispersing the extract in appropriate amount of water, sequentially extracting with petroleum ether, dichloromethane, ethyl acetate and n-butanol; recovering the solvent under reduced pressure to obtain 15.6g of petroleum ether extract, 43.1g of dichloromethane extract, 256.8g of ethyl acetate extract and 843.2g of n-butanol extract; the detection proves that the activity of the ethyl acetate layer is optimal; the ethyl acetate extract 256.8g was passed through a silica gel column, eluting with dichloromethane-methanol 100: 1-1:100, obtaining 15 flow portions; separating Fr.12, 10g with ODS column chromatography, eluting with methanol-water 10:90-100:0 to obtain 18 fractions; performing ODS column chromatography on the flow Fr.12-10, and eluting with methanol-water 10:90-100:0 to obtain 10 flow parts; fraction Fr.12-10-4, 800mg preparative liquid chromatography, chromatography conditions, JASCO preparative high performance liquid chromatography, YMC-Pack Pro ODS-A C18, phi 250X 10mm,10 μm, water: acetonitrile: trifluoroacetic acid 77.5: 22.5: 1, a, 18mg, rt 65min and B, 80mg, rt 48 min.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1270955A (en) * | 1999-04-16 | 2000-10-25 | 中国人民解放军军事医学科学院放射医学研究所 | Preparation of 1,5-di-o-coffeic acyl quininic acid derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1270955A (en) * | 1999-04-16 | 2000-10-25 | 中国人民解放军军事医学科学院放射医学研究所 | Preparation of 1,5-di-o-coffeic acyl quininic acid derivative |
Non-Patent Citations (2)
| Title |
|---|
| Compound MQA, a Caffeoylquinic Acid Derivative, Protects Against NMDA-Induced Neurotoxicity and Potential Mechanisms In Vitro;Xing Tian,et al.,;《CNS Neuroscience & Therapeutics》;20150616;第21卷(第7期);第575-584页 * |
| 牛蒡根中咖啡酸类化学成分及其神经保护活性研究;白俊鹏等;《中草药》;20150131;第46卷(第2期);第163-168页 * |
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