CN111825646B - Butylphenylpeptide compound and preparation method and application thereof - Google Patents
Butylphenylpeptide compound and preparation method and application thereof Download PDFInfo
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- CN111825646B CN111825646B CN201910307851.3A CN201910307851A CN111825646B CN 111825646 B CN111825646 B CN 111825646B CN 201910307851 A CN201910307851 A CN 201910307851A CN 111825646 B CN111825646 B CN 111825646B
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Images
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Toxicology (AREA)
- Biochemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention researches the material basis of the ligusticum wallichii medicinal material, obtains the following butyl benzene peptide compound, and discovers that the compound has antioxidant activity through modern pharmacological experiments, and has good research and development prospects.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a plant source compound and a preparation method and application thereof.
Background
Rhizoma Ligustici Chuanxiong is dried root of Ligusticum chuanxiong Hort (Ligusticum chuanxiong Hort.) belonging to Umbelliferae (Umbelliferae). Mainly produced in Pengzhou, dujiang weir, etc. of Sichuan province. Pungent in flavor and entering liver, gallbladder and pericardium meridians. Has effects in promoting blood circulation, activating qi-flowing, dispelling pathogenic wind, and relieving pain. Can be used for treating thoracic obstruction, cardialgia, stabbing pain in chest and hypochondrium, traumatic injury, menoxenia, amenorrhea, dysmenorrhea, abdominal mass, headache, and rheumatalgia. Modern pharmacological research shows that the chuanxiong rhizome is mainly used for treating cardiovascular and cerebrovascular diseases, respiratory diseases, urinary diseases and gynecological diseases.
Free radicals, which are harmful compounds produced in the oxidation reaction of the body, have strong oxidizing properties and may damage tissues and cells of the body, thereby causing chronic diseases and aging effects. Modern research shows that when various factors break the dynamic balance of free radical generation and elimination in vivo, free radicals exceed physiological limits, thereby causing damage to biological macromolecules, enzyme inactivation and the like. Due to these injuries, aging of the body may occur, resulting in various diseases including stroke, heart disease, tumor, diabetes, hyperlipidemia, chronic renal failure, neurodegenerative disease, cataract, etc. A large number of people and experimental researches show that the occurrence of the diseases can be effectively controlled by reasonably taking the antioxidant or the free radical scavenger, and a good prevention effect is achieved. Therefore, the focus of attention has been on finding drugs against free radicals.
Disclosure of Invention
In view of the above, the present invention provides a compound with antioxidant activity separated and prepared from traditional Chinese medicine ligusticum wallichii, and a preparation method and an application thereof.
The invention provides a butyl benzene peptide compound which has a structure shown in a formula I:
the invention also provides a preparation method of the compound, which is characterized by comprising the following steps:
step 1: extracting rhizoma Ligustici Chuanxiong with ethanol water solution, and concentrating the extractive solution to obtain extract;
step 2: suspending the extract in water, sequentially extracting with petroleum ether and ethyl acetate, and concentrating the ethyl acetate extract part to obtain ethyl acetate extract;
and step 3: performing column chromatography separation on the ethyl acetate extract, performing gradient elution by using a dichloromethane-acetone mixed solvent, wherein the dichloromethane-acetone volume ratio of the gradient elution is 0-20;
and 4, step 4: purifying the part obtained in the step 3 by gel column chromatography, eluting by methanol, and collecting the eluent;
and 5: and (5) carrying out chromatographic separation and purification on the eluent obtained in the step (4), eluting by using 12-40% of organic solvent water solution, and treating the eluent to obtain the compound shown in the formula I.
Preferably, the volume fraction of the ethanol aqueous solution in the step 1 is 75%.
Further, the weight ratio of the ligusticum wallichii medicinal material to the ethanol water solution in the step 1 is 1 (8-12).
Specifically, in step 4, the gel used in the gel column chromatography is selected from Sephadex LH-20, sephadex G15 or Sephadex G50.
Further, the chromatography in the step 5 is selected from high performance liquid chromatography, medium and low pressure preparative chromatography or dynamic axial compression column chromatography separation.
Specifically, in step 5, the organic solvent for elution is methanol, ethanol or acetonitrile.
Preferably, the preparation method of the aforementioned compound of the present invention comprises: pulverizing rhizoma Ligustici Chuanxiong, adding 10 times of 75% ethanol, reflux-extracting for 2 times (2 hr each time), filtering, recovering ethanol from filtrate, and concentrating to obtain extract; suspending the extract in water, sequentially extracting with petroleum ether and ethyl acetate, collecting ethyl acetate extraction part, recovering ethyl acetate under reduced pressure, and concentrating to obtain ethyl acetate extract; the ethyl acetate extract was subjected to silica gel column chromatography, gradient elution with dichloromethane-acetone (20, 10, 1, 5, 1, 3, 1, 0.
The invention provides a compound and pharmaceutically acceptable salt or hydrate thereof, wherein the compound is as follows: 1-isobenzofuranone,3-butyl-3,3a,4,5,6-pentahydro-3a,6-dihydroxy- (3S, 3 aS).
The invention provides application of the compound in preparing an antioxidant medicament.
The invention also provides an antioxidant medicine which is prepared from the compound and a pharmaceutically acceptable carrier.
Specifically, the dosage form of the antioxidant drug is an oral administration dosage form, an injection administration dosage form or an external administration preparation.
Furthermore, the medicine can be any one of the dosage forms in pharmaceutics, including tablets, capsules, soft capsules, gels, oral preparations, suspensions, granules, patches, ointments, pills, powders, injections, infusion solutions, freeze-dried injections, intravenous emulsions, liposome injections, suppositories, sustained-release preparations or controlled-release preparations.
The invention researches the material basis of the ligusticum wallichii medicinal material to obtain a new butyl benzene peptide active component and provides a corresponding extraction and separation method thereof. The invention also discovers that the compound has antioxidant activity and has good research and development prospects through modern pharmacological experiments.
Drawings
FIG. 1 shows the structure and key elements of the compounds of the present invention 1 H- 1 HCOSY and HMBC correlation spectra;
FIG. 2 is a photograph of a compound prepared in example 1 of the present invention 1 H NMR chart;
FIG. 3 is a photograph of a compound prepared in example 1 of the present invention 13 C NMR chart;
FIG. 4 is a HSQC plot of the compound prepared in example 1 of the present invention;
FIG. 5 is a HMBC plot of the compound prepared in example 1 of the present invention;
FIG. 6 is a photograph of a compound prepared in example 1 of the present invention 1 H- 1 H COSY picture;
FIG. 7 is a NOESY plot of the compound prepared in example 1 of the present invention.
Detailed Description
The embodiments of the present invention will be described in more detail below with reference to the drawings and examples, so that the aspects of the present invention and the advantages of its various aspects can be better understood. However, the specific embodiments and examples described below are for illustrative purposes only and are not intended to limit the invention.
It is specifically noted that similar alterations and modifications made with respect to the present invention will be apparent to those skilled in the art and are intended to be included in the present invention. It will be apparent to those skilled in the art that the techniques of the present invention may be implemented and applied by modifying or appropriately combining the methods and applications described herein without departing from the spirit, scope, and content of the present invention.
Secondly, it is to be noted that the concentrations referred to in the present invention are in volume percent (v/v). All percentages, ratios, proportions, or parts are by weight unless otherwise specified. In addition, if the specific conditions are not indicated, the invention is carried out according to the conventional conditions or the conditions suggested by the manufacturer, and the used raw material drugs or auxiliary materials and the used reagents or instruments are the conventional products which can be obtained commercially.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention.
The compound shown in the formula I, the preparation method thereof and the raw materials and reagents used in the application can be purchased from the market, and the other reagents are analytically pure except that methanol and acetonitrile used for liquid chromatography are used as chromatographic pure substances. Rhizoma Ligustici Chuanxiong is dried root of Ligusticum chuanxiong Hort (Ligusticum chuanxiong) belonging to Umbelliferae (Umbelliferae), and is purchased from Anhui, bozhou, anhui.
The invention is further illustrated by the following examples:
EXAMPLE 1 preparation and structural characterization of Compounds of formula I
1.1 preparation of Compounds of formula I
10kg of ligusticum wallichii medicinal material is crushed, then 10 times of 75% ethanol is added for reflux extraction for 2 times, each time lasts for 2 hours, filtration is carried out, and ethanol is recovered from filtrate and concentrated to obtain extract. Suspending the extract in water, sequentially extracting with petroleum ether and ethyl acetate, collecting ethyl acetate extract, recovering ethyl acetate under reduced pressure, and concentrating to obtain ethyl acetate extract. The ethyl acetate extract was subjected to silica gel column chromatography, and eluted with a dichloromethane-acetone (20, 10, 1, 5, 1, 3, 1, 0.
1.2 structural characterization of Compounds
The compound was a colorless oil, as shown in Table 1 and FIGS. 1-7, according to 1 H NMR(400MHz，CD 3 OD) spectrum, the low field region shows an olefinic hydrogen signal δ 6.80 (1h, d, j =3.8 hz, h-7), coupled with hydrogen on an oxygen-linked carbon δ 4.32 (1h, t, j =3.8 hz, h-6). The high field region has a hydrogen signal delta 4.50 (1H, dd, J =10.3,3.5 Hz, H-3) on oxygen-bonded carbon, delta 0.93 (3H, t, J =7.0 Hz, CH 3 ) There are 10 hydrogen signals between 1.3 and 2.0 for one methyl signal. 13 C NMR(100MHz，CD 3 OD) spectrum showed 12 carbons, combined with DEPT spectrum (100MHz 3 OD) one of the ester carbonyl groups is delta 170.1 (C-1), two sp 2 Hybrid carbon signals delta 138.3 (C-7), 132.4 (C-7 a), three vicinal oxygen carbon signals delta 90.6 (C-3), 72.2 (C-3 a), 61.8 (C-6), one methyl carbon signal delta 12.8 (C-11), five methylene carbon signals delta 31.5 (C-8), 27.3 (C-9), 25.7 (C-5), 24.1 (C-4), 22.0 (C-10). By HSQC, HMBC and 1 H- 1 h COSY spectrum, observed fragment a and fragment b. Segment a and segment b in the HMBC spectra correlate with the quaternary carbon delta 72.2 (C-3 a). This is judged to be a five-membered lactone ring by δ 4.50 (1H, dd, J =10.3,3.5 Hz, H-3) and δ 170.1 (C-1), 132.4 (C-7 a) and 72.2 (C-3 a).Delta 1.80 (1H, m, H-4 a) and 1.68 (1H, m, H-4 b) are related to delta 25.7 (C-5), 72.2 (C-3 a), 90.6 (C-3), 61.8 (C-6) and 132.4 (C-7 a). Delta 6.80 (1H, d, J =3.8 Hz, H-7) is related to Delta 170.1 (C-1), 72.2 (C-3 a) and 25.7 (C-5), which is judged to be an unsaturated six-membered ring linked to a five-membered lactone ring at C-3a and C-7a, and Delta 61.8 (C-6) and 72.2 (C-3 a) are judged to contain two hydroxyl groups.
In the NOESY spectrum, δ 4.50 (1H, dd, J =10.3,3.5 Hz, H-3) and 1.68 (1H, m, H-4 a) are correlated, δ 1.62 (1H, m, H-8 a), 1.32 (1H, m, H-8 b) and 1.80 (1H, m, H-4 e) are correlated, suggesting that H-3 is heterotopic to OH-3 a. Delta 4.32 (1H, t, J =3.8 Hz, H-6) was associated with 1.86 (1H, m, H-5 a), 2.16 (1H, m, H-5 e) with 1.68 (1H, m, H-4 a), delta 4.50 (1H, dd, J =10.3,3.5 Hz, H-3) and 1.68 (1H, m, H-4 a), indicating H-3, the same side as OH-6. Analysis of the above data combined, the compound was identified as 1-isobenzofuranone,3-butyl-3,3a,4,5,6-pentahydro-3a,6-dihydroxy- (3S, 3 aS).
TABLE 1 Nuclear magnetic data for Compounds of formula (I) provided herein
Note: the test conditions were that of deuterated methanol, 1 H NMR 400MHz， 13 C NMR 100MHz。
example 2 preparation and Structure identification of Compounds of formula I
2.1 preparation of Compounds of formula I
5kg of ligusticum wallichii medicinal material is crushed, then added with 75% ethanol with the amount of 12 times of the weight of the medicinal material for reflux extraction for 2 times, each time lasts for 2 hours, filtration is carried out, and the ethanol is recovered from the filtrate and concentrated to obtain an extract. Suspending the extract in water, sequentially extracting with petroleum ether and ethyl acetate, collecting the ethyl acetate extract, recovering ethyl acetate under reduced pressure, and concentrating to obtain ethyl acetate extract. The ethyl acetate extract was subjected to silica gel column chromatography, and eluted with a gradient of petroleum ether-ethyl acetate (10.
2.2 structural characterization of Compounds
The above compound, which was also 1-isobenzofuranone,3-butyl-3,3a,4,5,6-pentahydro-3a,6-dihydroxy- (3S, 3aS), was identified by the same method as in example 1.
EXAMPLE 3 preparation and structural characterization of Compounds of formula I
3.1 preparation of the Compounds of formula I
8kg of ligusticum wallichii medicinal material is crushed, then is added with 75 percent ethanol with the amount of 15 times for reflux extraction for 2 times, each time lasts for 2 hours, the filtration is carried out, and the ethanol is recovered from the filtrate and is concentrated to obtain an extract. Suspending the extract in water, sequentially extracting with petroleum ether and ethyl acetate, collecting the ethyl acetate extract, recovering ethyl acetate under reduced pressure, and concentrating to obtain ethyl acetate extract. The ethyl acetate extract was subjected to silica gel column chromatography, and eluted with a dichloromethane-ethyl acetate (20.
3.2 structural characterization of Compounds
The above compound, which was also 1-isobenzofuranone,3-butyl-3,3a,4,5,6-pentahydro-3a,6-dihydroxy- (3S, 3aS), was identified by the same method as in example 1.
Example 4 preparation and structural characterization of Compounds of formula I
4.1 preparation of Compounds of formula I
15kg of ligusticum wallichii medicinal material is crushed, then 10 times of 75% ethanol is added for reflux extraction for 2 times, 2 hours are carried out each time, filtration is carried out, ethanol is recovered from filtrate, and concentration is carried out to obtain extract. Suspending the extract in water, sequentially extracting with petroleum ether and ethyl acetate, collecting ethyl acetate extract, recovering ethyl acetate under reduced pressure, and concentrating to obtain ethyl acetate extract. The ethyl acetate extract was subjected to silica gel column chromatography, gradient elution with petroleum ether-acetone (10, 1, 5, 1, 3.
4.2 structural characterization of Compounds
The above-mentioned compound was identified as 1-isobenzofuranone,3-butyl-3,3a,4,5,6-pentahydro-3a,6-dihydroxy- (3S, 3aS) by the same method as in example 1.
EXAMPLE 5 Experimental study of the antioxidant Activity of the Compound of the present invention
5.1 Experimental materials and Equipment
DPPH is analytically pure and is purchased from national pharmaceutical chemicals, inc.; flxtstation 3 calflow workstation, molecular Devices, USA.
5.2 Experimental methods
Accurately weighing a certain amount of DPPH free radicals, dissolving with 70% ethanol to prepare a solution with a concentration of 50 mg.L -1 The free radical solution of (1). Respectively and precisely weighing the compound and the vitamin C to prepare 5 sample solutions with different concentrations of 25, 50, 100, 200 and 400 mu g/mL, respectively and precisely sucking 1mL of the sample solution and 2mL of the DPPH free radical ethanol solution, uniformly mixing, reacting for 40min at room temperature, and measuring the absorbance at 517 nm. DPPH clearance = [1- (As-Ax)/A0]And multiplying by 100% (in the formula, as is the absorbance of the sample, A0 is the absorbance value of the DPPH ethanol solution, and Ax is the absorbance of a blank control of the sample solution), and calculating the DPPH free radical scavenging rate of each sample. DPPH free radical scavenging Rate the results of IC50 value in the in vitro antioxidant activity test are shown in Table 2. The results show thatThe antioxidant activity of the compound is dose-dependent, and y =0.221x +11.013R 2 ＝0.9937。
Table 2 example 5 summary of the results of the antioxidant experiments
The experimental results show that the antioxidant activity of the compound provided by the invention is stronger than that of vitamin C, and the compound has good antioxidant activity.
Example 6 Capsule
350g of the compound with the structure shown in the formula I, 32g of starch, 6g of low-substituted hydroxypropyl cellulose, 4.5g of aerosil, 1.5g of magnesium stearate and a proper amount of 10% starch slurry are mixed and encapsulated to obtain 1000 capsules of the compound shown in the formula I.
Example 7 granules
350g of the compound with the structure shown in the formula I, 1000g of cane sugar and 500g of dextrin are mixed, and 1000-pack compound granules with the structure shown in the formula I are prepared according to a conventional method.
EXAMPLE 8 tablets
350g of the compound with the structure shown in the formula I, 50g of starch, 7.5g of sodium carboxymethyl starch, 0.8g of talcum powder, 50g of dextrin, 0.8g of magnesium stearate and a proper amount of 10% starch slurry are mixed appropriately, and 1000 tablets of the compound with the structure shown in the formula I are prepared according to a conventional method.
EXAMPLE 9 pellets
350g of the compound with the structure shown in the formula I, 12g of polyethylene glycol-6000, 80.5g of polysorbate-80 and a proper amount of liquid paraffin are mixed, and 1000 pills of the compound with the structure shown in the formula I are prepared according to a conventional method.
EXAMPLE 10 injection
200g of the compound with the structure shown in the formula I, 15g of soybean phospholipid for injection and 25g of glycerol for injection are mixed, the volume of water for injection is fixed to 1000mL, and 1000 compound injections with the structure shown in the formula I are prepared according to a conventional method.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (5)
1. An application of a butyl benzene peptide compound in preparing an antioxidant drug has a structure shown in a formula I:
2. use according to claim 1, wherein the compound is prepared by a process comprising the steps of:
step 1: extracting rhizoma Ligustici Chuanxiong with ethanol water solution, and concentrating the extractive solution to obtain extract;
step 2: suspending the extract in water, sequentially extracting with petroleum ether and ethyl acetate, and concentrating the ethyl acetate extract to obtain ethyl acetate extract;
and 3, step 3: performing column chromatography separation on the ethyl acetate extract, performing gradient elution by using a dichloromethane-acetone mixed solvent, wherein the dichloromethane-acetone volume ratio of the gradient elution is 0-1;
and 4, step 4: purifying the part obtained in the step 3 by gel column chromatography, eluting by methanol, and collecting eluent, wherein the gel is selected from Sephadex LH-20, sephadex G15 or Sephadex G50;
and 5: and (5) carrying out chromatographic separation and purification on the eluent obtained in the step (4), eluting by using 12-40% of organic solvent water solution, and treating the eluent to obtain the compound shown in the formula I.
3. Use according to claim 2, wherein the chromatography in step 5 is selected from high performance liquid chromatography, medium low pressure preparative chromatography or dynamic axial compression column chromatography.
4. The use according to claim 2, wherein in step 5, the organic solvent for elution is methanol, ethanol or acetonitrile.
5. The application of any one of claims 1-4, wherein rhizoma Ligustici Chuanxiong is pulverized, added with 10 times of 75% ethanol, and extracted under reflux for 2 times, each time for 2h, filtered, and the filtrate is subjected to ethanol recovery and concentration to obtain extract; suspending the extract in water, sequentially extracting with petroleum ether and ethyl acetate, collecting ethyl acetate extraction part, recovering ethyl acetate under reduced pressure, and concentrating to obtain ethyl acetate extract; the ethyl acetate extract was subjected to silica gel column chromatography, gradient elution with dichloromethane-acetone (20, 10, 1, 5, 1, 3, 1, 0.
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| CN1569848A (en) * | 2003-07-14 | 2005-01-26 | 中国中医研究院中药研究所 | Ligustilide for treating ischemic heart disease and its preparing method |
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| CN102108072A (en) * | 2009-12-24 | 2011-06-29 | 上海张江中药现代制剂技术工程研究中心 | Method for preparing senkyunolide I from extract of Chinese angelica |
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| CN1569848A (en) * | 2003-07-14 | 2005-01-26 | 中国中医研究院中药研究所 | Ligustilide for treating ischemic heart disease and its preparing method |
| WO2007036074A1 (en) * | 2005-09-30 | 2007-04-05 | Fei Chen | The use of phthalide derivatives |
| CN101272779A (en) * | 2005-09-30 | 2008-09-24 | 陈菲 | Usage of phthalide derivant |
| CN102108072A (en) * | 2009-12-24 | 2011-06-29 | 上海张江中药现代制剂技术工程研究中心 | Method for preparing senkyunolide I from extract of Chinese angelica |
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