CN109705077B - Coumarin compound and preparation method and application thereof - Google Patents
Coumarin compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a coumarin compound and a preparation method and application thereof. The invention researches the material basis of the radix angelicae pubescentis medicinal material to obtain an extraction and separation method capable of obtaining a new coumarin active component, and the compound with the structure shown in the formula I extracted according to the method has obvious inhibition effect on inflammatory factor NO of an A7r5 rat thoracic aorta smooth muscle cell inflammation model and shows good in-vitro anti-inflammatory effect.
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
Radix Angelicae Pubescentis is dried root of Angelica gigas nakai (Angelica gigas L.) belonging to Angelica of Umbelliferae (Umbelliferae). Mainly produced in Sichuan, Hubei, Anhui, etc. Pungent, bitter and slightly warm in nature. It enters kidney and bladder meridians. Has the effects of dispelling pathogenic wind, removing dampness, relieving arthralgia and relieving pain, and can be used for treating arthralgia due to wind-cold-dampness, lumbago, gonalgia, shaoyin wind-cold headache, and headache due to wind-cold-dampness. Modern pharmacological research shows that the radix angelicae pubescentis has various activities of resisting tumors, resisting inflammation, relieving pain, calming, inhibiting platelet aggregation, reducing blood pressure and the like.
Hitherto, the roots and rhizomes of pubescent angelica root have been mainly separated into coumarins and volatile oil components, and a small amount of sterol and saccharide components. The volatile oil of radix angelicae pubescentis has obvious anti-inflammatory and analgesic effects, the coumarin compound is a plant secondary metabolite, and has biological activities of diminishing inflammation, resisting bacteria, resisting oxidation, resisting tumors, inhibiting platelet aggregation, inhibiting thrombosis and the like, and the compound is widely applied to the fields of medicine, agriculture and the like. The Chinese patent medicines using the radix angelicae pubescentis as the main raw material are various, and include radix angelicae pubescentis pain-relieving liniment, radix angelicae pubescentis and herba taxilli mixture, radix angelicae pubescentis and herba taxilli pills, compound radix angelicae pubescentis and indometacin capsules and the like. Meanwhile, the application history of the radix angelicae pubescentis in the field of health care is long, records about 'long-term taking, weight reducing and aging resistance' of the radix angelicae pubescentis in the 'Shen nong Ben Cao Jing', and the radix angelicae pubescentis has entered the field of livestock health care in recent years. The radix angelicae pubescentis ethanol extract has good inhibitory activity on penicillium citrinum, green mould, anthrax and acidovorax citrulli, also has application in the field of plant protection, and has very wide development prospect of botanical pesticides taking radix angelicae pubescentis as a raw material. In view of the diverse biological activities and wide market prospects of radix angelicae pubescentis, further research on chemical components of radix angelicae pubescentis is necessary to explore the material basis of the radix angelicae pubescentis for exerting the drug effect, and a reference basis is provided for developing and utilizing radix angelicae pubescentis resources.
Modern medical research has shown that vascular smooth muscle is an important component of the vascular wall, playing an important role in maintaining vascular structure and function. The occurrence and development processes of a plurality of diseases such as atherosclerosis, hypertension and the like are related to the abnormal proliferation of arterial smooth muscle, and a large number of inflammatory factors are involved in the development processes. There are many factors that induce inflammation, such as burns, chemical stimuli, physical damage, toxins, and the like. Lipopolysaccharide (LPS) is the most important proinflammatory factor in bacterial infectious inflammatory reaction, and can induce inflammatory cells to synthesize and release various inflammatory factors, so that a series of pathophysiological reactions occur in an organism. LPS-induced abnormal proliferation and dysfunction of vascular smooth muscle cells play an important role in the process of vascular pathology.
Disclosure of Invention
The invention separates and prepares a compound with anti-inflammatory activity from the traditional Chinese medicine pubescent angelica root, and provides the application of the compound in preparing anti-inflammatory drugs.
Specifically, the invention provides a coumarin compound which has a structure shown in a formula I:
the invention also provides a preparation method of the compound shown in the formula I, which is characterized by comprising the following steps:
step 1: extracting radix Angelicae Pubescentis with ethanol, and concentrating the extractive solution to obtain extract;
step 2: suspending the extract in water, sequentially extracting with petroleum ether, ethyl acetate and n-butanol, 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 petroleum ether-ethyl acetate mixed solvent, wherein the volume ratio of petroleum ether to ethyl acetate of the gradient elution is 50: 1-1: 1, and collecting the part of the petroleum ether-ethyl acetate with the volume ratio of 10: 1-15: 1;
and 4, step 4: purifying the part obtained in step 3 by gel column chromatography, eluting with methanol or 50% methanol-water, and collecting the eluate;
and 5: and (4) carrying out chromatographic separation and purification on the eluent obtained in the step (4), eluting by using 5-30% of organic solvent water solution, and treating the eluent to obtain the compound shown in the formula I.
Specifically, the volume fraction of ethanol in the step 1 is 75%.
Preferably, the weight ratio of the radix angelicae pubescentis medicinal material to the ethanol in the step 1 is 1 (8-15).
Specifically, in the step 4, the gel used in the gel column chromatography is Sephadex LH-20, Sephadex G15 or Sephadex G50.
Further, in the step 5, the chromatographic separation and purification is high performance liquid chromatography, medium and low pressure preparative chromatography or dynamic axial compression column chromatographic separation.
Specifically, in the step 5, the organic solvent for elution is methanol, ethanol or acetonitrile.
The invention also provides application of the compound shown in the formula I in preparing anti-inflammatory drugs.
The invention also provides an anti-inflammatory drug which comprises the coumarin compound shown in the formula I.
Furthermore, the anti-inflammatory drug is prepared into oral administration dosage forms, injection administration dosage forms and external administration preparations by using various pharmaceutically acceptable auxiliary materials.
The invention researches the material basis of the radix angelicae pubescentis medicinal material, obtains an extraction and separation method capable of obtaining a new coumarin active component, and verifies that the coumarin active component has a good anti-inflammatory effect by utilizing A7r5 rat thoracic aorta smooth muscle cells.
Drawings
FIG. 1 is an ESI-MS diagram of a compound prepared according to example 1 of the present invention;
FIG. 2 is a diagram of the 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 diagram of HMBC for the compound prepared in example 1 of the present invention;
FIG. 6 is a compound prepared according to example 1 of the present inventionOf an object 1 H- 1 H COSY picture.
Detailed Description
The following detailed description of the present invention, taken in conjunction with the accompanying drawings and examples, is provided to enable the invention and its various aspects and advantages to be better understood. However, the specific embodiments and examples described below are for illustrative purposes only and are not limiting of the invention.
It is specifically noted that similar alternatives and modifications will be apparent to those skilled in the art, which are also intended to be included within the present invention. It will be apparent to those skilled in the art that modifications or appropriate variations and combinations of the methods and applications described herein can be made to implement and use the present technology 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.
Extraction, isolation and characterization of Compounds of formula I
Firstly, extraction and separation of compounds
1. Medicinal materials and reagents
The reagents were analytically pure except for the chromatographic purities of methanol and acetonitrile used in the liquid chromatography. The radix Angelicae Pubescentis is dried root of Angelica gigas nakai (Angelica L.) belonging to Umbelliferae (Umbelliferae), which is purchased from Anhui Bozhou.
2. Preparation of the Compounds
Preparation example 1
10kg of radix angelicae pubescentis 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, ethanol is recovered from filtrate, and the filtrate is concentrated to obtain extract. Suspending the extract in water, sequentially extracting with petroleum ether, ethyl acetate and n-butanol, recovering ethyl acetate from the ethyl acetate extraction part under reduced pressure, concentrating to obtain ethyl acetate extract, subjecting the ethyl acetate extract to silica gel column chromatography, gradient eluting with petroleum ether-ethyl acetate (50:1, 20:1, 10:1, 5:1, 3:1, 1:1) to receive one fraction per 500mL, collecting petroleum ether-ethyl acetate (10:1) fraction, concentrating under reduced pressure, purifying with Sephadex LH-20 gel column, eluting with methanol, collecting one fraction per 5mL, concentrating under reduced pressure, separating with high performance liquid chromatography, eluting with C18 column (21.2 × 250mm, 5 μm) at detection wavelength of 230nm and flow rate of 15mL/min with 20% acetonitrile aqueous solution to obtain 6mg of the compound shown in formula I.
Preparation example 2
The preparation method comprises the following steps of crushing 15kg of radix angelicae pubescentis, adding 8 times of 75% ethanol, carrying out reflux extraction for 3 times, each time for 1.5 hours, filtering, recovering ethanol from filtrate, and concentrating to obtain an extract. Suspending the extract in water, sequentially extracting with petroleum ether, ethyl acetate and n-butanol, taking the ethyl acetate extraction part, recovering ethyl acetate under reduced pressure, concentrating to obtain ethyl acetate extract, subjecting the ethyl acetate extract to silica gel column chromatography, gradient eluting with petroleum ether-ethyl acetate (50:1, 30:1, 10:1, 5:1, 3:1, 1:1) and receiving one fraction per 500mL, collecting petroleum ether-ethyl acetate (10:1) component, concentrating under reduced pressure, purifying with Sephadex LH-20 gel column, eluting with methanol, collecting one fraction per 8mL, concentrating under reduced pressure, separating with medium-low pressure preparative chromatography, eluting with C18 column (30 × 150mm, 10 μm), detecting wavelength 230nm, flow rate 20mL/min, and eluting with 30% methanol aqueous solution to obtain 8mg of compound shown in formula I.
Preparation example 3
5kg of radix angelicae pubescentis medicinal material is crushed, then is added with 15 times of 75% ethanol 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, ethyl acetate and n-butanol, recovering ethyl acetate from the ethyl acetate extraction part under reduced pressure, concentrating to obtain ethyl acetate extract, subjecting the ethyl acetate extract to silica gel column chromatography, gradient eluting with petroleum ether-ethyl acetate (50:1, 30:1, 10:1, 5:1, 3:1, 1:1) to receive one fraction per 500mL, collecting petroleum ether-ethyl acetate (10:1) fraction, concentrating under reduced pressure, purifying with Sephadex LH-20 gel column, eluting with methanol, collecting one fraction per 5mL, concentrating under reduced pressure, separating with high performance liquid chromatography, eluting with C18 column (30 × 250mm, 5 μm) at detection wavelength of 230nm and flow rate of 20mL/min with 22% acetonitrile water solution to obtain 5mg of compound shown in formula I.
Preparation example 4
8kg of radix angelicae pubescentis medicinal material is crushed, then added with 75% ethanol in an amount which is 12 times that of the medicinal material, refluxed and extracted for 2 times, each time lasts for 2 hours, filtered, and the filtrate is subjected to ethanol recovery and concentration to obtain an extract. Suspending the extract in water, sequentially extracting with petroleum ether, ethyl acetate and n-butanol, collecting ethyl acetate extraction part, recovering ethyl acetate under reduced pressure, concentrating to obtain ethyl acetate extract, performing silica gel column chromatography on the ethyl acetate extract, gradient eluting with petroleum ether-ethyl acetate (50:1, 30:1, 15:1, 8:1, 5:1, 1:1) to receive one fraction per 500ml, collecting petroleum ether-ethyl acetate (15:1) component, concentrating under reduced pressure, purifying with Sephadex LH-20 gel column, eluting with methanol, collecting one fraction per 8ml, concentrating under reduced pressure, separating by reversed phase C18 dynamic axial compression column chromatography (60 × 800mm, 75 μm), detecting wavelength of 230nm, flow rate of 70mL/min, and carrying out gradient elution by using 5-30% acetonitrile water solution to obtain 6mg of the compound shown in the formula I.
II, structural identification of compound
The compounds obtained in examples 1-4 were all white powders obtained by ESI-MS, 1 H NMR、 13 C NMR, HSQC, HMBC and 1 H- 1 the H COSY spectra carried out the structural identification of the finished products obtained in examples 1-4.
FIG. 1 is an ESI-MS spectrum of the compound obtained in example 1, and FIG. 2 is a ESI-MS spectrum of the compound obtained in example 1 1 H NMR spectrum, FIG. 3, of the compound obtained in example 1 13 C NMR spectrum, FIG. 4 of the compound obtained in example 1HSQC spectrum, FIG. 5 is HMBC spectrum of the compound prepared in example 1, and FIG. 6 is HMBC spectrum of the compound prepared in example 1 1 H- 1 H COSY spectrum.
HR-ESI-MS (positive) gave M/z of 377.1605[ M + H ]] + ，399.1426[M+Na] + (theoretical calculation value is 376.1522), and the molecular formula of the compound is presumed to be C 20 H 24 O 7 。
According to 1 H NMR(400MHz，CD 3 OD) spectrum, low field δ 6.24(1H, d, J ═ 9.5Hz), 7.88(1H, d, J ═ 9.5Hz), 7.67(1H, s) and 6.86(1H, s) are characteristic proton signals of the 6, 7-disubstituted coumarin backbone; δ 5.40(1H, d, J ═ 8.5Hz) and 5.07(1H, d, J ═ 8.5Hz) are the methine proton signals for the two vicinal oxygens; one methoxy proton signal is shown at δ 3.89(3H, s) in the high field region. δ 1.22(3H, s), 1.37(3H, s), 1.58(3H, m), 1.69(3H, dd, J ═ 7.1,1.1Hz) and 6.61(1H, dd, J ═ 7.1,1.5Hz) are the four methyl protons and one alkene proton signals. Bonding of 1 H NMR and 13 c NMR spectrum data analysis shows that the compound is possible angelol coumarin. According to HSQC and HMBC spectra, methyl protons δ 1.22(3H, s) and 1.37(3H, s) are remotely related to C-12(δ 80.8) and C-13(δ 073.9), respectively, δ 15.40(1H, d, J ═ 8.5Hz) and 5.07(1H, d, J ═ 8.5Hz) are proton signals on C-11(δ 268.1) and C-12(δ 380.8), respectively, and δ 45.40(1H, d, J ═ 8.5Hz) is remotely related to C-12(δ 580.8) and C-13(δ 673.9), and 5.07(1H, d, J ═ 8.5Hz) is remotely related to C-11(δ 768.1) and C-13(δ 873.9), further demonstrating the presence of a trioxodiamyl fragment. In HMBC spectra, methyl protons δ 91.58(3H, m) and 1.69(3H, dd, J ═ 7.1,1.1Hz) were associated with C-2' (δ 129.3) and C-3' (δ 0138.9), respectively, and δ 11.58(3H, m) and δ 6.61(1H, dd, J ═ 7.1,1.5Hz) were associated with C-1' (δ 168.0), suggesting that the structure contains a cis-ionyl (δ 168.0) fragment; h-11(δ 5.40(1H, d, J ═ 8.5Hz)) was remotely associated with C-6(δ 129.6) and C-7(δ 162.0), suggesting that C-11 is linked to coumarin nucleus C-6; h-12(δ 5.07(1H, d, J ═ 8.5Hz)) and C-1' (δ 168.0) are related, suggesting that the tigloyl fragment is attached to C-12. Taken together, the compound is very similar to angelol B, the main difference being that the compound has a coupling constant J of 8.5Hz between H-11 and H-12, whereas angelol B has both hydrogens as mono-sPeaks, indicating that the compound is a stereoisomer of angelol B. Therefore, the relative configuration of the compound C-11 and the compound C-12 is the same as that of the angelol M, the C-11 is in an S configuration, and the absolute configuration of the compound C-12 cannot be determined by combining the existing literature data because the configuration of the compound C-11 is opposite to that of the angelol B. In conclusion, the compound was concluded to be 6- [ (1S, 2S) -2-cistanoyl-1, 3-dihydroxy-3-methylbutyl]The-7-methoxy coumarin is named angelol N, has a structure shown in a formula I, and is a novel angelol coumarin compound. The nuclear magnetic data attribution of the compound is shown in the table 1, and the structural formula of the compound is shown in the formula I.
TABLE 1 Nuclear magnetic data for the Compounds of formula (I) provided herein
Note: the test conditions were that of deuterated methanol, 1 H NMR 400MHz， 13 C NMR 100MHz。
ESI-MS spectra of examples 2 to 4, 1 H NMR spectrum, 13 C NMR spectrum, HSQC spectrum, HMBC spectrum and 1 H- 1 the H COSY spectrogram is the same as that in example 1, which shows that the structural formulas are all shown as formula I.
In vitro anti-inflammatory assay of Compounds of formula I
1. Test materials
1.1 cells: a7r5 rat thoracic aortic smooth muscle cells were purchased from Shanghai academy of sciences cell banks and passed to the third generation for testing.
1.2 reagent: DMEM medium (Gibco), fetal bovine serum (Hyclone), trypsin (Gibco), lps (sigma), dmso (sigma), Nitric Oxide (NO) detection kit (bio-technical institute in cloudy days); coumarin compound (structural formula shown in formula I) is provided.
1.3 instruments and devices: clean bench (Sujing Antai), carbon dioxide incubator (Thermo sc)ientific 3100), inverted microscope (OLYPUS), 96-well cell culture plate (Costar, USA), 25cm 2 Cell culture flasks (Costar, USA), enzyme labeling Machine (MD), pipette gun (Eppendorf), BXM-30R vertical pressure steam sterilization pot (Shanghai Bingfeng industry Co., Ltd., medical facilities Co., Ltd.), LD4-2A centrifuge (Beijing Zhongyi neutralization Biotechnology Co., Ltd.), cell automatic counter (Invitrogen, Cl 028).
3. Test method
3.1 preparation of test article
The compound shown in formula I is weighed and dissolved in DMSO to prepare a storage solution with the concentration of 50mM, and the solution is diluted 1/1000 by serum-free DMEM culture solution as a test sample solution during detection.
3.2 cell culture and detection of inflammatory factors
Cells were cultured at 8X 10 4 The cells were plated at a concentration of 100. mu.L/well in 96-well cell culture plates at 37 ℃ with 5% CO 2 The cells were cultured in a cell incubator for 24 hours.
The supernatant was aspirated and divided into a blank group, a model group and an administration group as required, the blank group was administered with 100. mu.L of a serum-free medium, the model group was administered with 100. mu.L of LPS at a final concentration of 3. mu.g/mL in a serum-free medium, and the administration group was administered with 3. mu.g/mL of LPS at a final concentration of 50. mu.M at 37 ℃ in 5% CO 2 The cells were cultured in a cell incubator for 24 hours. Each group is provided with three multiple holes.
And (3) sucking 50 mu L of cell supernatant, adding the cell supernatant into a blank 96-well plate, adding 50 mu L of Griess Reagent I at room temperature, adding 50 mu L of Griess Reagent II at room temperature, measuring absorbance at 540nm, and detecting NO by referring to a Nitric Oxide (NO) detection kit.
4. Statistical method
The analysis is carried out by using SPSS 16.0 statistical software, and the experimental data are all as follows
Is represented by the formula p<A difference of 0.05 is statistically significant.
5. As a result, the
In the experiment of inflammatory response of LPS stimulating A7r5 cells, the administration group had no significant effect on the growth of A7r5 cells at a concentration of 50. mu.M, compared to the blank group. Compared with the blank group, the content of NO in the supernatant of A7r5 cells after 24h of LPS stimulation in the model group is obviously increased, while the release of NO in the supernatant of the cells is obviously inhibited in the administration group (namely the compound shown in the formula I + the LPS group after 24h of culture), and the results are shown in Table 2.
TABLE 2 Effect of drugs on the stimulation of NO production by A7r5 cells by LPS
(p ≦ 0.01 for blank group; p ≦ 0.01 for model group; p ≦ 0.05 for model group)
In conclusion, the structural compound shown in the formula I provided by the invention has an obvious inhibition effect on inflammatory factors NO of a rat thoracic aorta smooth muscle cell inflammation model of A7r5, and the compound has a good in-vitro anti-inflammatory effect.
The above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (5)
1. A preparation method of coumarin compounds, wherein the compounds have a structure shown in formula I:
the method is characterized by comprising the following steps:
step 1: extracting radix Angelicae Pubescentis with ethanol, and concentrating the extractive solution to obtain extract;
step 2: suspending the extract in water, sequentially extracting with petroleum ether, ethyl acetate and n-butanol, 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 petroleum ether-ethyl acetate mixed solvent, wherein the volume ratio of petroleum ether to ethyl acetate of the gradient elution is 50: 1-1: 1, and collecting the part of the petroleum ether-ethyl acetate with the volume ratio of 10: 1-15: 1;
and 4, step 4: purifying the part obtained in step 3 by gel column chromatography, eluting with methanol or 50% methanol-water, and collecting the eluate;
and 5: and (4) carrying out chromatographic separation and purification on the eluent obtained in the step (4), eluting with 5-30% methanol or acetonitrile aqueous solution, and treating the eluent to obtain the compound shown in the formula I.
2. The method according to claim 1, wherein the ethanol volume fraction in the step 1 is 75%.
3. The preparation method of claim 2, wherein the weight ratio of the radix angelicae pubescentis medicinal material to the ethanol is 1 (8-15).
4. The method according to claim 1, wherein the gel used in the gel column chromatography in step 4 is Sephadex LH-20, Sephadex G15 or Sephadex G50.
5. The preparation method according to claim 1, wherein in the step 5, the chromatographic separation and purification is high performance liquid chromatography, medium-low pressure preparative chromatography or dynamic axial compression column chromatographic separation.
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