CN113402528B - Celastracene type macrocyclic diterpenoid compound, preparation method, pharmaceutical composition and application - Google Patents
Celastracene type macrocyclic diterpenoid compound, preparation method, pharmaceutical composition and application Download PDFInfo
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Abstract
The application relates to the technical field of medicines, and particularly discloses a series of cembrane type macrocyclic diterpenoid compounds extracted and separated from frankincense (Boswellia sacra Flueck) resin, and a preparation method, a pharmaceutical composition and application thereof. Pharmacological research shows that the obtained compound has remarkable nerve cell protection effect in a primary neuron cell model of glutamate injury and an oxygen glucose deprivation injury model, and has good medicinal prospect in the preparation of nerve cell protection medicines.
Description
Technical Field
The application relates to the technical field of medicines. Relates to a series of cembrane type macrocyclic diterpenoid compounds extracted and separated from olibanum (Boswellia sacra Flueck) resin, a preparation method thereof and application thereof in the preparation of nerve cell protection drugs.
Background
Celastracene diterpene is one of the diterpenes with the largest number, and has a 14-membered ring mother nucleus skeleton formed by first connecting 4 isoprene units. Such compounds are most commonly found in marine organisms, especially in the genus sarcandra and coral. A few of cembrane diterpenoid compounds are found in terrestrial plants such as tobacco, pine and myrrh, and in recent years, a plurality of the compounds are sequentially separated from frankincense, and pharmacological activity researches show that the compound has good anti-inflammatory, anti-depression, anti-colitis, antibacterial, anti-tumor and other activities.
The Olibanum is gum resin exuded or cut by skin of Boswellia carterii (Boswellia carterii birdw.) of Boswellia (Boswellia) of Burseraceae, boswellia carterii (Boswellia bhawdajiana Birdw) and Boswellia carterii (Boswellia neglecta M. Moor) of the same genus, and is a common traditional Chinese medicine. The Olibanum is pungent and warm to dispel and unblock, and has effects of regulating qi, promoting blood circulation, relieving pain, and expelling toxin. Is mainly used for treating stagnation of qi and blood, heart and abdomen pain, carbuncle, sore, toxic swelling, traumatic injury, dysmenorrhea, postpartum blood stasis and pricking pain, etc.; the main components in the olibanum are tetracyclic triterpene, pentacyclic triterpene and macrocyclic diterpenoid compounds, and modern pharmacological research shows that the compounds have better anti-inflammatory and anti-tumor activities. The nerve cell protection activity of the cembrane type macrocyclic diterpenoid compound is not reported yet.
Disclosure of Invention
The application solves the technical problem of providing a cembrane diterpenoid compound separated and purified from olibanum, a preparation method thereof, a pharmaceutical composition and application of the compound in preparation of nerve cell protection drugs.
In order to solve the technical problems of the application, the application provides the following technical scheme:
the first aspect of the technical scheme of the application is to provide a kind of cembrane type macrocyclic diterpenoid compounds and pharmaceutically acceptable salts thereof, which are respectively named as compound 1 (bosssacirin E), compound 2 (bosssacirin J) and compound 3 (bosssacirin G), and the structural formulas of the compounds are respectively as follows:
the second aspect of the technical scheme of the application provides a method for separating and purifying the cembrane diterpene from the olibanum.
The preparation method of the compound 1 in the first aspect comprises the following steps:
(1) Pulverizing Olibanum, extracting with 95% ethanol under reflux under heating for 3 hr each time, and extracting three times. Mixing the extractive solutions, and removing solvent to obtain Olibanum crude extract.
(2) Subjecting Olibanum crude extract to silica gel column chromatography, eluting with petroleum ether, ethyl acetate and 95% ethanol in sequence, and collecting one column volume per unit. Crude sections A-F were obtained.
(3) And (3) performing silica gel column chromatography on the crude section A, eluting with petroleum ether ethyl acetate gradient, wherein the volume ratio is 1:0, 20:1, 4:1, 1:1 and 0:1 respectively, and eluting two column volumes in each gradient.
(4) And (3) performing silica gel column chromatography on a first crude part A5 eluted by petroleum ether and ethyl acetate in a volume ratio of 4:1, eluting by methylene dichloride and acetone in a volume ratio of 30:1, and combining similar components to obtain fractions A-5-1 to A-5-12.
(5) Taking the fraction A-5-2, preparing by adopting a reversed phase C18 semi-preparation high performance liquid phase method, taking methanol and water with a volume ratio of 85:15 as mobile phases, and detecting the wavelength of 210nm to obtain the compound 1.
The structural formula of the compound 1 is as follows:
the preparation method of the compounds 2 and 3 in the first aspect comprises the following steps:
(1) Pulverizing Olibanum, extracting with 95% ethanol under reflux under heating for 3 hr each time, and extracting three times. Mixing the extractive solutions, and removing solvent to obtain Olibanum crude extract.
(2) Subjecting Olibanum crude extract to silica gel column chromatography, eluting with petroleum ether, ethyl acetate and 95% ethanol in sequence, and collecting one column volume per unit. Crude sections A-F were obtained.
(3) And (3) performing silica gel column chromatography on the crude section A, eluting with petroleum ether ethyl acetate gradient, wherein the volume ratio is 1:0, 20:1, 4:1, 1:1 and 0:1 respectively, and eluting two column volumes in each gradient.
(4) And (3) performing silica gel column chromatography on a first crude part A5 eluted by petroleum ether and ethyl acetate in a volume ratio of 4:1, eluting by methylene dichloride and acetone in a volume ratio of 30:1, and combining similar components to obtain fractions A-5-1 to A-5-12.
(5) Taking the fraction A-5-5, preparing by adopting a reversed phase C18 semi-preparation high performance liquid phase method, taking methanol and water with the volume ratio of 82:18 as mobile phases, and detecting the wavelength of 210nm to obtain the compounds 2 and 3.
The structural formulas of the compounds 2 and 3 are as follows:
according to a third aspect of the present application, there is provided a pharmaceutical composition comprising the cembrane diterpene compound of the first aspect and a pharmaceutically acceptable salt or pharmaceutically acceptable carrier or excipient thereof.
According to a fourth aspect of the present application, there is provided an application of the cembrane diterpene compound and its pharmaceutically acceptable salt in the preparation of a medicament for protecting nerve cells
The protection effect of the compound on glutamate-induced cortical neuron injury is measured and evaluated in vitro, and the result shows that the compound 2 shows the protection effect of the compound on glutamate-induced cortical neuron injury at the concentration of 10 mu M, which is equivalent to that of a positive control.
The protective effect of the compound on oxygen glucose deprived cortical neuron hypoxia injury is measured and evaluated in vitro, and the result shows that the compound 1 shows the protective effect on oxygen glucose deprived cortical neuron hypoxia injury which is superior to that of a positive control at the concentration of 10 mu M.
Beneficial technical effects
1. The application firstly separates and purifies the frankincense to obtain three novel compounds 1,2 and 3 of the cembrane type diterpene.
2. The method for measuring and evaluating the protection effect of the monomer compound on the glutamate-induced cortical neuron cell injury is adopted, and the fact that the compound has a certain protection effect on the glutamate-induced cortical neuron injury at the concentration of 10 mu M is proved, wherein the compound 2 has the optimal effect and good medicinal prospect.
3. The method for measuring and evaluating the protective effect of the monomer compound on the oxygen-glucose deprived cortical neuron hypoxia injury proves that the compound 1 shows better protective effect on the oxygen-glucose deprived cortical neuron hypoxia injury at the concentration of 10 mu M, and has good medicinal prospect.
Drawings
The drawings of the present application are intended to provide a further explanation of the application, and exemplary embodiments of the application and their descriptions are intended to explain the application and are not to be limiting in any way.
FIG. 1 Compound 1 (bosssacrin E) 1 H NMR
FIG. 2 Compound 1 (bosssacrin E) 13 C NMR
FIG. 3 HRESIMS of Compound 1 (bosssacrin E)
FIG. 4 Compound 2 (bosssacrin J) 1 H NMR
FIG. 5 Compound 2 (bosssacrin J) 13 C NMR
FIG. 6 HRESIMS of Compound 2 (bosssacrin J)
FIG. 7 Compound 3 (bosssacrin G) 1 H NMR
FIG. 8 Compound 3 (bosssacrin G) 13 C NMR
FIG. 9 HRESIMS of Compound 3 (bosssacrin G)
Detailed Description
The application is further illustrated by the following detailed description of specific examples, which are intended to be purely illustrative and are not intended to limit the application to the exemplary embodiments according to the application.
Pharmaceutical chemistry experiments:
example 1
The preparation of compounds 1-3 was as follows:
(1) Pulverizing 19.0kg of Olibanum, and extracting with 95% ethanol under reflux with solid-liquid ratio of 1:3.5 (kg/L) for 3 hr for three times. Mixing the extractive solutions, and evaporating solvent under reduced pressure to obtain Olibanum crude extract.
(2) The crude extract of Olibanum was subjected to silica gel column chromatography eluting with two portions of petroleum ether, two portions of ethyl acetate, and two portions of 95% ethanol in this order, each portion receiving a column volume of about 35L. Crude sections A-F were obtained.
(3) And (3) performing silica gel column chromatography on the crude section A, eluting with petroleum ether ethyl acetate gradient, wherein the volume ratio is 1:0, 20:1, 4:1, 1:1 and 0:1 respectively, eluting two column volumes by each gradient, and receiving one column volume for each part, wherein the volume is about 5L.
(4) And (3) performing silica gel column chromatography on a first crude part A5 eluted by petroleum ether and ethyl acetate in a volume ratio of 4:1, eluting by methylene dichloride and acetone in a volume ratio of 30:1, and combining similar components to obtain fractions A-5-1 to A-5-12.
(5) Taking the flow A-5-2, adopting a reversed phase C18 semi-preparation high performance liquid phase method to prepare the flow A-5-2 by MeOH/H 2 O (85:15) is used as a mobile phase for preparation, the flow rate is 3ml/min, and the detection wavelength is 210nm, so that the compound 1 is obtained.
(6) Taking the flow A-5-5, adopting a reversed phase C18 semi-preparation high performance liquid phase method to prepare the flow A-5 by MeOH/H 2 O (82:18) is used as a mobile phase for preparation, the flow rate is 3ml/min, the detection wavelength is 210nm, and the compounds 2 and 3 are obtained.
And (3) structural identification: the structure of 3 new compounds is determined by the separated compounds through methods of nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum, mass spectrum, two-dimensional nuclear magnetic resonance spectrum and the like. See fig. 1-9.
Compound 1: bosdacrin E, colorless oil, anisaldehyde-sulfuric acid, developed purple. Optical rotation value [ alpha ]]20d+18.7 (c 0.18, meoh); maximum ultraviolet absorbance UV (MeOH) lambda max (log ε) 204.0 (2.92); infrared spectrum data IR v max 3415,2960,1736,1468,1436,1370,1239,1038cm -1 ； 1 H NMR 13 The C NMR data are shown in Table 1.HRESIMS m/z 387.25009[ M+Na ]] + Calculated as C 20 H 36 O 4 Na：m/z 387.25058。
Compound 2: bosdacrin J, colorless oil, anisaldehyde-sulfuric acid, developed purple. Optical rotation value [ alpha ]]20D-87.8 (c 0.13, meOH); maximum ultraviolet absorbance UV (MeOH) lambda max (log ε) 204.0 (3.10); infrared spectrum data IR v max 3297,2924,1643,1440,1376,1039,1005,888cm -1 ； 1 H NMR 13 CNMR data are shown in table 1.HRESIMS m/z 327.22916[ M+Na ]] + Calculated as C 20 H 32 O 2 Na,327.22945。
Compound 3: bosdacrin G, colorless oil, anisaldehyde-sulfuric acid developed purple. Optical rotation value [ alpha ]]20D-16.2 (c 0.08, meOH); maximum ultraviolet absorbance UV (MeOH) lambda max (log ε) 204.0 (2.55); infrared spectrum data IR v max 3452,2960,2927,1731,1715,1461,1371,1244,1045cm -1 ； 1 H NMR 13 The C NMR data are shown in Table 1.HRESIMS m/z 387.25043[ M+Na ]] + Calculated as C 20 H 36 O 4 Na：m/z 387.25058.
TABLE 1 Compounds 1-3 1 H NMR 13 C NMR data
Pharmacological experiments:
experimental example 1
The neuroprotective effect of screening compounds 1-3 was evaluated using a fetal mouse primary neuronal glutamate model, SK-N-SH cell trioxyse-device oxygen deprivation model.
1. Materials and reagents: cortical neurons of the wistar rat embryo (glutamate model) at 17 days of pregnancy, the damaging agent glutamate (final concentration: 200 μm); SK-N-SH cell 14 th generation (three-gas incubator oxygen glucose deprivation model), low sugar medium, hypoxia device; screening the compound, positive drug PHPB (final concentration 10. Mu.M).
2. Method of
1) Glutamate injury model: cortical neurons of the wistar rat embryos were taken from the cortex on day 17 of pregnancy and neurons were cultured. After one week, PHPB (10. Mu. Mol/L) a positive tool drug was pre-incubated/screening compound (10. Mu. Mol/L) for 1 hour. After adding a glutamic acid dilution at a final concentration of 200. Mu.M and PHPB/compound at a final concentration of 10. Mu.M to each well and co-culturing for 20 hours, the MTT assay was used to determine cell viability.
2) Three-gas hypoxia device oxygen glucose deprivation model: SK-N-SH cells were plated. After one week, positive tool PHPB (10 umol/L)/screening compound (10 umol/L) was incubated with SK-N-SH cells for 1 hour, respectively. The three-gas incubator is subjected to anoxic and sugar-deficient culture for 5.5 hours, reoxygenation is performed for 20 hours, and the cell survival rate is detected by an MTT method.
3) Experimental group: normal control group, model group: glutamic acid group (final concentration: 200 uM)/OGD group, positive tool PHPB group (final concentration 10 umol/L), screening compound group.
3. Experimental results
1) Glutamic acid model:
TABLE 2 Effect of Compounds 1-3 on the cell survival of the primary neuronal cell glutamate model of fetal mice
* P <0.001 compared to control group; # P <0.05 vs. model group, # P <0.01 vs. model group, # P <0.001 vs. model group
2) Oxygen sugar deprivation model:
TABLE 3 effects of Compounds 1-3 on the survival of SK-N-SH cell oxygen glucose deprivation model cells.
* P <0.001 compared to control group; # P <0.05 vs. model group, # P <0.01 vs. model group, # P <0.001 vs. model group
4. Experimental discussion and conclusion:
the experiment applies a primary neuron glutamic acid model and an SK-N-SH cell trioxyglucose deprivation model to evaluate whether the compound has a neuroprotective effect, and the experimental result can be seen as follows:
(1) Glutamic acid model:
1) The primary neurons are damaged by the glutamic acid for 20 hours, so that the survival rate of the primary neurons in the model group can be reduced to 53.1 percent respectively, which indicates that the glutamic acid model is successfully established.
2) PHPB (10 mmol/L), a positive tool, has a tendency to neuroprotection.
3) Compound 2 can increase survival rate of primary neuronal cells damaged by glutamate in a glutamate injury model, and has nerve cell protection effect in the model.
(1) Three-gas device oxygen glucose deprivation model:
1) After the oxygen sugar deprivation model of the three-gas device is reoxygenated for 20h, the survival rate of SK-N-SH cells can be obviously reduced to 65.3 percent, which indicates that the oxygen sugar deprivation model is successfully established.
2) PHPB (10 mmol/L) as positive tool has neuroprotective effect.
3) In the screening of the model, the compound 1 can obviously improve the survival rate of the oxygen glucose deprivation SK-N-SH cells, and has the function of protecting nerve cells in the model.
The foregoing is only a preferred example of the present application and is not intended to limit the present application. Any modifications, equivalent substitutions, improvements, or the like, which are within the spirit and principles of the present application, are intended to be included within the scope of the present application.
Claims (6)
1. The cembrane type macrocyclic diterpenoid compounds and pharmaceutically acceptable salts thereof are characterized by being compounds 1-3, and the structural formulas are respectively as follows:
2. a process for the preparation of a cembrane type macrocyclic diterpenoid compound as claimed in claim 1, characterized in that it comprises the steps of:
(1) Pulverizing Olibanum, extracting with 95% ethanol under reflux under heating for 3 hr each time, and extracting for three times; mixing the extractive solutions, and removing solvent to obtain Olibanum crude extract;
(2) Subjecting Olibanum crude extract to silica gel column chromatography, eluting sequentially with petroleum ether two parts, ethyl acetate two parts, and 95% ethanol two parts, each part having a column volume to obtain crude sections A-F;
(3) Performing silica gel column chromatography on the crude section A, eluting with petroleum ether ethyl acetate gradient, wherein the volume ratio of petroleum ether ethyl acetate is respectively 1:0, 20:1, 4:1, 1:1 and 0:1, and each gradient elutes two column volumes;
(4) Taking a first crude part A5 eluted by petroleum ether and ethyl acetate in the volume ratio of 4:1 in the step (3), performing silica gel column chromatography, eluting by methylene dichloride and acetone in the volume ratio of 30:1, and combining similar components to obtain fractions A-5-1 to A-5-12;
(5) Taking a fraction A-5-2, preparing by adopting a reversed phase C18 semi-preparation high performance liquid phase method, taking methanol and water with a volume ratio of 85:15 as mobile phases, and detecting the wavelength of 210nm to obtain a compound 1;
(6) Taking the fraction A-5-5, preparing by adopting a reversed phase C18 semi-preparation high performance liquid phase method, taking methanol and water with the volume ratio of 82:18 as mobile phases, and detecting the wavelength of 210nm to obtain the compounds 2 and 3.
3. The method according to claim 2, wherein the volume ratio of the mass of the olibanum material in step (1) to the 95% ethanol used each time is 1kg:3.5l.
4. The method according to claim 2, wherein the solvent is removed in step (1) by rotary evaporation under reduced pressure.
5. A pharmaceutical composition comprising a cembrane type macrocyclic diterpenoid compound according to claim 1, and a pharmaceutically acceptable salt or pharmaceutically acceptable carrier or excipient thereof.
6. Use of a cembrane type macrocyclic diterpenoid compound as claimed in claim 1 and its pharmaceutically acceptable salts for the preparation of a medicament for protecting nerve cells.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5661318A (en) * | 1979-10-26 | 1981-05-26 | Mitsubishi Chem Ind Ltd | Cembranolide diterpen |
| EP0455826A1 (en) * | 1989-11-29 | 1991-11-13 | Mitsubishi Chemical Corporation | Substituted open-chain terpene compound |
| CN102481265A (en) * | 2009-07-14 | 2012-05-30 | 莫尔豪斯医学院 | Methods and compositions for protecting and treating neuroinjury |
| CN108640890A (en) * | 2018-04-10 | 2018-10-12 | 山东省分析测试中心 | A method of isolating and purifying frankincense Chinese and Western pine alkane type macrocyclic diterpene compounds |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2003095404A1 (en) * | 2002-05-09 | 2003-11-20 | University Of Mississippi | Cembranoids with chemopreventive activity |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5661318A (en) * | 1979-10-26 | 1981-05-26 | Mitsubishi Chem Ind Ltd | Cembranolide diterpen |
| EP0455826A1 (en) * | 1989-11-29 | 1991-11-13 | Mitsubishi Chemical Corporation | Substituted open-chain terpene compound |
| CN102481265A (en) * | 2009-07-14 | 2012-05-30 | 莫尔豪斯医学院 | Methods and compositions for protecting and treating neuroinjury |
| CN108640890A (en) * | 2018-04-10 | 2018-10-12 | 山东省分析测试中心 | A method of isolating and purifying frankincense Chinese and Western pine alkane type macrocyclic diterpene compounds |
Non-Patent Citations (1)
| Title |
|---|
| New Hydroquinone Monoterpenoid and Cembranoid-Related Metabolites from the Soft Coral Sarcophyton tenuispiculatum;Tzu-Yin Huang等;《marine drugs》;第第19卷卷(第第1期期);第1-11页 * |
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