CN114349623A - Enantiomer-isopimarane diterpene with nerve cell protection activity and preparation method and application thereof - Google Patents
Enantiomer-isopimarane diterpene with nerve cell protection activity and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an enantiomer-isopimarane diterpene with nerve cell protection activity, a preparation method and application thereof. The invention separates and obtains an enantiomer-isopimarane diterpene EP-1 with novel structure and nerve cell protection activity from euphorbia pekinensis, and the in vitro activity test result shows that the compound has better nerve cell protection activity, under the concentration of 50 mu mol/L, the EP-1 can lead the survival rate of induced damaged PC12 cells to be increased by 23 percent, and can effectively inhibit H from2O2Induced ROS produced by PC12 cells accumulate in the cells. EP-1 is a potential lead compound for the treatment of neurodegenerative diseases.
Description
Technical Field
The invention belongs to the technical field of biochemical engineering, and particularly relates to an enantiomer-isopimarane diterpene with nerve cell protection activity, and a preparation method and application thereof.
Background
Neurodegenerative diseases are diseases in which the neuronal structure or function is gradually lost or even died to cause dysfunction, and mainly include Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), and the like. From 2015-2035 years, China enters a rapid aging stage, the elderly population is increased from 2.12 to 4.18 billion, and the population percentage is increased to 29%. By taking the Parkinson's disease as an example, the incidence rate of the Parkinson's disease of the old people over 65 years old in China is 1.7%, and the number of new-onset patients is about 10 ten thousand per year, so that the Parkinson's disease is rapidly increased. At present, the etiology of the diseases is not clear and can not be cured, and the health and the daily life of the human are seriously threatened.
In recent decades, with the rapid development of knowledge and research means of molecular biology, neurobiology, behavioral science and other subjects, many new discoveries have been made on the research of the pathological mechanism of neurodegenerative diseases. The research result shows that the mechanisms causing the nerve cell death mainly include an oxidative stress mechanism, a mitochondrial dysfunction mechanism, an excitotoxicity mechanism, an inflammation mechanism, an apoptosis mechanism and the like, which influence each other to finally cause the nerve function imbalance and the cell death. The research results provide a new idea and action target point for searching a novel medicament for treating neurodegenerative diseases. Among them, oxidative stress refers to the excessive production of highly active molecules such as Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) in the body when the body is subjected to various harmful stimuli, the degree of oxidation exceeds the scavenging ability of oxides, and the imbalance between the oxidation system and the oxidation resistance system results in the accumulation of oxidation products, the reduction of reductase activity, the peroxidation of DNA/RNA, proteins, lipids, and tissue damage. Nerve cells are particularly sensitive to oxidative stress, and oxidative damage to nerve tissue is found in neurodegenerative diseases. Therefore, how to protect the body from oxidative stress and metabolize excess ROS produced in the body becomes an important research direction for treating neurodegenerative diseases.
Euphorbia pekinensis Rupr is a perennial herb of Euphorbia of Euphorbiaceae. It is used as a medicine and has the effects of purging water, expelling retained fluid, relieving swelling and dissipating stagnation. Literature reports indicate that diterpenoids are the main active ingredients of the plant. The invention separates and obtains an enantiomer-isopimarane diterpenoid with nerve cell protection activity from euphorbia pekinensis, and the in vitro activity test result shows that the compound has better nerve cell protection activity, under the concentration of 50 mu mol/L, EP-1 can increase the survival rate of induced damaged PC12 cells by 23 percent, and can effectively inhibit H-induced damage2O2Induced ROS produced by PC12 cells accumulate in the cells. It may be used as lead compound for treating neurodegenerative diseases.
Disclosure of Invention
The invention aims to provide an enantiomorph-isopimarane diterpene EP-1 with a novel structure and a preparation method and application thereof, and the preparation method specifically comprises the following steps:
in a first aspect, the present invention provides an enantiomeric-isopimarane diterpene, which has a structure represented by the following formula (i):
in a second aspect, the present invention provides the use of the above-mentioned enantiomer-isopimarane diterpene in the first aspect for the preparation of a medicament for the treatment of neurodegenerative diseases.
Preferably, the neurodegenerative disease includes parkinson's disease, alzheimer's disease, huntington's disease, amyotrophic lateral sclerosis.
In a third aspect, the present invention provides a process for producing an enantiomeric-isopimarane-type diterpene according to the first aspect described above, which comprises the steps of:
(1) pulverizing radix Euphorbiae Pekinensis, soaking in methanol, and concentrating the extractive solution to obtain crude extract; dispersing the crude extract in water, and extracting with ethyl acetate;
(2) the ethyl acetate extract was subjected to coarse fractionation using a macroporous resin and gradient elution with methanol/water as mobile phase in a volume ratio of 0:100, 30:70, 50:50, 80:20, 100:0, in a volume ratio of 5:1, performing TLC detection on dichloromethane/ethyl acetate, and collecting RfA component EPR-3 having a value of 0.5 to 0.6;
(3) separating the component EPR-3 in the step (2) by MCI column chromatography, and performing gradient elution by using methanol/water as a mobile phase at a volume ratio of 10:80, 20:80, 30:70, 40:60, 50:50, 60:40, 70:30, 80:20, 90:10 and 100:0, wherein the volume ratio is 5:1, performing TLC detection on dichloromethane/ethyl acetate, and collecting RfA component EPR-3.5 having a value of 0.5 to 0.6;
(4) and (3) performing silica gel column chromatography separation on the component EPR-3.5 in the step (3), performing gradient elution by using petroleum ether/ethyl acetate as a mobile phase in a volume ratio of 10:1, 5:1, 3:1, 1:1 and 1:2, and performing gradient elution by using petroleum ether/ethyl acetate as a mobile phase in a volume ratio of 5:1, performing TLC detection on dichloromethane/ethyl acetate, and collecting RfComponent EPR-3.5.3 having a value of 0.55 to 0.6;
(5) and (3) performing silica gel column chromatography separation on the component EPR-3.5.3 in the step (4), performing gradient elution by using petroleum ether/ethyl acetate as a mobile phase in a volume ratio of 50:1, 30:1, 15:1, 8:1, 4:1, 2:1 and 1:1, and performing gradient elution by using petroleum ether/ethyl acetate as a mobile phase in a volume ratio of 5:1, performing TLC detection on dichloromethane/ethyl acetate, and collecting RfComponent EPR-3.5.3.2 having a value of 0.55 to 0.6;
(6) the component EPR-3.5.3.2 in the step (5) is purified by semi-preparative liquid chromatography, the mobile phase is methanol/water with the volume ratio of 49:51, the flow rate is 2.0 mL/min, the detection wavelength is 200-400nm,obtaining the target compound enantiomer-isopimarane diterpene, tR＝51min。
Preferably, the methanol in the step (2) is soaked for 3 times, and 40L of methanol is soaked for 7 days each time.
Preferably, the liquid chromatograph of the semi-preparative liquid chromatography in the step (7) is a Waters 1525, the detector is a Waters2998 photodiode array detector, and the chromatographic column is a Waters Sunfire C18 semi-preparative column with the specification of 10 × 250 mm.
The invention has the beneficial effects that: the invention separates the antimer-isopimarane diterpene EP-1 with a novel structure from the root of Euphorbia pekinensis Rupr; the compound has good nerve cell protection activity, can increase the survival rate of the induced damaged PC12 cells by 23% at 50 mu mol/L, and can effectively inhibit the growth of H2O2Induced ROS produced by PC12 cells accumulate in the cells; the compound can be used as a potential lead compound for treating neurodegenerative diseases and is used for preparing medicaments for treating the neurodegenerative diseases.
Drawings
Of the compound EP-1 of FIG. 11HNMR spectra;
FIG. 2 preparation of compound EP-113A CNMR spectrum;
FIG. 3 preparation of Compound EP-11H-1H COSY spectrum;
FIG. 4 HSQC spectra of compound EP-1;
FIG. 5 HMBC spectra of compound EP-1;
FIG. 6 NOESY spectrum of compound EP-1;
FIG. 7 IR spectrum of compound EP-1;
FIG. 8 HRESIMS spectrum of Compound EP-1;
FIG. 9 Effect of Compound EP-1 on PC12 cell viability;
FIG. 10DCFH-DA fluorescent probes detecting changes in ROS levels in PC12 cells after treatment with compound EP-1.
Detailed Description
The technical solution of the present invention will be further specifically described below by way of specific examples.
In the following examples of the present invention, the raw materials and equipment used are commercially available or commonly used in the art, unless otherwise specified.
In the following examples of the present invention, the methods are all conventional in the art unless otherwise specified.
EXAMPLE 1 preparation of the Compound EP-1
The preparation process of the compound EP-1 of the invention is as follows:
(1) pulverizing dried root of Euphorbiae Pekinensis (16.5kg), soaking in methanol at room temperature for 3 times, soaking in 40L methanol for 7 days, and concentrating under reduced pressure to obtain total extract 3.6 kg;
(2) dispersing the crude extract in water and extracting with ethyl acetate to obtain ethyl acetate extract;
(3) carrying out coarse segmentation on the ethyl acetate extract by using macroporous resin, carrying out gradient elution by using methanol/water with volume ratios of 0:100, 30:70, 50:50, 80:20 and 100:0 as a mobile phase, collecting elution components, and carrying out gradient elution on the elution components in a volume ratio of 5:1, performing TLC detection on dichloromethane/ethyl acetate, and combining and collecting RfA component EPR-3 having a value of 0.5 to 0.6;
(4) separating the component EPR-3 by MCI column chromatography, performing gradient elution by using methanol/water as a mobile phase with the volume ratio of 10:80, 20:80, 30:70, 40:60, 50:50, 60:40, 70:30, 80:20, 90:10 and 100:0, collecting each eluted component, and performing gradient elution by using methanol/water as a mobile phase with the volume ratio of 5:1, performing TLC detection on dichloromethane/ethyl acetate, and combining and collecting RfA component EPR-3.5 having a value of 0.5 to 0.6;
(5) separating the component EPR-3.5 by silica gel column chromatography, performing gradient elution by using petroleum ether/ethyl acetate as a mobile phase with the volume ratio of 10:1, 5:1, 3:1, 1:1 and 1:2, collecting each elution component, and performing gradient elution by using a solvent with the volume ratio of 5:1, performing TLC detection on dichloromethane/ethyl acetate, and combining and collecting RfComponent EPR-3.5.3 having a value of 0.55 to 0.6;
(6) separating the component EPR-3.5.3 by silica gel column chromatography, performing gradient elution by using petroleum ether/ethyl acetate as mobile phase with volume ratio of 50:1, 30:1, 15:1, 8:1, 4:1, 2:1 and 1:1, collecting each elution component, and performing gradient elution by using petroleum ether/ethyl acetate as mobile phase with volume ratio of 5:1 dichloromethane/ethyl acetate for TLC detectionAnd combining and collecting RfComponent EPR-3.5.3.2 having a value of 0.55 to 0.6;
(7) the component EPR-3.5.3.2 is purified by semi-preparative liquid chromatography, the mobile phase is methanol/water with the volume ratio of 49:51, the flow rate is 2.0 mL/min, the detection wavelength is 200-400nm, and the target compound EP-1, tR＝51min。
The structure of the above-mentioned object compound EP-1, which has the structural formula shown in the following formula (I) and is an ent-isopimarane diterpene, was determined by various spectroscopic methods and literature references.
Wherein the nuclear magnetic data of EP-1 are shown in Table 1,1HNMR spectrum,13CNMR spectrum,1H-1The results of H COSY spectrum, HSQC spectrum, HMBC spectrum, NOESY spectrum, IR spectrum and HRESIMS spectrum are shown in FIGS. 1-8 respectively.
TABLE 1 NMR data of the compound EP-1
Example 2 neuroprotective Activity of EP-1
PC12 cells which grow well and are in logarithmic growth phase are digested to prepare cell suspension, and the cell suspension is prepared according to the proportion of 1 × 104cells/mL were plated in 96-well cell culture plates at 100. mu.L medium per well, 5% CO at 37 ℃2The test sample (EP-1) was added to the sample test group, and a final sample concentration of 50 μm was added to the sample test group, and an equal volume of fresh medium was added to the blank control group and the model test group. After pre-incubation for 24h, the old medium was aspirated off, and then fresh medium containing hydrogen peroxide at a final concentration of 500 μm was added to the model group and the sample test group, respectively, and the same volume of medium was added to the blank control group.
The culture was continued for 6h and the cell viability was determined by the MTT assay. The specific method comprises the following steps: the medium in the above 96-well plate was aspirated off, and a medium containing 0.5mg/mL MTT was added to each well, and after 4 hours of incubation, 100. mu.L of a triple lysis solution (10% SDS, 5% isobutanol, and 0.1% HCl) was added to each well. After overnight incubation, complete dissolution of the precipitate was observed and the absorbance value at 570nm was determined. After blank subtraction, cell viability was expressed as a percentage of control groups: cell growth survival (%) - (experimental absorbance-blank absorbance)/(control absorbance-blank absorbance) × 100%
The results are shown in FIG. 9, and indicate that the enantiomeric-isopimarane diterpene EP-1 of the present invention can increase the survival rate of induced injury PC12 cells by 23%.
Example 3ROS index determination
The PC12 cells with good growth state were cultured at 1X 104cells/mL were plated in 6-well plates, 2mL of medium per well, 5% CO at 37 ℃2The culture was carried out for 24 hours, and the blank control group, the model group and the sample test group (low dose group, high dose group) were set up respectively by removing the old medium by aspiration, wherein the sample test group was added with fresh medium containing the test sample (EP-1) at a final concentration of 20 μm (low dose group) and 40 μm (high dose group), and the blank control group and the model group were added with the same volume of medium, respectively. After pre-culturing for 24h, the old culture medium was aspirated, and then fresh culture medium containing hydrogen peroxide at a final concentration of 500 μm was added to the model group and the sample experiment group, respectively, and an equal volume of culture medium was added to the blank control group. Incubation was continued for 6h, the medium was aspirated, washed with PBS, and serum-free medium containing DCFH-DA at a concentration of 10 μm was added to each well and incubated in the incubator for 30 min. The medium was aspirated, washed with PBS and imaged with a fluorescence microscope. The stronger the fluorescence intensity, the higher the intracellular level of ROS.
The results are shown in FIG. 10, and indicate that the ent-isopimarane diterpene EP-1 of the present invention is effective in inhibiting the accumulation of ROS produced by PC12 cells induced by hydrogen peroxide in the cells.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, improvement and the like made within the content and principle of the present invention shall be included in the protection scope of the present invention.
Claims (6)
1. An ent-isopimarane diterpene, which has a structure represented by the following formula (I):
2. use of an ent-isopimarane diterpene according to claim 1 for the preparation of a medicament for the treatment of neurodegenerative diseases.
3. The use of claim 2, wherein the neurodegenerative disease comprises parkinson's disease, alzheimer's disease, huntington's disease, amyotrophic lateral sclerosis.
4. A process for the preparation of an ent-isopimarane-type diterpene according to claim 1, which comprises the steps of:
(1) pulverizing radix Euphorbiae Pekinensis, soaking in methanol, and concentrating the extractive solution to obtain crude extract; dispersing the crude extract in water, and extracting with ethyl acetate;
(2) the ethyl acetate extract was subjected to coarse fractionation using a macroporous resin and gradient elution with methanol/water as mobile phase in a volume ratio of 0:100, 30:70, 50:50, 80:20, 100:0, in a volume ratio of 5:1, performing TLC detection on dichloromethane/ethyl acetate, and collecting RfA component EPR-3 having a value of 0.5 to 0.6;
(3) separating the component EPR-3 in the step (2) by MCI column chromatography, and using the bodyPerforming gradient elution by taking methanol/water with volume ratio of 10:80, 20:80, 30:70, 40:60, 50:50, 60:40, 70:30, 80:20, 90:10 and 100:0 as a mobile phase, and performing gradient elution by taking methanol/water with volume ratio of 5:1, performing TLC detection on dichloromethane/ethyl acetate, and collecting RfA component EPR-3.5 having a value of 0.5 to 0.6;
(4) and (3) performing silica gel column chromatography separation on the component EPR-3.5 in the step (3), performing gradient elution by using petroleum ether/ethyl acetate as a mobile phase in a volume ratio of 10:1, 5:1, 3:1, 1:1 and 1:2, and performing gradient elution by using petroleum ether/ethyl acetate as a mobile phase in a volume ratio of 5:1, performing TLC detection on dichloromethane/ethyl acetate, and collecting RfComponent EPR-3.5.3 having a value of 0.55 to 0.6;
(5) and (3) performing silica gel column chromatography separation on the component EPR-3.5.3 in the step (4), performing gradient elution by using petroleum ether/ethyl acetate as a mobile phase in a volume ratio of 50:1, 30:1, 15:1, 8:1, 4:1, 2:1 and 1:1, and performing gradient elution by using petroleum ether/ethyl acetate as a mobile phase in a volume ratio of 5:1, performing TLC detection on dichloromethane/ethyl acetate, and collecting RfComponent EPR-3.5.3.2 having a value of 0.55 to 0.6;
(6) purifying the component EPR-3.5.3.2 in the step (5) by semi-preparative liquid chromatography, wherein the mobile phase is methanol/water with the volume ratio of 49:51, the flow rate is 2.0 mL/min, the detection wavelength is 200-400nm, and the target compound, namely the enantiomer-isopimarane diterpene, t is obtainedR＝51min。
5. The method according to claim 4, wherein the methanol in the step (2) is soaked 3 times with 40L of methanol for 7 days.
6. The method of claim 4, wherein the semi-preparative liquid chromatography of step (7) is performed using a Waters 1525, a Waters2998 photodiode array detector, and a Waters Sunfire C18 semi-preparative column having a size of 10X 250 mm.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117398370A (en) * | 2023-05-23 | 2024-01-16 | 湖北天勤生物科技有限公司 | Preparation method and application of diterpenoid compound Libertellenone C |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2015113570A1 (en) * | 2014-01-31 | 2015-08-06 | University Of Copenhagen | Methods for producing diterpenes |
| CN108840792A (en) * | 2018-04-27 | 2018-11-20 | 兰州大学 | A kind of mapping isopimarane type diterpene and its preparation method and application |
| CN111423310A (en) * | 2020-04-29 | 2020-07-17 | 沈阳药科大学 | Pimarane diterpenoid and preparation method and application thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015113570A1 (en) * | 2014-01-31 | 2015-08-06 | University Of Copenhagen | Methods for producing diterpenes |
| CN108840792A (en) * | 2018-04-27 | 2018-11-20 | 兰州大学 | A kind of mapping isopimarane type diterpene and its preparation method and application |
| CN111423310A (en) * | 2020-04-29 | 2020-07-17 | 沈阳药科大学 | Pimarane diterpenoid and preparation method and application thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN117398370A (en) * | 2023-05-23 | 2024-01-16 | 湖北天勤生物科技有限公司 | Preparation method and application of diterpenoid compound Libertellenone C |
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