CN113956320B - Triterpenoid compound with remarkable acetylcholinesterase and butyrylcholinesterase inhibition activities and preparation method and application thereof - Google Patents
Triterpenoid compound with remarkable acetylcholinesterase and butyrylcholinesterase inhibition activities and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a triterpenoid, which is obtained by separating sporocarp of trichoderma lucidum to obtain two triterpenoids shown in formulas I and II, wherein the two triterpenoids have obvious acetylcholinesterase and butyrylcholinesterase inhibition activities and can be used as potential medicines for treating Alzheimer disease or development and application of lead compounds. The invention also provides a preparation method and application of the triterpenoid.
Description
Technical Field
The invention belongs to the technical field of natural medicines, and particularly relates to a triterpenoid with remarkable acetylcholinesterase and butyrylcholinesterase inhibitory activities, and a preparation method and application thereof.
Background
Alzheimer's Disease (AD) is a multifaceted neurodegenerative disorder, characterized by memory impairment, gradual cognitive impairment, and severe behavioral abnormalities. It is known that about 4680 million people worldwide have AD. This figure is expected to increase by a factor of two by 2050 as the global population ages. The pathogenesis of AD involves multiple pathways, including deficiency of alkaline neurotransmitters, the β -amyloid (a β) and Tau protein phosphorylation pathways. Recently published therapies with inhibitors of a β aggregation or inhibitors of tau protein aggregation have been declared ineffective, and enhancement of brain cholinergic neurotransmission by increasing the levels of acetylcholine (ACh) is currently the most effective method for treating AD. Acetylcholine in the brain is predominantly hydrolyzed by cholinesterase (ChE), and inhibition of ChE has thus proven to be an effective approach. There are two types of ChE in the nervous system: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Currently, four acetylcholinesterase inhibitors have been approved by the FDA, including tacrine, donepezil, galantamine, and rivastigmine. These acetylcholinesterase inhibitors can improve memory and cognitive functions of AD patients, but tacrine quits clinical trials in the united states in 2013 due to its hepatotoxicity, and other three inhibitors, etc. also fail to cure AD or arrest the progress of the disease. The study shows that BChE has a compensation function on AChE, and the AChE/BchE double-target inhibitor is an AD treatment strategy with great development prospect.
Disclosure of Invention
In view of this, the present invention aims to provide a triterpenoid with significant acetylcholinesterase and butyrylcholinesterase inhibitory activities, and a preparation method and an application thereof.
The invention provides a triterpenoid compound with obvious acetylcholinesterase and butyrylcholinesterase inhibition activities, which comprises the following components in part by weight: a compound of the structure of formula I and/or a compound of the structure of formula II:
the invention provides a preparation method of triterpenoids with significant acetylcholinesterase and butyrylcholinesterase inhibitory activities, which comprises the following steps:
leaching inonotus obliquus fruiting body to obtain extract;
extracting the extract to obtain an extract;
performing gradient elution on the extract to obtain a fraction;
and spreading the flow parts to obtain the triterpenoids with remarkable acetylcholinesterase and butyrylcholinesterase inhibition activities.
Preferably, the leaching liquor in the leaching process is an ethanol water solution.
Preferably, the extraction comprises:
petroleum ether and ethyl acetate are sequentially adopted for extraction.
Preferably, the gradient elution comprises:
subjecting the extract to a first gradient elution with petroleum ether-ethyl acetate through a reduced pressure normal phase silica gel column to obtain 28 fractions;
performing second gradient elution on the 19 th flow through a C18 reverse phase silica gel column by using methanol-water to obtain 32 flow;
the 23 rd fraction was subjected to a third gradient elution through a normal phase silica gel column with petroleum ether-chloroform-ethyl acetate to obtain 4 fractions.
6. The method of claim 5, wherein the deploying comprises:
and (4) performing preparative TLC (thin layer chromatography) on the 3 rd flow fraction obtained after the third gradient elution, and developing by using petroleum ether-chloroform-isopropanol to obtain the compound with the structure shown in the formula I.
Preferably, the gradient elution comprises:
performing fourth gradient elution on the 11 th flow fraction obtained after the first gradient elution through a C18 reverse phase silica gel column by using methanol-water to obtain 33 flow fractions;
performing fifth gradient elution on the 27 th flow fraction by using a silica gel column and petroleum ether-ethyl acetate to obtain 24 flow fractions;
the 14 th fraction was separated by semi-preparative HPLC to give the compound of formula II.
Preferably, a C18 column is adopted in the semi-preparative HPLC process, acetonitrile and water are used as mobile phases, the flow rate is 3-5 mL/min, and the detection wavelength is 200-220 nm.
The invention provides application of triterpenoids with remarkable acetylcholinesterase and butyrylcholinesterase inhibition activities in preparation of acetylcholinesterase and butyrylcholinesterase inhibitors.
The invention provides application of triterpenoids with significant acetylcholinesterase and butyrylcholinesterase inhibitory activities in preparation of drugs for treating and/or preventing Alzheimer's disease.
The invention discovers a new triterpenoid with remarkable acetylcholinesterase and butyrylcholinesterase inhibition activities; the compound is derived from medicinal fungus inonotus obliquus, and has good application prospect in the aspect of developing medicaments for treating and preventing Alzheimer disease.
Drawings
FIG. 1 is a schematic representation of a compound of formula I prepared in example 1 1 H NMR spectrum;
FIG. 2 is a schematic representation of a compound of formula I prepared in example 1 13 A C NMR spectrum;
FIG. 3 is an HSQC map of the compound of the structure of formula I prepared in example 1;
FIG. 4 is an HMBC map of a compound of the structure of formula I prepared in example 1;
FIG. 5 is a photograph of a compound of formula I prepared in example 1 1 H- 1 H COSY map;
FIG. 6 is a ROESY plot of a compound of the structure of formula I prepared in example 1;
FIG. 7 is a HRESIMS profile of the compound of formula I prepared in example 1;
FIG. 8 is a graphic representation of a compound of the structure of formula I prepared in example 1 1 An H NMR spectrum;
FIG. 9 shows a compound of formula II prepared in example 1 13 A C NMR spectrum;
FIG. 10 is an HSQC spectrum of the compound of structure II prepared in example 1;
FIG. 11 is an HMBC map of a compound of the structure of formula II prepared in example 1;
FIG. 12 shows a compound of formula II prepared in example 1 1 H- 1 H COSY map;
FIG. 13 is a ROESY plot of a compound of the structure II prepared in example 1;
FIG. 14 is an HRESIMS profile of a compound of formula II prepared in example 1.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other examples, which may be modified or appreciated by those of ordinary skill in the art based on the examples given herein, are intended to be within the scope of the present invention. It should be understood that the embodiments of the present invention are only for illustrating the technical effects of the present invention, and are not intended to limit the scope of the present invention. In the examples, the methods used were all conventional methods unless otherwise specified.
The invention provides a triterpenoid compound with obvious acetylcholinesterase and butyrylcholinesterase inhibition activities, which comprises the following components in part by weight: a compound of the structure of formula I and/or a compound of the structure of formula II:
in the invention, the end groups not shown in the compound with the structure of formula I and the compound with the structure of formula II are both methyl.
The invention provides a preparation method of triterpenoids with remarkable acetylcholinesterase and butyrylcholinesterase inhibition activities, which comprises the following steps:
leaching inonotus obliquus fruiting body to obtain extract;
extracting the extract to obtain an extract;
performing gradient elution on the extract to obtain a fraction;
and unfolding the flow parts to obtain the triterpenoids with remarkable acetylcholinesterase and butyrylcholinesterase inhibition activities.
In the invention, the Inonotus obliquus (Inonotus obliquus), also called as Inonotus obliquus and Inonotus obliquus, is a folk medicinal fungus in Russia, is mainly produced in a high-cold area with 40-50 degrees north latitude, is mainly distributed in Jilin and Heilongjiang province in China, is parasitic on the Inonotus obliquus, has a growth period of 15-20 years, and can resist extreme cold at minus 40 ℃. The part of the inonotus obliquus used as a medicine is mainly sclerotia, and a large number of pharmacological experiments show that the inonotus obliquus has the effects of treating diabetes, resisting cancers (breast cancer, liver cancer, gastric cancer, lung cancer and cervical cancer), resisting viruses, protecting the liver, enhancing the immunity and the like.
In the present invention, it is preferable that the fruiting body of Inonotus obliquus is pulverized and then extracted.
In the present invention, the leaching liquor in the leaching process is preferably an ethanol water solution, and the volume fraction of the ethanol water solution is preferably not less than 95%.
In the present invention, it is preferable that the leaching is completed, and further comprises:
filtering the leached liquid, merging and concentrating to obtain extract.
In the present invention, the extraction process preferably comprises:
and mixing the extract with water to prepare suspension for extraction.
In the present invention, the extraction preferably comprises:
petroleum ether and ethyl acetate are sequentially adopted for extraction.
In the present invention, the extraction preferably further comprises:
in the present invention, the extraction is preferably carried out in each extraction layer until the extract is colorless.
In the present invention, it is preferable that the extraction is completed by further including:
concentrating the extraction layer obtained after ethyl acetate extraction to obtain ethyl acetate extract.
In the present invention, the concentration is preferably an evaporative concentration.
In the present invention, the gradient elution preferably includes:
the extract is passed through a reduced pressure normal phase silica gel column and subjected to first gradient elution with petroleum ether-ethyl acetate to obtain 28 fractions, which are recorded as Fr.1-Fr.28.
In the present invention, the volume ratio of petroleum ether-ethyl acetate during the first gradient elution is preferably from 100:1 to 1:1 is varied.
In the present invention, it is preferable that the first gradient elution further includes, after completion of the first gradient elution:
the 19 th fraction obtained after the first gradient elution (fr.19, obtained by eluting with petroleum ether-ethyl acetate = 4) was subjected to a second gradient elution with methanol-water by C18 reverse phase silica gel column chromatography to obtain 32 fractions, which were designated as fr.19-1 to fr.19-32.
In the present invention, the volume ratio of methanol to water in the second gradient elution is preferably from 3:7 to 1:0 is changed.
In the present invention, it is preferable that the second gradient elution further includes, after completion of the second gradient elution:
subjecting the 23 rd fraction (Fr.19-23) obtained by the second gradient elution to normal phase silica gel column, and performing third gradient elution with petroleum ether-chloroform-ethyl acetate to obtain 4 fractions, which are marked as Fr.19-23-1-Fr.19-23-4.
In the present invention, the volume ratio of petroleum ether, chloroform and ethyl acetate during the third gradient elution is preferably from 10:5:1 to 1:2:1 is varied.
In the present invention, it is preferable that the third gradient elution further includes:
and (3) performing preparative TLC on the 3 rd flow fraction (Fr.19-23-3) eluted by the third gradient, and developing the flow fraction by using petroleum ether-chloroform-isopropanol to obtain the compound with the structure shown in the formula I.
In the present invention, the petroleum ether-chloroform-isopropanol volume ratio is preferably (3 to 7): (3-7): (0.4 to 0.8), more preferably (4 to 6): (4-6): (0.5 to 0.7), most preferably 5:5:0.6.
in the present invention, it is preferable that the first gradient elution further includes, after completion of the first gradient elution:
subjecting the 11 th fraction (Fr.11) obtained by the first gradient elution to C18 reverse phase silica gel column chromatography, and performing fourth gradient elution with methanol-water to obtain 33 fractions, which are recorded as Fr.11-1-Fr.11-33.
In the present invention, the volume ratio of methanol to water in the fourth gradient elution is preferably from 1:1 to 1:0 is changed.
In the present invention, it is preferable that the fourth gradient elution further includes, after completion of the fourth gradient elution:
and (3) performing fifth gradient elution on the 27 th flow part (Fr.11-27) obtained after the fourth gradient elution by using petroleum ether-ethyl acetate through a silica gel column to obtain 24 flow parts which are marked as Fr.11-27-1-Fr.11-27-24.
In the present invention, the volume ratio of petroleum ether to ethyl acetate in the fifth gradient elution is preferably from 40:1 to 2:1 is varied.
In the present invention, it is preferable that the fifth gradient elution further includes:
the 14 th fraction (Fr.11-27-14) from the fifth gradient was separated by semi-preparative HPLC to give the compound of formula II.
In the present invention, a C18 column is preferably used in the semi-preparative HPLC process; acetonitrile and water as mobile phases; the volume fraction of acetonitrile in the mobile phase is preferably 75 to 85%, more preferably 78 to 82%, most preferably 80%; the flow rate of the mobile phase is preferably 3 to 5mL/min, more preferably 3.5 to 4.5mL/min, and most preferably 4mL/min; the detection wavelength is preferably 200 to 220nm, more preferably 205 to 215nm, and most preferably 210nm.
The invention provides application of triterpenoids with remarkable acetylcholinesterase and butyrylcholinesterase inhibition activities in preparation of acetylcholinesterase and butyrylcholinesterase inhibitors.
The dosage forms of the acetylcholinesterase and diacetyl cholinesterase inhibitor are not particularly limited, and the acetylcholinesterase and diacetyl cholinesterase inhibitor can be tablets, capsules, powder injection or suspensions and other dosage forms which are well known to a person skilled in the art.
The invention provides application of triterpenoids with remarkable acetylcholinesterase and butyrylcholinesterase inhibition activities in preparation of drugs for treating acetylcholinesterase and butyrylcholinesterase mediated diseases.
In the present invention, the acetylcholinesterase and diacetylcholinesterase-mediated disease is preferably a neurodegenerative disease.
The invention provides application of triterpenoids with remarkable acetylcholinesterase and butyrylcholinesterase inhibition activities in preparation of a medicine for treating and/or preventing Alzheimer's disease.
The invention provides a new triterpenoid compound with obvious acetylcholinesterase and butyrylcholinesterase inhibition activities; the compound provided by the invention is derived from medicinal fungus inonotus obliquus, and has good application prospect in the aspect of developing medicaments for treating and preventing Alzheimer's disease.
The invention provides a compound with acetylcholinesterase and butyrylcholinesterase inhibitory activity, and a person skilled in the art can use the content for reference and appropriately modify the process parameters to realize the purpose. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The test materials used in the following examples of the present invention are all commercially available products, and are commercially available.
Example 1
1.1 instruments and reagents
Bruker AV-500 type superconducting nuclear magnetic resonance spectrometer (Bruker, switzerland); autospec300 mass spectrometer (VG, uk); analytical high performance liquid chromatograph (Agilent corporation, usa); semi-preparative high performance liquid chromatography (Dionex corporation, usa); n-1000 (2L) vertical rotary evaporator and CA-1111 cooling water circulation device (Shanghai Ailang instruments Co., ltd.); SHZ-D (iii) circulating vacuum pump (shanghai long instruments ltd); AS 220.R2 ten-thousandth electronic scale (RADWAG Wagi elektronizne); sephadex LH-20 gel (Merck Co. Ltd); c18 reverse phase silica gel (20 to 45 μm, fuji Silysia Chemical Ltd, japan); silica gel for column chromatography and thin layer chromatography silica gel plate (Qingdao ocean chemical plant); deuterated reagents and chromatographic methanol (Merck, germany); 95% ethanol, redistilled methanol, ethyl acetate, chloroform, petroleum ether, acetone, etc. (available from Tianjin Koniu, tianjin Fuchen, guangzhou Guanghua, etc.).
1.2 preparation and structural characterization of Compounds
Inonotus obliquus samples were purchased from Russia in 2017 and specimens were stored at the research institute for tropical biotechnology, institute of tropical agrology, china.
Pulverizing Fuscoporia obliqua fruiting body into powder, extracting with ethanol water solution with volume concentration of above 95% for 3 times, filtering the obtained extractive solution, mixing, and concentrating into extract.
Adding water, stirring to obtain suspension, sequentially extracting with petroleum ether and ethyl acetate, and extracting the extractive layers until the extractive solution is colorless; evaporating and concentrating each extraction layer to prepare extract for later use.
Taking ethyl acetate layer extract, passing through a reduced pressure column (silica gel H), and adopting petroleum ether: ethyl acetate (100
The 19 th fraction (Fr.19 (7.4 g)) C18 was subjected to reverse phase silica gel column chromatography and methanol-water gradient elution with a concentration change of 30% to 100% to give 32 fractions (Fr.19-1 to Fr.19-32).
The 23 rd fraction (fr.19-23 (155.9 mg)) was gradient-eluted through a silica gel column petroleum ether-chloroform-ethyl acetate (10.
The 3 rd fraction (fr.. 19-23-3 (11.9 mg)) was developed by preparative TLC in petroleum ether-chloroform-isopropanol (5.
The 11 th fraction (Fr.11 (4.3 g)) was subjected to C18 reverse phase silica gel column chromatography and methanol-water gradient elution with a concentration change of 50% to 100% to give 33 fractions (Fr.11-1 to Fr.11-33).
The 27 th fraction (fr.11-27 (840.6 mg)) was eluted through a silica gel column with a petroleum ether-ethyl acetate (40.
The 14 th fraction (Fr.11-27-14 (105.0 mg)) was separated by semi-preparative HPLC (C18 column, 80% acetonitrile/water as the mobile phase, flow rate: 4mL/min, detection wavelength 210 nm) to give a structural compound of formula II (3.0 mg, t; R ＝30min)。
the structural identification is carried out on the compound with the structure shown in formula I and the compound with the structure shown in formula II prepared in example 1, the detection results are shown in figures 1-14, and the high resolution mass spectrum m/z 481.3662[ M + Na ] of the compound with the structure shown in formula I] + Molecular formula is C 30 H 50 O 3 (ii) a High resolution mass spectrum m/z of compound with structure as shown in formula II 481.3652[ M + Na ]] + Molecular formula is C 30 H 50 O 3 (ii) a Of compounds of the formulae I and II 1 H NMR (500 MHz) and 13 c NMR (125 MHz) data are shown in Table 1:
TABLE 1 NMR data for compounds of formula I and formula II (deuterated chloroform as solvent)
Example 2 determination of the inhibitory Activity of Compounds of formula I and II on Acetylcholinesterase and Butyrylcholinesterase
The inhibition activity of acetylcholinesterase and butyrylcholinesterase of the monomeric compound is determined by the Ellman method: mu.L of PBS buffer (pH 8.0), 10. Mu.L of a test compound solution (dissolved in DMSO) and 20. Mu.L of a 0.1U/mL acetylcholinesterase or butyrylcholinesterase solution were added simultaneously to a 96-well plate, incubated at 30 ℃ for 15min, followed by addition of 10. Mu.L of a 5,5' -dithio-bis-2-nitrobenzoic acid solution (DTNB, concentration 2 mM) and 10. Mu.L of a 10mM iodothioacetylcholine (AICI) or iodothiobutyrylcholine solution (BICI) in this order, well mixed, and after 30min, the absorbance of each well was measured at a wavelength of 412nm using a microplate reader. The test was repeated three times with Tacrine as a positive control and DMSO as a negative control to obtain an average.
The formula for calculating the acetylcholinesterase inhibitory activity is as follows:
inhibition (%) = (A2-A1)/(A2-A0) × 100%;
in the formula: a0, A1 and A2 are absorbance values of blank group, experimental group and negative group measured at 412nm, respectively. The inhibition rate at each concentration was calculated, and the IC was calculated 50 The values and the detection results are shown in Table 2.
TABLE 2 acetylcholinesterase and butyrylcholinesterase inhibitory Activity of Compounds of formula I and II
| Compound (I) | Acetylcholinesterase (IC) 50 ±SDμM) | Butyrylcholinesterase (IC) 50 ±SDμM) |
| A compound of the structure of formula I | 5.92±0.20 | 4.12±0.16 |
| A compound of the formula II | 9.28±0.47 | 14.75±0.38 |
| Tacrine | 0.50±0.02 | 0.16±0.02 |
From the above examples, the invention finds a new class of triterpenoids with significant acetylcholinesterase and butyrylcholinesterase inhibitory activities; the compound is derived from medicinal fungus inonotus obliquus, and has good application prospect in the aspect of developing medicaments for treating and preventing Alzheimer disease.
While only the preferred embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention.
Claims (6)
1. A triterpenoid with significant acetylcholinesterase and butyrylcholinesterase inhibitory activity comprising: a compound of formula I and/or a compound of formula II:
2. a method of preparing the triterpenoid with significant acetylcholinesterase and butyrylcholinesterase inhibitory activity of claim 1, comprising:
leaching inonotus obliquus fruiting body to obtain extract;
extracting the extract to obtain an extract;
performing gradient elution on the extract to obtain a fraction;
spreading the flow portions to obtain triterpenoids with remarkable acetylcholinesterase and butyrylcholinesterase inhibition activities;
the leaching liquor in the leaching process is ethanol water;
the extraction comprises the following steps: sequentially extracting by adopting petroleum ether and ethyl acetate;
the gradient elution comprises:
subjecting the extract to a first gradient elution with petroleum ether-ethyl acetate through a reduced pressure normal phase silica gel column to obtain 28 fractions;
performing second gradient elution on the 19 th flow fraction obtained after the first gradient elution through a C18 reverse phase silica gel column by using methanol-water to obtain 32 flow fractions;
and (3) performing third gradient elution on the 23 th flow fraction obtained after the second gradient elution through a normal-phase silica gel column by using petroleum ether-chloroform-ethyl acetate to obtain 4 flow fractions.
3. The method of claim 2, wherein the deploying comprises:
and (3) performing preparative TLC (thin layer chromatography) on the 3 rd flow fraction obtained after the third gradient elution, and developing by using petroleum ether-chloroform-isopropanol to obtain the compound with the structure shown in the formula I.
4. The method of claim 2, wherein the gradient elution comprises:
performing fourth gradient elution on the 11 th flow fraction obtained after the first gradient elution through a C18 reverse phase silica gel column by using methanol-water to obtain 33 flow fractions;
performing fifth gradient elution on the 27 th flow fraction obtained after the fourth gradient elution by using petroleum ether-ethyl acetate through a silica gel column to obtain 24 flow fractions;
separating the 14 th flow fraction obtained after the fifth gradient is firstly removed by using semi-preparative HPLC to obtain a compound with a structure shown in a formula II;
in the semi-preparative HPLC process, a C18 column is adopted, acetonitrile and water are used as mobile phases, the flow rate is 3-5 mL/min, and the detection wavelength is 200-220 nm.
5. Use of a triterpenoid with significant acetylcholinesterase and butyrylcholinesterase inhibitory activity as defined in claim 1 in the preparation of acetylcholinesterase and butyrylcholinesterase inhibitors.
6. Use of the triterpenoids with significant acetylcholinesterase and butyrylcholinesterase inhibitory activities according to claim 1 in the preparation of a medicament for treating and/or preventing Alzheimer's disease.
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| WO2019129249A1 (en) * | 2017-12-29 | 2019-07-04 | 上海蓝木化工有限公司 | Triterpenoid-containing pharmaceutical composition and use thereof |
| CN110721190A (en) * | 2019-11-21 | 2020-01-24 | 中国热带农业科学院热带生物技术研究所 | Medicine for preventing and treating senile dementia |
| CN111253460A (en) * | 2020-03-17 | 2020-06-09 | 中国热带农业科学院热带生物技术研究所 | Triterpenoid medicine with anti-inflammatory activity and preparation method and application thereof |
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| WO2019129249A1 (en) * | 2017-12-29 | 2019-07-04 | 上海蓝木化工有限公司 | Triterpenoid-containing pharmaceutical composition and use thereof |
| CN110721190A (en) * | 2019-11-21 | 2020-01-24 | 中国热带农业科学院热带生物技术研究所 | Medicine for preventing and treating senile dementia |
| CN111253460A (en) * | 2020-03-17 | 2020-06-09 | 中国热带农业科学院热带生物技术研究所 | Triterpenoid medicine with anti-inflammatory activity and preparation method and application thereof |
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| Title |
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