CN107496420B - Application of cyclopiazonic acid alkaloid compound - Google Patents

Application of cyclopiazonic acid alkaloid compound Download PDF

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CN107496420B
CN107496420B CN201710748797.7A CN201710748797A CN107496420B CN 107496420 B CN107496420 B CN 107496420B CN 201710748797 A CN201710748797 A CN 201710748797A CN 107496420 B CN107496420 B CN 107496420B
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CN107496420A (en
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刘宏伟
刘丽
宝丽
韩俊杰
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Abstract

The invention relates to a preparation method and a new application of cyclopiazonic acid compounds. Aspergillus oryzae is fermented in solid or liquid state, the fermented product is separated and purified, and 3 compounds prepared by the method are characterized by applying the technologies of mass spectrum, nuclear magnetic resonance spectrum, infrared spectrum and the like and documents. The invention also provides application of the cyclopiazonic acid compound in preparing a medicament for preventing and/or treating neurodegenerative diseases.

Description

Application of cyclopiazonic acid alkaloid compound
Technical Field
The invention relates to the technical field of medicines, in particular to a new application of cyclopiazonic acid alkaloid compounds from aspergillus oryzae in medicines for preventing and/or treating neurodegenerative diseases.
Background
With the coming of the age-old population age, neurodegenerative diseases tend to rise year by year, have higher morbidity and seriously threaten the life quality and body health of middle-aged and elderly people. Neurodegenerative diseases are a group of diseases caused by loss of neurons and/or their myelin, the main pathological features are neuronal loss and dysfunction, and can be classified into acute neurodegenerative diseases (mainly including cerebral ischemia, brain injury, epilepsy, and the like) and chronic neurodegenerative diseases (including alzheimer's disease, parkinson's disease, huntington's disease, amyotrophic lateral sclerosis, different types of spinocerebellar ataxia, Pick's disease, and the like).
At present, no effective treatment method for neurodegenerative diseases exists, and the neuroprotective agent is mainly adopted for clinical treatment. The common neuroprotective agents include glutamate antagonists, anti-inflammatory factors, calcium channel blockers, free radical scavengers, GABA receptor antagonists, 5-hydroxytryptamine antagonists, etc., which are limited to symptomatic relief with most of the side effects evident. Therefore, the development of effective neuroprotective drugs becomes a research hotspot for preventing and treating neurodegenerative diseases.
The prevalence studies show that the number of Alzheimer's disease cases in the United states in 2000 is 450 ten thousand. Every 5 years of age, the percentage of patients with senile dementia will increase 2-fold, i.e. the prevalence is 1% in the 60-year-old population and 30% in the 85-year-old population. Senile dementia is a group of primary degenerative brain degenerative diseases with unknown causes, and the currently accepted pathogenesis is mainly two: (1) since the abnormality of the pre-amyloid protein causes the protein component to leak out of the cell membrane, leading to neurofibrillary tangles and cell death, the gene is located on chromosome 21 (Arch Gen Psychiatry, 2005; 62(11): 1186-92.). (2) An increase in APO-E4, in relation to the gene for apolipoprotein E (APO-E4), is able to counteract the function of APO-E2 or APO-E3. APO-E4 decreased the stability of the nerve cell membrane, leading to neurofibrillary tangles and cell death. The probability of the APO-gene being homozygous is higher than that of heterozygotes (Proc. Natl. Acad. Sci. USA, 2005; 102(4): 1211-6). Therefore, promoting repair and regeneration of damaged nerves is a problem to be solved urgently.
Disclosure of Invention
The invention aims to provide a new application of cyclopiazonic alkaloid compounds derived from Aspergillus oryzae (Aspergillus oryzae).
The cyclopiazonic acid alkaloid compound can be used for preparing medicines for preventing and/or treating neurodegenerative diseases.
The cyclopiazonic acid alkaloid compound can be any one of the following 1-3:
Figure GDA0002471459140000021
pharmaceutically acceptable salts, esters and solvates of the above formulas I-III are also within the scope of the invention.
The invention also provides a preparation method of the cyclopiazonic acid alkaloid compound, which comprises the following steps:
(1) inoculating Aspergillus oryzae (Aspergillus oryzae) strain to slant of agar culture medium in PDA test tube, and pre-culturing; the conditions of the preculture were: culturing at 25 deg.C in dark for 7 days (PDA culture medium composition: potato 200g, glucose 20g, agar powder 16g, purified water to volume of 1L (pH is natural)).
(2) After the mycelia grow over the whole inclined plane, transferring the mycelia into a liquid culture medium under aseptic conditions for culture to obtain a seed culture solution; the culture conditions were: culturing at 25 deg.C in dark for 7 days. Liquid culture medium: glucose 4.0g/L, Malt Extract 10.0g/L, Yeast Extract 4.0g/L, and water to volume of 1L; yeastextract (yeast extract) was purchased from Oxoid Ltd, lot 1074139.
(3) And respectively inoculating 10 ml of seed culture solution into sterilized 500 ml triangular flasks filled with solid culture medium, inoculating 10 flasks, culturing at 25 ℃ in the dark for 40 days (the solid culture medium consists of 80g of long-shaped rice and 120ml of water).
(4) After fermentation, 3L of organic solvent is added into a triangular flask, soaking and extracting are carried out for one week at normal temperature, extraction is carried out repeatedly for 3 times, and organic solvent extracting solutions are combined and distilled under reduced pressure and dried to obtain 80g of extract.
(5) The organic solvent extract was subjected to silica gel open column chromatography (Qingdao ocean chemical Co., Ltd., 200-300 mesh, column chromatography silica gel 150 g; phi 4.5 × 80cm) and n-hexane-ethyl acetate gradient elution (100:0,80:1,50:1,30:1,20:1,10: 1; v/v), dichloro-methanol mixed solvent gradient elution (100:0,100:1,80:1,50:1,30:1,20:1,10:1,5:1,3:1,2: 1; v/v), 5000 ml of each gradient elution solvent was collected as one fraction per 500 ml, and the fraction eluted from n-hexane-ethyl acetate 20:1 was concentrated and dried under reduced pressure, and then subjected to reverse phase column gradient elution (methanol-water ODS 30%, 40%, 50%, 60%, 70%, 80%, 100%).
(6) Gel fraction LH20 (dichloro-methanol 1:1) eluted with 40% methanol-water gave compound of formula I (compound 1).
(7) The 40% methanol-water eluted fraction was recrystallized from methanol to give the compound of formula II (Compound 2).
(8) The second fraction eluted with dichloro-methanol 50:1 was concentrated under reduced pressure and separated by HPLC (38% acetonitrile-water, YMC-ODS C18 column; 5 μm; 9.4 × 250mm) to give the compound of formula III (Compound 3).
In the method of the present invention as described above, it will be understood by those skilled in the art that the organic solvent includes various water-insoluble organic solvents which are liquid at room temperature, such as petroleum ether, chloroform, ethyl acetate, acetone, methanol, etc., and the organic solvent in step (4) is ethyl acetate.
The invention provides a method for preparing compounds 1-3 by Aspergillus oryzae fermentation, and provides application of the compounds 1-3 in preparation of medicines for treating neurodegenerative diseases, and compared with other medicines for treating neurodegenerative diseases reported in literatures, the method has obvious activity. The invention provides a candidate compound for researching and developing new neurodegenerative disease medicines.
Drawings
FIG. 1 is a graph of the effect of varying concentrations of Compound 1 on the neurite outgrowth of undifferentiated PC12 cells.
FIG. 2 is a representative graph of the effect of varying concentrations of Compound 1 on the neurite outgrowth of undifferentiated PC12 cells.
FIG. 3 is a graph of the effect of different concentrations of Compound 2 on the neurite outgrowth of undifferentiated PC12 cells.
FIG. 4 is a representative graph of the effect of different concentrations of Compound 2 on the neurite outgrowth of undifferentiated PC12 cells.
FIG. 5 graph of the effect of different concentrations of Compound 3 on the neurite outgrowth of undifferentiated PC12 cells.
FIG. 6 is a representative graph of the effect of different concentrations of Compound 3 on the neurite outgrowth of undifferentiated PC12 cells.
Detailed Description
The present invention will be described in further detail with reference to examples, but the present invention is not limited thereto.
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and biomaterials, if not specifically indicated, are commercially available.
Example 1 cultivation of Aspergillus oryzae strains, isolation of Compounds
(1) Activating and culturing strain
Inoculating aspergillus oryzae strain to a slant of a PDA test tube agar culture medium for pre-culture; the conditions of the preculture were: culturing at 25 deg.C in dark for 7 days (PDA culture medium composition: potato 200g, glucose 20g, agar powder 16g, purified water to volume of 1L (pH is natural)). After the mycelia grow over the whole inclined plane, transferring the mycelia into a liquid culture medium under aseptic conditions for culture to obtain a seed culture solution; the culture conditions were: culturing at 25 deg.C in dark for 7 days. Liquid culture medium: glucose 4.0g/L, Malt Extract 10.0g/L, Yeast Extract 4.0g/L, and water to volume of 1L; yeastextract (yeast extract) was purchased from Oxoid Ltd, lot 1074139.
And respectively inoculating 10 ml of seed culture solution into sterilized 500 ml triangular flasks filled with solid culture medium, inoculating 10 flasks, culturing at 25 ℃ in the dark for 40 days (the solid culture medium consists of 80g of long-shaped rice and 120ml of water).
(2) And extraction and separation of the compound
After fermentation, 3L of ethyl acetate is added into a triangular flask, soaking and extraction are carried out for one week at normal temperature, extraction is carried out for 3 times repeatedly, the combined ethyl acetate extract is subjected to reduced pressure distillation and drying to obtain 80g of extract, the ethyl acetate extract is subjected to silica gel open column chromatography (200-300 mesh, column chromatography silica gel 150g, phi 4.5 3580 cm) to obtain 80g of extract, n-hexane-ethyl acetate gradient elution (100:0,80:1,50:1,30:1,20:1,10:1, 2: 1; v/v), dichloro-methanol mixed solvent gradient elution (100:0,100:1,80:1,50:1,30:1,20:1,10:1,5:1,3:1,2: 1; v/v) is carried out for 5000 ml of each gradient elution solvent, the fraction eluted by each 500 ml of n-ethyl acetate 20:1 is collected, subjected to reduced pressure concentration and drying, the fraction eluted by reversed phase ODS column gradient elution (30%, 50%, 60%, 70%, 80%, 40%.
The structure of the compound: the structural formula of the compound of formula I (compound 1) is:
Figure GDA0002471459140000041
the structural formula of the compound of formula II (compound 2) is:
Figure GDA0002471459140000042
the structural formula of the compound of formula III (compound 3) is:
Figure GDA0002471459140000043
physical Properties of the Compounds:
the compound of formula I is yellow powder and has specific rotation luminosity value of α]25D＝-94.39(c 0.14CDCl3)；CD(c 4.2×10-5M,CDCl3)λmax(△ε)295(-5.2),325(-4.1).HRESIMS m/z339.1705[M+H]+(ii) a The structure of the compound is determined to be the same as Bissecorehydrocyclopedic acid according to the physicochemical properties, hydrogen spectrum and carbon spectrum data of the compound and the numerical comparison of the compound and the reference (Tetrahedron 26(1970) 5239-5246).
A compound of formula II: a light yellow powder; HRESIMS M/z 367.1229[ M + H ]]+(ii) a Based on the physicochemical properties, hydrogen spectrum and carbon spectrum data of the compound, and compared with the reference value (Heterocycles 7(2014)1662-1669),the structure of the compound was determined to be identical to Speradine E.
A compound of formula III: a light yellow powder; specific rotation photometric value
Figure GDA0002471459140000052
(c 0.26 MeOH); the structure of the compound is determined to be the same as Speradine D according to the physicochemical properties, hydrogen spectrum and carbon spectrum data of the compound and the numerical comparison with the reference (Tetrahedron 71(2015)3522e 3527).
TABLE 1 NMR data
Figure GDA0002471459140000051
Example 2.
Growth promoting effect of undifferentiated PC12 cell process by using compounds of formula I-III
(1) The experimental principle is as follows: under the action of nerve growth factor, the undifferentiated PC12 cell can enlarge sensory neuron and sympathetic neuron, accelerate mitosis, increase the number of nerve cells and induce nerve fiber to grow directionally. It also increases the number of neurons surviving, stimulates the development of neuronal soma and dendrites, increases the density of nerve fibers in the innervating target area, and has protective effect on injured neurons. This experiment was based on the above principle to see if the compound had a nerve growth factor-like effect and promoted growth of undifferentiated PC12 cell process.
(2) Experimental procedure all compounds were dissolved in 10-2M with 100% DMSO, digested with undifferentiated PC12 cells, suspended in DMEM medium (Gibco) containing 5% fetal calf serum (Gibco), 10% horse serum (Gibco) and incubated at 8 × 104cells/ml undifferentiated PC12 cells were seeded in 12-well plates at a volume of 1 ml/well in a medium containing 5% CO2Culturing in a constant temperature incubator at 37 ℃. After 24 hours of culture of undifferentiated PC12 cells, the culture medium of each group was replaced with serum-free DMEM. The test compound and NGF (Upstate) were added to the administration group and the positive control group at the corresponding concentrations, and the culture medium was added to the normal control group, followed by incubation for 48 hours. After 48 hours incubation, observing synaptic growth under a microscopeAnd photographing a growth state image.
(3) The experimental results are as follows: the compounds 1-3 have potential effect of promoting synaptic growth of undifferentiated PC12 cell at 25, 50 and 100. mu.M. (FIGS. 1 to 6)
Example 3.
Repair of damaged PC12 cells by Compounds of formulae I-III
Cell culture: the PC12 cell strain is inoculated in a culture bottle by DMEM medium containing 10% fetal calf serum, 100U/ml penicillin and 100U/ml streptomycin, the culture conditions of a CO2 cell culture box are 37 ℃, the concentration of 5% CO2 and the saturation humidity, and the passage or inoculation is started when the cells grow to about 80%. And (4) observing the growth condition of the cells by an inverted microscope, and taking the cells in the logarithmic growth phase for experiment.
Medicine treatment and grouping, wherein the cells are divided into 5 groups in total, medicine intervention is carried out after 12H of serum-free culture medium inoculation, ① positive medicine control group comprises luteolin, ② negative control group comprises 400 mu mol/L H2O2Making mold liquid 100 mul/hole, acting for 4H, ③ compound group 400 mul mol/L H2O2+ 0.1. mu.M compound. After 24h of action, 10 mu of LCCK8 apoptosis detection solution is added into each well, and the absorbance is measured at 450nm after 4 h.
TABLE 2 repair of damaged PC12 cells by Compounds of formulae I-III
Figure GDA0002471459140000061
Figure GDA0002471459140000071

Claims (2)

1. The application of the cyclopiazonic alkaloid compound as the only active component in the preparation of the medicine for preventing and/or treating the neurodegenerative diseases is senile dementia, and is characterized in that: the compound is one or more of a compound shown in a formula I, a compound shown in a formula II or a compound shown in a formula III;
the structural formula of the compound of the formula I is as follows:
Figure FDA0002468957020000011
the structural formula of the compound of the formula II is as follows:
Figure FDA0002468957020000012
the structural formula of the compound of the formula III is as follows:
Figure FDA0002468957020000021
2. use according to claim 1, wherein the pharmaceutical dosage form comprises a tablet, capsule, oral liquid, emulsion, injection, suspension, tincture, granule or aerosol.
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