CN108314618A - The medical usage of sesquiterpenoids and extracting method and anti-alzheimer's disease - Google Patents
The medical usage of sesquiterpenoids and extracting method and anti-alzheimer's disease Download PDFInfo
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- CN108314618A CN108314618A CN201810420521.0A CN201810420521A CN108314618A CN 108314618 A CN108314618 A CN 108314618A CN 201810420521 A CN201810420521 A CN 201810420521A CN 108314618 A CN108314618 A CN 108314618A
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- C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/24—Preparation of oxygen-containing organic compounds containing a carbonyl group
- C12P7/26—Ketones
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Medicines Containing Plant Substances (AREA)
Abstract
The present invention provides sesquiterpenoids, and by solvent distribution, chromatography post separation, the series flow such as high-efficient liquid phase chromatogram purification has obtained two sesquiterpenoids.As micromolecular compound, naturally isolated reactive compound shows significantly to intend NGF activity in the in-vitro screening model PC12 cells of senile dementia.Using such compound as primer, optimize structure, the new drug development for neurodegenerative diseases such as prevention and treatment senile dementias carries out basic research, will have important practical significance.Sesquiterpenoids provided by the invention has the activity of significant quasi- nerve growth factor, can be applied in preventing the neurodegenerative diseases drugs such as senile dementia and health products.Preparation method of the present invention is simple, quick, and the compound purity of acquisition is high.The structural formula of compound 2 is as follows：
Description
Technical field
The invention belongs to pharmaceutical technology field, be related to a kind of new sesquiterpenoids and extracting method and its
Prepare the application for preventing and treating in the neurodegenerative diseases drugs such as senile dementia.
Background technology
Senile dementia (Alzheimer ' s disease, AD) be happened at senilism and senescence phase with progressive dementia and
Central nervous system degenerative disease based on mental act exception, be only second in the elderly's cause of the death heart disease, tumour and in
Wind accounts for the 4th.AD is a kind of lethal neurodegenerative disease carrying out sexual development, and clinical manifestation is cognition and memory function
Constantly deteriorate, the decline of activity of daily living progressive, and has various neuropsychic symptoms and behavior disorder.In international alzheimer '
It is pointed out in Mo Zheng associations annual report, 2015, there are about 46,800,000 people to suffer from dementia in the whole world, it is contemplated that the year two thousand thirty is up to 7470
Ten thousand people, the year two thousand fifty will more break through 100,000,000 3,150 ten thousand people, and wherein about half is AD patient.58% Dementia patients live in now
Middle and low income country, in the year two thousand thirty, this number will be added to 63%, and the year two thousand fifty then reaches 68%.Global dementia is looked after within 2015
Cost adds up to 818,000,000,000 dollars.3 years short, this amount of money will be increased to 1,000,000 dollars, and the year two thousand thirty but will be up to 2,000,000 dollars.China
Alzheimer's are estimated to exceed 5,000,000, account for about the 1/4 of the total case load in the world；Moreover, with China human mortality aging
The quickening of process, this number will be more huge, and great influence is brought to social stability and development.
The key pathological feature of senile dementia is：Big intracerebral neuronal cell surface is due to abnormal amyloid plaque
Precipitation and the senile plaque (Senile plaque, SP) presented, neurofilaments tangle (NFT) and selective neuronal and
Synaptic loss, various neurotransmitters especially acetylcholine degradation.Amyloid plaque is mainly by intracellular abnormal production
What raw a large amount of amyloid betas (A β) were formed in extracellular accumulation.Current well accepted " A beta hypothesis " is exactly to think cell
The amyloid beta of outer abnormal deposition passes through a series of cell cascade reactions（Including radical reaction, Mitochondrial oxidative damage and
Inflammatory reaction etc.）, it is added directly or indirectly to neuron and spongiocyte, eventually leads to neuronal function exception or dead,
Cause cognitive disorder.
There are many drug for being used to treat AD now, are suitable for different mechanism of action, wherein the drug therapy to AD is mainly logical
Acetylcholine esterase inhibition (Acetylcholinesterase, AChE) is crossed to improve the levels of acetylcholine of patient's body,
That is AChE inhibitor.It is clinically to be used to treat AD a kind of drugs the most ripe earliest, is suitable for light, moderate AD patients
Treatment, the drug through U.S. FDA approval listing share 4 kinds, Tacrine (Tacrine), donepezil (Donepezil), Li Si
Bright (Rivastigmine), galanthamine (Galantamine).Although it is old to play alleviation for these drugs to a certain extent
The effect of dementia disease, but have certain toxic side effect, therefore, find for the AD causes of disease new effective medicine and
Method becomes the hot and difficult issue studied now.In numerous candidate drugs, sight has been turned to nerve growth factor by we
(Nerve growth factor, NGF).Zoopery proves that NGF can promote to be proliferated and break up, and adjust AD neuronal survivals
And growth, moreover it is possible to have repairing and protective effect to injured neurons, be the free-revving engine for the treatment of.But it may be controlled as a kind of
The effective ways of AD are treated, NGF is expensive, and relative molecular mass is big, cannot penetrate blood-brain barrier (Blood Brain
Barrier, BBB), only intraventricular injection, there are many technical problems for long-term treatment.Therefore, it finds and intends nerve growth factor
Activity and the micromolecular compound that can pass through BBB, have become research hotspot.Up to the present, scientific research
Person has discovered that nearly hundred kinds of quasi- Nerve Growth Factor Activity compounds, can be effectively promoted nerve cell growth, partization
It closes object and has been completed structural modification or fully synthetic.
China's abundant in natural resources, research active to new component in natural products and new pharmacology are also increasingly extensive.
Wherein, Chinese medicine has significant curative effect to senile dementia, and foremost is from Huperziaceae plants of Huperzia Huperzia serrata (serrate clubmoss herb)
Alkaloid compound-the huperzine (huperzine A) extracted.It is the selectivity of China's developmental research for the first time
The efficient highly selective invertibity acetylcholinesterase (AChE) for acting on brain inhibits drug.
One of the main source of constituent or its metabolite as natural products in microbial body, the exploitation to it
It is also important one of goal in research with utilizing.Fusarium graminearum（Fusarium graminearum）Caused gibberella zeaze petch of wheat and barley
It is a kind of destructive disease, gibberellin（gibberellin, GA）It is found in Study On Rice bakanae disease, it refers to having
Gibbane skeleton can stimulate a kind of compound of cell division and elongation.Nineteen thirty-five Japanese Scientists are red from hair bakanae disease again
The isolated non-crystalline solid that can promote growth in mould, and referred to as gibberellin.1938, the scientist was again from red mould
Two kinds of biologically active crystallizations have been isolated in the filtered fluid of bacterium culture medium, are named as " gibberellin A " and " gibberellin B ".
With going deep into for research, it is found that there are many type of gibberellin, be distributed widely in plant kingdom, from angiosperm, gymnosperm, fern
The presence of gibberellin is found in plant, brown alga, green alga, fungi and bacterium.It can be said that gibberellin is type in plant hormone
A kind of most hormones.Gibberellin is that coordinate plant growth develops one of indispensable plant hormone, and regulation and control seed is sprouted, under
Embryo stem extension, vane extension, numerous physiology courses such as flower, fruit and seed development.The compound found from gibberella is in crowd
Exist in more plants, and have effect similar with plant hormone, therefore seems for the research of the fungi and mean a great.
Invention content
The object of the present invention is to provide an active sesquiterpenoids, the compound has the following structure：
Second object of the present invention is to provide the extracting method of the sesquiterpenoids, is extracted from red mould culture solution
The method of new sesquiterpenoids, is achieved through the following technical solutions：
（1）Red mould culture solution respectively obtains water layer and ethyl acetate layer after water and ethyl acetate solvent distribution；
（2）Pass through silica gel opening post separation（200-300 mesh, n-hexane:Ethyl acetate=10:0, 9:1, 8:2, 7:3, 0:
10）Ethyl acetate layer sample is detached, obtained component obtains five samples of I-1 ~ I-5 after merging；
（3）It collects and merges n-hexane:Ethyl acetate is 7:3 elution position obtains I-4 and carries out reverse phase ODS opening post separations（First
Alcohol:Water=6:4, 7:3, 8:2, 10:0）Second of separation, obtained component obtain 4 sample II-1 ~ 4 after merging；
（4）It collects and merges methanol:Water is 7:3 elution position obtains sample II-2 and carries out HPLC purifying（Condition is：ODS-UG-
5,3 ml/min of flow velocity, 210 nm of Detection wavelength, mobile phase are 65%-80% aqueous methanol gradients, 45 min）, every five minutes
A component is collected, if there is apparent peak appearance to be individually collected to the peak within five minutes, obtains III-1 ~ 100
Sample；
（5）Then, to active sample（Retention time is 20-25 min）Second of HPLC purifying is carried out（Condition is：
PAKC18,3 ml/min of flow velocity, 210 nm of Detection wavelength, mobile phase are 30%-80% acetonitrile solution gradients, 60 min）, separation
Obtain active fractions；
（6）Then, to active sample（Retention time is 28-32 min）Third time HPLC purifying is carried out（Condition is：Ph-UG-
5,1 ml/min of flow velocity, 210 nm of Detection wavelength, mobile phase are 65% methanol aqueous solution）, isolated reactive compound 1（Retain
Time is respectively 14 min）With new sesquiterpenoids 2（Retention time is 28 min）；
。
Third object of the present invention is to provide sesquiterpenoids to prepare the neurologicals such as prevention senile dementia
Application in property disease medicament.The sesquiterpenoids is compound 1 and compound 2.The drug sesquiterpenoids chemical combination
Object is formed with pharmaceutically acceptable carrier.
Fourth object of the present invention is to provide the sesquiterpenoids extracted by the above method and is preparing anti-A Er
Application in the health products of Zi Haimo diseases, the sesquiterpenoids are compound 1 and compound 2.The health products are by again
Half terpenoid is formed with food or the acceptable carrier of health products.
Pharmaceutically acceptable carrier described here refers to the pharmaceutical carrier of pharmaceutical field routine, such as diluent etc.,
Filler such as sucrose, starch etc.；Adhesive such as hydroxypropylcellulose, starch slurry etc.；Wetting agent such as magnesium stearate, superfine silica gel powder etc.；
The poly- sorb fat of sorbefacient, lecithin etc., smooth, poloxamer of surfactant fatty acid sorb etc., in addition it can in group
It closes in object and other adjuvants such as sweetener, flavouring agent etc. is added.
Sesquiterpenoids of the present invention can be administered in a unit, and administration route can be enteron aisle and non-
Enteron aisle.
Sesquiterpenoids administration route of the present invention can be intravenously administrable.Injection includes intravenous injection, abdominal cavity
Injection, intramuscular injection, acupoint injection therapy and hypodermic injection.
The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to the conventional production process of pharmaceutical field, such as be made
Cucurbitane compound is mixed with one or more carriers, is then made into required dosage form.
Form of administration can be solid pharmaceutical preparation, capsule or liquid preparation, including tablet, capsule, oral solution, small needle,
Infusion, ointment, freeze-dried powder, liniment or suppository.
It is an advantage of the invention that：(1) pass through solvent distribution, chromatography post separation, high performance liquid chromatography（HPLC）Purifying etc. be
Row flow has obtained two sesquiterpenoids, and wherein compound 1 is noval chemical compound, preparation method have it is simple, quickly, obtain
The advantages that compound purity obtained is high.(2) micromolecular compound 1 and compound 2, naturally isolated reactive compound is used as to exist
It shows significantly to intend NGF activity in the in-vitro screening model PC12 cells of senile dementia.Using such compound as guide
Object optimizes structure, and the new drug development for neurodegenerative diseases such as prevention and treatment senile dementias carries out basic research, will
It has important practical significance.(3) such sesquiterpenoids has the activity of significant quasi- nerve growth factor, can be with
Prevent to apply in the neurodegenerative diseases drugs such as senile dementia and health products preparing.
Description of the drawings
The COSY and HMBC of Fig. 1 compounds 2 scheme.
Fig. 2 compounds 1 and 2 significantly improve the nervous process differentiation rate of PC12 cells.
Cell microscopic piece of Fig. 3 compounds 1 and 2 in 48 h of PC12 cytosiies.
Specific implementation mode
The present invention in conjunction with the accompanying drawings and embodiments, is described in further detail the above of the present invention, but should not incite somebody to action
This range for being interpreted as the above-mentioned theme of the present invention is only limitted to the example of subordinate, all technologies realized based on the above of the present invention
It all belongs to the scope of the present invention.
The preparation of 1 sesquiterpenoids of embodiment
The preparation method that the compound 1 and 2 with significant quasi- NGF activity is obtained from red mould culture solution, the specific steps are：
（1）The acquisition of culture solution：100 L CMC are red mould（Gibberella strain purchase is in China General Microbiological culture presevation management
The heart）Culture solution（Condition of culture：The PH-1 fungus blocks of 100 a diameter of 0.8 cm, concussion training are added in 1 L CMC fluid nutrient mediums
72 h are supported, rotating speed is 155 rpm.Culture solution is obtained into the red mould culture solutions of CMC through filtered through gauze later, co-cultures 100 L.）Through
After water and ethyl acetate solvent distribution, water layer and ethyl acetate layer (1.9 g) are respectively obtained；
（2）Separation and purifying：By ethyl acetate layer study through a silica gel opening post separation（200-300 mesh is solvent body below
Product ratio, n-hexane:Ethyl acetate=10:0, 9:1, 8:2, 7:3, 0:10）, collect merge n-hexane respectively:Ethyl acetate is
7:3 elution position (124 mg), concentration；By this sample, inverted ODS is open post separation again（Methanol:Water=6:4, 7:3,
8:2, 10:0）, collect merge methanol respectively:Water is 7:3 elution position (66 mg), concentration；The sample is through for the first time
HPLC is purified, and condition is：ODS-UG-5,3 ml/min of flow velocity, 210 nm of Detection wavelength, mobile phase are that 65%-80% methanol is water-soluble
Liquid gradient, 45 min, obtains active fractions（25 mg）, retention time is 20-25 min；The sample is pure through second of HPLC
Change, condition is：PAKC18,3 ml/min of flow velocity, 210 nm of Detection wavelength, mobile phase be 30%-80% acetonitrile solution gradients, 60
Min, obtains active fractions, and retention time is 28-32 min；The sample is purified through third time HPLC later, and condition is：Ph-
UG-5,1 ml/min of flow velocity, 210 nm of Detection wavelength, mobile phase are 65% methanol aqueous solution, obtain two active fractions, are retained
Time is respectively that 14 min obtain compound 1（16 mg）, retention time is that 28 min obtain compound 2（400）；It is final total
Obtain 800Compound 2.
Structural Identification of the embodiment 2 to 1 obtained compound 1 and 2 of embodiment：
The structure of compound 1 through LC-MS,1H NMR and with document compare after determine.Compound 1:White solid；ESI-MS
[High-resolution ESI-MS found 275.1626, calculated for C15H24O3Na (M + Na)
275.1618]. 1H NMR (500 MHz, CDCl3)：δ 0.84 (d, 3H, J = 6.8), 0.89 (d, 3H, J =
6.8), 1.49 (m, 1H), 1.62 (m, 1H), 1.77 (m, 2H), 2.11 (s, 3H), 2.35 (m, 2H),
2.54 (m, 4H), 4.92 (br s, 1H), 4.96 (br s, 1H), 5.41 (dd, 1H, J = 16.0, 9.5),
5.99 (d, 1H, J = 16.0)。
The structure of compound 2 through LC-MS,1H NMR、13C NMR,1H-1It is determined after H COSY, HMBC, HSQC tests.Chemical combination
Object 2:White solid；[]D 25 +7.0 (c 0.42, benzene); ESI-MS [High-resolution ESI-MS
found 261.1827, calculated for C15H26O2Na (M + Na) 261.1825]. 1H NMR and13C NMR numbers
According to see the table below 1.Further two dimension COSY, HSQC, HMBC data demonstrate this supposition（COSY and main HMBC correlations
See Fig. 1）.The configuration of C-6 and C-7 double bonds is by between H-6 and H-7J 6-7 =15.8 Hz are determined.
a 500 MHz for 1H NMR and 125 MHz for 13C NMR, coupling constants (J in
Hz) are in parentheses.
b Numbering of 1.
The bioactivity of 3 sesquiterpenoids of embodiment
The study found that in the animal model of neurodegeneration, NGF can prevent or reduce the regression of neuron, to a certain degree
AD can be prevented to be in progress, have and promote neurotrophy and neuroprotection.12 cells of PC are exactly one and are widely used simulation god
Successful external model through member.It derives from the pheochromocytoma of rat adrenal medulla, with sympathetic neuron and sensory nerve
It is first the same, originate from neural crest, after NGF is handled, cell stops proliferation, grows nervous process, shows as ripe sympathetic god
Through first like cell phenotype.Therefore, using PC12 cell bio-activity identification systems, screening, which has, from natural products intends nerve life
The active ingredient of long factor active, will be as the active drug of prevention and treatment senile dementia.
Experimental method：
1）The culture of 12 cells of PC：Containing 10 mL DMEM culture mediums（Wherein contain 10% horse serum, 5% fetal calf serum）100
In mm culture dishes, access 20 × 10412 cells of a PC, replaced a subculture two days later, after three days subcultures.First with 5 mL
PBS washes cell twice, adds 10 mL in culture dish, at 37 DEG C, 5% CO2Carbon dioxide incubator in culture 10
Minute, it gently purges, and be transferred to the disposable centrifuge tube of 15 mL and counted on blood counting chamber after 800 rpm centrifuge 5 min
Number.Per hole, DMEM culture mediums of 1 mL containing serum is first added in examination to 24 porocyte culture plates, and 2 × 10 are connect per hole4A cell, CO2Culture
Case culture is ready for active testing after 24 hours.
2）Active testing：Using 0.5% DMSO as negative control, 40 ng/mL of NGF are positive control, by cucurbitacine
Close the DMSO solution that object is configured to various concentration.Contain the DMEM solution of 1% DMSO and sample with 1 mL（Without serum）By 24 holes
After every hole original culture medium substitution of cell plates, 37 DEG C are put into, 5% CO2Incubator in cultivate.Every 24 under inverted microscope
Hour, observation cellular morphology variation for three days on end, recording the nervous process differentiation rate of cell, (nervous process is longer than cell space diameter one
Times cell number and the visual field under total cell number purpose ratio), about 100 cells under each visual field randomly select at 3, and unite
It is counted as map analysis.
3）Experimental result:In Fig. 2-3, Fig. 2 is the compound 1 of various concentration to be added and when 2, the neural process of PC12 cells
Play differentiation rate.Wherein, it is positive control that 0.5% DMSO, which is negative control Control, NGF (40 ng/mL),.*** P< 0.001。
Fig. 3 is that PC12 cell microscopic pieces after various concentration compound 1 and 2 48 h of compound are added.(a) 0.5% DMSO,
Control; (b) 40 ng/mL NGF; (c) 1, 1 ; (d) 1, 3 ; (e) 1, 10 ; (f) 2,
1 ; (g) 2, 3 ; (h) 2, 10 ; (i) 2, 30 。
The present invention provides a kind of extracting method of sesquiterpenoids, by by the red mould culture solution ethyl acetate of fungi
It is extracted with water, obtains the crude extract of ester layer, isolated and purified, obtain target compound.Sesquiterpenoids provided by the invention
Conjunction object is a new compound, and extracting method is simple and practicable.Sesquiterpenoids provided by the invention is in anti-alzheimer
In the in-vitro screening model of disease, the nervous process differentiation rate of PC12 cells is significantly improved, anti-alzheimer's disease medicine can prepared
It is applied in object and health products.Foundation is provided for the new drug development and basic research of anti-alzheimer's disease, there is important show
Sincere justice.
Claims (9)
1. a kind of sesquiterpenoids, which is characterized in that the structure of the compound is as follows：
。
2. a kind of extracting method of sesquiterpenoids, which is characterized in that realized by following steps：
（1）Red mould culture solution respectively obtains water layer and ethyl acetate layer after water and ethyl acetate solvent distribution；
（2）Pass through silica gel opening post separation, 200-300 mesh, n-hexane:Ethyl acetate=10:0, 9:1, 8:2, 7:3, 0:
10, ethyl acetate layer sample is detached, obtained component obtains five samples of I-1 ~ I-5 after merging；
（3）It collects and merges n-hexane:Ethyl acetate is 7:3 elution position obtains I-4 and carries out reverse phase ODS opening post separations, first
Alcohol:Water=6:4, 7:3, 8:2, 10:0, second of separation, obtained component obtains 4 sample II-1 ~ 4 after merging；
（4）It collects and merges methanol:Water is 7:3 elution position obtains sample II-2 and carries out HPLC purifying, collects one within every five minutes
A component obtains III-1 ~ 100 sample if there is apparent peak appearance to be individually collected to the peak within five minutes；
（5）To the active sample that retention time is 20-25 min, second of HPLC purifying, isolated active fractions are carried out；
（6）Third time HPLC purifying is carried out to the active sample that retention time is 28-32 min, isolated retention time is
The compound 1 of 14 min, and retention time are the sesquiterpenoids 2 of 28 min；
。
3. a kind of extracting method of sesquiterpenoids according to claim 2, which is characterized in that step（4）HPLC
Purification condition is：ODS-UG-5,3 ml/min of flow velocity, 210 nm of Detection wavelength, mobile phase are 65%-80% methanol aqueous solution ladders
Degree, 45 min.
4. a kind of extracting method of sesquiterpenoids according to claim 2, which is characterized in that step（5）HPLC
Purification condition is：PAKC18,3 ml/min of flow velocity, 210 nm of Detection wavelength, mobile phase are 30%-80% acetonitrile solution gradients,
60 min。
5. a kind of extracting method of sesquiterpenoids according to claim 2, which is characterized in that step（6）HPLC
Purification condition is：Ph-UG-5,1 ml/min of flow velocity, 210 nm of Detection wavelength, mobile phase are 65% methanol aqueous solution.
6. the sesquiterpenoids that claim 2 the method obtains is preparing prevention senile dementia neurodegenerative disease
Application in drug, which is characterized in that the sesquiterpenoids is compound 1 and compound 2, the drug sesquiterpenoids
Compound is formed with pharmaceutically acceptable carrier.
7. sesquiterpenoids the answering in the health products for preparing anti-alzheimer's disease that claim 2 the method obtains
With the sesquiterpenoids is compound 1 and compound 2, and the health products are by sesquiterpenoids and food or guarantor
The strong acceptable carrier composition of product.
8. application according to claim 6, which is characterized in that the dosage form of the drug be solid pharmaceutical preparation or liquid preparation,
The administration route of the drug is enteron aisle and non-bowel.
9. application according to claim 7, which is characterized in that the health products dosage form is solid or liquid.
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