CN104693267B - Nodulisporium viridian E and application thereof - Google Patents
Nodulisporium viridian E and application thereof Download PDFInfo
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- CN104693267B CN104693267B CN201510112075.3A CN201510112075A CN104693267B CN 104693267 B CN104693267 B CN 104693267B CN 201510112075 A CN201510112075 A CN 201510112075A CN 104693267 B CN104693267 B CN 104693267B
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- C07—ORGANIC CHEMISTRY
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- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
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Abstract
The invention belongs to the field of natural product medicines, and particularly relates to nodulisporium viridian E used as a viridian compound and application of the nodulisporium viridian E. The nodulisporium viridian E has a structure shown in a formula (I) in the specification. The invention also provides application of the compound in the general formula (I) in preparation of a medicine for preventing or treating neurodegenerative diseases.
Description
Technical field
The invention belongs to natural product drug world, and in particular to more piece spore viridin E and application thereof.
Background technology
Senile dementia be it is a kind of caused by brain diseasess, be characterized with progressive cognitive dysfunction and memory impairment
Central nervous system degenerative disease syndrome, it shows as intelligence (including memory, learning capacity, direction identification capacity, language
Speech ability, understandability and judgment) on go down.Senile dementia typically common are Alzheimer
(Alzheimer ' s disease, AD), vascular dementia (Vascular dementia, VA), dementia with Lewy body disease
(Dementia with Lewy bodies, DLB) and frontotemporal dementia (Frontotemporal dementia, FTD) etc..
In all of dementia patients, patients with Alzheimer disease accounts for 50~70%, is modal type in senile dementia.
The medicine for the treatment of senile dementia has been listed at present mainly with acetylcholinesteraseinhibitors inhibitors and N- methyl Ds-day
Based on aspartate receptor antagonist (NMDA), these medicines can to a certain extent improve the dementia symptom of patient, but can not
Deterioration, the reverse disease of the state of an illness are fundamentally prevented, therefore the development of searching anti-senile dementia disease drug has caused the whole world
Attention, and set up it is many correlation bioactivity screenings and appraisement system.In existing numerous whole animal models, fruit bat
It is one of people model organism the most well known.Fruit bat has the advantage that other model animals can not compare, such as：Individual space is accounted for
Position minimum (can cultivate thousands of fruit bats in a general reagent bottle), low feeding cost, easy culture, reproduction speed is fast and breeds
Ability strong (screening flux is high), sample consumption few (5-50mg), life cycle short (about 50 days, active testing cycle is short) and
The deterioration of neurons of age correlation is the preferable mould of the research of the neurodegenerative diseases such as senile dementia and drug screening substantially
Type.
Viridin class compound is by a series of sweetening treatment of mycetogenetic C cyclophanes and C-4 and C-6 positions a pair of horses going side by side unification furan
The steroidal compounds of ring.Such compound has antibacterial activity, phytotoxicity, anti-inflammatory activity, and finds such chemical combination recently
Piptonychia viridin in thing has suppression A β42Aggregation activity.
The content of the invention
It is an object of the present invention to provide a kind of viridin class compound more piece spore viridin E or its pharmaceutically may be used
The salt of acceptance, concrete structure formula is as follows：
In the present invention, the pharmaceutically acceptable salt of the more piece spore viridin E of formula (I), is that the more piece spore of formula (I) is green
Mineral acid or acetic acid, propanoic acid, malonic acid, butanoic acid, lactic acid, methanesulfonic acid, the second such as gliotoxin E and hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid
Sulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, maleic acid, benzoic acid, succinic acid, picric acid, tartaric acid, citric acid, fumaric acid etc. are organic
The salt that acid is formed.
It is a further object to provide above-claimed cpd is preparing prevention or is treating neurodegenerative diseases medicine
In application.Neurodegenerative diseases refer to the gradual forfeiture of the structure or function of neuron, including neuronal death.Institute
State neurodegenerative diseases to include but is not limited to one in senile dementia, Parkinson's disease, multiple sclerosis and Huntington's disease
Plant or several；Preferably senile dementia, the senile dementia is Alzheimer, vascular dementia, dementia with Lewy body disease
And frontotemporal dementia.
Above-claimed cpd is to belong to funguses (Nodulisporium sp.) (strain number by more piece spore：65-12-7-1) send out
It is ferment, isolated.The bacterial strain is separated from the bar clothing possession clothing for pick up from Chinese yunnan Mt. Zixi, and categorized research is accredited as many
Section spore belongs to funguses (Nodulisporium sp.), and the GenBank accession number of its 18S rRNA gene order is KC894854, and
China Committee for Culture Collection of Microorganisms's common micro-organisms center's (numbering is preserved on March 29th, 2013：7332, ground
Point：BeiJing, China Chaoyang District great Tun roads institute of microbiology of the Chinese Academy of Sciences, 100101).
Although the compound of the present invention can be directly administered without any preparation, described various compounds preferably with
Pharmaceutically acceptable adjuvant is prepared into pharmaceutical preparation and uses.Pharmaceutically acceptable adjuvant includes diluent, lubricant, bonding
Agent, disintegrating agent, stabilizer, solvent etc..
Diluent of the present invention includes but is not limited to starch, Microcrystalline Cellulose, sucrose, dextrin, Lactose, Icing Sugar, Fructus Vitis viniferae
Sugar etc.；The lubricant includes but is not limited to magnesium stearate, stearic acid, Sodium Chloride, enuatrol, sodium laurylsulfate, Bo Luosha
Mother etc.；Described adhesive includes but is not limited to water, ethanol, starch slurry, syrup, hydroxypropyl methyl cellulose, carboxymethyl cellulose
Sodium, sodium alginate, polyvinylpyrrolidone etc.；The disintegrating agent include but is not limited to starch effervescent mixture i.e. sodium bicarbonate and
Citric acid, tartaric acid, low-substituted hydroxypropyl cellulose etc.；The stabilizer include but is not limited to polysaccharide for example acacin, agar,
Alginic acid, cellulose ether and carboxymethyl crusta ester etc.；The solvent includes but is not limited to water, saline solution of balance etc..
The preparation includes various solid orally ingestibles, liquid oral medicine, injection etc..Pharmaceuticss are acceptable oral
Agent solid preparation has：Conventional tablet, dispersible tablet, enteric coatel tablets, granule, capsule, drop pill, powder etc., oral liquid has orally
Liquid, Emulsion；Injection has：Little liquid drugs injection, transfusion, freeze-dried powder etc..Each preparation can be prepared from according to conventional technique.
The amount of the active ingredient (i.e. the compounds of this invention) contained in pharmaceutical preparation can be examined according to the state of an illness of patient, doctor
Disconnected situation is specifically applied, and the amount or concentration of compound used are adjusted in a wider scope, generally, activity
The amount scope of compound is 1%~90% (weight) of compositionss.
The present invention has the following advantages that and beneficial effect relative to prior art：The green glue of more piece spore shown in the present invention
Mycin E is new viridin class compound；The present invention shows that more piece spore viridin E has by biological activity test experiment
Significant anti-senile dementia disease activity.More piece spore viridin E as prevention is prepared or can treat the medicine of neurodegenerative diseases
Thing.
Specific embodiment
Below by further illustrating the present invention.It is pointed out that following explanation is only will to the present invention
The illustration of the technical scheme of protection is asked, not to any restriction of these technical schemes.Protection scope of the present invention is with institute
The content that attached claims are recorded is defined.
In the following example, mass spectrograph is the amaZon SL mass spectrographs of German Bruker companies production.Superconduction nuclear magnetic resonance, NMR
Instrument is Bruker AV-400 and Bruker AV-500.Silica gel for thin layer chromatography GF254 and column chromatography silica gel (200-300 mesh) are
For Haiyang Chemical Plant, Qingdao's product.50 μm of anti-phase ODS fillers are Japan's YMC Products.Mesolow chromatograph of liquid is Shanghai
Li Sui Electronic Science and Technology Co., Ltd.s product.It is Phenomex Gemini C18column (10.0 that liquid phase separation uses chromatographic column
× 250mm, 5 μm).Phase chromatography-use acetonitrile is chromatographically pure, and water is dual distilled water, and it is pure that other reagents are analysis.
The more piece spore of embodiment 1 belongs to funguses 65-12-7-1 bulk fermentations and its sample-pretreating method
(1) more piece spore belongs to funguses 65-12-7-1 PDB culture medium is inoculated in Jing after PDA slant activations, at 25 DEG C with
200r.min-1Concussion and cultivate 5d prepares seed liquor, is inoculated into 165 triangles equipped with PDB culture medium according still further to 5% inoculum concentration and burns
In bottle (500mL), with 200r.min at 25 DEG C-1Lower concussion and cultivate 12d, obtains fermentation liquid.The PDB culture medium is by following by weight
The component composition of amount volume ratio：Rhizoma Solani tuber osi 200g/L, glucose 20g/L, pure water 1L.
(2) fermented product addition ethyl acetate is carried out into soak extraction 2 times, extracting solution is evaporated to dry, slightly carried
Thing (11.5g).
The preparation of the more piece spore viridin E of embodiment 2
Crude extract Jing silicagel columns, Jing hexamethylene and methanol-eluted fractions, obtain cyclohexane moiety C (3.8g) and methanol fractions M
(5.6g)；Then mesolow ODS column chromatographies are carried out to methanol fractions M, are successively 30: 70,50: 50,70: 30,90 with volume ratio:
10 and 100: 0 methanol-water gradient elution obtains 5 fractions (M1, M2, M3, M4, M5)；Again by the methanol-water of volume ratio 50: 50
The sub- fraction M2 (1.8g) for affording crosses mesolow liquid phase ODS column chromatography, successively with volume ratio 30: 70,35: 65,40: 60,
45: 55,50: 50,55: 45,100: 0 methanol-water gradient elution, obtains M2a, M2b, M2c, M2d, M2e, M2f, M2g, M2h,
M2i, M2j and M2k totally 11 sub- fractions.Sub- fraction M2a (105mg) Jing that the methanol-water that volume ratio is 35: 65 is afforded
Reversed-phase HPLC preparation is crossed, eluting is carried out for 3mL/min using acetonitrile-water (18: 82, v/v) flow velocity, obtain formula (II) compound
(tR：27.8min, 3.3mg), compound purity is obtained for 95%.
The physicochemical constant of obtained compound is as follows：
More piece spore viridin E：White amorphous powder；+ 35.3 (c0.10, MeOH)；UV(MeOH)λmax(log
ε) 203 (4.29), 248 (4.42), 312 (2.96) nm；CD(c1.5×10-4M, MeOH) λ max (Δ ε)：214 (+4.14), 233
(+4.29), 260 (- 3.55), 303 (+1.91), 353 (- 1.54)；IR(KBr)vmax3429,2936,1698,1688,1588,
1062cm-1；ESI-MS(positive)m/z 325[M+H]+, 649 [2M+H]+；ESI-MS(negative)m/z 323[M-
H]-, 647 [2M-H]-；HRESIMS(positive)m/z 325.1076[M+H]+(calcd.for C19H17O5, 325.1076)
The molecular formula for determining the compound is C19H16O5；13C and1HNMR is shown in Table 1.
The more piece spore viridin E's of table 113C NMR (100MHz) and1H NMR (400MHz) data and ownership (DMSO-d6
For test solvent)
The compound of embodiment 3 improves senile dementia fruit bat learning and memory activity test method
(1) cultivation of senile dementia fruit bat
w1118(isoCJ1) as the matched group background fruit bat of experiment, it is abbreviated as " 2U ".Successfully proceed to pathogenic A β42Albumen
Fruit bat be (UAS-A β42；It is abbreviated as " H29.3 ").The strain fruit bat is miscellaneous by carrying out with full brain expression Gal4 promoteres fruit bat
Hand over, obtain and carry elav-GAL4c155(P35) with A β42Drosophila strains.
(2) administration of senile dementia fruit bat
Test arranges healthy fruit bat without the three kinds of groups of medicine control, disease fruit bat without medicine control and the administration of disease fruit bat.
The parents of all test fruit bats in 24 DEG C of constant temperature, raise by the fly house of constant humidity 42%RH (Relative humidity)
Support and breed.First day after fruit bat emergence is by matched group fruit bat and disease group fruit bat and treats that medicine feed group fruit bat passes through carbon dioxide
After anesthesia, the fruit bat of correct character is selected in the glass tubing containing food.In the administration stage, all test fruit bats are at 28 DEG C
Raise in the couveuse of constant temperature and 42% constant humidity, to ensure the efficiency that fruit bat takes medicine.Daily fruit bat medicine feed 4 hours, from choosing fruit
The medicine feed to the 8th day always of second day of fly.
Institute's medicine feed thing is prepared and gives fruit bat medicine feed with the same day is prepared choosing fly second day.100%DMSO dissolvings make its concentration
For 10mM.When working solution is prepared, 10mM mother solutions are diluted to into 100 μM using containing 4% sucrose.In addition, matched group fruit bat
It is fed with the sucrose solution of 1%DMSO.For each Activity Index (Performance Index), it is desirable to have 2 pipe fruit bat groups, often manage
In contain about 100 fruit bats.
Experiment is carried out in 25 DEG C of constant temperature, constant humidity 70%, the behavior room of lucifuge, the visible list of references of method[1-3]。
1) in the training stage, the fruit bat of about 100 or so is loaded the training pipe for being mounted with copper mesh crossed electrode, successively
It is passed through capryl alcohol (OCT) and each 60s of two kinds of abnormal smells from the patients of methyl cyclohexanol (MCH), the fresh air of midfeather 45s.It is being passed through first
The pulse electric shock of fruit bat 60V is given while planting abnormal smells from the patient (CS+) to stimulate (US, pulse duration 1.5s are spaced 3.5s).It is passed through second
Do not give when planting abnormal smells from the patient (CS-) and shock by electricity.So complete a cycle of training.
2) in immediate memory (study) aptitude tests, the fruit bat for completing a cycle of training is typically immediately transferred to T-Maze
Selected element, while being passed through CS+ and CS- from relative both direction.The fruit bat of both sides is received respectively after the selection of 2min
Counted after collection, anesthesia or execution.The computing formula of Activity Index (Performance index, PI) is as follows：PI=
[(CS-)-(CS+)]/[(CS-)+(CS+)]×100。
It is trained as CS+ and tests using OCT and MCH respectively, the meansigma methodss of two for obtaining PI is used as once real
The PI for testing is used.PI=0 represents that fruit bat for the selection of two kinds of abnormal smells from the patients is 50: 50, i.e., does not form memory in test；PI=
100 abnormal smells from the patients for representing the adjoint electric shock of fruit bat whole escape in test, i.e. perfect memory.When carrying out active testing, while carrying out not
Same genetic background health fly (2U*H29.3) of medicine feed, not senile dementia disease fly (P35*H29.3) of medicine feed, feed test medicine
The olfactory sensation impermanent memory defect test of senile dementia disease fly, calculates respectively their total learning and memory behavior index (PI).Will
Feed the senile dementia disease fly learning and memory behavior index of test medicine and same genetic background health fly (2U*H29.3) of not medicine feed
Senile dementia disease fly (P35*H29.3) Activity Index of Activity Index, not medicine feed compares, and evaluation test medicine anti-ageing year is crazy about
Slow-witted effect.The senile dementia disease fly learning and memory behavior index of feeding tester is relatively more high then to illustrate tester anti-ageing year
Dementia effect is stronger.Compared using T inspections, the senile dementia disease fly learning and memory behavior index of feeding tester and not medicine feed
The senile dementia disease fly learning and memory behavior index of (only to the solvent of not pastille sample), P ＜ 0.05 are have significant difference, P
To there is marked difference, P ＜ 0.001 are have pole marked difference to ＜ 0.01.
Data analysiss and figure displaying are processed by using GraphPad Prism 5.03；Concrete outcome is shown in Table 2：
The compound of table 2 improves senile dementia fruit bat learning and memory Activity Results
2U*H29.3 represent healthy fruit bat；P35*H29.3 represents disease fruit bat；Memantine represents positive control drug treatment
Group.Medication therapy groups administration concentration is 100 μM.Compare with 2U*H29.3 groups,*P ＜ 0.001；Compare with P35*H29.3 groups,#P ＜
0.001；Compare with control compounds group,N=8, t-test.
Control compounds are piptonychia viridin concrete structure formula disclosed in CN103316020A.
More piece spore viridin E is to A β for embodiment 442The impact of amyloid aggregation
0.1mgAβ42Protein freeze-dried powder is dissolved in 10 μ LDMSO and 543.78 μ L phosphoric acid buffer liquid systems and is configured to final concentration
For 40 μM of A β42Protein stock solution.12.5 μ L detected sample solution (concentration is 100 μM), 25 μ LA β42Protein stock is molten
During liquid and 12.5 μ LThT storing solutions (concentration is 80 μM) are added on 96 orifice plate plate holes, the mixing orifice plate shaker of juxtaposition 96 is shaken with 90rpm
15min is swung after 37 DEG C of CO2 gas incubator stationary incubation 16h.After 16h, using the high speed of TTP Labtech companies of Britain
Cytoanalyze (Acumene X3Type) 405 passages determine its fluorescence intensity.
The anti-A β of active substance42The calculating of protein aggregation activity：Vi=[(F0-Fi)/F0]×100.Wherein, ViIt is relative
Suppression ratio, FiA β after to add testing sample42The fluorescence intensity of aggregation, F0Not add A β during testing sample42Aggregation
The fluorescence intensity of thing.
Concrete outcome such as table 3：
The compound of table 3 suppresses A β42Protein aggregation Activity Results
Present invention merely illustrates some claimed specific embodiments, one of them or more skill
Described technical characteristic can be combined with arbitrary one or more technical schemes in art scheme, these are combined and obtain
Technical scheme also in the application protection domain, technical scheme is disclosed in the present invention just as obtained from these are combined
It is concrete in content to record the same.
Claims (4)
1. a kind of viridin class compound or its pharmaceutically acceptable salt are preparing prevention or are treating neurodegenerative diseases
Application in medicine, the viridin class compound concrete structure formula is as follows：
2. application according to claim 1, it is characterised in that the pharmaceutically acceptable salt of formula (I) compound, is formula
(I) compound and hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, acetic acid, propanoic acid, malonic acid, butanoic acid, lactic acid, methanesulfonic acid, ethyl sulfonic acid, benzene
Sulfonic acid, p-methyl benzenesulfonic acid, maleic acid, the salt that benzoic acid, succinic acid, picric acid, tartaric acid, citric acid or fumaric acid are formed.
3. application according to claim 1, the neurodegenerative diseases include but is not limited to senile dementia, parkinson
In disease, multiple sclerosis and Huntington's disease one or more.
4. application according to claim 3, the senile dementia is Alzheimer, vascular dementia, Louis body
Dementia and frontotemporal dementia.
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| CN104693267B true CN104693267B (en) | 2017-05-17 |
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