CN104774239B - More piece spore viridin compounds and application thereof - Google Patents
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- CN104774239B CN104774239B CN201510112090.8A CN201510112090A CN104774239B CN 104774239 B CN104774239 B CN 104774239B CN 201510112090 A CN201510112090 A CN 201510112090A CN 104774239 B CN104774239 B CN 104774239B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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Abstract
The invention belongs to natural product drug world, be specifically related to more piece spore viridin compounds and application thereof.Described more piece spore viridin compounds has the structure shown in formula (I).Present invention also offers the application in preparation prevention or treatment neurodegenerative diseases medicine of formula (I) compound.
Description
Technical field
The invention belongs to natural product drug world, be specifically related to more piece spore viridin compounds and application thereof.
Background technology
Senile dementia is a kind of to be caused by brain diseases, with Progressive symmetric erythrokeratodermia cognitive dysfunction and memory impairment as spy
The central nervous system degenerative disease syndrome levied, its show as intelligence (include memory, learning capacity,
Direction identification capacity, linguistic competence, understandability and judgment) on go down.One is common for senile dementia
Have Alzheimer (Alzheimer ' s disease, AD), vascular dementia (Vascular dementia,
VA), dementia with Lewy body sick (Dementia with Lewy bodies, DLB) and frontotemporal dementia
(Frontotemporal dementia, FTD) etc..In all of dementia patients, patients with Alzheimer disease
Account for 50～70%, be modal type in senile dementia.
The drug main having listed treatment senile dementia at present will be with acetylcholinesteraseinhibitors inhibitors and N-methyl
-D-ASP receptor antagonist (NMDA) is main, and these medicines can improve patient to a certain extent
Dementia symptom, but can not fundamentally stop the deterioration of the state of an illness, reverse disease, therefore find anti-senile dementia
The development of disease drug has caused global attention, and the relevant bioactivity screening of built vertical many and evaluation
System.In existing numerous whole animal models, fruit bat be people the most known to one of model organism.Fruit bat
There is the advantage that other model animal can not be compared, such as: individual space occupy-place is minimum (in one reagent bottle
Thousands of fruit bats can be cultivated), feeding cost cultivation low, easy, reproduction speed are fast and fertility strong (screening
Flux is high), sample consumption few (5-50mg), life cycle short (about 50 days, the active testing cycle is short),
Age-related deterioration of neurons is obvious, is neurodegenerative diseases research and the drug screenings such as senile dementia
Ideal model.
Viridin compounds is to be closed by mycetogenetic a series of C cyclophane sweetening treatments and C-4 and C-6 position a pair of horses going side by side
The steroidal compounds of one furan nucleus.This compounds has antibacterial activity, phytotoxicity, anti-inflammatory activity, with
And find that the piptonychia viridin in this compounds has suppression A β recently42Aggregation activity.
Summary of the invention
It is an object of the present invention to provide a class more piece spore viridin compounds or it is pharmaceutically acceptable
Salt, concrete structure formula is as follows:
Wherein:
R1、R2、R3And R4For hydrogen, hydroxyl, ketone group or optionally substituted C1-14Alkyl, wherein said
Choose on behalf of optionally by the one or more replacements in following substituent group: halogen, cyano group, hydroxyl, amino and
Ketone carbonyl, one or more CH of wherein said alkyl2Group can independently of one another by-O-,-S-,-CO-O-,
-O-CO-,-O-CO-O-or-CH=CH-replace, and premise is in addition in listed group beyond permission, miscellaneous former
Son is not directly connected to each other.
In the present invention further carries out scheme, described formula (I) compound preferably has following structure
The compound of formula:
In the present invention, the pharmaceutically acceptable salt of the more piece spore viridin compounds of formula (I), for
Mineral acid or the second such as the more piece spore viridin compounds of formula (I) and hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid
Acid, propanoic acid, malonic acid, butanoic acid, lactic acid, methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, Malaysia
Acid, the salt that the organic acid such as benzoic acid, succinic acid, picric acid, tartaric acid, citric acid, fumaric acid is formed.
It is a further object to provide above-claimed cpd at preparation prevention or treatment neurodegenerative diseases
Application in medicine.Neurodegenerative diseases refers to the structure of neuron or the forfeiture of the gradual of function, including
Neuronal death.Described neurodegenerative diseases includes but not limited to senile dementia, Parkinson's disease, multiple
In sclerosis and Huntington's disease one or more；Being preferably senile dementia, described senile dementia is alzheimer '
Silent disease, vascular dementia, dementia with Lewy body disease and frontotemporal dementia.
Above-claimed cpd is to belong to fungus (Nodulisporium sp.) (strain number: 65-12-7-1) by more piece spore
Fermentation, isolated.This bacterial strain separates from the bar clothing possession clothing picking up from Chinese yunnan Mt. Zixi, categorized
Research is accredited as more piece spore and belongs to fungus (Nodulisporium sp.), the GenBank of its 18S rRNA gene order
Accession number is KC894854, and on March 29th, 2013 be preserved in Chinese microorganism strain preservation management committee
Member can common micro-organisms center (numbering: 7332, place: great Tun road, Chaoyang District, BeiJing, China Chinese Academy of Sciences microorganism
Institute, 100101).
Although the compound of the present invention can be directly administered without any preparation, but described various compounds are preferred
To be prepared as pharmaceutical preparation use with pharmaceutically acceptable adjuvant.Pharmaceutically acceptable adjuvant includes dilution
Agent, lubricant, binding agent, disintegrating agent, stabilizer, solvent etc..
Diluent of the present invention includes but not limited to starch, microcrystalline Cellulose, sucrose, dextrin, lactose, sugar
Powder, glucose etc.；Described lubricant include but not limited to magnesium stearate, stearic acid, sodium chloride, enuatrol,
Sodium laurylsulfate, pool Lip river sand are female；Described binding agent include but not limited to water, ethanol, starch slurry, syrup,
Hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, sodium alginate, polyvinylpyrrolidone etc.；Described disintegrate
Agent includes but not limited to starch effervescent mixture i.e. sodium bicarbonate and citric acid, tartaric acid, low substituted hydroxy-propyl fibre
Dimension element etc.；Described stabilizer includes but not limited to polysaccharide such as acacin, agar, alginic acid, cellulose ether and carboxylic
Methyl carapace ester etc.；Described solvent includes but not limited to the saline solution etc. of water, balance.
Described preparation includes various solid orally ingestible, liquid oral medicine, injection etc..Pharmaceutics can accept
Oral agents solid preparation have: conventional tablet, dispersible tablet, enteric coatel tablets, granule, capsule, drop pill, powder etc.,
Oral liquid has oral 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 according to the state of an illness of patient,
The situation of diagnosis is specifically applied, and the amount of compound used or concentration are in a wider scope
Regulation, generally, the weight range of reactive compound is 1%～90% (weight) of compositions.
The present invention, relative to prior art, has the following advantages that and beneficial effect: the more piece spore shown in the present invention
Viridin compounds is new viridin compounds；The present invention is shown by biological activity test experiment
More piece spore viridin compounds has significant anti-senile dementia disease activity.More piece spore viridin can conduct
Preparation prevention or the medicine for the treatment of neurodegenerative diseases.
Detailed description of the invention
To further illustrate the present invention below.It is pointed out that following description is only to this
The illustration of bright claimed technical scheme, the not any restriction to these technical schemes.The present invention's
The content that protection domain is recorded with appended claims is as the criterion.
In the following example, mass spectrograph is the amaZon SL mass spectrograph that Bruker company of Germany produces.Superconduction
Nuclear magnetic resonance analyser is Bruker AV-400 and Bruker AV-500.Thin layer chromatography silica GF254 and column chromatography
Silica gel (200-300 mesh) is Haiyang Chemical Plant, Qingdao's product.Anti-phase ODS filler 50 μm is Japan YMC
Products.Mesolow chromatograph of liquid is Shanghai Lisui E-Tech Co., Ltd..'s product.Sephadex
LH-20 is U.S. Amersham Pharmacia Biotech company limited product.Liquid phase separation is used half system
Standby level chromatographic column is Phenomex Gemini C18column (10.0 × 250mm, 5 μm), preparation scale chromatograph
Post is Phenomex Gemini C18column (21.2 × 250mm, 5 μm).Phase chromatography-use acetonitrile is color
Composing pure, water is dual distilled water, and other reagent are analytical pure.
Embodiment 1 more piece spore belongs to fungus 65-12-7-1 bulk fermentation and sample-pretreating method thereof
(1) more piece spore belongs to fungus 65-12-7-1 and is inoculated in PDB culture medium after PDA slant activation,
With 200r.min at 25 DEG C-1Concussion is cultivated 5d and is prepared seed liquor, is inoculated into 165 according still further to 5% inoculum concentration
Equipped with in the conical flask (500mL) of PDB culture medium, with 200r.min at 25 DEG C-1Lower concussion is cultivated
12d, obtains fermentation liquid.Described PDB culture medium is made up of the component of following volume ratio by weight: Rhizoma Solani tuber osi 200
G/L, glucose 20g/L, pure water 1L.
(2) fermented product is added ethyl acetate and carries out soak extraction 2 times, be evaporated to do by extracting solution,
Obtain crude extract (11.5g).
The preparation of embodiment 2 formula (II)-formula (IV) compound
Crude extract is through silicagel column, through hexamethylene and methanol-eluted fractions, obtains cyclohexane moiety C (3.8g) and methanol
Part M (5.6g)；Then methanol fractions M is carried out mesolow ODS column chromatography, by volume ratio is successively
The methanol-water gradient elution of 30: 70,50: 50,70: 30,90: 10 and 100: 0 obtain 5 fraction M1, M2,
M3、M4、M5)；The sub-fraction M2 (1.8g) again volume ratio 50: 50 methanol-water afforded excessively in
Low pressure liquid phase ODS column chromatography, successively by volume ratio 30: 70,35: 65,40: 60,45: 55,50: 50,55: 45,
The methanol-water gradient elution of 100: 0, obtains M2a, M2b, M2c, M2d, M2e, M2f, M2g, M2h, M2i,
M2j and M2k totally 11 sub-fractions.The sub-fraction M2a that the methanol-water that volume ratio is 35: 65 is afforded
(105mg) preparing through anti-phase half preparation scale HPLC, using acetonitrile-water (18: 82, v/v) flow velocity is 3
ML/min carries out eluting, obtains formula (IV) compound (tR: 31.6min, 13.5mg, purity 95%)；Will
Sub-fraction M2b (371.0mg) the inverted preparation scale HPLC that volume ratio 35: 65 methanol-water affords
Preparation, it is that 10mL/min carries out eluting that flowing uses acetonitrile-water (20: 80, v/v) flow velocity mutually, obtains formula (II)
Compound (tR: 68.4min, 54.5mg, purity 95%)；The methanol-water of volume ratio 35: 65 is afforded
Sub-fraction M2d (189.5mg) again through Sephadex LH-20 gel filtration chromatography, use methanol for stream
Dynamic phase, eluting 600mL obtains M2da, M2db, M2dc, M2dd and M2de totally five sub-fractions, then will
Collect from 320mL to 385mL and obtain sub-fraction M2dd (54.2mg) through anti-phase half preparation scale
Prepared by HPLC, using acetonitrile-water (25: 75, v/v) flow velocity is that 4mL/min carries out the formula that affords (III) change
Compound (tR: 44.2min, 2.2mg, purity 95%).
The physicochemical constant of the compound obtained is as follows:
Formula (II) compound: colorless plate crystal；UV(MeOH)λmax
(log ε) 203 (3.90), 220 (3.75), 261 (3.91), 315 (3.81) nm；CD(c 2.9×10-4M, MeOH)
λ max (Δ ε): 209 (+1.78), 225 (-5.60), 246 (+2.61), 271 (-8.97), 307 (+4.78), 357 (-
0.81)；IR(KBr)vmax3509,3361,2958,2934,2863,1728,1649,1614,1444,1397,
1338,1074,1057cm-1；ESI-MS(positive)m/z 365[M+Na]+, 707 [2M+Na]+；
HRESIMS(positive)m/z 343.1543[M+H]+(calcd.for C20H23O5, 343.1545) and determine this
The molecular formula of compound is C20H22O5；13C and1H NMR is shown in Table 1.
Formula (III) compound: faint yellow amorphous powder；UV(MeOH)
λmax(log ε) 205 (4.18), 231 (3.96), 261 (3.91), 302 (3.75) nm；CD(c 2.9×10-4M,
MeOH) λ max (Δ ε): 224 (-4.66), 267 (-6.28), 305 (+3.02)；IR(KBr)vmax3390,3094,
2931,2869,1742,1694,1619,1517,1473,1146,1106cm-1；ESI-MS(positive)m/z
363[M+Na]+, 703 [2M+Na]+；ESI-MS(negative)m/z 339[M-H]-, 375 [M+C1]-；
HRESIMS(positive)m/z 341.1384[M+H]+(calcd.for C20H21O5, 341.1389) and determine this
The molecular formula of compound is C20H22O5；3C and1H NMR is shown in Table 1.
Formula (IV) compound: white powder；UV(MeOH)λmax(log
ε) 204 (3.97), 220 (3.81), 261 (3.97), 310 (3.86) nm；CD(c 2.9×10-4M, MeOH) λmax
(Δ ε): 209 (+3.79), 226 (-4.30), 246 (+0.89), 268 (-3.04), 307 (+3.59), 348 (-0.95)；IR
(KBr)vmax3421,2922,2851,1729,1658,1618,1458,1420,1380,1040cm-1；
ESI-MS(positive)m/z 343[M+H]+；ESI-MS(negative)m/z 341[M-H]-；
HRESIMS(positive)m/z 343.1550[M+H]+(calcd.for C20H23O5, 343.1545) and determine this
The molecular formula of compound is C20H22O5；13C and1H NMR is shown in Table 1.
Table 1 formula (II)-formula (IV) compound13C NMR and1H NMR data and ownership (DMSO-d6
For test solvent)
A: δ in ppm, Jin Hz,1H NMR (400MHz),13C NMR (100MHz), in DMSO-d6
B: δ in ppm, Jin Hz,1H NMR (500MHz),13C NMR (125MHz), in DMSO-d6
C:Overlapped signals are reported without designating multiplicity.
Embodiment 3 compound 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
Aβ42The fruit bat of albumen is (UAS-A β42；It is abbreviated as " H29.3 ").This strain fruit bat by with full brain table
Reach Gal4 promoter fruit bat to hybridize, it is thus achieved that carry elav-GAL4c155(P35) with A β42Drosophila strains.
(2) administration of senile dementia fruit bat
Test arranges three kinds of groups that healthy fruit bat is administered without medicine comparison and disease fruit bat without medicine comparison, disease fruit bat
Not.
The parent of all test fruit bats is all constant temperature 24 DEG C, the fly of constant humidity 42%RH (Relative humidity)
Room is raised and breeding.Within first day after fruit bat sprouts wings, by matched group fruit bat and disease group fruit bat and treat medicine feed group fruit bat
After carbon dioxide narcosis, select the fruit bat of correct character in the glass tubing containing food.It is being administered rank
Section, all test fruit bats are raised, to ensure what fruit bat was taken medicine in the couveuse of 28 DEG C of constant temperature and 42% constant humidity
Efficiency.Every day fruit bat medicine feed 4 hours, from choosing second day of fruit bat medicine feed to the 8th day always.
Institute's medicine feed thing is choosing fly second day preparation and with preparation same day to fruit bat medicine feed.100%DMSO dissolves and makes
Its concentration is 10mM.When preparing working solution, the sucrose containing 4% is utilized to be diluted to by 10mM mother solution
100μM.It addition, matched group fruit bat 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 containing about 100 fruit bats in pipe.
Experiment is carried out in constant temperature 25 DEG C, constant humidity 70%, the behavior room of lucifuge, list of references seen from method[1-3]。
1) in the training stage, the fruit bats of about about 100 are loaded the training pipe being mounted with copper mesh crossed electrode, first
After be passed through capryl alcohol (OCT) and two kinds of each 60s of abnormal smells from the patient of methyl cyclohexanol (MCH), the fresh sky of midfeather 45s
Gas.Give while being passed through the first abnormal smells from the patient (CS+) fruit bat 60V pulse electric shock stimulate (US, during pulse
Long 1.5s, is spaced 3.5s).Do not shock by electricity when being passed through the second abnormal smells from the patient (CS-).So complete a training week
Phase.
2) in immediate memory (study) aptitude tests, complete the fruit bat of a cycle of training and be typically immediately transferred to
The selected element of T-Maze, is passed through CS+ and CS-from relative both direction simultaneously.After the selection of 2min two
The fruit bat of side is collected separately, and counts after anaesthetizing or putting to death.Activity Index (Performance index, PI)
Computing formula as follows: PI=[(CS-)-(CS+)]/[(CS-)+(CS+)] × 100.
OCT and MCH is used to be trained as CS+ and test respectively, the meansigma methods of two PI obtained
Use as the PI once tested.PI=0 represents that in test, fruit bat is chosen as 50 for two kinds of abnormal smells from the patients∶50,
I.e. it is formed without memory；PI=100 represents that in test, fruit bat all escapes the abnormal smells from the patient with electric shock, i.e. perfect note
Recall.When carrying out active testing, carry out same genetic background health fly (2U*H29.3) of not medicine feed simultaneously, do not feed
Senile dementia disease fly (P35*H29.3) of medicine, feed the olfactory sensation impermanent memory of the senile dementia disease fly of test medicine
Defect test, calculates their total learning and memory behavior index (PI) respectively.The senile dementia of test medicine will be fed
Same genetic background health fly (2U*H29.3) Activity Index of disease fly learning and memory behavior index and not medicine feed,
Senile dementia disease fly (P35*H29.3) Activity Index of medicine feed does not compares, evaluation test medicine anti-ageing year
Dull-witted effect.The senile dementia disease fly learning and memory behavior index of feeding tester is the highest, illustrates to survey
Examination thing anti-senile dementia effect is the strongest.Using T inspection to compare, the senile dementia disease fly of feeding tester is learned
The senile dementia disease fly learning and memory of habit memory behavior index and not medicine feed (only giving the solvent of not pastille sample)
Activity Index, P ＜ 0.05 is for there being significant difference, and P ＜ 0.01 is for there being marked difference, and P ＜ 0.001 is for there being pole significance difference
Not.
Data analysis and figure are shown by using GraphPad Prism 5.03 to process；Concrete outcome is shown in Table
2:
Table 2 compound 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 is table positive control drug treatment group.Medicine
Treatment group administration concentration is 100 μMs.Compare with 2U*H29.3 group, * P ＜ 0.001；Compare with P35*H29.3 group, #P ＜ 0.001；
Compare with control compounds group,N=8, t-test.
Control compounds is piptonychia viridin concrete structure formula disclosed in CN103316020A.
Embodiment 4 more piece spore viridin compounds is to A β42The impact of amyloid aggregation
0.1mgAβ42Protein freeze-dried powder is dissolved in 10 μ LDMSO and 543.78 μ L phosphoric acid buffer liquid system joins
It is set to the A β of final concentration of 40 μMs42Protein stock solution.(concentration is 12.5 μ L detected sample solution
100μM)、25μLAβ42Protein stock solution and 12.5 μ LThT storing solutions (concentration is 80 μMs) are added on
In 96 orifice plate plate holes, mixing juxtaposition 96 orifice plate shaker with 90rpm vibration 15min after in 37 DEG C of titanium dioxide
Carbon incubator stationary incubation 16h.After 16h, utilize the high speed cell analysis instrument of TTP Labtech company of Britain
(Acumene X3Type) 405 passages measure its fluorescence intensity.
The anti-A β of active substance42The calculating of protein aggregation activity: Vi=[(F0-Fi)/F0]×100.Wherein, Vi
For relative inhibition, FiFor the A β after addition testing sample42The fluorescence intensity of aggregation, F0Treat for not adding
A β during test sample product42The fluorescence intensity of aggregation.
Concrete outcome such as table 3:
Table 3 compound suppression A β42Protein aggregation Activity Results
Present invention merely illustrates some claimed specific embodiments, one of them or more
Technical characteristic described in individual technical scheme can be combined with arbitrary one or more technical schemes, these
Combined and the technical scheme that obtains also in the application protection domain, and the technology that obtain combined just as these
As scheme is specifically recorded in the disclosure of invention.
Claims (6)
1. class more piece spore viridin compounds or its pharmaceutically acceptable salt, concrete structure formula is as follows:
More piece spore viridin compounds the most according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that formula
(II) pharmaceutically acceptable salt of the more piece spore viridin compounds of-formula (IV) is many for formula (II)-formula (IV)
Joint spore viridin compounds and hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid mineral acid or acetic acid, propanoic acid, malonic acid, butanoic acid,
Lactic acid, methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, maleic acid, benzoic acid, succinic acid, picric acid, tartaric acid,
The salt that citric acid, fumaric acid organic acid are formed.
3. more piece spore viridin compounds or its pharmaceutically acceptable salt described in claim 1 are neural in preparation prevention or treatment
Application in degenerative disease medicine.
Application the most according to claim 3, described neurodegenerative diseases include but not limited to senile dementia, Parkinson's disease,
In multiple sclerosis and Huntington's disease one or more.
Application the most according to claim 4, described senile dementia is Alzheimer, vascular dementia, dementia with Lewy body
Disease and frontotemporal dementia.
6. a pharmaceutical preparation, its by the more piece spore viridin compounds described in claim 1 or its pharmaceutically acceptable salt with
Pharmaceutically acceptable carrier forms.
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|---|---|---|---|
| CN201510112090.8A CN104774239B (en) | 2015-03-13 | 2015-03-13 | More piece spore viridin compounds and application thereof |
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| CN104774239B true CN104774239B (en) | 2017-01-04 |
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Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5378725A (en) * | 1993-07-19 | 1995-01-03 | The Arizona Board Of Regents | Inhibition of phosphatidylinositol 3-kinase with wortmannin and analogs thereof |
| CA2133815A1 (en) * | 1993-10-12 | 1995-04-13 | Jeffrey Alan Dodge | Inhibition of phosphatidylinositol 3-kinase with viridin, demethoxyviridin, viridiol, demethoxyviridiol, virone, wortmannolone, and analogs thereof |
| US20090324489A1 (en) * | 2005-09-01 | 2009-12-31 | Hushan Yuan | Wortmannin conjugates and uses thereof |
| CN103316020A (en) * | 2013-05-23 | 2013-09-25 | 暨南大学 | Applications of demethoxyviridin in preparing Amyloid-beta aggregation inhibitor |
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