CN104844544B - Split-ring knobbed spore viridin type compound and application thereof - Google Patents
Split-ring knobbed spore viridin type compound and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
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Abstract
The invention belongs to the field of natural product medicines, and in particular relates to a split-ring knobbed spore viridin type compound and an application thereof. The split-ring knobbed spore viridin type compound has a structure shown in a formula (I). The invention further provides the application of the chemical compound in the formula (I) in preparing medicines for preventing or treating neurodegenerative diseases. The split-ring knobbed spore viridin type compound is shown in the specification.
Description
Technical field
The invention belongs to natural product drug world, and in particular to driffractive ring more piece spore viridin class compound and its use
On the way.
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
Aspartate receptor is picked up based on anti-agent (NMDA), and 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, phytotoxicity, anti-inflammatory activity, and finds recently in such compound
Piptonychia viridin have suppress A β42Aggregation activity.
The content of the invention
It is an object of the present invention to provide a class driffractive ring more piece spore viridin class compound or its is pharmaceutically acceptable
Salt, concrete structure formula is as follows：
Wherein：
R1、R2And R3For hydrogen, hydroxyl or optionally substituted C1-14Alkyl, wherein described optionally substituted optionally to be taken by following
One or more replacements of Dai Jizhong：Halogen, cyano group, hydroxyl and amino, wherein one or more CH of the alkyl2Group can
Replaced by-O- ,-S- ,-CO-O- ,-O-CO- ,-O-CO-O- or-CH=CH- independently of one another, on condition that except in listed group
Beyond allowing, hetero atom is not directly connected to each other.
Further carry out in scheme in the present invention, formula (I) the compound preferably chemical combination with following structural formula
Thing：
In the present invention, the pharmaceutically acceptable salt of the driffractive ring more piece spore viridin class compound of formula (I), is formula
(I) mineral acids such as driffractive ring more piece spore viridin class compound and hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid or acetic acid, propanoic acid, third
Diacid, butanoic acid, lactic acid, methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, maleic acid, benzoic acid, succinic acid, picric acid, wine
The salt that the organic acid such as stone acid, citric acid, fumaric acid are 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：Driffractive ring more piece spore shown in the present invention
Viridin class compound is new viridin class compound；The present invention shows driffractive ring more piece by biological activity test experiment
Spore viridin class compound has significant anti-senile dementia disease activity.Driffractive ring more piece spore viridin class compound can conduct
Prepare prevention or treat the medicine of neurodegenerative diseases.
Specific embodiment
The present invention is will be further illustrated below.It is pointed out that following explanation is only that application claims are protected
The illustration of the technical scheme of shield, not to any restriction of these technical schemes.Protection scope of the present invention is with appended power
The content that sharp claim is 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.Silica gel for thin layer chromatography GF254 and column chromatography silica gel (200-300 mesh) are Qingdao Haiyang chemical industry
Factory's product.50 μm of anti-phase ODS fillers are Japan's YMC Products.Mesolow chromatograph of liquid is that Shanghai profit fringe electronics technology has
Limit Products.Sephadex LH-20 are Amersham Pharmacia Biotech company limiteies of U.S. product.Liquid phase point
From using half preparation scale chromatographic column for Phenomex Gemini C18 column (10.0 × 250mm, 5 μm), preparation scale color
Spectrum post is Phenomex Gemini C18 column (21.2 × 250mm, 5 μm).Phase chromatography-use acetonitrile is chromatographically pure, and water is
Dual distilled water, 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 formula of embodiment 2 (II)-formula (V) compound
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 water-methanol of volume ratio 50: 50
The sub- fraction M2 (1.8g) for affording crosses mesolow liquid phase ODS column chromatography, is successively 30: 70,35: 65,40 with volume ratio:
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.The sub- fraction M2a that the methanol-water that volume ratio is 35: 65 is afforded
(105mg) prepare through anti-phase half preparation scale HPLC, eluting carried out for 3mL/min using acetonitrile-water (18: 82, v/v) flow velocity,
Obtain formula (II) compound (tR：26.0min, 26.2mg, purity 95%)；Volume ratio is afforded for 35: 65 methanol-water
The inverted preparation scale HPLC of sub- fraction M2b (371.0mg) prepare, mobile phase is using acetonitrile-water (20: 80, v/v) flow velocity
10mL/min carries out eluting, obtains formula (V) compound (tR：62.4min, 67.2mg, purity 95%)；It is 35: 65 by volume ratio
The sub- fraction M2c (108mg) that affords of methanol-water prepare through anti-phase half preparation scale HPLC, using acetonitrile-water (25:
75, v/v) flow velocity carries out eluting for 4mL/min, obtains formula (IV) compound (tR：14.6min, 8.9mg, purity 95%)；By body
The long-pending sub- fraction M2d (189.5mg) afforded than 50: 50 water-methanols makes again through Sephadex LH-20 gel filtration chromatographies
It is mobile phase with methanol, eluting 600mL obtains M2da, M2db, M2dc, M2dd and M2de totally five sub- fractions, then by sub- fraction
M2dd (54.2mg) is prepared through anti-phase half preparation scale HPLC, is carried out for 4mL/min using acetonitrile-water (25: 75, v/v) flow velocity
Afford formula (III) compound (tR：25.8min, 7.0mg, purity 95%).
The physicochemical constant of the compound for being obtained is as follows：
Formula (II) compound：Colorless plate crystal；UV(MeOH)λmax(logε)
202 (4.02), 246 (4.22), 315 (3.90) nm；CD(c 1.5×10-4M, MeOH) λmax(Δε)：232 (- 5.69), 271 (+
2.82), 334 (- 0.55), 357 (+1.48)；IR(KBr)vmax3403,3337,2935,1688,1671,1589,1432,
1325,1190,1066cm-1；ESI-MS(negative)m/z 341[M-H]-, 683 [2M-H]-；HRESIMS(positive)
m/z 343.1175[M+H]+(calcd.for C19H19O6, the molecular formula for 343.1182) determining the compound is C19H18O6；13C
With1H NMR are shown in Table 1.
Formula (III) compound：Faint yellow amorphous powder；UV(MeOH)λmax
(log ε) 202 (4.22), 246 (4.37), 317 (4.02) nm；CD(c 1.5×10-4M, MeOH) λmax(Δε)：233(-
1.99), 273 (+0.80), 323 (- 0.21), 366 (+0.47)；IR(KBr)vmax3425,2926,2851,1702,1668,
1584,1428,1327,1071cm-1；ESI-MS(positive)m/z 349[M+Na]+, 675 [2M+Na]+；HRESIMS
(positive)m/z 327.1235[M+H]+(calcd.for C19H19O5, the molecular formula for 327.1232) determining the compound is
C19H18O5；13C and1H NMR are shown in Table 1.
Formula (IV) compound：Faint yellow amorphous powder；UV(MeOH)λmax(log
ε) 202 (4.24), 246 (4.42), 317 (4.09) nm；CD(c 1.6×10-4M, MeOH) λmax(Δε)：233 (- 2.91), 274
(+1.51), 333 (- 0.36), 360 (+0.71)；IR(KBr)vmax3416,3347,2947,1688,1671,1589,1540,
1430,1070,1051cm-1；ESI-MS(positive)m/z 335[M+Na]+, 647 [2M+Na]+；HRESIMS
(positive)m/z 313.1074[M+H]+(calcd.for C18H17O5, the molecular formula for 313.1076) determining the compound is
C18H16O5；13C and1H NMR are shown in Table 1.
Formula (V) compound：Faint yellow amorphous powder；UV(MeOH)λmax(log
ε) 202 (4.20), 245 (4.36), 314 (4.05) nm；CD(c 1.5×10-4M, MeOH) λmax(Δε)：230 (+7.95), 266
(- 2.68), 312 (+1.72), 356 (- 1.52)；IR(KBr)vmax3365,2938,1716,1686,1540,1420,1321,
1085cm-1；ESI-MS(positive)m/z 365[M+Na]+, 707 [2M+Na]+；HRESIMS(positive)m/z
343.1175[M+H]+(calcd.for C19H19O6, the molecular formula for 343.1182) determining the compound is C19H18O6；13C and1H
NMR is shown in Table 1.
The formula of table 1 (II)-formula (V) compound13C NMR (100MHz) and1H NMR (400MHz) data and ownership (DMSO-
d6For 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 instruction
Practice the stage, the fruit bat of about 100 or so is loaded the training pipe for being mounted with copper mesh crossed electrode, be successively passed through capryl alcohol (OCT)
60s each with two kinds of abnormal smells from the patients of methyl cyclohexanol (MCH), the fresh air of midfeather 45s.It is being passed through the first abnormal smells from the patient (CS+)
Giving the pulse electric shock of fruit bat 60V simultaneously stimulates (US, pulse duration 1.5s are spaced 3.5s).When being passed through second abnormal smells from the patient (CS-)
Do not give 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 is 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 derived from piptonychia viridin concrete structure formula disclosed in patent CN103316020A.
The driffractive ring more piece spore viridin class compound of embodiment 4 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 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, Fi is to add the A β after 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 (6)
1. a class driffractive ring more piece spore viridin class compound or its pharmaceutically acceptable salt, it is characterised in that the chemical combination
Thing has the compound of following structural formula：
2. driffractive ring more piece spore viridin class compound according to claim 1 or its pharmaceutically acceptable salt, it is special
Levy and be, the driffractive ring more piece spore viridin class compound of formula (II)-formula (V) and hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, 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, hardship
The salt that sour in the mouth, tartaric acid, citric acid or fumaric acid are formed.
3. the driffractive ring more piece spore viridin class compound or its pharmaceutically acceptable salt described in claim 1 is preparing prevention
Or the application in treatment neurodegenerative diseases medicine.
4. application according to claim 3, the neurodegenerative diseases include but is not limited to senile dementia, parkinson
In disease, multiple sclerosis and Huntington's disease one or more.
5. application according to claim 4, the senile dementia is Alzheimer, vascular dementia, Louis body
Dementia and frontotemporal dementia.
6. a kind of pharmaceutical preparation, its by the driffractive ring more piece spore viridin class compound described in claim 1 or its pharmaceutically may be used
The salt of acceptance is constituted with pharmaceutically acceptable carrier.
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