CN104774239A - Nodulisporium viridin compound and applications thereof - Google Patents

Nodulisporium viridin compound and applications thereof Download PDF

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CN104774239A
CN104774239A CN201510112090.8A CN201510112090A CN104774239A CN 104774239 A CN104774239 A CN 104774239A CN 201510112090 A CN201510112090 A CN 201510112090A CN 104774239 A CN104774239 A CN 104774239A
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acid
viridin
disease
compounds
formula
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CN104774239B (en
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高昊
陈国栋
姚新生
郭良栋
胡丹
于洋
赵琴
冯晓琳
李小霞
王高乾
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Jinan University
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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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  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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Abstract

The invention belongs to the field of natural product medicine, and specifically relates to a nodulisporium viridin compound and applications thereof. The structure of the nodulisporium viridin compound is represented by the formula (I) as described in the description. The invention further provides applications of the compound (I) in preparation of drugs for preventing or treating neurodegenerative diseases.

Description

More piece spore viridin compounds and uses thereof
Technical field
The invention belongs to natural product pharmaceutical field, be specifically related to more piece spore viridin compounds and uses thereof.
Background technology
Senile dementia a kind ofly to be caused by encephalopathy, with the central nervous system degenerative disease syndrome that Progressive symmetric erythrokeratodermia cognition dysfunction and memory impairment are feature, it shows as going down in intelligence (comprising memory, learning capacity, direction identification capacity, language ability, understandability and judgement).Senile dementia one common are alzheimer's disease (Alzheimer ' s disease, AD), vascular dementia (Vascular dementia, VA), dementia with Lewy body disease (Dementia with Lewy bodies, and frontotemporal dementia (Frontotemporal dementia, FTD) etc. DLB).In all dementia patients, patients with Alzheimer disease accounts for 50 ~ 70%, is modal type in senile dementia.
The drug main for the treatment of senile dementia of having gone on the market at present will based on acetylcholinesterase depressant and NMDA receptor antagonist (NMDA), these medicines can improve the dementia symptom of patient to a certain extent, but fundamentally can not stop deterioration, the reverse disease of the state of an illness, therefore the development finding anti-senile dementia disease drug has caused global attention, and has set up many relevant bioactivity screenings and appraisement system.In existing numerous whole animal model, fruit bat is one of model animals of knowing the most of people.The advantage that fruit bat has other model animal not compare, as: individual space occupy-place minimum (can cultivate thousands of fruit bats in one reagent bottle), low, the easy cultivation of feeding cost, reproduction speed is fast and fecundity is strong (screening flux is high), sample consumption few (5-50mg), life cycle are short (about 50 days, the active testing cycle is short), relevant to age deterioration of neurons is obvious, is the ideal model of the nerve degenerative diseases researchs such as senile dementia and drug screening.
Viridin compounds is by the sweetening treatment of mycetogenetic a series of C cyclophane and the steroidal compounds of C-4 and C-6 position a pair of horses going side by side unification furan nucleus.This compounds has anti-microbial activity, phytotoxicity, anti-inflammatory activity, and finds that the piptonychia viridin in this compounds has suppression A β recently 42aggregation activity.
Summary of the invention
An object of the present invention is to provide class more piece spore viridin compounds or its pharmacy acceptable salt, concrete structure formula is as follows:
Wherein:
R 1, R 2, R 3and R 4for hydrogen, hydroxyl, ketone group or the optional C replaced 1-14alkyl, is wherein saidly optionally substituted by optionally by the one or more replacements in following substituting group: halogen, cyano group, hydroxyl, amino and ketone carbonyl, one or more CH of wherein said alkyl 2group can be replaced by-O-,-S-,-CO-O-,-O-CO-,-O-CO-O-or-CH=CH-independently of one another, and prerequisite is except allowing in listed group, and heteroatoms is not directly interconnected.
In the present invention further embodiment, described formula (I) compound preferably has the compound of following structural formula:
In the present invention, the pharmacy acceptable salt of the more piece spore viridin compounds of formula (I), for mineral acid or acetic acid, propionic acid, propanedioic acid, butyric acid, lactic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, tosic acid, toxilic acids such as the more piece spore viridin compounds of formula (I) and hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, the salt that the organic acids such as phenylformic acid, succsinic acid, picric acid, tartrate, citric acid, fumaric acid are formed.
Another object of the present invention is to provide the application of above-claimed cpd in preparation prevention or treatment nerve degenerative diseases medicine.Nerve degenerative diseases refers to the gradual forfeiture of neuronic structure or function, comprises neuronal death.Described nerve degenerative diseases includes but not limited to one or more in senile dementia, Parkinson's disease, multiple sclerosis and Huntington's disease; Be preferably senile dementia, described senile dementia is alzheimer's disease, vascular dementia, dementia with Lewy body disease and frontotemporal dementia.
Above-claimed cpd be by more piece spore belong to fungi (Nodulisporium sp.) (strain number: 65-12-7-1) fermentation, be separated obtain.This bacterial strain is separated from the bar clothing possession clothing picking up from Chinese yunnan Mt. Zixi, be accredited as more piece spore through means of taxonomic research and belong to fungi (Nodulisporium sp.), the GenBank accession number of its 18S rRNA gene order is KC894854, and be preserved in China Committee for Culture Collection of Microorganisms's common micro-organisms center (numbering: 7332 on March 29th, 2013, place: great Tun road, Chaoyang District, BeiJing, China institute of microbiology of the Chinese Academy of Sciences, 100101).
Although compound of the present invention can without the direct administration of any preparation, described various compounds preferably use to be prepared into pharmaceutical preparation with pharmaceutically acceptable auxiliary material.Pharmaceutically acceptable auxiliary material comprises thinner, lubricant, tackiness agent, disintegrating agent, stablizer, solvent etc.
Thinner of the present invention includes but not limited to starch, Microcrystalline Cellulose, sucrose, dextrin, lactose, Icing Sugar, glucose etc.; Described lubricant includes but not limited to Magnesium Stearate, stearic acid, sodium-chlor, sodium oleate, sodium laurylsulfate, the husky mother in pool Lip river etc.; Described tackiness agent includes but not limited to water, ethanol, starch slurry, syrup, Vltra tears, Xylo-Mucine, sodium alginate, polyvinylpyrrolidone etc.; Described disintegrating agent includes but not limited to starch effervescent mixture and sodium bicarbonate and Citric Acid, tartrate, low-substituted hydroxypropyl cellulose etc.; Described stablizer includes but not limited to that polysaccharide is as kordofan gum, agar, alginic acid, ether of cellulose and carboxymethyl crusta ester etc.; Described solvent includes but not limited to the salts solution etc. of water, balance.
Described preparation comprises various solid orally ingestible, liquid oral medicine, injection etc.The acceptable oral preparation solid preparation of pharmaceutics has: conventional tablet, dispersible tablet, enteric coated tablet, particle, capsule, dripping pill, powder etc., and 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 the technique of routine.
The amount of the active ingredient (i.e. the compounds of this invention) contained in pharmaceutical preparation specifically can be applied according to the situation of the state of an illness of patient, diagnosis, the amount of compound used or concentration regulate in a wider scope, usually, the weight range of active compound is 1% ~ 90% (weight) of composition.
The present invention, relative to prior art, has following advantage and beneficial effect: illustrated more piece spore viridin compounds is new viridin compounds; By biological activity test experiment, the present invention shows that more piece spore viridin compounds has significant anti-senile dementia disease active.More piece spore viridin can be used as the medicine of preparation prevention or treatment nerve degenerative diseases.
Embodiment
Further will illustrate the present invention below.It is pointed out that following explanation is only illustrating the technical scheme that application claims is protected, any restriction not to these technical schemes.The content that protection scope of the present invention is recorded with appended claims is as the criterion.
In the following example, mass spectrograph is the amaZon SL mass spectrograph that German Bruker company produces.NMR spectrometer with superconducting magnet is Bruker AV-400 and Bruker AV-500.Thin-layer chromatography silica GF254 and column chromatography silica gel (200-300 order) are Haiyang Chemical Plant, Qingdao's product.Anti-phase ODS filler 50 μm is Japanese YMC Products.Mesolow liquid chromatograph is Shanghai Lisui E-Tech Co., Ltd..'s product.SephadexLH-20 is Amersham Pharmacia Biotech company limited of U.S. product.Liquid phase separation uses half preparation scale chromatographic column for Phenomex Gemini C18column (10.0 × 250mm, 5 μm), and preparation scale chromatographic column is Phenomex Gemini C18column (21.2 × 250mm, 5 μm).Phase chromatography-use acetonitrile is chromatographically pure, and water is dual distilled water, and other reagent are analytical pure.
Embodiment 1 more piece spore belongs to fungi 65-12-7-1 bulk fermentation and sample-pretreating method thereof
(1) more piece spore belongs to fungi 65-12-7-1 and after PDA slant activation, is inoculated in PDB substratum, with 200r.min at 25 DEG C -1concussion is cultivated 5d and is prepared seed liquor, then is inoculated into 165 according to 5% inoculum size and is equipped with in the Erlenmeyer flask (500mL) of PDB substratum, with 200r.min at 25 DEG C -112d is cultivated in lower concussion, obtains fermented liquid.Described PDB substratum is made up of the component of following volume ratio by weight: potato 200g/L, glucose 20g/L, pure water 1L.
(2) fermented product is added ethyl acetate and carry out soak extraction 2 times, extracting solution is evaporated to dry, obtain crude extract (11.5g).
The preparation of embodiment 2 formula (II)-Shi (IV) compound
Crude extract, through silicagel column, through hexanaphthene and methanol-eluted fractions, obtains cyclohexane moiety C (3.8g) and methanol fractions M (5.6g); Then mesolow ODS column chromatography is carried out to methanol fractions M, obtain 5 cuts M1, M2, M3, M4, M5 with the methanol-water gradient elution that volume ratio is 30: 70,50: 50,70: 30,90: 10 and 100: 0 successively); The sub-cut M2 (1.8g) obtained by volume ratio 50: 50 methanol-water wash-out again crosses mesolow liquid phase ODS column chromatography, uses volume ratio 30: 70 successively, 35: 65,40: 60,45: 55,50: 50, the methanol-water gradient elution of 55: 45,100: 0, obtains M2a, M2b, M2c, M2d, M2e, M2f, M2g, M2h, M2i, M2j and M2k be totally 11 sub-cuts.By volume ratio be 35: 65 the sub-cut M2a (105mg) that obtains of methanol-water wash-out prepare through anti-phase half preparation scale HPLC, use acetonitrile-water (18: 82, v/v) flow velocity is that 3mL/min carries out wash-out, obtains formula (IV) compound (t r: 31.6min, 13.5mg, purity 95%); The sub-cut M2b (371.0mg) obtained by volume ratio 35: 65 methanol-water wash-out is prepared through anti-phase preparation scale HPLC, moving phase uses acetonitrile-water (20: 80, v/v) flow velocity is that 10mL/min carries out wash-out, obtains formula (II) compound (t r: 68.4min, 54.5mg, purity 95%); The sub-cut M2d (189.5mg) obtained by the methanol-water wash-out of volume ratio 35: 65 is again through Sephadex LH-20 gel filtration chromatography, use methyl alcohol is moving phase, wash-out 600mL obtains M2da, M2db, M2dc, M2dd and M2de be totally five sub-cuts, to collect from 320mL to 385mL again and obtain sub-cut M2dd (54.2mg) and prepare through anti-phase half preparation scale HPLC, acetonitrile-water (25: 75, v/v) flow velocity is used to be that 4mL/min carries out wash-out and obtains formula (III) compound (t r: 44.2min, 2.2mg, purity 95%).
The physicochemical constant of the compound obtained is as follows:
Formula (II) compound: colorless plate crystal; uV (MeOH) λ max(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) v max3509,3361,2958,2934,2863,1728,1649,1614,1444,1397,1338,1074,1057cm -1; ESI-MS (positive) m/z 365 [M+Na] +, 707 [2M+Na] +; HRESIMS (positive) m/z 343.1543 [M+H] +(calcd.for C 20h 23o 5, 343.1545) and determine that the molecular formula of this compound is C 20h 22o 5; 13c and 1h NMR is in table 1.
Formula (III) compound: faint yellow amorphous powder; uV (MeOH) λ max(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) v max3390,3094,2931,2869,1742,1694,1619,1517,1473,1146,1106cm- 1; ESI-MS (positive) m/z363 [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 C 20h 21o 5, 341.1389) and determine that the molecular formula of this compound is C 20h 22o 5; 3c and 1h NMR is in table 1.
Formula (IV) compound: white powder; uV (MeOH) λ max(log ε) 204 (3.97), 220 (3.81), 261 (3.97), 310 (3.86) nm; CD (c 2.9 × 10 -4m, MeOH) λ max(Δ ε): 209 (+3.79), 226 (-4.30), 246 (+0.89), 268 (-3.04), 307 (+3.59), 348 (-0.95); IR (KBr) v max3421,2922,2851,1729,1658,1618,1458,1420,1380,1040cm -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 C 20h 23o 5, 343.1545) and determine that the molecular formula of this compound is C 20h 22o 5; 13c and 1h NMR is in table 1.
Table 1 formula (II)-Shi (IV) compound 13c NMR and 1h NMR data and ownership (DMSO-d 6for test solvent)
a：δin ppm，Jin Hz， 1H NMR(400MHz)， 13C NMR(100MHz)，in DMSO-d 6
b：δin ppm，Jin Hz， 1H NMR(500MHz)， 13C NMR(125MHz)，in DMSO-d 6
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
W 1118(isoCJ1) as the control group background fruit bat of experiment, referred to as " 2U ".Successfully proceed to pathogenic A β 42the fruit bat of albumen is (UAS-A β 42; Referred to as " H29.3 ").This strain fruit bat hybridizes by expressing Gal4 promotor fruit bat with full brain, obtains and carries elav-GAL4 c155(P35) with A β 42drosophila strains.
(2) administration of senile dementia fruit bat
Test arranges healthy fruit bat without medicine contrast, disease fruit bat without medicine contrast and three kinds of groups of disease fruit bat administration.
All test fruit bat parent all constant temperature 24 DEG C, the fly house feeding of constant humidity 42%RH (Relative humidity) and breeding.First day after fruit bat sprouts wings is by control group fruit bat and disease group fruit bat and treat that medicine feed group fruit bat is by after carbon dioxide narcosis, and the fruit bat selecting correct proterties is containing in the Glass tubing of food.In the administration stage, all test fruit bats are raised, to ensure the efficiency that fruit bat is taken medicine in the insulation can of 28 DEG C of constant temperature and 42% constant humidity.Every day fruit bat medicine feed 4 hours, from choose second day of fruit bat always medicine feed by the 8th day.
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 be 10mM.When preparing working fluid, utilize the sucrose containing 4% that 10mM mother liquor is diluted to 100 μMs.In addition, control group fruit bat is fed with the syrup of 1%DMSO.For each Activity Index (Performance Index), need 2 pipe fruit bat groups, every Guan Zhonghan has an appointment 100 fruit bats.
Experiment, in constant temperature 25 DEG C, constant humidity 70%, is carried out in the behavior room of lucifuge, the visible reference of method [1-3].
1) in the training stage, the fruit bat of about about 100 is loaded the training pipe being mounted with copper mesh crossed electrode, successively pass into octanol (OCT) and methyl-cyclohexanol (MCH) two kinds of each 60s of smell, the fresh air of midfeather 45s.The pulse electric shock giving fruit bat 60V while passing into the first smell (CS+) stimulates (US, pulse duration 1.5s, interval 3.5s).Do not shock by electricity when passing into the second smell (CS-).So complete a cycle of training.
2) in immediate memory (study) aptitude tests, the fruit bat completing a cycle of training is typically immediately transferred to the selected element of T-Maze, passes into CS+ and CS-from relative both direction simultaneously.After the selection of 2min, the fruit bat of both sides is collected separately, and counts after anesthesia or execution.The calculation formula of Activity Index (Performance index, PI) is as follows: PI=[(CS-)-(CS+)]/[(CS-)+(CS+)] × 100.
Use OCT and MCH to carry out training and testing as CS+ respectively, the mean value of two PI obtained uses as the PI once tested.PI=0 represents that fruit bat in test is chosen as 50 for two kinds of smells :50, namely do not form memory; PI=100 represents that in test, fruit bat all escapes the smell with electric shock, i.e. perfect memory.When carrying out active testing, carry out the senile dementia disease fly (P35*H29.3) of same genetic background healthy fly (2U*H29.3), the not medicine feed of not medicine feed simultaneously, feed the sense of smell short-term memory defect test of the senile dementia disease fly of test medicine, calculate their total learning and memory behavior index (PI) respectively.Compared with senile dementia disease fly (P35*H29.3) Activity Index of same genetic background health fly (2U*H29.3) Activity Index, the not medicine feed of the senile dementia disease fly learning and memory behavior index with not medicine feed of feeding test medicine, the effect of evaluation test medicine anti-senile dementia.The senile dementia disease fly learning and memory behavior index of feeding tester is relatively higher then illustrates that the effect of tester anti-senile dementia is stronger.T inspection is adopted to compare, the senile dementia disease fly learning and memory behavior index of the senile dementia disease fly learning and memory behavior exponential sum of feeding tester not medicine feed (only giving the solvent of not pastille sample), P < 0.05 is for there being significant difference, P < 0.01 is for there being marked difference, and P < 0.001 is for there being pole marked difference.
Data analysis and pattern exhibiting process by using GraphPad Prism 5.03; Concrete outcome is 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.Medication therapy groups 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 β 42the impact of amyloid aggregation
0.1mgA β 42protein freeze-dried powder is dissolved in 10 μ LDMSO and 543.78 μ L phosphoric acid buffer liquid system and is configured to the A β that final concentration is 40 μMs 42protein stock solution.12.5 μ L detected sample solution (concentration is 100 μMs), 25 μ LA β 42protein stock solution and 12.5 μ LThT storing solutions (concentration is 80 μMs) are added in 96 orifice plate plate holes, and mixing juxtaposition 96 orifice plate shaker vibrates after 15min in 37 DEG C of CO2gas incubator stationary incubation 16h with 90rpm.After 16h, utilize high speed cell analysis instrument (the Acumene X of TTP Labtech company of Britain 3type) 405 passages measure its fluorescence intensity.
The anti-A β of active substance 42the calculating of protein aggregation activity: V i=[(F 0-F i)/F 0] × 100.Wherein, V ifor relative inhibition, F ifor adding the A β after testing sample 42the fluorescence intensity of aggregation, F 0for not adding A β during testing sample 42the fluorescence intensity of aggregation.
Concrete outcome is as table 3:
Table 3 compound suppresses A β 42protein aggregation Activity Results
Content of the present invention merely illustrates some claimed specific embodiments; one of them or more described technical characteristic can be combined with arbitrary one or more technical scheme in technical scheme; these technical schemes obtained through combination also in the application's protection domain, just as these technical schemes obtained through combination in the disclosure of invention concrete record.

Claims (7)

1. class more piece spore viridin compounds or its pharmacy acceptable salt, concrete structure formula is as follows:
Wherein: R 1, R 2, R 3and R 4for hydrogen, hydroxyl, ketone group or the optional C replaced 1-14alkyl, is wherein saidly optionally substituted by optionally by the one or more replacements in following substituting group: halogen, cyano group, hydroxyl, amino and ketone carbonyl, one or more CH of wherein said alkyl 2group can be replaced by-O-,-S-,-CO-O-,-O-CO-,-O-CO-O-or-CH=CH-independently of one another, and prerequisite is except allowing in listed group, and heteroatoms is not directly interconnected.
2. more piece spore viridin compounds according to claim 1 or its pharmacy acceptable salt, is characterized in that, described formula (I) compound preferably has the compound of following structural formula:
3. more piece spore viridin compounds according to claim 1 or its pharmacy acceptable salt, it is characterized in that, the pharmacy acceptable salt of the more piece spore viridin compounds of formula (I), for mineral acid or acetic acid, propionic acid, propanedioic acid, butyric acid, lactic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, tosic acid, toxilic acids such as the more piece spore viridin compounds of formula (I) and hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, the salt that the organic acids such as phenylformic acid, succsinic acid, picric acid, tartrate, citric acid, fumaric acid are formed.
4. more piece spore viridin compounds according to claim 1 or the application of its pharmacy acceptable salt in preparation prevention or treatment nerve degenerative diseases medicine.
5. application according to claim 4, described nerve degenerative diseases includes but not limited to one or more in senile dementia, Parkinson's disease, multiple sclerosis and Huntington's disease.
6. application according to claim 5, described senile dementia is alzheimer's disease, vascular dementia, dementia with Lewy body disease and frontotemporal dementia.
7. a pharmaceutical preparation, it is made up of more piece spore viridin compounds according to claim 1 or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
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Publication number Priority date Publication date Assignee Title
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US5726167A (en) * 1993-10-12 1998-03-10 Eli Lilly And Company Inhibition of phosphatidylinositol 3-kinase with viridin, demethoxyviridin, viridiol, demethoxyviridiol, virone, wortmannolone, and analogs thereof
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