CN104387353B - α gives birth to the application in preparing nerve protection medicine of the spiral shell quinone - Google Patents
α gives birth to the application in preparing nerve protection medicine of the spiral shell quinone Download PDFInfo
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- CN104387353B CN104387353B CN201410608337.0A CN201410608337A CN104387353B CN 104387353 B CN104387353 B CN 104387353B CN 201410608337 A CN201410608337 A CN 201410608337A CN 104387353 B CN104387353 B CN 104387353B
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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
- C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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Abstract
The present invention relates to a kind of compound α and give birth to spiral shell quinone and its production and use。This compound is the α-fertility spiral shell quinone adopting extraction, concentrating under reduced pressure, extraction, silica gel column chromatography and gel column chromatography purification from Caulerpa racemosa (Forssk) Web V. Bos and obtaining, its structure measured by physicochemical constant and spectral data analysis and determine。Prove through preliminary Activity Screening Test: this compound is to amyloid beta 25 35 (A β25-35) the SH-SY5Y cell that damages has significant protective effect, can be used for preparing neuroprotective and preventing Alzheimer disease drug。
Description
Technical field
The present invention relates to a kind of α that extracts from Caulerpa racemosa (Forssk) Web V. Bos and give birth to spiral shell quinone and preparation method thereof；The invention still further relates to this compound for A β25-35The SH-SY5Y cell of damage has the active component of protective effect, thus it can be used for preparing nerve protection medicine and preventing and treating Alzheimer disease drug。
Background technology
Caulerpa racemosa (Forssk) Web V. BosCaulerparacemosa(Forssk?L) J.Agardh system Chlorophyta (Chlorophyta) Chlorophyceae (Chlorophyceae) Siphonales (Siphonales) Caulerpaceae (Caulerpaceae) Caulerpa belong to (Caulerpa) sea-plant, be distributed mainly on Perenniporia martius marine site, be grown on the rock of below Intertidal zone, coral reef or in, on the sand ground of low tide band。Also have widely distributed in China marine site, focus primarily upon Dongshan, Fujian, Taiwan, Hainan, Xisha, Coast of Guangdong Province。Research both at home and abroad shows, in Caulerpa racemosa (Forssk) Web V. Bos containing the compositions such as sesquiterpenoids, Diterpenes, steroid, glyceride type, aromatics, amide-type and alkaloids (Alarif, W.M.etal,Clean:Soil,Air,Water, 2010,38 (5-6), 548 557；Wang, H.etal,BotanicaMarina,2007,50(3),185–190;Ayyad,S.-E.N.etal,AlexandriaJournalofPharmaceuticalSciences,1994,8(3),217–219;Anjaneyulu,A.S.R.etal,JournalofNaturalProducts, 1992,55 (4), 496 499)。Wherein most terpenoids contain Isosorbide-5-Nitrae-diacetoxy (aldehyde radical) the butadiene structure segment that nature is rare, and alkaloids is then the bis-indole compounds that structure is peculiar。Modern pharmacology research shows, the secondary metabolite found from Caulerpa racemosa (Forssk) Web V. Bos often show very strong antibacterial, antiinflammatory, antiviral, parasite killing, antitumor and poison various biological activity such as fish (Anjaneyulu, A.S.R.etal,Phytochemistry,1991,30(9),3041-3042;Anjaneyulu,A.S.R.etal,JournaloftheIndianChemicalSociety,1991,68(8),480;Capon,R.J.Phytochemistry,1983,22(6),1465-1467;Nielsen,P.G.etal,Phytochemistry,1982,21(7),1643–1645;Doty,M.S.etal,Nature, 1966,211 (5052), 990)。
Summary of the invention
A kind of compound α of offer is provided and gives birth to spiral shell quinone and its production and use。This compound is the α fertility spiral shell quinone adopting extractions, concentrating under reduced pressure, extraction, silica gel column chromatography and gel column chromatography purification from Caulerpa racemosa (Forssk) Web V. Bos and obtaining, its structure measured by physicochemical constant and spectral data analysis and determine。Showing through pharmacological testing research, this compound is to A β25-35The SH-SY5Y cell of damage has significant protective effect。
Therefore, it is an object of the present invention to provide a kind of method preparing compound α fertility spiral shell quinone from Caulerpa racemosa (Forssk) Web V. Bos。
It is a further object to provide compound α and give birth to the purposes of spiral shell quinone。Specifically, this compound is to A β25-35The SH-SY5Y cell of damage has significant protective effect, can be used for the medicine preparing neuroprotective and preventing and treating Alzheimer's disease。
First purpose according to the present invention, the present invention provides a kind of and adopts extraction, concentrating under reduced pressure, extraction, silica gel column chromatography and gel column chromatography to prepare the compound α method giving birth to spiral shell quinone from Caulerpa racemosa (Forssk) Web V. Bos, specifically comprises the following steps that
1) extract extractum is prepared
By freezing Caulerpa racemosa (Forssk) Web V. Bos (C.racemosa) thaw under room temperature, with ethanol seepage pressure effects three times routinely, each 24 hours, obtain extracting solution, extracting solution concentrating under reduced pressure is reclaimed ethanol, obtains crude extract；
2) purification is separated
(1) above-mentioned crude extract is scattered in water and becomes suspension, being extracted respectively three times with petroleum ether, ethyl acetate and n-butyl alcohol successively by suspension, the concentration of gained extract respectively obtains Petroleum ether extraction extractum, ethyl acetate extracts extractum and n-butanol extraction extractum；
(2) ethyl acetate extract is carried out silica gel column chromatography, with petroleum ether/acetone gradient elution, merge similar stream part according to TLC colour developing and obtain 5 component A, B, C, D, E；Wherein component C and petroleum ether/acetone volume ratio 8:2 and 7:3 elution fraction are successively through SephadexLH-20 gel filtration chromatography (with methylene chloride/methanol eluting), silica gel column chromatography (with petroleum ether/methylene chloride volume ratio for 6:4 4:6 gradient elution), obtain compound α and give birth to spiral shell quinone, chemistry α-tocospirone by name, chemical structural formula is:
In above-mentioned preparation method, in preparing extract extractum step, the described ethanol adopted that extracts is 95% ethanol。
In above-mentioned preparation method, in purification procedures, the methylene chloride/methanol eluting concentration in described SephadexLH-20 gel filtration chromatography is volume ratio 1:1。
Second purpose according to the present invention, the invention provides α and gives birth to the purposes of spiral shell quinone。
The present invention adopts mtt assay to test α fertility spiral shell quinone antagonism A β25-35The activity that the neuroblastoma SH-SY5Y cell survival rate caused declines。It is experimentally confirmed that α gives birth to spiral shell quinone, and the SH-SY5Y cell injury in above-mentioned model is had significant protective effect。
Therefore, the α fertility spiral shell quinone of the present invention can be used as preparation protection neurocyte (such as, through A β25-35The SH-SY5Y cell of damage) medicine, and then can be used as preparing nerve protection medicine and preventing and treating Alzheimer disease drug。
Accompanying drawing explanation
Fig. 1: α gives birth to spiral shell quinone under variable concentrations to A β25-35The cell survival rate block diagram of the SH-SY5Y cell injury brought out。
Detailed description of the invention
Embodiment 1 α gives birth to the preparation of spiral shell quinone
(1) by freezing Chinese Caulerpa racemosa (Forssk) Web V. Bos (C.racemosa) (picking up from Zhanjiang coastal) 5kg(dry weight) use 30L95% ethanol percolate extraction three times respectively, each percolation 1 day, united extraction liquid；
(2) said extracted liquid is reclaimed ethanol at temperature≤45 DEG C concentrating under reduced pressure, obtain crude extract 350g；This extract extractum is scattered in water and becomes suspension, being extracted three times respectively by petroleum ether (1.5L), ethyl acetate (1.5L) and n-butyl alcohol (1L) successively by suspension, gained extract concentrating under reduced pressure respectively obtains Petroleum ether extraction extractum (38g), ethyl acetate extracts extractum (160g) and n-butanol extraction extractum (120g)；
(3) ethyl acetate extract is carried out silica gel column chromatography, with petroleum ether/acetone gradient elution, merge similar stream part according to TLC colour developing and obtain 5 components (A-E)；Wherein component C and petroleum ether/acetone volume ratio 8:2 and 7:3 elution fraction are successively through SephadexLH-20 gel filtration chromatography (methylene chloride/methanol volume ratio 1:1 eluting), silica gel column chromatography (petroleum ether/methylene chloride volume than for 6:4 4:6 gradient elution), obtain compound α and give birth to spiral shell quinone。
Embodiment 2 α gives birth to spiral shell quinone to A β25-35The protective effect of induction SH-SY5Y cellular damage
1, laboratory sample and experimental technique
The preparation of sample solution: test sample is that in above-described embodiment 1, the sterling compound α of preparation gives birth to spiral shell quinone。Accurately weigh appropriate amount of sample, be configured to the solution of desired concn with DMSO, test for pharmacologically active。
The successive transfer culture of cell line and cell: active testing adopts SH-SY5Y cell line (purchased from American ATCC (Americantypeculturecollection))。With the DMEM culture medium containing 10%FBS, successive transfer culture in 37 DEG C of incubators passing into 5% carbon dioxide。
Cytoactive method of testing (mtt assay): the present invention adopts mtt assay, the tested sample of test evaluation is to A β25-35Cause the protective effect that SH-SY5Y cell viability declines。In living cells mitochondrion dehydrogenase can metabolism reduction yellow bromination 3-(4,5-dimethylthiazole)-2,5-diphenyltetrazolium bromide is hepatic water-fast first hairpin (formazan), first hairpin number can measure its trap by microplate reader and try to achieve。Owing to the amount of formazan is directly proportional to living cells, so the number of living cells can be obtained according to trap, thus understanding the sample impact on cell。
During active testing, the SH-SY5Y cell of trophophase of taking the logarithm, being configured to density by fresh DMEM culture medium is every milliliter 5 × 104The cell suspension of individual cell, is inoculated in 96 orifice plates by every hole 100 μ L, adds medicinal liquid 10 μ L/ hole after cultivating 24h, each concentration is all provided with six multiple holes, separately sets blank and model group。Cell 37 DEG C, cultivate 2h under 5% carbon dioxide conditions after, except blank group, every hole adds A β25-35(ultimate density is 1 μM) damaging cells, 37 DEG C, 5%CO2After cultivating 24h under condition, every hole adds MTT solution 10 μ L (5mg/mL), after continuing cultivation 4h, carefully removes supernatant, adds DMSO100 μ L/ hole, then survey OD by microplate reader570/630Value。The measured object protective effect to cell is calculated by following equation:
Survival rate %=100 × administration group OD/ matched group OD
Evaluation of result: the survival rate of sample group is more high, test sample is more strong to the protective effect of cell。
2, experimental result
α gives birth to spiral shell quinone to A β25-35The protective effect Activity Results of induction SH-SY5Y cellular damage is shown in Fig. 1。(##P < 0.01 compared to blank group,**P < 0.01 is compared to model group): α gives birth to spiral shell quinone when 10 μMs of concentration to A β25-35The SH-SY5Y cell injury caused has significant protective effect。
3, conclusion
α gives birth to spiral shell quinone and at low concentrations neuroblastoma cell is had significant protective effect, thus can be used as preparing nerve protection medicine and preventing and treating Alzheimer disease drug。
Embodiment 3
Example 1 gained compound, adds common drug adjuvant, makes the dosage forms such as tablet, capsule, oral agents。
Claims (2)
1. α gives birth to spiral shell quinone in preparation protection through A β25-35Purposes in the medicine of the SH-SY5Y cell of damage。
2. α gives birth to spiral shell quinone in the purposes preparing nerve protection medicine and preventing and treating Alzheimer disease drug。
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