CN105153072B - Nardosinone C and preparation method and application - Google Patents
Nardosinone C and preparation method and application Download PDFInfo
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- CN105153072B CN105153072B CN201510612530.6A CN201510612530A CN105153072B CN 105153072 B CN105153072 B CN 105153072B CN 201510612530 A CN201510612530 A CN 201510612530A CN 105153072 B CN105153072 B CN 105153072B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/32—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by aldehydo- or ketonic radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/32—Separation; Purification
Abstract
The present invention relates to nardosinone C and preparation method and application, the nardosinone C is isolated and purified from the rhizome of Valerianaceae rhizoma nardostachyos platymiscium rhizoma nardostachyos and is obtained, with 5 hydroxytryptamine transporter (SERT) inhibitory activity, it can be applied in terms of the drug for treating the digestive system functions disorders such as the neuropsychiatric diseases such as depression, anxiety disorder, schizophrenia, obsessive-compulsive disorder, neurodegenerative disease, drug addiction and slow Constipation, irritable bowel syndrome and functional distension is prepared, there is important drug development to be worth.
Description
Technical field
The present invention relates to Plant Extracts and preparation method and application, especially nardosinone C and its preparation side
Method and application.
Background technology
Serotonin transporter (SERT) is a kind of transmembrane transporter for having high affinity to 5-HT, containing about 630
Amino acid residue, encoding gene (SLC6A4) are located on No. 7 and No. 11 chromosomes respectively, are about outside 14 of 35kb by span
Aobvious son composition.SERT albumen includes 12-13 transmembrane region, and N-terminal and C-terminal are located in cytoplasm, has cAMP dependence eggs at N-terminal
White kinases binding site has one to be located at extracellular annulus between third and the 4th transmembrane region, is the glycosyl of N- connections
Change site.
SERT belongs to Na+/Cl-Dependent form transport protein is predominantly located at 5-HT serotonergic neurons.SERT is from nerve synapse gap
In reuptake 5-HT and enter presynaptic neuron, directly affect synaptic cleft 5-HT concentration, change postsynaptic receptor mediation letter
Number amount and acting duration.It moreover has been found that SERT is by placenta tissue, marrow, kidney, lung, the heart, adrenal gland, liver, first shape
The organs such as gland, thyroid gland, pancreas and small intestine are also distributed, and SERT is prompted to participate in different physiological roles.
SERT is the important molecule for transporting 5-HT, with many Physiological Psychology functions such as mood, appetite, sleep, memory, study
Correlation, SERT and 5-HT expression, which change, can cause anxiety, depression, obsessive-compulsive disorder, neurosis or even schizophrenia, and and drug
It is additive closely related；It moreover has been found that SERT plays key player in gastrointestinal function disease, such as clinically slow transmission
The functional gastrointestinal diseases such as property constipation, irritable bowel syndrome, functional distension, using antidepressants, the anti-coke for SERT
Consider drug and achieve curative effect.
SERT is the important target spot of clinical medicine research and development, and selective serotonin reuptake depressant (SSRI) includes fluorine west
Spit of fland, Paxil, Sertraline, Fluvoxamine, Citalopram etc., clinic are usually used in treating depression, anxiety disorder and obsessive-compulsive disorder etc.,
Such drug sedation is small, does not also damage Psychomotor ability, influences very little to cardiovascular and autonomic nervous system function.
Rhizoma nardostachyos (Nardostachys chinensis Batal.) is Valerianaceae rhizoma nardostachyos platymiscium, has regulating qi-flowing for relieving pain, opens
It is strongly fragrant to be amusing；The effect of external application clearing damp is subsided a swelling, rhizoma nardostachyos it has been reported that bioactivity act on nervous system including (1), such as anti-suppression
Strongly fragrant, calm and anticonvulsion, anti-Parkinson and reminiscence；(2) cardiovascular system is acted on, such as blood pressure lowering, anti-arrhythmia, is resisted
Myocardial ischemia, anti-cardiovascular injury；(3) respiratory system is acted on, such as enhances hypoxia-bearing capability；(4) it is antibacterial；(5) anti-liver injury
Deng.The chemical composition of rhizoma nardostachyos includes sequiterpene, triterpene, iridoid, cumarin, phenolic acid, flavones etc., sequiterpene be its mainly into
Point, but have no report of this kind of compound in terms of SERT inhibitory activity.
Invention content
The technical problems to be solved by the invention are to provide a kind of nardosinone C.
Another technical problem to be solved by this invention is to provide the preparation method of above-mentioned nardosinone C.
Another technical problem to be solved by this invention is to provide the application of above-mentioned nardosinone C.
In order to solve the above technical problems, the technical scheme is that：
A kind of nardosinone C (kanshone C), has the following structure logical formula (I),
Preferably, above-mentioned nardosinone C, physical chemistry and Spectroscopic Properties：Colourless powder (dichloromethane).UV(MeOH)
λmax:197、333nm；CD(c 0.05,MeOH)λ(Δε):251(+0.72)、224(+0.19)、203(+0.94)nm；1H-NMR
(CDCl3,400MHz):δH 3.63(1H,br s,H-1)、1.82(1H,m,H-2α)、2.17(1H,m,H-2β)、1.24(1H,m,
H-3 α), 1.45 (1H, ddd, 4.0,13.2,16.8, H-3 β), 1.67 (1H, m, H-4), 2.01 (1H, d, J=8.0Hz, H-6),
2.31 (1H, d, J=8.0Hz, H-7), 1.31 (3H, s, 12-CH3)、1.41(3H,s,13-CH3)、1.21(3H,s,14-CH3)、
1.02 (3H, d, J=6.8Hz, 15-CH3)；13C-NMR(CDCl3,100MHz):δC66.0(C-1)、26.0(C-2)、24.3(C-
3)、38.4(C-4)、36.8(C-5)、44.2(C-6)、39.6(C-7)、194.1/188.9(C-8)、188.9/194.1(C-9)、
64.6(C-10)、31.1(C-11)、19.8(C-12)、30.8(C-13)、17.8(C-14)、15.8(C-15)。
Preferably, above-mentioned nardosinone C, chemical constitution feature：1,10- formation on aristolane type sequiterpene parent nucleus
Three membered oxygen rings, 8, the substitution of 9- diketone carbonyls.
The preparation method of above-mentioned nardosinone C, is as follows：
(1) rhizoma nardostachyos rhizome 70% (v/v) alcohol steep 3 times 48 hours every time, merges extracting solution, is concentrated under reduced pressure, obtains slightly
Extract medicinal extract；Then put on 70% ethyl alcohol heat and state the dregs of a decoction 3 times, 2 hours every time, merge extracting solution, be concentrated under reduced pressure, again slightly
Extract medicinal extract；Merge crude extract medicinal extract twice and obtain the total medicinal extract of crude extract；
(2) gained the total medicinal extract of crude extract after moisture dissipates, respectively with isometric petroleum ether, ethyl acetate and n-butanol according to
Secondary extraction obtains petroleum ether part, ethyl acetate extract, n-butanol portion and water layer；
(3) by petroleum ether part through silica gel column chromatography, petroleum ether：Ethyl acetate=100:0(100:0 refers to 100% petroleum ether
Elution profile) -100:50 solvent system gradient elutions obtain 22 fraction Fr.1-22；
(4) petroleum ether：Ethyl acetate=100:5-100:Fraction --- fraction Fr.9 is through silica gel column layer repeatedly for the elution of 7 solvents
Analysis, petroleum ether：Ethyl acetate=100:0(100:0 refers to 100% petroleum ether elution profile) -100:10 gradient elutions, it is isolated
Nardosinone C.
Above-mentioned nardosinone C answering in terms of the drug for treating neuropsychiatric disease and/or drug addiction is prepared
With, wherein, neuropsychiatric disease includes depression, anxiety disorder, schizophrenia, obsessive-compulsive disorder or neurodegenerative disease.
Applications of the above-mentioned nardosinone C in terms of the drug for treating digestive system function disorders is prepared, wherein,
Digestive system function disorders include slow Constipation, irritable bowel syndrome or functional distension.
Pharmaceutical composition with above-mentioned nardosinone C, the above compound comprising treatment and/or prevention effective dose are (sweet
Colophonone C) and optional pharmaceutically acceptable excipient.
Above-mentioned pharmaceutically acceptable excipient can be any conventional excipient, particular excipient in field of pharmaceutical preparations
Selection by depending on being used to treat the administering mode of particular patient or disease type and state, for the conjunction of specific administration pattern
The preparation method of suitable pharmaceutical composition is completely in the knowledge of drug field technical staff.For example, can as pharmacy
The excipient of receiving includes the diluent of pharmaceutical field routine, carrier, filler, adhesive, wetting agent, disintegrant, absorbs rush
Into agent, surfactant, absorption carrier and lubricant etc., when necessary, flavouring agent, anti-corrosion can also be added in pharmaceutical composition
Agent and sweetener etc..
Tablet, pulvis, granule, capsule, oral liquid, paste, creme, injection breast can be made in aforementioned pharmaceutical compositions
The diversified forms such as agent, aseptic powder needle for injection, the drug of various dosage forms can be prepared according to the conventional method of pharmaceutical field.
The beneficial effects of the invention are as follows：
Above-mentioned nardosinone C is from Valerianaceae rhizoma nardostachyos platymiscium rhizoma nardostachyos (Nardostachys chinensis Batal.)
Isolate and purify and obtain in rhizome, have inhibit serotonin transporter (SERT) activity, can be used as treatment depression, anxiety disorder,
The nervous system diseases such as schizophrenia, obsessive-compulsive disorder, neurodegenerative disease, drug addiction and slow Constipation, intestines
The medicine of the digestive system functions disorders such as road irritable syndrome and functional distension has important drug development
Value.
Description of the drawings
Fig. 1 is inhibiting effect of the nardosinone C to SERT activity, wherein, positive control drug is respectively 2.0
MFluoxetine and 1.0 M Tianeptine, * p<0.05, * * * p<0.001.
Specific embodiment
In order to which those skilled in the art is made to be better understood from technical scheme of the present invention, With reference to embodiment
Technical solution of the present invention is described in further detail.
Laboratory apparatus and reagent：Fourier transform nuclear magnetic resonance spectrometer (Bruker companies of Switzerland, AVIII types 400MHz
And 600MHz)；Color developing agent：10% sulfuric acid ethyl alcohol.
Embodiment 1
The preparation (extraction separation process) of active constituent nardosinone C compounds：
Rhizoma nardostachyos pharmaceutical decocting piece is purchased from Anhui Jiren Pharmacy Co., Ltd.'s (lot number：110709, specification：1kg/ bags, the place of production：Four
River), about 20kg.Rhizoma nardostachyos rhizome 20kg 70% (v/v) alcohol steeps 3 times 48 hours every time, merge extracting solution, are concentrated under reduced pressure,
Obtain crude extract medicinal extract 3kg；Then it is put on 70% ethyl alcohol heat and states the dregs of a decoction 3 times, 2 hours every time, merged extracting solution, be concentrated under reduced pressure,
Obtain crude extract medicinal extract 400g；Merge crude extract twice and obtain total medicinal extract 3.4kg；The total medicinal extract of gained crude extract, after moisture dissipates, successively
Extracted with isometric petroleum ether, ethyl acetate, n-butanol, obtain petroleum ether part 320g, ethyl acetate extract 1kg,
N-butanol portion 600g, water layer 1.2kg；By petroleum ether part 320g through silica gel column chromatography (100-200 mesh mixes sample silica gel 400g,
200-300 mesh column silica gel 3.3kg, petroleum ether：Ethyl acetate=100:0-100:50 solvent system gradient elutions), obtain 22 streams
Part Fr.1-22；Fraction Fr.9 (petroleum ethers：Ethyl acetate=100:5-100:7 solvents elute fraction), through silica gel column chromatography repeatedly
(petroleum ether：Ethyl acetate=100:0-100:10 gradient elutions), isolated compound nardosinone C.
After measured, nardosinone C (Kanshone C), colourless powder (dichloromethane).UV(MeOH)λmax:197、
333nm；CD(c 0.05,MeOH)λ(Δε):251(+0.72)、224(+0.19)、203(+0.94)nm；1H-NMR(CDCl3,
400MHz):δH 3.63(1H,br s,H-1)、1.82(1H,m,H-2α)、2.17(1H,m,H-2β)、1.24(1H,m,H-3α)、
1.45 (1H, ddd, 4.0,13.2,16.8, H-3 β), 1.67 (1H, m, H-4), 2.01 (1H, d, J=8.0Hz, H-6), 2.31
(1H, d, J=8.0Hz, H-7), 1.31 (3H, s, 12-CH3)、1.41(3H,s,13-CH3)、1.21(3H,s,14-CH3)、1.02
(3H, d, J=6.8Hz, 15-CH3)；13C-NMR(CDCl3,100MHz):δC 66.0(C-1)、26.0(C-2)、24.3(C-3)、
38.4(C-4)、36.8(C-5)、44.2(C-6)、39.6(C-7)、194.1/188.9(C-8)、188.9/194.1(C-9)、
64.6(C-10)、31.1(C-11)、19.8(C-12)、30.8(C-13)、17.8(C-14)、15.8(C-15).The nard
1,10- three membered oxygen rings of formation on aristolane type sequiterpene parent nucleus in the structure of ketone C compounds, 8,9- diketone carbonyls take
Generation.Structural formula is as follows：
Embodiment 2
Influence of the compound of the present invention to serotonin transporter (SERT)
Using the hSERT-HEK293 cell strains of stable transfection, with 4- (4- (dimethylamino) phenyl) -1-
methylpyridinium(APP+) it is fluorogenic substrate, detection compound nardosinone C is to SERT activity in high intension system
Influence.
1) laboratory apparatus and reagent
Laboratory apparatus：
High intension Operetta systems and Columbus data managements and analysis system (PerkinElmer), super-clean bench move
Liquid rifle (1000 μ L, 200 μ L, 20 μ L, 10 μ L, 2.5 μ L, Eppendorf companies of the U.S.)
Reagent and material：
Human embryonic kidney cell line HEK293 (the American Type Culture Collection committee of Chinese Academy of Sciences cell bank), hSERT pcDNA3
Plasmid (Addgene, plasmid 15483), MEM culture mediums (Gibco), APP+(Sigma), 33342 (Cell of Hoechst
Signaling Technology), 96 orifice plates (Costar 3605)
2) experimental implementation process
It initially sets up and identifies stable expression hSERT-HEK293 cell strains and { pacify the people source 5- such as of heap of stone, Li Jing, golden blast
The foundation of hydroxytryptamine transporter stable expression cell line and its function investigation [J] military medicines 2011,35 (9):681-684}.
With APP+For fluorogenic substrate, function { Fowler A, Seifert N, the Acker V.et based on high intension system detectio SERT
al.A nonradioactive high-throughput/high-content assay for measurement of the
human serotonin reuptake transporter function in vitro[J].Journal of
Biomolecular Screening,2006,11(8):1027-1034}
Specific steps：
(1) precision weighs 1 gained nardosinone C of embodiment, the mother liquor of 20mM is configured to DMSO, with without phenol red MEM bases
Plinth training base dilutes drug to 10.0 μM, 1.0 μM, 0.1 μM.
(2) by 1.0 × 104In the hSERT-HEK293 cells to 96 orifice plates of the density inoculation stable transfection of cells/well,
37 DEG C, 5%CO2Under the conditions of cultivate for 24 hours.
(3) blank control group, 2.0 μM of Prozac groups of positive control and 1.0 μM of Tianeptine groups, testing drug are set up in experiment
Set up 10.0 μM respectively, 1.0 μM, 0.1 μM of group.Cell discards culture medium, is washed 2 times with PBS buffer solution, according to 80 μ L/ pore volumes
Add in each sample to be tested, each 3 multiple holes of concentration, at 37 DEG C, 5%CO2Under the conditions of be protected from light be incubated 2-3h.
(4) after the completion of being incubated, 20 μ L APP are added in per hole+, it is incubated 10 minutes.
(5) liquid in hole is discarded, is washed 2 times with PBS buffer solution, 1.0 μ g/mL Hoechst50 μ L are added in per hole, are protected from light
It is incubated 20min.
(6) liquid in orifice plate is discarded, PBS is washed 2-3 times, using the intracellular fluorescence intensity of high intension system detectio
Hoechst 33342Excitation：360-400nm, Emission：410-480nm
APP+Excitation：460-490nm, Emission：505-550nm
3) data analysis：
Image analysis is carried out using Columbus data managements and analysis system, according to 33342 fluorescence identifyings of Hoechst
Nuclear pattern determines cell, according to intracellular APP+Fluorescence intensity determines SERT transport activities, calculates relative intensity of fluorescence
=(the intracellular APP of medicine group+The intracellular APP of fluorescence intensity/control group+Fluorescence intensity) carry out one-way analysis of variance (one
way ANOVA)。
4) experimental result
As shown in Figure 1, one-way analysis of variance result shows that nardosinone C significantly inhibits SERT transport activities (F (5,36)
=344.3, p<0.0001), Dunnett Multiple range tests post-hoc tests (Dunnett's multiple comparison post
Hoc test) confirm that 3 proof load nardosinone C and blank control group more significantly suppress SERT activity, 10.0 μM
(q=23.66, p<0.001), 1.0 μM of (q=4.938, p<0.001), 0.1 μM of (q=2.788, p<0.05), positive controls
2.0 μM of Prozacs significantly suppress SERT activity (q=28.20, p compared with blank control group<0.001), positive controls thiophene
Nai Puting can significantly increase SERT activity (q=5.053, p at 1.0 μM<0.001).
In summary, the serotonin transporter (SERT) is a kind of Na for having high affinity to 5-HT+/Cl-It relies on
Type turns transmembrane transporter, and 5-HT serotonergic neurons are predominantly located in central nervous system, by from nerve synapse gap again
Intake 5-HT enters presynaptic neuron, directly affects synaptic cleft 5-HT concentration, changes the amount of postsynaptic receptor mediation signal
And acting duration, so as to participate in a variety of Physiological Psychology functions (such as mood, appetite, sleep, memory, study)；It is digesting
System SERT is predominantly located at intestinal epithelial cell, reuptakes the 5-HT of intestinal mucosa layer chromaffin cell release to adjust stomach and intestine
Function, in addition, in devices such as placenta tissue, genital tract, marrow, kidney, lung, the heart, adrenal gland, liver, parathyroid gland, thyroid gland and pancreas
Official is distributed, and SERT is prompted to participate in different physiological roles.
SERT is the important target spot of clinical medicine research and development, and the serotonin reuptake transporter accelerating agent (SSRE) reported so far has thiophene
Nai Puting, clinic are mainly used for antidepression and antianxiety.Tianeptine includes the action character of human body：Have one to mental state disorder
It is set for using, between sedating antidepressants and excitability antidepressants；To Somatic discomfort, especially for anxiety and mental state
Disorderly related upset,gastro-intestinal has obvious effect；The personality and conduct disorder occur during abstinence from alcohol to alcoholism patient has one
It is set for using；Moreover, Tianeptine to following aspect without ill-effect：Sleep and vigilance；Cardiovascular system；Cholinergic system (nothing
Anticholinergic symptom)；Drug habit.Tianeptine belongs to a kind of SSRE, and action character has prompted serotonin reuptake transporter rush
Into agent (SSRE) in clinical practice the characteristics of and advantage.
The present invention is by carrying out isolated nardosinone C from rhizoma nardostachyos rhizome external influence serotonin transporter
(SERT) active research finds that nardosinone C can significantly inhibit SERT transport activities, so as to confirm nardosinone C to adjust
Save the unbalance caused relevant physiological mental diseases of SERT and digestive system function disorders active ingredient.Therefore, nardosinone C
It can be used for preparing the treatment functional disturbances of gastrointestinal tract such as the neuropsychiatric diseases such as depression and anxiety disorder and irritable bowel syndrome
The drug of disease.
Embodiment 3
Preparation method：Nardosinone C, newborn sugar and starch are uniformly mixed according to the above ratio, cross 200 mesh sieve, it is uniform with water
Mixture after wetting is dried re-sieving, adds in magnesium stearate by wetting, and then by mixture tabletting, every weight 250mg lives
Property component content be 10mg.
Embodiment 4
Capsule：Nardosinone C 20mg
Galactolipin 188mg
Magnesium stearate 2mg
Preparation method：Nardosinone C with galactolipin is uniformly mixed according to the above ratio, 200 mesh sieve is crossed, obtained mixing
Object, add in magnesium stearate, be packed into No. 2 capsules to get.
The above-mentioned detailed description carried out to nardosinone C and preparation method and application with reference to specific embodiment is
It is illustrative rather than limited, several embodiments can be enumerated according to limited range, therefore do not departing from the present invention
Change and modification under general plotting should belong within protection scope of the present invention.
Claims (1)
1. a kind of application of nardosinone C drugs in terms of inhibition serotonin transporter activity is prepared, the nardosinone C tools
Lead to formula (I) just like lower structure,
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| US20130012462A1 (en) * | 2007-05-11 | 2013-01-10 | Biotechnology Research Corporation Limited | Receptor modulators exhibiting neuroprotective and memory enhancing activities |
| CN101468048A (en) * | 2007-12-24 | 2009-07-01 | 浙江正方医药科技有限公司 | Spikenard volatile oil and use of composition containing spikenard volatile oil in pharmacy |
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