CN105152894A - Rhizoma nardostachyos birthwort alkane sesquiterpene compound and preparation method and application thereof - Google Patents
Rhizoma nardostachyos birthwort alkane sesquiterpene compound and preparation method and application thereof Download PDFInfo
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- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
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Abstract
The invention provides a rhizoma nardostachyos birthwort alkane sesquiterpene compound and a preparation method and application thereof. The rhizoma nardostachyos birthwort alkane sesquiterpene compound is obtained through separation and purification from rhizomes of a nardostachys chinensis batal plant of rhizoma nardostachyos, and the compound has 5-serotonin transporter (S-ERT) to enhance activity, belongs to rare SERT activity promoters, can be used for preparing drugs for treating depression, anxiety disorder, schizophrenia, obsessive-compulsive disorder, the neurodegenerative disease, drug addiction and other neuropsychological diseases, and drugs for treating slow transit constipation, irritable bowel syndromes, functional bloating and other dysfunction diseases of the digestive system, and has important medicine development value.
Description
Technical field
The present invention relates to research and develope of TCD field, especially rhizoma nardostachyos Virginia snakeroot alkane type sesquiterpene compound and preparation method and application.
Background technology
Serotonin transporter (SERT) is a kind of transmembrane transporter 5-HT being had to high affinity, about containing 630 amino-acid residues, its encoding gene (SLC6A4) lays respectively on No. 7 and No. 11 karyomit(e)s, and 14 exons being about 35kb by span form.SERT albumen comprises 12 ~ 13 cross-film districts, and N end and C end are arranged in kytoplasm, have cAMP deopendent protein kinase binding site, between the 3rd and the 4th cross-film district, have one to be positioned at extracellular circular part near N end place, are the glycosylation sites that N-connects.
SERT belongs to Na
+/ Cl
-dependent form translocator, 5-HT serotonergic neuron is mainly positioned in central nervous system, SERT reuptakes 5-HT and enters presynaptic neuron from nerve synapse gap, directly affects synaptic cleft 5-HT concentration, changes amount and the acting duration of postsynaptic receptor mediation signal.Mainly be positioned at intestinal epithelial cell at Digestive tract SERT, reuptake the 5-HT of the pheochromocyte release of intestinal mucosa layer to regulate gastrointestinal function.In addition, SERT also has distribution at thrombocyte, placenta tissue, marrow, kidney, lung, the heart, suprarenal gland, liver, parathyroid gland, Tiroidina, pancreas etc., and prompting SERT participates in different physiological roles.
SERT is the important molecule of transhipment 5-HT, relevant to many Physiological Psychology functions such as mood, appetite, sleep, memory, study in central nervous system, SERT and 5-HT expresses change can cause anxiety, depression, obsession, phobia, even schizophrenia, and closely related with drug addiction; In gastrointestinal function disease, SERT plays key player, 5-HT signalling system can cause gastrointestinal tract dynamia and pathocrinia, visceral hypersensitivity extremely, closely related with gastrointestinal function diseases such as chronic constipation, irritable bowel syndrome, diarrhoea and functional dyspepsias.
SERT is the important target spot of clinical medicine research and development.Classical thymoleptic based on SERT target spot belong to selectivity SERT inhibitor (SSRI) more, as fluoxetine (Fluoxetine) etc.; Serotonin reuptake transporter promotor (SSRE) then rare report, so far reported that SSRE has tianeptine (tianeptine), another name Tatinol (stablon), its chemical structure belongs to tricyclic antidepressant, is clinically mainly used in antidepressant and anxiety.Experimental studies have found that tianeptine can promote 5-HT re-uptake, in neuromechanism plasticity-, tianeptine to stress/Kendall compound induction the atrophy of hippocampal neuron dendron there is prophylactic effect, hippocampus precursor cell propagation, the hippocampus volume that can resist stress induction decline and N-acetyl aspartate density loss, and prevent amygdala dendron hyperplasia.In nerve excitability, tianeptine can overcome stress block hippocampal long-term enhancement, and reversing stress to the restraining effect etc. of hippocampus-front cortex cynapse.In neuroprotective, tianeptine can reduce the apoptosis of hippocampus and cortex of temporal lobe.In memory function, tianeptine is to having blocking effect by reduced space memory impairment, increase memory to retain, contribute to visual cognitive ability behavior, (McEwenBS, OlieJP.2005.Neurobiologyofmood, the anxiety such as the deleterious effect of antagonism alcohol, andemotionsasrevealedbystudiesofauniqueantidepressant:ti aneptine.MolecularPsychiatry10,525 – 537).In addition, tianeptine can make maincenter 5-HT metabolite 5-hydroxyindoleacetic acid raise, and deduction may due to after presynaptic membrane re-uptake-5-HT increases, in neural 5-HT katabolism corresponding increase relevant; Tianeptine can act on hypothalmus-pituitary-adrenal axis, and hypothalamus cortin releasing hormone and anterior pituitary adrenal cortical hormone concentration are declined.
Tianeptine is effective to major depressive disorder, fluoxetine is better than to dysthymia disorders long-term efficacy, and security is high, untoward reaction is few, be suitable for depression in old age, anxiolytic effect be better than fluoxetine [recklessly sprout, Li Zhen .2007. tianeptine pharmacological research and Clinical advances. Guangdong medical science 28 (7): 1192-1193.] action character of tianeptine to human body comprise: have certain effect to mental state disorder, between sedating antidepressants and excitability thymoleptic; To Somatic discomfort, especially there is obvious effect for the disorderly relevant gastrointestinal upset of anxiety and mental state; The personality occur during abstinence from alcohol alcoholism patient and conduct disorder have certain effect; And, tianeptine to following aspect without undesirable action: sleep and vigilance; Cardiovascular systems; Cholinergic system (nonreactive cholinergic symptoms); Drug habit.More than serotonin reuptake transporter promotor (SSRE) characteristics and advantages in clinical application has been pointed out in research.
Rhizoma nardostachyos (NardostachyschinensisBatal.) is Valerianaceae rhizoma nardostachyos platymiscium, has regulating QI to relieve pain, relieving stagnation and activating the spleen; Effect of external application clearing damp detumescence, the biological activity that rhizoma nardostachyos has been reported comprises (1) and acts on neural system, as antidepressant, calmness and anticonvulsion, anti-Parkinson and reminiscence; (2) act on cardiovascular systems, as hypotensive, anti-arrhythmia, resist myocardial ischemia, anti-cardiovascular injury; (3) respiratory system is acted on, as strengthened hypoxia-bearing capability; (4) antibacterial; (5) anti-liver injury etc.The chemical composition of rhizoma nardostachyos comprises sesquiterpene, triterpene, iridoid, tonka bean camphor, phenolic acid, flavones etc., sesquiterpene is its main component, wherein the research such as nardosinone, aristolene report is more, other activeconstituents particularly a small amount of or trace ingredients rarely has report, and biological activity and related mechanism need further discovery.
Summary of the invention
Technical problem to be solved by this invention is to provide rhizoma nardostachyos Virginia snakeroot alkane type sesquiterpene compound.
Another technical problem to be solved by this invention is the preparation method providing above-mentioned rhizoma nardostachyos Virginia snakeroot alkane type sesquiterpene compound.
Another technical problem to be solved by this invention is the application providing above-mentioned rhizoma nardostachyos Virginia snakeroot alkane type sesquiterpene compound.
For solving the problems of the technologies described above, technical scheme of the present invention is:
Rhizoma nardostachyos Virginia snakeroot alkane type sesquiterpene compound
there is following structural formula (I) formula:
Wherein,
A: aristolene-9 β-ol (A:1 (10)-aristolene-9 β-ol [1 (10)-aristolen-9 beta-ol]);
B jatamansone (B:1 (10), 8 (9)-diene-2-aristolones [1 (10), 8 (9)-dien-2-aristolone]);
C nardosinone H (C:1 (2), 9 (10)-diene-8-aristolones [1 (2), 9 (10)-dien-8-arstolone]);
D3-oxo nardosinone H
(D: aristolane-1 (2), 9 (10)-diene-3,8-diketone [aristol-1 (2), 9 (10)-dien-3,8-dione]);
E3-hydroxyl nardosinone
(E: aristolane-1-(2), 9 (10)-diene-3 β-ol [aristol-1 (2), 9 (10)-dien-3 beta-ols]).
Preferably, above-mentioned rhizoma nardostachyos Virginia snakeroot alkane type sesquiterpene compound, physical chemistry and the Spectroscopic Properties of each described aristolane type sesquiterpene and derivative thereof are:
Aristolene-9 β-ol [(1,10)-aristolen-9 beta-ol, A], pale yellow powder (ethyl acetate).UV(MeOH)λ
max:200nm；CD(c0.05,MeOH)λ(Δε):215(-0.21)、232(+0.30)、332(-0.56)、352(-0.29)、378(-0.71)nm；
1H-NMR(CDCl
3,400MHz):δ
H5.51(1H,m,H-1)、1.94(2H,m,H-2)、1.38(2H,m,H-3)、1.70(1H,m,H-4)、0.56(1H,d,J＝9.2Hz,H-6)、0.77(1H,m,H-7)、1.28(1H,m,H-8α)、2.31(1H,m,H-8β)、4.27(1H,m,H-9)、1.25(3H,s,12-CH
3)、1.25(3H,s,13-CH
3)、1.09(3H,s,14-CH
3)、0.98(3H,d,J＝6.8Hz,15-CH
3)、2.59(1H,brs,-OH)；
13C-NMR(CDCl
3,100MHz):δ
C116.3(C-1)、25.3(C-2)、26.6(C-3)、36.8(C-4)、38.6(C-5)、32.7(C-6)、18.2(C-7)、30.6(C-8)、67.4(C-9)、145.6(C-10)、18.6(C-11)、23.8(C-12)、16.5(C-13)、29.6(C-14)、15.9(C-15)；
Jatamansone (nardostachone, B), pale yellow oil (ethyl acetate).UV(MeOH)λ
max:198、228、329nm；CD(c0.05,MeOH)λ(Δε):206(-6.06)、237(+3.35)、294(-0.55)、355(+7.70)nm；
1H-NMR(CDCl
3,400MHz):δ
H5.67(1H,s,H-1)、2.31～2.37(3H,overlapped,H-3,H-4)、0.86(1H,d,J＝7.6Hz,H-6)、1.49(1H,dd,J＝5.6,7.6Hz,H-7)、6.36(1H,dd,J＝5.6,9.6Hz,H-8)、6.09(1H,d,J＝9.6Hz,H-9)、0.86(3H,s,12-CH
3)、1.20(3H,s,13-CH
3)、1.08(3H,s,14-CH
3),1.11(3H,d,J＝6.8Hz,15-CH
3)；
13C-NMR(CDCl
3,100MHz):δ
C122.7(C-1)、199.8(C-2)、43.3(C-3)、34.0(C-4)、38.1(C-5)、36.3(C-6)、28.0(C-7)、199.8(C-8)、125.2(C-9),163.1(C-10)、26.2(C-11)、14.8(C-12)、29.0(C-13)、15.3(C-14)、22.2(C-15)；
Nardosinone H (kanshoneH, C), colorless needle crystals (methylene dichloride).UV(MeOH)λ
max:287、195nm；CD(c0.05,MeOH)λ(Δε):332(-7.91)、247(+4.97)、222(+2.32)、213(+2.46)、202(+1.22)nm；
1H-NMR(CDCl
3,400MHz):δ
H6.07(1H,dd,2.0,10.0,H-1)、6.12(1H,ddd,1.6,5.2,9.6,H-2)、2.03(1H,m,H-3α)、2.20(1H,m,H-3β),1.98(1H,m,H-4)、1.35(1H,d,J＝8.0Hz,H-6)、1.75(1H,dd,J＝1.2,8.0Hz,H-7)、5.67(1H,s,H-9)、1.20(3H,s,12-CH
3)、1.17(3H,s,13-CH
3)、1.11(3H,s,14-CH
3)、1.08(3H,d,J＝6.8Hz,15-CH
3)；
13C-NMR(CDCl
3,100MHz):δ
C128.1(C-1)、137.2(C-2)、32.6(C-3)、34.6(C-4)、37.1(C-5)、37.3(C-6)、36.1(C-7)、196.8(C-8)、123.2(C-9)、160.1(C-10)、25.6(C-11)、29.5(C-12)、15.8(C-13)、22.2(C-14)、15.3(C-15)。
3-oxo nardosinone H (3-oxokanshoneD), pale yellow powder (methylene dichloride); UV (MeOH) λ
max: 198,290nm;
cD (c0.05, MeOH) λ (Δ ε): 197 (-1.11), 221 (9.40) nm; (-)-ESI-MSm/z229.97 [M-H]
-, (+)-ESI-MS:m/z231.33 [M+H]
+; Hydrogen spectrum, carbon spectrum nuclear magnetic data are shown in embodiment part table 1;
3-hydroxyl nardosinone H (3-hydroxylkanshoneH, E), colorless oil (ethyl acetate).UV (MeOH) λ
max: 283.0nm;
cD (c0.05, MeOH) λ (Δ ε): 213.5 (+1.32), 275.5 (+0.08), 296.0 (+0.66), 336.5 (-3.55) nm; (-)-ESI-MS:m/z231.30 [M-H]
-, (+)-ESI-MS:m/z255.28 [M+Na]
+; Hydrogen spectrum, carbon spectrum nuclear magnetic data are shown in embodiment part table 1.
Preferably, above-mentioned rhizoma nardostachyos Virginia snakeroot alkane type sesquiterpene compound, each described aristolane type sesquiterpene and derivative thereof, its chemical structure feature is: (1) 1,10-position forms double bond, 9-position hydroxyl replaces, and wherein 9-position hydroxyl can be substituted base acidylate, phenolic ether, acid amides change into ester, phenolic ether or nitrogenous compound; (2) 1,10-position and 8,9-position form double bond, 3 ketone carbonyl substituted; (3) on aristolane type sesquiterpene parent nucleus 1,2-position and 9,10-position form double bond; 8-position ketone carbonyl substituted; 3 methylene radical, hydroxyl or ketone carbonyl substituted, wherein 3-position hydroxyl can be substituted base acidylate, phenolic ether, acid amides change into ester, phenolic ether or nitrogenous compound.
The preparation method of above-mentioned rhizoma nardostachyos Virginia snakeroot alkane type sesquiterpene compound, concrete steps are as follows:
(1) the every 20kg of rhizoma nardostachyos (NardostachyschinensisBatal.) rhizome 70% (v/v) alcohol steep 3 times, each 48 hours, united extraction liquid, concentrating under reduced pressure, obtains crude extract medicinal extract; Then put on by 70% ethanol heat and state the dregs of a decoction 3 times, each 2 hours, united extraction liquid, concentrating under reduced pressure, again obtain crude extract medicinal extract; Merge twice crude extract and obtain total medicinal extract;
(2) the total medicinal extract of gained crude extract is after water-dispersion, extracts successively respectively, obtain petroleum ether part, ethyl acetate extract, n-butanol portion and water layer with isopyknic sherwood oil, ethyl acetate and propyl carbinol;
(3) by petroleum ether part, through silica gel column chromatography, (100-200 order mixes sample silica gel 400g, 200-300 order post silica gel 3.3kg,), sherwood oil: ethyl acetate=100:0 (100:0 refers to 100% sherwood oil elution profile) ~ 100:50 solvent systems gradient elution, obtains 22 stream part Fr.1 ~ 22;
(4) sherwood oil: ethyl acetate=100:2 solvent elution stream part---stream part Fr.6, through silica gel column chromatography repeatedly, is separated and obtains compound aristolene-9 β-ol, is one of the main component of rhizoma nardostachyos;
Sherwood oil: ethyl acetate=100:2-100:3 solvent elution stream part---stream part Fr.7, through silica gel column chromatography repeatedly, is separated and obtains compound 3-oxo nardosinone H; Stream part Fr.7 silicagel column obtained component is through sherwood oil: methylene dichloride: ethyl acetate=7:2:1 thin layer is prepared into nardosinone H and 3-hydroxyl nardosinone H;
Sherwood oil: ethyl acetate=100:5-100:7 solvent elution stream part---stream part Fr.9, through silica gel column chromatography repeatedly, sherwood oil: ethyl acetate=100:0 (100:0 refers to 100% sherwood oil elution profile) ~ 100:10 gradient elution, is separated and obtains jatamansone.
Above-mentioned rhizoma nardostachyos Virginia snakeroot alkane type sesquiterpene compound promotes the application in serotonin transporter (SERT) active medicine in preparation.
Preferably, the application of above-mentioned rhizoma nardostachyos Virginia snakeroot alkane type sesquiterpene compound in the medicine preparing the diseases such as depression, anxiety disorder, schizophrenia, obsession, nerve degenerative diseases, drug addiction or digestive system function disorder.
There is the pharmaceutical composition of above-mentioned rhizoma nardostachyos Virginia snakeroot alkane type sesquiterpene compound, comprise the above-claimed cpd and the acceptable vehicle of optional pharmacy that treat and/or prevent significant quantity.
The acceptable vehicle of above-mentioned pharmacy can be the vehicle of any routine in field of pharmaceutical preparations, the selection of particular excipient will depend on the administering mode or disease type and state that are used for the treatment of particular patient, for the preparation method of the said synthetic processes of specific administration pattern completely in the ken of pharmaceutical field technician.Such as, the thinner of pharmaceutical field routine, carrier, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier and lubricant etc. can be comprised as the acceptable vehicle of pharmacy, if desired, flavouring agent, preservative and sweetener etc. can also be added in pharmaceutical composition.
Aforementioned pharmaceutical compositions can make the various ways such as tablet, pulvis, granule, capsule, oral liquid, paste, creme, injectable emulsion, aseptic powder needle for injection.The medicine of above-mentioned various formulation all can be prepared according to the ordinary method of pharmaceutical field.
The invention has the beneficial effects as follows:
Rhizoma nardostachyos Virginia snakeroot alkane type sesquiterpene compound of the present invention, separation and purification from the rhizome of Valerianaceae rhizoma nardostachyos platymiscium rhizoma nardostachyos (NardostachyschinensisBatal.) and obtaining, have and promote that serotonin transporter (SERT) is active, can be used as the medicine of the digestive system function disorders such as the nervous system disorderss such as Cure of depression, anxiety disorder, schizophrenia, obsession, nerve degenerative diseases, drug addiction and slow Constipation, irritable bowel syndrome and functional distension, there is important drug development and be worth.
Accompanying drawing explanation
Fig. 1 be rhizoma nardostachyos aristolane type sesquiterpene and derivative thereof to the enhancement of SERT activity, wherein, positive control drug is respectively 2.0 μMs of Fluoxetine and 1.0 μMs of Tianeptine, * * p<0.01, * * * P<0.001;
Fig. 2 is the NMR spectrogram of new compound 3-hydroxyl nardosinone H;
Fig. 3 is new compound 3-oxo nardosinone H
13c-NMR spectrogram.
Embodiment
In order to make those skilled in the art better understand technical scheme of the present invention, below in conjunction with embodiment, technical scheme of the present invention is described in further detail.
Laboratory apparatus and reagent: Fourier transform nuclear magnetic resonance spectrometer (Bruker company of Switzerland, AVIII type 400MHz and 600MHz); Developer: 10% sulfuric acid ethanol.
Embodiment 1
The preparation (extraction and isolation flow process) of activeconstituents rhizoma nardostachyos aristolane type sesquiterpene and derivative thereof:
Rhizoma nardostachyos pharmaceutical decocting piece is purchased from Anhui Jiren Pharmacy Co., Ltd. (lot number: 110709, specification: 1kg/ bag, the place of production: Sichuan), about 20kg, rhizoma nardostachyos rhizome 20kg 70% alcohol steep 3 times, each 48 hours, united extraction liquid, concentrating under reduced pressure, obtains crude extract medicinal extract 3kg; Then put on by 70% ethanol heat and state the dregs of a decoction 3 times, each 2 hours, united extraction liquid, concentrating under reduced pressure, obtain crude extract medicinal extract 400g; Merge twice crude extract and obtain total medicinal extract 3.4kg; The total medicinal extract of gained crude extract, after water-dispersion, extracts with isopyknic sherwood oil, ethyl acetate, propyl carbinol successively, obtains 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 (mixing sample silica gel 100-200 order 400g, post silica gel 200-300 order 3.3kg, sherwood oil: ethyl acetate=100:0 ~ 100:50 solvent systems gradient elution), obtain 22 stream part Fr.1 ~ 22; Stream part Fr.6 (sherwood oil: ethyl acetate=100:2 solvent elution stream part), through silica gel column chromatography repeatedly, is separated and obtains compound aristolene-9 β-ol (about 50mg), is one of the main component of rhizoma nardostachyos; Stream part Fr.7 (sherwood oil: ethyl acetate=100:2-100:3 solvent elution stream part), through silica gel column chromatography repeatedly, is separated and obtains compound 3-oxo nardosinone H; Stream part Fr.7 silicagel column obtained component is through sherwood oil: methylene dichloride: ethyl acetate=7:2:1 thin layer is prepared into nardosinone H and 3-hydroxyl nardosinone H; Stream part Fr.9 (sherwood oil: ethyl acetate=100:5-100:7 solvent elution stream part), through silica gel column chromatography (sherwood oil: ethyl acetate=100:0 ~ 100:10 gradient elution) repeatedly, is separated and obtains jatamansone.
Aristolene-9 β-ol [(1,10)-aristolen-9 beta-ol, A], pale yellow powder (ethyl acetate).UV(MeOH)λ
max:200nm；CD(c0.05,MeOH)λ(Δε):215(-0.21)、232(+0.30)、332(-0.56)、352(-0.29)、378(-0.71)nm；
1H-NMR(CDCl
3,400MHz):δ
H5.51(1H,m,H-1)、1.94(2H,m,H-2)、1.38(2H,m,H-3)、1.70(1H,m,H-4)、0.56(1H,d,J＝9.2Hz,H-6)、0.77(1H,m,H-7)、1.28(1H,m,H-8α)、2.31(1H,m,H-8β)、4.27(1H,m,H-9)、1.25(3H,s,12-CH
3)、1.25(3H,s,13-CH
3)、1.09(3H,s,14-CH
3)、0.98(3H,d,J＝6.8Hz,15-CH
3)、2.59(1H,brs,-OH)；
13C-NMR(CDCl
3,100MHz):δ
C116.3(C-1)、25.3(C-2)、26.6(C-3)、36.8(C-4)、38.6(C-5)、32.7(C-6)、18.2(C-7)、30.6(C-8)、67.4(C-9)、145.6(C-10)、18.6(C-11)、23.8(C-12)、16.5(C-13)、29.6(C-14)、15.9(C-15)。
Jatamansone (nardostachone, B), pale yellow oil (ethyl acetate).UV(MeOH)λ
max:198、228、329nm；CD(c0.05,MeOH)λ(Δε):206(-6.06)、237(+3.35)、294(-0.55)、355(+7.70)nm；
1H-NMR(CDCl
3,400MHz):δ
H5.67(1H,s,H-1)、2.31～2.37(3H,overlapped,H-3,H-4)、0.86(1H,d,J＝7.6Hz,H-6)、1.49(1H,dd,J＝5.6,7.6Hz,H-7)、6.36(1H,dd,J＝5.6,9.6Hz,H-8)、6.09(1H,d,J＝9.6Hz,H-9)、0.86(3H,s,12-CH
3)、1.20(3H,s,13-CH
3)、1.08(3H,s,14-CH
3),1.11(3H,d,J＝6.8Hz,15-CH
3)；
13C-NMR(CDCl
3,100MHz):δ
C122.7(C-1)、199.8(C-2)、43.3(C-3)、34.0(C-4)、38.1(C-5)、36.3(C-6)、28.0(C-7)、199.8(C-8)、125.2(C-9),163.1(C-10)、26.2(C-11)、14.8(C-12)、29.0(C-13)、15.3(C-14)、22.2(C-15)。
Nardosinone H (kanshoneH, C), colorless needle crystals (methylene dichloride).UV(MeOH)λ
max:287、195nm；CD(c0.05,MeOH)λ(Δε):332(-7.91)、247(+4.97)、222(+2.32)、213(+2.46)、202(+1.22)nm；
1H-NMR(CDCl
3,400MHz):δ
H6.07(1H,dd,2.0,10.0,H-1)、6.12(1H,ddd,1.6,5.2,9.6,H-2)、2.03(1H,m,H-3α)、2.20(1H,m,H-3β),1.98(1H,m,H-4)、1.35(1H,d,J＝8.0Hz,H-6)、1.75(1H,dd,J＝1.2,8.0Hz,H-7)、5.67(1H,s,H-9)、1.20(3H,s,12-CH
3)、1.17(3H,s,13-CH
3)、1.11(3H,s,14-CH
3)、1.08(3H,d,J＝6.8Hz,15-CH
3)；
13C-NMR(CDCl
3,100MHz):δ
C128.1(C-1)、137.2(C-2)、32.6(C-3)、34.6(C-4)、37.1(C-5)、37.3(C-6)、36.1(C-7)、196.8(C-8)、123.2(C-9)、160.1(C-10)、25.6(C-11)、29.5(C-12)、15.8(C-13)、22.2(C-14)、15.3(C-15)。
3-oxo nardosinone H (3-oxokanshoneH, D), pale yellow powder (methylene dichloride).UV (MeOH) λ
max: 198,290nm;
cD (c0.05, MeOH) λ (Δ ε): 197 (-1.11), 221 (9.40) nm; (-)-ESI-MSm/z229.97 [M-H]
-, (+)-ESI-MS:m/z231.33 [M+H]
+; Hydrogen spectrum, carbon spectrum nuclear magnetic data are shown in embodiment part table 1.
1h-NMR (CDCl
3, 400MHz) spectrum in, δ
h1.28 (3H, s), 1.26 (3H, s), 1.24 (3H, s) and δ
hthe peak at 1.30 (3H, d, J=6.4Hz) place is 4 methyl signals; δ
h6.98 (1H, d, J=10.0Hz), 6.18 (1H, d, J=10.0Hz), 6.08 (1H, s) are 3 alkene Hydrogen Proton signals.
13c-NMR spectrum provides 15 carbon atom signals altogether, comprises 2 groups of double key carbon signal (δ
c142.4,131.6,129.1 and 156.3), 2 carbonyl carbon signals δ
c(199.6,195.8).Compare with compound nardosinone H, this compound difference is at δ
cthe carbon signal at 199.6 (C-3) place is 1 carbonyl carbon signals.Comprehensively
1h-NMR,
13the information such as C-NMR, HSQC, HMBC spectrum infer the two dimensional structure (Fig. 3) this compound.
The relative configuration of 3-oxo nardosinone H is determined by NOESY spectrum, finally determines the said structure of this compound.
3-hydroxyl nardosinone H (3-hydroxylkanshoneH, E), colorless oil (ethyl acetate).UV (MeOH) λ
max: 283.0nm;
cD (c0.05, MeOH) λ (Δ ε): 213.5 (+1.32), 275.5 (+0.08), 296.0 (+0.66), 336.5 (-3.55) nm; (-)-ESI-MS:m/z231.30 [M-H]
-, (+)-ESI-MS:m/z255.28 [M+Na]
+; Hydrogen spectrum, carbon spectrum nuclear magnetic data are shown in embodiment part table 1.
13c-NMR (CDCl
3, 400MHz) spectrum provide 15 carbon signals altogether, δ
c, in prompting structure, there are 2 groups of double bonds in 128.4, the carbon signal at 139.2,124.5,158.6 places.Compose with the NMR of compound nardosinone H and compare, this compound difference is at δ
cthe carbon signal at 71.4 (C-3) place is 1 even oxygen carbon signal.Comprehensively
1h-NMR,
13the information such as C-NMR, HSQC, HMBC spectrum infer the two dimensional structure (Fig. 2) compound.
In NOESY spectrum, δ
h4.04 (d, J=9.6Hz, H-3) and δ
h1.17 (s, Me-13), 1.27 (d, J=6.8Hz, Me-15) spatial correlation, prompting C
3-O key, C
4-C
15key, C
5-C
14key is in reverse direction; δ
h1.45 (d, J=8.0Hz, H-6) and δ
h1.29 (d, J=6.8Hz, Me-15) spatial correlation, prompting C
6-C
11key, C
4-C
15key is in reverse direction, finally determines the said structure of this compound.
Nuclear magnetic data (the CDCl of table 1.3-oxo nardosinone H and 3-hydroxyl nardosinone H
3,
1h-NMRin400MHz,
13c-NMRin100MHz)
Embodiment 2
Compound of the present invention is on the impact of serotonin transporter (SERT)
Adopt the hSERT-HEK293 cell strain of stable transfection, with 4-(4-(dimethylamino) phenyl)-1-methylpyridinium (APP
+) be fluorogenic substrate, in high intension system, detection compound rhizoma nardostachyos aristolane type sesquiterpene and derivative thereof are on the impact of SERT activity.
1) laboratory apparatus and reagent
Laboratory apparatus:
High intension Operetta system and Columbus data management and analytical system (PerkinElmer), super clean bench, liquid-transfering gun (1000 μ L, 200 μ L, 20 μ L, 10 μ L, 2.5 μ L, Eppendorf company of the U.S.)
Reagent and material:
Human embryonic kidney cell line HEK293 (the American Type Culture Collection council of Chinese Academy of Sciences cell bank), hSERTpcDNA3 plasmid (Addgene, plasmid15483), MEM substratum (Gibco), APP
+(Sigma), Hoechst33342 (CellSignalingTechnology), 96 orifice plates (Costar3605)
2) experimental implementation process
First set up and identify stably express hSERT-HEK293 cell strain peace is of heap of stone, Li Jing, golden blast etc. the foundation of people source serotonin transporter stable expression cell line and function investigation [J] thereof. military medicine 2011,35 (9): 681-684}.With APP
+for fluorogenic substrate, based on the function { FowlerA of high intension systems axiol-ogy SERT, SeifertN, AckerV.etal.Anonradioactivehigh-throughput/high-contenta ssayformeasurementofthehumanserotoninreuptaketransporter functioninvitro [J] .JournalofBiomolecularScreening, 2006,11 (8): 1027-1034}
Concrete steps:
(1) precision takes embodiment 1 gained rhizoma nardostachyos aristolane type sesquiterpene and derivative thereof, is mixed with the mother liquor of 20mM with DMSO, dilutes medicine to 10.0 μM, 1.0 μMs, 0.1 μM with without phenol red MEM basis training base.
(2) by 1.0 × 10
4in hSERT-HEK293 cell to 96 orifice plate of the density inoculation stable transfection of cells/well, at 37 DEG C, 5%CO
224h is cultivated under condition.
(3) experiment sets up blank group, positive control 2.0 μMs of Fluoxetine groups and 1.0 μMs of Tianeptine groups, and testing drug sets up 10.0 μMs respectively, 1.0 μMs, 0.1 μM of group.Cell discards substratum, washes 2 times with PBS damping fluid, adds each testing sample according to 80 μ L/ pore volumes, the multiple hole of each concentration 3, at 37 DEG C, and 5%CO
2under condition, lucifuge hatches 2-3h.
(4), after having hatched, every hole adds 20 μ LAPP
+, hatch 20 minutes.
(5) discard the liquid in hole, wash 2 times with PBS damping fluid, every hole adds 1.0 μ g/mLHoechst50 μ L, and lucifuge hatches 20min.
(6) discard the liquid in orifice plate, PBS washes 2-3 time, adopts the intracellular fluorescence intensity of high intension systems axiol-ogy
Hoechst33342Excitation：360-400nm，Emission：410-480nm
APP
+Excitation：460-490nm，Emission：505-550nm
3) data analysis:
Adopt Columbus data management and analytical system to carry out image analysis, determine cell, according to APP in born of the same parents according to Hoechst33342 fluorescence identifying nuclear pattern
+fluorescence intensity determines SERT transport activity, calculates relative intensity of fluorescence=(APP in the born of the same parents of medicine group
+aPP in the born of the same parents of fluorescence intensity/control group
+fluorescence intensity) carry out ANOVA analysis.
4) experimental result
As shown in Figure 1, aristolene-9 β-ol significance ground strengthens (F (5, 62)=304.7, p<0.0001) SERT is active, Dunnett multiple comparisons post-hoc tests (Dunnett'smultiplecomparisonposthoctest) confirms that aristolene-9 β-ol is 10.0 μMs of (q=6.942 in concentration, p<0.001), 1.0 μMs of (q=8.720, p<0.001) and 0.1 μM of (q=7.519, p<0.001) SERT activity can significantly be strengthened time compared with blank group, positive drug control group fluoxetine significantly can suppress the activity (q=23.95 of SERT 2.0 μMs time, p<0.001), positive drug control group tianeptine significantly can strengthen SERT activity (q=3.641 1.0 μMs time, p<0.01).
Jatamansone strengthens (F (5,36)=289.8, p<0.0001) SERT activity with having significance.It is 10.0 μMs of (q=5.317 in concentration that Dunnett'smultiplecomparisonposthoctest shows jatamansone, p<0.001) SERT activity is strengthened significantly time, but be 1.0 μMs of (q=0.7635 in concentration, n.s.) and 0.1 μM of (q=0.1819, n.s.) SERT activity is not had a significant impact, positive drug control group fluoxetine significantly can suppress the activity (q=27.07 of SERT 2.0 μMs time, p<0.001), an other positive drug control group tianeptine significantly can strengthen SERT activity (q=4.193 1.0 μMs time, p<0.01)
Nardosinone H has the enhancing (F (5 of significance to SERT activity, 51)=436.7, p<0.0001), it is 10.0 μMs of (q=4.991 in concentration that Dunnett'smultiplecomparisonposthoctest shows nardosinone H, p<0.001) and 1.0 μMs of (q=3.777, p<0.01) SERT activity can significantly be strengthened time compared with blank group, and be 0.1 μM of (q=2.113 in concentration, n.s.) SERT activity is not had a significant impact, positive drug control group fluoxetine significantly can suppress the activity (q=33.32 of SERT 2.0 μMs time, p<0.001), an other positive drug control group tianeptine significantly can strengthen SERT activity (q=4.680 1.0 μMs time, p<0.001).
3-oxo nardosinone H has the enhancing (F (5 of significance to SERT activity, 46)=685.5, p<0.0001), it is 10.0 μMs of (q=5.815 in concentration that Dunnett'smultiplecomparisonposthoctest shows compound G-9, p<0.001) and 1.0 μMs of (q=3.428, p<0.01) SERT activity can significantly be strengthened time compared with blank group, be 1.0 μMs of (q=2.105 in concentration, n.s.) time, SERT activity is not had a significant impact, positive drug control group fluoxetine significantly can suppress the activity (q=42.89 of SERT 2.0 μMs time, p<0.0001), an other positive drug control group tianeptine significantly can strengthen SERT activity (q=7.473 1.0 μMs time, p<0.001).
3-hydroxyl nardosinone H has the enhancing (F (5 of significance to SERT activity, 37)=410.1, p<0.0001) .Dunnett'smultiplecomparisonposthoctest shows compound 3-hydroxyl nardosinone H is 10.0 μMs of (q=3.488 in concentration, p<0.01) and 1.0 μMs of (q=2.727, p<0.05) SERT activity can significantly be strengthened time compared with blank group, be 0.1 μM of (q=06674 in concentration, n.s.) time, SERT activity is not had a significant impact, positive drug control group fluoxetine significantly can suppress the activity (q=31.96 of SERT 2.0 μMs time, p<0.001), an other positive drug control group tianeptine significantly can strengthen SERT activity (q=5.595 1.0 μMs time, p<0.001).
In summary, described serotonin transporter (SERT) is a kind of Na 5-HT being had to high affinity
+/ Cl
-dependent form turns transmembrane transporter, 5-HT serotonergic neuron is mainly positioned in central nervous system, presynaptic neuron is entered by reuptaking 5-HT from nerve synapse gap, directly affect synaptic cleft 5-HT concentration, change amount and the acting duration of postsynaptic receptor mediation signal, thus participate in multiple Physiological Psychology function (as mood, appetite, sleep, memory, study etc.); Mainly intestinal epithelial cell is positioned at Digestive tract SERT, reuptake the 5-HT of intestinal mucosa layer pheochromocyte release to regulate gastrointestinal function, in addition, all have distribution at organs such as placenta tissue, reproductive tract, marrow, kidney, lung, the heart, suprarenal gland, liver, parathyroid gland, Tiroidina and pancreas, prompting SERT participates in different physiological roles.
SERT is the important target spot of clinical medicine research and development, and the serotonin reuptake transporter promotor (SSRE) reported so far has tianeptine (tianeptine), is clinically mainly used in antidepressant and anxiety.The action character of tianeptine to human body comprises: have certain effect to mental state disorder, between sedating antidepressants and excitability thymoleptic; To Somatic discomfort, especially there is obvious effect for the disorderly relevant gastrointestinal upset of anxiety and mental state; The personality occur during abstinence from alcohol alcoholism patient and conduct disorder have certain effect; And, tianeptine to following aspect without undesirable action: sleep and vigilance; Cardiovascular systems; Cholinergic system (nonreactive cholinergic symptoms); Drug habit.Tianeptine belongs to a kind of SSRE, and its action character has pointed out serotonin reuptake transporter promotor (SSRE) characteristics and advantages in clinical application.
The present invention is by carrying out externally affecting the active research of serotonin transporter (SERT) on being separated the rhizoma nardostachyos aristolane type sesquiterpene that obtains and derivative thereof from rhizoma nardostachyos rhizome, find that these compounds all can significantly strengthen SERT transport activity, thus confirmation rhizoma nardostachyos aristolane type sesquiterpene and derivative thereof are regulate the unbalance relevant physiological mental illness that causes of SERT and digestive system function disorders effective constituent.Therefore, rhizoma nardostachyos aristolane type sesquiterpene and derivative thereof can be used for preparing the medicine of the functional gastrointestinal disorder diseases such as the neuropsychiatric disease such as Cure of depression and anxiety disorder and irritable bowel syndrome.
In the structure of above-mentioned rhizoma nardostachyos aristolane type sesquiterpene and derivative thereof: (1) 1,10-position forms double bond, 9-position hydroxyl replaces, and wherein 9-position hydroxyl can be substituted base acidylate, phenolic ether, acid amides change into ester, phenolic ether or nitrogenous compound; (2) 1,10-position and 8,9-position form double bond, 3 ketone carbonyl substituted; (3) on aristolane type sesquiterpene parent nucleus 1,2-position and 9,10-position form double bond; 8-position ketone carbonyl substituted; 3 methylene radical, hydroxyl or ketone carbonyl substituted, wherein 3-position hydroxyl can be substituted base acidylate, phenolic ether, acid amides change into ester, phenolic ether or nitrogenous compound.
Embodiment 3
Preparation method: according to the above ratio by aristolene-9 β-ol/jatamansone/nardosinone H/3-hydroxyl nardosinone H/3-oxo nardosinone H, newborn sugar and starch Homogeneous phase mixing, cross 200 mesh sieves, use water uniform wet, dry after sieve for the mixture after wetting, add Magnesium Stearate, then by mixture compressing tablet, the heavy 250mg of every sheet, active component content is 10mg.
Embodiment 4
Capsule: aristolene-9 β-ol/jatamansone/nardosinone H/3-hydroxyl nardosinone H/3-oxo nardosinone H20mg
Semi-lactosi 188mg
Magnesium Stearate 2mg
Preparation method: according to the above ratio by aristolene-9 β-ol/jatamansone/nardosinone H/3-hydroxyl nardosinone H/3-oxo nardosinone H and semi-lactosi Homogeneous phase mixing, crosses 200 mesh sieves, the mixture obtained, adds Magnesium Stearate, load No. 2 capsules, to obtain final product.
Above-mentioned detailed description of this rhizoma nardostachyos Virginia snakeroot alkane type sesquiterpene compound and preparation method thereof being carried out with application with reference to embodiment; illustrative instead of determinate; several embodiments can be listed according to institute's limited range; therefore in the change do not departed under general plotting of the present invention and amendment, should belong within protection scope of the present invention.
Claims (5)
1. rhizoma nardostachyos Virginia snakeroot alkane type sesquiterpene compound, has following structural formula (I) formula:
Wherein, A: aristolene-9 β-ol; B jatamansone; C nardosinone H; D3-oxo nardosinone H; E3-hydroxyl nardosinone.
2. the preparation method of rhizoma nardostachyos Virginia snakeroot alkane type sesquiterpene compound described in claim 1, is characterized in that: concrete steps are as follows:
(1) the every 20kg of rhizoma nardostachyos rhizome 70% (v/v) alcohol steep 3 times, each 48 hours, united extraction liquid, concentrating under reduced pressure, obtains crude extract medicinal extract; Then put on by 70% ethanol heat and state the dregs of a decoction 3 times, each 2 hours, united extraction liquid, concentrating under reduced pressure, again obtain crude extract medicinal extract; Merge twice crude extract and obtain total medicinal extract;
(2) the total medicinal extract of gained crude extract is after water-dispersion, extracts successively respectively, obtain petroleum ether part, ethyl acetate extract, n-butanol portion and water layer with isopyknic sherwood oil, ethyl acetate and propyl carbinol;
(3) by petroleum ether part through silica gel column chromatography, sherwood oil: ethyl acetate=100:0 ~ 100:50 solvent systems gradient elution, obtain 22 stream part Fr.1 ~ 22;
(4) sherwood oil: ethyl acetate=100:2 solvent elution stream part---stream part Fr.6, through silica gel column chromatography repeatedly, is separated and obtains compound aristolene-9 β-ol, is one of the main component of rhizoma nardostachyos;
Sherwood oil: ethyl acetate=100:2-100:3 solvent elution stream part---stream part Fr.7, through silica gel column chromatography repeatedly, is separated and obtains compound 3-oxo nardosinone H; Stream part Fr.7 silicagel column obtained component is through sherwood oil: methylene dichloride: ethyl acetate=7:2:1 thin layer is prepared into nardosinone H and 3-hydroxyl nardosinone H;
Sherwood oil: ethyl acetate=100:5-100:7 solvent elution stream part---stream part Fr.9, through silica gel column chromatography repeatedly, sherwood oil: ethyl acetate=100:0 ~ 100:10 gradient elution, is separated and obtains jatamansone.
3. the application of rhizoma nardostachyos Virginia snakeroot alkane type sesquiterpene compound described in claim 1 in preparation promotion serotonin transporter (SERT) active medicine.
4. the application of rhizoma nardostachyos Virginia snakeroot alkane type sesquiterpene compound in the medicine preparing depression, anxiety disorder, schizophrenia, obsession, nerve degenerative diseases, drug addiction or digestive system function disorders described in claim 1.
5. there is the pharmaceutical composition of rhizoma nardostachyos Virginia snakeroot alkane type sesquiterpene compound described in claim 1, comprise the described compound and the acceptable vehicle of optional pharmacy that treat and/or prevent significant quantity.
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| CN113666897A (en) * | 2021-08-30 | 2021-11-19 | 中国科学院兰州化学物理研究所 | Nardostachys chinensis terpenoid, separation method thereof and application of nardostachys chinensis terpenoid in preparation of anti-pancreatic cancer drugs |
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| CN113666897A (en) * | 2021-08-30 | 2021-11-19 | 中国科学院兰州化学物理研究所 | Nardostachys chinensis terpenoid, separation method thereof and application of nardostachys chinensis terpenoid in preparation of anti-pancreatic cancer drugs |
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