CN105152894B - Rhizoma nardostachyos birthwort alkane type sesquiterpene compound and preparation method and application - Google Patents
Rhizoma nardostachyos birthwort alkane type sesquiterpene compound and preparation method and application Download PDFInfo
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- CN105152894B CN105152894B CN201510629121.7A CN201510629121A CN105152894B CN 105152894 B CN105152894 B CN 105152894B CN 201510629121 A CN201510629121 A CN 201510629121A CN 105152894 B CN105152894 B CN 105152894B
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- 230000002441 reversible effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000000697 serotonin reuptake Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000006886 spatial memory Effects 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/613—Unsaturated compounds containing a keto groups being part of a ring polycyclic
- C07C49/617—Unsaturated compounds containing a keto groups being part of a ring polycyclic a keto group being part of a condensed ring system
- C07C49/643—Unsaturated compounds containing a keto groups being part of a ring polycyclic a keto group being part of a condensed ring system having three rings
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
- C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C35/22—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system
- C07C35/37—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with a hydroxy group on a condensed system having three rings
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/79—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/723—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic
- C07C49/727—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic a keto group being part of a condensed ring system
- C07C49/737—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic a keto group being part of a condensed ring system having three rings
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Abstract
The invention provides rhizoma nardostachyos birthwort alkane type sesquiterpene compound and preparation method and application, the rhizoma nardostachyos birthwort alkane type sesquiterpene compound is isolated and purified from the rhizome of Valerianaceae rhizoma nardostachyos platymiscium rhizoma nardostachyos and is obtained, strengthen activity with 5 hydroxytryptamine transporters (SERT), belong to rare SERT accelerative activators, can prepare for treating depression, anxiety disorder, schizophrenia, obsession, nerve degenerative diseases, the neuropsychiatric diseases such as drug addiction and slow Constipation, irritable bowel syndrome, with applied in terms of the medicine of the digestive system function disorders such as functional distension, it is worth with important drug development.
Description
Technical Field
The invention relates to the field of traditional Chinese medicine research and development, in particular to a nardostachys aristolochiane type sesquiterpene compound and a preparation method and application thereof.
Background
The 5-hydroxytryptamine transporter (SERT) is a transmembrane transporter with high affinity for 5-HT, contains about 630 amino acid residues, and its coding gene (SLC6A4) is located on chromosome 7 and 11, respectively, and consists of 14 exons spanning about 35 kb. The SERT protein comprises 12-13 transmembrane regions, wherein the N end and the C end are positioned in cytoplasm, a cAMP-dependent protein kinase binding site is arranged near the N end, and a ring part positioned outside cells is arranged between the third transmembrane region and the fourth transmembrane region and is an N-connected glycosylation site.
SERT belongs to Na+/Cl-The dependent transporter is mainly located in 5-HT energy neurons in the central nervous system, and SERT reuptakes 5-HT from the synaptic cleft into presynaptic neurons, directly influences the 5-HT concentration of the synaptic cleft and changes the amount and action duration of postsynaptic receptor mediated signals. SERT is mainly located in intestinal mucosa epithelial cells in the digestive system, and 5-HT released by chromaffin cells in intestinal mucosa is reuptake to regulate gastrointestinal function. In addition, SERT is distributed in platelets, placental tissue, bone marrow, kidney, lung, heart, adrenal gland, liver, parathyroid gland, thyroid gland, pancreas, etc., suggesting SERT participates in a variety of physiological functions.
SERT is an important molecule for transporting 5-HT, and is related to a plurality of physiological and psychological functions such as emotion, appetite, sleep, memory, learning and the like in the central nervous system, and the SERT and 5-HT expression change can cause anxiety, depression, obsessive compulsive disorder, phobia and even schizophrenia and is closely related to drug addiction; SERT plays an important role in gastrointestinal functional diseases, and abnormal 5-HT signal system can cause gastrointestinal motility and secretion function abnormality and viscus hypersensitiveness, and is closely related to gastrointestinal functional diseases such as chronic constipation, irritable bowel syndrome, diarrhea and functional dyspepsia.
SERT is an important target for clinical drug development. Classical antidepressants based on SERT targets are mostly selective SERT inhibitors (SSRIs), such as Fluoxetine (fluoxeine) and the like; the 5-hydroxytryptamine reuptake promoter (SSRE) has few reports, and the SSRE has been reported to date to be tianeptine (tiazeptine), namely danan (stablon), and the chemical structure of the SSRE belongs to tricyclic antidepressants and is mainly used for resisting depression and anxiety clinically. Experimental research shows that the tianeptine can promote 5-HT reuptake, has a prevention effect on stress/corticosterone-induced hippocampal dendritic atrophy in the aspect of neural structure plasticity, can resist stress-induced hippocampal precursor cell proliferation, hippocampal volume reduction and N-acetyl aspartic acid concentration reduction, and can prevent amygdala dendritic hyperproliferation. In the aspect of nerve excitability, the tianeptine can overcome the stress to block the enhancement of the hippocampal long-term process, reverse the inhibition of stress to the hippocampal-anterior cortical synapse and the like. In terms of neuroprotection, tianeptine is able to reduce apoptosis in the hippocampal and temporal cortex. In terms of memory function, tianeptine has a blocking effect on stress-induced spatial memory impairment, increases memory retention, contributes to attention-focusing behavior, antagonizes the harmful effects of alcohol, and the like (McEwen BS, OlieJP.2005.neurobiology of food, society, and genetics as transformed by students of alcoholic antidepressants: tianeptine. molecular psychological 10,525 and 537). Furthermore, tianeptine was able to elevate the central 5-HT metabolite 5-oxindole acetate, presumably due to a corresponding increase in the intracerebral 5-HT catabolism following increased presynaptic membrane reuptake-5-HT; tianeptine acts on the hypothalamic-pituitary-adrenal axis to decrease the concentration of hypothalamic corticoid releasing factor and anterior pituitary adrenocorticoid.
Tianeptine is effective in major depression, has a longer-term efficacy in depression than fluoxetine, is highly safe, has few adverse reactions, is suitable for senile depression, and has an anxiolytic effect superior to fluoxetine [ humeng, li zhen.2007. tianeptine pharmacological research and clinical application progress. guangdong medicine 28 (7): the characteristics of the action of 1192-1193 ] tianeptine on human bodies include: has certain effect on mood disorder, and is between sedative antidepressant and excitatory antidepressant; has obvious effect on physical discomfort, especially on gastrointestinal discomfort related to anxiety and mood disorder; has certain effect on personality and behavior disorder of alcoholism patients during abstinence period; furthermore, tianeptine had no adverse effects on: sleep and alertness; the cardiovascular system; cholinergic system (no anticholinergic symptoms); drug addiction. The above studies suggest the characteristics and advantages of 5-hydroxytryptamine reuptake enhancers (SSRE) in clinical applications.
Rhizoma Nardostachyos (Nardostachys chinensis Batal) is a plant of genus Nardostachys of family Valerianaceae, and has effects of regulating qi-flowing, relieving pain, resolving stagnation and activating spleen; topical application for eliminating dampness and relieving swelling, and reported biological activities of Nardostachys chinensis include (1) action on nervous system, such as antidepressant, sedative and anticonvulsant, antiparkinson and memory recovery; (2) acting on cardiovascular system, such as lowering blood pressure, resisting arrhythmia, myocardial ischemia, and cardiovascular injury; (3) acting on the respiratory system, such as enhancing hypoxia tolerance; (4) bacteriostasis; (5) anti-liver damage, etc. The chemical components of the nardostachys chinensis bunge comprise sesquiterpenes, triterpenes, iridoids, coumarins, phenolic acids, flavones and the like, wherein the sesquiterpenes are main components of the nardostachys chinensis bunge, the nardostachys chinensis bunge and the like, the research reports are more, other active components, particularly small amount or trace components, are only reported, and the biological activity and related mechanisms are yet to be further discovered.
Disclosure of Invention
The invention aims to solve the technical problem of providing a nardostachys aristolochiane type sesquiterpene compound.
The invention also aims to provide a preparation method of the nardostachys chinensis aristolochiane type sesquiterpene compound.
The invention also aims to provide application of the nardostachys chinensis aristolochiane type sesquiterpene compound.
In order to solve the technical problems, the technical scheme of the invention is as follows:
nardostachys aristolochiane type sesquiterpenoidsHaving the following structural formula (I):
wherein,
a is aristolochene-9 beta-ol (A: 1(10) -aristolochene-9 beta-ol [1(10) -aristolen-9 beta-ol ]);
b nardostachyne (B: 1(10), 8(9) -diene-2-aristolocone [1(10), 8(9) -dien-2-aristolone ]);
c nardosolone H (C: 1(2), 9(10) -diene-8-aristolocone [1(2), 9(10) -dien-8-arsolone ]);
D3-Oxoglycorosinone H
(D: aristolochiane-1 (2), 9(10) -diene-3, 8-dione [ aristol-1(2), 9(10) -dien-3, 8-dione ]);
E3-Hydroxynarwedinone
(E: aristolochiane-1- (2), 9(10) -diene-3. beta. -ol [ aristol-1(2), 9(10) -dien-3. beta. -ol ]).
Preferably, the aristolochiane-type sesquiterpene compound of nardostachys chinensis has the following physicochemical and spectral properties of each aristolochiane-type sesquiterpene and the derivative thereof:
aristolocene-9 β -ol [ (1,10) -aristolen-9 β -ol, A]Pale yellow powder (ethyl acetate). UV (MeOH) lambdamax:200nm；CD(c 0.05,MeOH)λ(Δ):215(-0.21)、232(+0.30)、332(-0.56)、352(-0.29)、378(-0.71)nm；1H-NMR(CDCl3,400MHz):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-CH3)、1.25(3H,s,13-CH3)、1.09(3H,s,14-CH3)、0.98(3H,d,J＝6.8Hz,15-CH3)、2.59(1H,br s,-OH)；13C-NMR(CDCl3,100MHz):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)；
Nardostachyne (nardostachrone, B), light yellow oil (ethyl acetate). UV (MeOH) lambdamax:198、228、329nm；CD(c 0.05,MeOH)λ(Δ):206(-6.06)、237(+3.35)、294(-0.55)、355(+7.70)nm；1H-NMR(CDCl3,400MHz):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-CH3)、1.20(3H,s,13-CH3)、1.08(3H,s,14-CH3),1.11(3H,d,J＝6.8Hz,15-CH3)；13C-NMR(CDCl3,100MHz):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)；
Nardostachyne H (kanshone H, C), colorless needle crystals (dichloromethane). UV (MeOH) lambdamax:287、195nm；CD(c 0.05,MeOH)λ(Δ):332(-7.91)、247(+4.97)、222(+2.32)、213(+2.46)、202(+1.22)nm；1H-NMR(CDCl3,400MHz):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-CH3)、1.17(3H,s,13-CH3)、1.11(3H,s,14-CH3)、1.08(3H,d,J＝6.8Hz,15-CH3)；13C-NMR(CDCl3,100MHz):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-oxonarasin H (3-oxokanone D), light yellow powder (dichloromethane); UV (MeOH) lambdamax:198、290nm；CD(c 0.05,MeOH)λ(Δ):197(-1.11)、221(9.40)nm；(-)-ESI-MS m/z 229.97[M-H]-、(+)-ESI-MS:m/z 231.33[M+H]+(ii) a The nuclear magnetic data of hydrogen spectrum and carbon spectrum are shown in the table 1 in the detailed description part;
3-Hydroxynaridone H (3-hydroxykanshone H, E), a colorless oil (ethyl acetate). UV (MeOH) lambdamax:283.0nm；CD(c 0.05,MeOH)λ(Δ):213.5(+1.32)、275.5(+0.08)、296.0(+0.66)、336.5(-3.55)nm；(-)-ESI-MS:m/z 231.30[M-H]-、(+)-ESI-MS:m/z 255.28[M+Na]+(ii) a The nuclear magnetic data of hydrogen spectrum and carbon spectrum are shown in the table 1 of the detailed description part.
Preferably, the aristolochiane-type sesquiterpene compound of nardostachys chinensis, each aristolochiane-type sesquiterpene and the derivatives thereof have the following chemical structure characteristics: (1)1 and 10-positions form a double bond, and 9-positions are substituted by hydroxyl, wherein the 9-positions can be acylated, etherified and amidated by substituent groups to form ester, phenolic ether or nitrogen-containing compounds; (2) double bonds are formed at the 1, 10-position and the 8, 9-position, and the 3-position is substituted by ketone carbonyl; (3) double bonds are formed at the 1, 2-position and the 9, 10-position on the mother nucleus of the aristolochiane type sesquiterpene, the 8-position is substituted by ketocarbonyl, and the 3-position is substituted by methylene, hydroxyl or ketocarbonyl, wherein the 3-position hydroxyl can be acylated by substituent, etherified by phenol, amidated to form ester, phenol ether or nitrogen-containing compound.
The preparation method of the nardostachyne type sesquiterpene compound comprises the following specific steps:
(1) leaching rhizome of Nardostachys chinensis (Nardostachys chinensis Batal) 20kg with 70% (v/v) ethanol for 3 times, 48 hr each time, mixing extractive solutions, and concentrating under reduced pressure to obtain crude extract; extracting the residue with 70% ethanol for 3 times, each for 2 hr, mixing extractive solutions, and concentrating under reduced pressure to obtain crude extract; mixing the two crude extracts to obtain a total extract;
(2) dispersing the obtained crude extract in water, and sequentially extracting with petroleum ether, ethyl acetate and n-butanol to obtain petroleum ether fraction, ethyl acetate fraction, n-butanol fraction and water layer;
(3) subjecting the petroleum ether part to silica gel column chromatography (400 g of sample-mixing silica gel with 200 meshes 100 and 3.3kg of silica gel with 300 meshes 200), wherein the petroleum ether: gradient elution is carried out on ethyl acetate by a solvent system of 100:0(100:0 refers to the elution condition of 100 percent petroleum ether) to 100:50 to obtain 22 fractions Fr.1-22;
(4) petroleum ether: eluting with 100:2 parts of ethyl acetate-Fr.6, and separating by repeated silica gel column chromatography to obtain aristolocene-9 beta-alcohol as one of main components of rhizoma Nardostachyos;
petroleum ether: eluting with 100:2-100:3 ethyl acetate solvent, namely fraction Fr.7, and separating by repeated silica gel column chromatography to obtain compound 3-oxonarasin H; preparing the components obtained by the flow Fr.7 silica gel column by a thin layer of petroleum ether, dichloromethane and ethyl acetate (7: 2: 1) to obtain nardosolone H and 3-hydroxy nardosolone H;
petroleum ether: ethyl acetate 100:5-100:7 solvent elution fraction-fraction fr.9, by repeated silica gel column chromatography, petroleum ether: and (3) performing gradient elution with ethyl acetate of 100:0(100:0 refers to 100% petroleum ether elution condition) to 100:10, and separating to obtain the nardostachyne.
The nardostachyne type sesquiterpene compound is applied to preparation of medicines for promoting 5-hydroxytryptamine transporter (SERT) activity.
Preferably, the nardostachyne sesquiterpene compound is applied to preparation of medicaments for treating depression, anxiety, schizophrenia, obsessive-compulsive disorder, neurodegenerative diseases, drug addiction, digestive system dysfunction and other diseases.
The medicine composition containing the nardostachyne type sesquiterpenoids comprises the compounds with effective treatment and/or prevention amount and optional pharmaceutically acceptable excipient.
The pharmaceutically acceptable excipients mentioned above may be any conventional excipient in the art of pharmaceutical formulation, the selection of a particular excipient will depend on the mode of administration or disease type and state to be used for the treatment of a particular patient, and the method of preparation of a suitable pharmaceutical composition for a particular mode of administration is well within the knowledge of one skilled in the pharmaceutical art. For example, diluents, carriers, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants and the like, which are conventional in the pharmaceutical field, may be included as pharmaceutically acceptable excipients, and if necessary, flavors, preservatives, sweeteners and the like may also be added to the pharmaceutical composition.
The pharmaceutical composition can be made into tablet, powder, granule, capsule, oral liquid, unguent, cream, injectable emulsion, injectable sterile powder for injection, etc. The medicaments in various dosage forms can be prepared according to the conventional method in the pharmaceutical field.
The invention has the beneficial effects that:
the nardostachyne type sesquiterpenoids disclosed by the invention are obtained by separating and purifying roots and stems of Nardostachys chinensis Batal (Nardostachys chinensis Batal) of Nardostachys of Valerianaceae, have the effect of promoting the activity of a 5-hydroxytryptamine transporter (SERT), can be used as a therapeutic drug for treating nervous system diseases such as depression, anxiety, schizophrenia, obsessive compulsive disorder, neurodegenerative diseases and drug addiction, and digestive system dysfunction diseases such as slow-transmission constipation, irritable bowel syndrome and functional abdominal distension, and have important drug development value.
Drawings
Figure 1 is the enhancement of SERT activity by nardostachyne sesquiterpenes and derivatives thereof, wherein the positive control drugs were 2.0 μ M Fluoxetine and 1.0 μ M Tianeptine, respectively, P <0.01, P < 0.001;
FIG. 2 is an NMR spectrum of 3-hydroxynarcotone H, a novel compound;
FIG. 3 is a scheme showing that 3-oxonarcotone H is a novel compound13C-NMR spectrum.
Detailed Description
In order to make those skilled in the art better understand the technical solution of the present invention, the following detailed description will be given with reference to specific embodiments.
Laboratory instruments and reagents: fourier transform nuclear magnetic resonance spectrometer (Bruker, Switzerland, AVIII 400MHz and 600 MHz); color developing agent: 10% sulfuric acid ethanol.
Example 1
Preparation of active ingredient nardostachyne sesquiterpene and its derivatives (extraction and separation process):
the rhizoma Nardostachyos medicinal decoction pieces are purchased from Anhui Ji pharmaceutical Co., Ltd (batch number: 110709, specification: 1 kg/bag, production place: Sichuan), about 20kg, and 20kg of rhizoma Nardostachyos are extracted with 70% ethanol for 3 times, each time for 48 hours, the extracting solutions are combined, and the pressure reduction concentration is carried out to obtain 3kg of crude extract; then, extracting the dregs of a decoction with 70% ethanol for 3 times, 2 hours each time, combining the extracting solutions, and concentrating under reduced pressure to obtain 400g of crude extract; mixing the two crude extracts to obtain 3.4kg of total extract; dispersing the obtained crude extract in water, and sequentially extracting with petroleum ether, ethyl acetate and n-butanol with equal volume to obtain petroleum ether fraction 320g, ethyl acetate fraction 1kg, n-butanol fraction 600g and water layer 1.2 kg; subjecting 320g of petroleum ether part to silica gel column chromatography (sample mixing silica gel 100-; subjecting the eluate Fr.6 (petroleum ether: ethyl acetate: 100:2 solvent eluate) to repeated silica gel column chromatography to obtain aristolocene-9 β -ol (about 50mg) as one of main components of radix Et rhizoma Nardostachyos; subjecting the eluate Fr.7 (petroleum ether: ethyl acetate: 100:2-100:3 solvent eluate) to repeated silica gel column chromatography to obtain compound 3-oxonaridone H; preparing the components obtained by the flow Fr.7 silica gel column by a thin layer of petroleum ether, dichloromethane and ethyl acetate (7: 2: 1) to obtain nardosolone H and 3-hydroxy nardosolone H; the fraction fr.9 (petroleum ether: ethyl acetate: 100:5-100:7 solvent elution fraction) is subjected to repeated silica gel column chromatography (petroleum ether: ethyl acetate: 100: 0-100: 10 gradient elution), and the nardostachyne is separated.
Aristolocene-9 β -ol [ (1,10) -aristolen-9 β -ol, A]Pale yellow powder (ethyl acetate). UV (MeOH) lambdamax:200nm；CD(c 0.05,MeOH)λ(Δ):215(-0.21)、232(+0.30)、332(-0.56)、352(-0.29)、378(-0.71)nm；1H-NMR(CDCl3,400MHz):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-CH3)、1.25(3H,s,13-CH3)、1.09(3H,s,14-CH3)、0.98(3H,d,J＝6.8Hz,15-CH3)、2.59(1H,br s,-OH)；13C-NMR(CDCl3,100MHz):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)。
Nardostachyne (nardostachrone, B), light yellow oil (ethyl acetate). UV (MeOH) lambdamax:198、228、329nm；CD(c 0.05,MeOH)λ(Δ):206(-6.06)、237(+3.35)、294(-0.55)、355(+7.70)nm；1H-NMR(CDCl3,400MHz):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-CH3)、1.20(3H,s,13-CH3)、1.08(3H,s,14-CH3),1.11(3H,d,J＝6.8Hz,15-CH3)；13C-NMR(CDCl3,100MHz):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)。
Nardostachyne H (kanshone H, C), colorless needle crystals (dichloromethane). UV (MeOH) lambdamax:287、195nm；CD(c 0.05,MeOH)λ(Δ):332(-7.91)、247(+4.97)、222(+2.32)、213(+2.46)、202(+1.22)nm；1H-NMR(CDCl3,400MHz):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-CH3)、1.17(3H,s,13-CH3)、1.11(3H,s,14-CH3)、1.08(3H,d,J＝6.8Hz,15-CH3)；13C-NMR(CDCl3,100MHz):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-oxonarasin H (3-oxokanone H, D), light yellow powder (dichloromethane). UV (MeOH) lambdamax:198、290nm；CD(c 0.05,MeOH)λ(Δ):197(-1.11)、221(9.40)nm；(-)-ESI-MS m/z 229.97[M-H]-、(+)-ESI-MS:m/z 231.33[M+H]+(ii) a The nuclear magnetic data of hydrogen spectrum and carbon spectrum are shown in the table 1 of the detailed description part.
1H-NMR(CDCl3400MHz) in the spectrum of the signal,H1.28(3H, s), 1.26(3H, s), 1.24(3H, s) andHa peak at 1.30(3H, d, J ═ 6.4Hz) is 4 methyl signals;H6.98(1H, d, J ═ 10.0Hz), 6.18(1H, d, J ═ 10.0Hz), and 6.08(1H, s) are 3 alkene hydrogen proton signals.
13C-NMR spectrum gives a total of 15 carbon atom signals, including the carbon signals of the 2 groups of double bonds: (C142.4, 131.6, 129.1 and 156.3), 2 carbonyl carbon signalsC(199.6, 195.8). The difference between the compound and the compound galbanone H is thatCThe carbon signal at 199.6(C-3) is the 1 carbonyl carbon signal. Synthesis of1H-NMR、13The planar structure of the compound was deduced from the information such as C-NMR, HSQC, HMBC spectra (FIG. 3).
The relative configuration of 3-oxonarasin H was determined by NOESY spectroscopy, which ultimately determined the above structure of the compound.
3-Hydroxynaridone H (3-hydroxykanshone H, E), a colorless oil (ethyl acetate). UV (MeOH) lambdamax:283.0nm；CD(c 0.05,MeOH)λ(Δ):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/z 255.28[M+Na]+(ii) a The nuclear magnetic data of hydrogen spectrum and carbon spectrum are shown in the table 1 of the detailed description part.
13C-NMR(CDCl3400MHz) spectrum gives a total of 15 carbon signals,Ccarbon signals at 128.4, 139.2, 124.5, 158.6, suggesting the presence of 2 sets of double bonds in the structure. Compared with the NMR spectrum of the compound galbanone H, the difference of the compound isCThe carbon signal at 71.4(C-3) is the 1-oxo-carbon signal. Synthesis of1H-NMR、13The planar structure of the compound was deduced from the information such as C-NMR, HSQC, HMBC spectra (FIG. 2).
In the NOESY spectrum, the content of the amino acid,H4.04(d, J ═ 9.6Hz, H-3) andH1.17(s, Me-13), 1.27(d, J ═ 6.8Hz, Me-15) spatial correlation, suggesting C3-O bond, C4-C15Key, C5-C14The keys are in opposite directions;H1.45(d, J ═ 8.0Hz, H-6) andH1.29(d, J ═ 6.8Hz, Me-15) spatial correlation, suggesting C6-C11Key, C4-C15The bonds are in opposite directions, ultimately defining the above structure of the compound.
TABLE 1 Nuclear magnetic data (CDCl) of 3-oxonarasin H and 3-hydroxynarasin H3,1H-NMR in 400MHz,13C-NMR in 100MHz)
Example 2
Effect of the Compounds of the present invention on 5-hydroxytryptamine Transporter (SERT)
4- (4- (dimethylamino) phenyl) -1-methylpyridinium (APP) was used as a stably transfected hSERT-HEK293 cell line+) Detecting compound aristolochiane type sesquiterpene and derivative pair SER thereof on high content system by using fluorescent substrateInfluence of T Activity.
1) Laboratory apparatus and reagent
An experimental instrument:
high content Operetta System and Columbus data management and analysis System (PerkinElmer), clean bench, pipette gun (1000. mu.L, 200. mu.L, 20. mu.L, 10. mu.L, 2.5. mu.L, Eppendorf Co., USA)
Reagents and materials:
human embryonic kidney cell line HEK293 (China academy of sciences type culture Collection cell Bank), hSERT pcDNA3 plasmid (Addgene, plasmid 15483), MEM medium (Gibco), APP+(Sigma), Hoechst 33342(CellSignaling Technology), 96-well plate (Costar 3605)
2) Procedure of experiment
Firstly, establishing and identifying a cell line (Anilei, Lijing, Jinliang and the like) for stably expressing hSERT-HEK293 cell line, establishing a human 5-hydroxytryptamine transporter stably expressing cell line and researching functions thereof [ J]Military medicine 2011,35(9):681-684 }. With APP+As a fluorescent substrate, the function of SERT is detected based on a high content system { Fowler A, Seifert N, Acker V.et.A nonradioactive high-throughput/high-content assay for a measurement of the human serotonin reuptake transporter function in vitro [ J].Journal ofBiomolecular Screening,2006,11(8):1027-1034}
The method comprises the following specific steps:
(1) the aristolochiane sesquiterpene and its derivatives obtained in example 1 were weighed precisely, prepared into 20mM stock solution with DMSO, and diluted to 10.0. mu.M, 1.0. mu.M, 0.1. mu.M with phenol-free red MEM base medium.
(2) According to 1.0 × 104Cell/well Density stably transfected hSERT-HEK293 cells were seeded into 96-well plates at 37 ℃ with 5% CO2Culturing for 24h under the condition.
(3) The experiment sets up a blank control group, a positive control group of 2.0 mu M Fluoxetine and a positive control group of 1.0 mu M Tianeptine, and a test drugThe compositions were set up in 10.0. mu.M, 1.0. mu.M, and 0.1. mu.M groups, respectively. The cells were discarded from the medium, washed 2 times with PBS buffer, and each sample to be tested was added in a volume of 80. mu.L/well, 3 replicates per concentration, at 37 ℃ with 5% CO2Incubating for 2-3h in dark under the condition.
(4) After incubation was complete, 20. mu.L of APP was added per well+And incubated for 20 minutes.
(5) The wells were discarded, washed 2 times with PBS buffer, 1.0. mu.g/mL Hoechst 50. mu.L was added to each well, and incubated for 20min in the dark.
(6) Discarding the liquid in the pore plate, washing with PBS for 2-3 times, and detecting the fluorescence intensity in the cell by using high content system
Hoechst 33342 Excitation：360-400nm，Emission：410-480nm
APP+Excitation：460-490nm，Emission：505-550nm
3) And (3) data analysis:
adopting a Columbus data management and analysis system to carry out image analysis, determining cells according to a mode of Hoechst 33342 fluorescence recognition cell nucleus, and according to intracellular APP+The SERT transport activity was determined from the fluorescence intensity and the relative fluorescence intensity was calculated (intracellular APP from the drug group)+Intracellular APP in fluorescence intensity/control group+Fluorescence intensity) were analyzed by ANOVA.
4) Results of the experiment
As shown in fig. 1, aristolocene-9 β -ol significantly enhanced (F (5,62) ═ 304.7, p <0.0001) SERT activity, Dunnett multiple comparison post-hoc test (Dunnett's multiple complex post hoc test) confirmed that aristolocene-9 β -ol significantly enhanced SERT activity compared to the blank control at concentrations of 10.0 μ M (q ═ 6.942, p <0.001), 1.0 μ M (q ═ 8.720, p <0.001), and 0.1 μ M (q ═ 7.519, p <0.001), positive drug control fluoxetine significantly inhibited SERT activity at 2.0 μ M (q ═ 23.95, p <0.001), and positive drug control tiazepe significantly enhanced SERT activity at 1.0 SERT (q ═ 3.641, p < 0.01).
Nardostachyne significantly enhanced SERT activity (F (5,36) ═ 289.8, p <0.0001). Dunnett's smart composition post hoc test showed that nardostachyne significantly enhanced SERT activity at a concentration of 10.0 μ M (q-5.317, p <0.001), but had no significant effect on SERT activity at concentrations of 1.0 μ M (q-0.7635, n.s.) and 0.1 μ M (q-0.1819, n.s.), positive drug control fluxetine significantly inhibited SERT activity at 2.0 μ M (q-27.07, p <0.001), and additional positive drug control tiazetine significantly enhanced SERT activity at 1.0 μ M (q-4.193, p <0.01)
Narcotine H significantly enhanced SERT activity (F (5,51) ═ 436.7, p <0.0001), Dunnett's multiple study post hoc test showed that narcotine H significantly enhanced SERT activity at concentrations of 10.0 μ M (q ═ 4.991, p <0.001) and 1.0 μ M (q ═ 3.777, p <0.01) compared to the blank control, while it did not significantly affect SERT activity at concentrations of 0.1 μ M (q ═ 2.113, n.s.), the positive drug control fluxetine significantly inhibited SERT activity at 2.0 μ M (q ═ 33.32, p <0.001), and the other positive drug control tianeeptine significantly enhanced sertine activity at 1.0 μ M (q ═ 4.680, p < 0.001).
3-oxonarasin H significantly enhanced SERT activity (F (5,46) ═ 685.5, p <0.0001), Dunnett's multiple complex post hoc test showed that compound G-9 significantly enhanced SERT activity at concentrations of 10.0 μ M (q-5.815, p <0.001) and 1.0 μ M (q-3.428, p <0.01) compared to the blank control, had no significant effect on SERT activity at a concentration of 1.0 μ M (q-2.105, n.s.), and the positive drug control fluoxetine significantly inhibited SERT activity at 2.0 μ M (q-42.89, p <0.0001), and the other positive drug control tiazeptine significantly enhanced SERT activity at 1.0 μ M (q-7.473, p < 0.001).
Significant enhancement of SERT activity by 3-hydroxy narcotine H (F (5,37) ═ 410.1, p <0.0001). Dunnett's multiple complex hospital test showed that compound 3-hydroxy narcotine H significantly enhanced SERT activity at concentrations of 10.0 μ M (q ═ 3.488, p <0.01) and 1.0 μ M (q ═ 2.727, p <0.05) compared to the blank control, had no significant effect on SERT activity at a concentration of 0.1 μ M (q ═ 06674, n.s.), and fluxepin in the positive drug control group significantly inhibited SERT activity at 2.0 μ M (q ═ 31.96, p <0.001), while another positive drug control group significantly enhanced SERT activity at 1.0 μ M (q ═ 31.25, p <0. 5.595).
As can be seen from the above, the 5-hydroxytryptamine transporter (SERT) is Na having a high affinity for 5-HT+/Cl-Dependent transmembrane transporters, which are located mainly in 5-HT neurons in the central nervous system, directly affect synaptic cleft 5-HT concentrations by reuptaking 5-HT from the neurosynaptic gap into presynaptic neurons, and alter the amount and duration of postsynaptic receptor-mediated signaling, thereby participating in various physiological and psychological functions (e.g., emotion, appetite, sleep, memory, learning, etc.); SERT is mainly located in intestinal mucosa epithelial cells in a digestive system, and takes 5-HT released by chromaffin cells of intestinal mucosa to regulate gastrointestinal functions, and is distributed in placenta tissues, reproductive tracts, bone marrow, kidneys, lungs, hearts, adrenals, livers, parathyroids, thyroid glands, pancreas and other organs, so that SERT is suggested to participate in various physiological functions.
SERT is an important target point of clinical drug development, and the 5-hydroxytryptamine reuptake promoter (SSRE) reported so far is tianeptine (tiazeptine), and is mainly used for anti-depression and anti-anxiety in clinic. The action characteristics of tianeptine on human bodies include: has certain effect on mood disorder, and is between sedative antidepressant and excitatory antidepressant; has obvious effect on physical discomfort, especially on gastrointestinal discomfort related to anxiety and mood disorder; has certain effect on personality and behavior disorder of alcoholism patients during abstinence period; furthermore, tianeptine had no adverse effects on: sleep and alertness; the cardiovascular system; cholinergic system (no anticholinergic symptoms); drug addiction. The action characteristics of the tianeptine belong to SSRE, and suggest the characteristics and advantages of the 5-hydroxytryptamine reuptake promoter (SSRE) in clinical application.
According to the invention, the research on the influence of the in vitro 5-hydroxytryptamine transporter (SERT) activity on the nardostachys chinensis aristolochiane type sesquiterpenes and derivatives thereof separated from rhizomes of nardostachys chinensis is carried out, and the compounds can obviously enhance the SERT transport activity, so that the nardostachys chinensis aristolochiane type sesquiterpenes and the derivatives thereof are confirmed to be effective components for regulating related psychophysiological diseases and digestive system dysfunction diseases caused by SERT imbalance. Therefore, the nardostachyne sesquiterpene and the derivative thereof can be used for preparing the medicines for treating neuropsychiatric diseases such as depression and anxiety and gastrointestinal dysfunction diseases such as irritable bowel syndrome.
The structures of the nardostachyne sesquiterpenes and derivatives thereof are as follows: (1)1 and 10-positions form a double bond, and 9-positions are substituted by hydroxyl, wherein the 9-positions can be acylated, etherified and amidated by substituent groups to form ester, phenolic ether or nitrogen-containing compounds; (2) double bonds are formed at the 1, 10-position and the 8, 9-position, and the 3-position is substituted by ketone carbonyl; (3) double bonds are formed at the 1, 2-position and the 9, 10-position on the mother nucleus of the aristolochiane type sesquiterpene, the 8-position is substituted by ketocarbonyl, and the 3-position is substituted by methylene, hydroxyl or ketocarbonyl, wherein the 3-position hydroxyl can be acylated by substituent, etherified by phenol, amidated to form ester, phenol ether or nitrogen-containing compound.
Example 3
The preparation method comprises the following steps: according to the proportion, aristolochene-9 beta-alcohol/nardostachyne H/3-hydroxy nardostachyne H/3-oxo nardostachyne H, lactose and starch are uniformly mixed, the mixture is sieved by a 200-mesh sieve, the mixture is uniformly wetted by water, the wetted mixture is dried and sieved, magnesium stearate is added, and then the mixture is tabletted, wherein each tablet is 250mg in weight, and the content of active ingredients is 10 mg.
Example 4
And (3) capsule preparation: aristolocycline-9 beta-ol/nardostachyne H/3-hydroxynardostachyne H/3-oxonardostachyne H20 mg
188mg of galactose
Magnesium stearate 2mg
The preparation method comprises the following steps: uniformly mixing aristolochene-9 beta-alcohol/nardostachyne H/3-hydroxy nardostachyne H/3-oxo-nardostachyne H and galactose according to the proportion, sieving with a 200-mesh sieve, adding magnesium stearate into the obtained mixture, and filling into No. 2 capsules to obtain the capsule.
The above detailed description of the nardostachyne sesquiterpenes with the aid of specific embodiments, the preparation and use thereof, is intended to be illustrative and not limiting, and it is intended to cover within the scope of the invention variations and modifications within the scope of the general inventive concept.
Claims (5)
1. A nardostachyne sesquiterpene compound having the following structural formula (I):
wherein, D3-oxonarasin H; e3-hydroxy narcolenone.
2. The method for preparing aristolochiane type sesquiterpene compound of claim 1, wherein the method comprises the following steps: the method comprises the following specific steps:
(1) leaching rhizome of Nardostachys chinensis with 70% (v/v) ethanol for 3 times (48 hr each time) per 20kg, mixing extractive solutions, and concentrating under reduced pressure to obtain crude extract; extracting the residue with 70% ethanol for 3 times, each for 2 hr, mixing extractive solutions, and concentrating under reduced pressure to obtain crude extract; mixing the two crude extracts to obtain a total extract;
(2) dispersing the obtained crude extract in water, and sequentially extracting with petroleum ether, ethyl acetate and n-butanol to obtain petroleum ether fraction, ethyl acetate fraction, n-butanol fraction and water layer;
(3) subjecting the petroleum ether part to silica gel column chromatography, wherein the petroleum ether content: gradient elution is carried out on ethyl acetate (100: 0-100: 50) by a solvent system to obtain 22 fractions Fr.1-22;
(4) petroleum ether: eluting with 100:2 parts of ethyl acetate-Fr.6, and separating by repeated silica gel column chromatography to obtain aristolocene-9 beta-alcohol as one of main components of rhizoma Nardostachyos;
petroleum ether: eluting with 100:2-100:3 ethyl acetate solvent, namely fraction Fr.7, and separating by repeated silica gel column chromatography to obtain compound 3-oxonarasin H; preparing the components obtained by the flow Fr.7 silica gel column by a thin layer of petroleum ether, dichloromethane and ethyl acetate (7: 2: 1) to obtain nardosolone H and 3-hydroxy nardosolone H;
petroleum ether: ethyl acetate 100:5-100:7 solvent elution fraction-fraction fr.9, by repeated silica gel column chromatography, petroleum ether: and (3) carrying out gradient elution on ethyl acetate at a ratio of 100: 0-100: 10, and separating to obtain the nardostachyne.
3. Use of aristolochiane sesquiterpenes according to claim 1 for the preparation of a medicament intended to promote the activity of the 5-hydroxytryptamine transporter (SERT).
4. Use of the aristolochiane sesquiterpene compound of claim 1 for the preparation of a medicament for the treatment of depression, anxiety, schizophrenia, obsessive compulsive disorder, neurodegenerative disorders, drug addiction or disorders of digestive system function.
5. A pharmaceutical composition having a aristolochiane-type sesquiterpene compound of claim 1 comprising a therapeutically and/or prophylactically effective amount of said compound and optionally a pharmaceutically acceptable excipient.
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