CN116813462B - Degradation product of gancyclone and preparation method and application thereof - Google Patents
Degradation product of gancyclone and preparation method and application thereof Download PDFInfo
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- CN116813462B CN116813462B CN202310611641.XA CN202310611641A CN116813462B CN 116813462 B CN116813462 B CN 116813462B CN 202310611641 A CN202310611641 A CN 202310611641A CN 116813462 B CN116813462 B CN 116813462B
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- nardostachyne
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- 239000007857 degradation product Substances 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000003814 drug Substances 0.000 claims abstract description 16
- 238000010992 reflux Methods 0.000 claims abstract description 13
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 6
- 206010020772 Hypertension Diseases 0.000 claims abstract description 5
- 150000002576 ketones Chemical class 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 5
- 238000002347 injection Methods 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 241000195954 Lycopodium clavatum Species 0.000 claims description 2
- 239000006071 cream Substances 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 2
- 230000000694 effects Effects 0.000 abstract description 11
- 230000024883 vasodilation Effects 0.000 abstract description 9
- 238000011161 development Methods 0.000 abstract description 5
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 abstract description 4
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- 238000006243 chemical reaction Methods 0.000 abstract description 3
- 230000025033 vasoconstriction Effects 0.000 abstract description 3
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- 239000004593 Epoxy Substances 0.000 abstract 1
- 230000000593 degrading effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
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- 229910002027 silica gel Inorganic materials 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000010828 elution Methods 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 241000790228 Nardostachys jatamansi Species 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 210000004204 blood vessel Anatomy 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 5
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- ROAYSRAUMPWBQX-UHFFFAOYSA-N ethanol;sulfuric acid Chemical compound CCO.OS(O)(=O)=O ROAYSRAUMPWBQX-UHFFFAOYSA-N 0.000 description 3
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
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- PGTVWKLGGCQMBR-FLBATMFCSA-N Ganaxolone Chemical compound C([C@@H]1CC2)[C@](C)(O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1 PGTVWKLGGCQMBR-FLBATMFCSA-N 0.000 description 2
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
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- 229910000831 Steel Inorganic materials 0.000 description 2
- 208000006906 Vascular Ring Diseases 0.000 description 2
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 2
- 229960004373 acetylcholine Drugs 0.000 description 2
- JUGOREOARAHOCO-UHFFFAOYSA-M acetylcholine chloride Chemical compound [Cl-].CC(=O)OCC[N+](C)(C)C JUGOREOARAHOCO-UHFFFAOYSA-M 0.000 description 2
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- UGVIZCBJCSXBCJ-UHFFFAOYSA-N aristolone Natural products O=C1C2C(C)(C)C2C2(C)C(C)CCCC2=C1 UGVIZCBJCSXBCJ-UHFFFAOYSA-N 0.000 description 2
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- XEYBHCRIKKKOSS-UHFFFAOYSA-N disodium;azanylidyneoxidanium;iron(2+);pentacyanide Chemical compound [Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N XEYBHCRIKKKOSS-UHFFFAOYSA-N 0.000 description 2
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- LRMHFDNWKCSEQU-UHFFFAOYSA-N ethoxyethane;phenol Chemical compound CCOCC.OC1=CC=CC=C1 LRMHFDNWKCSEQU-UHFFFAOYSA-N 0.000 description 2
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
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- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 1
- 229960002963 ganciclovir Drugs 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a degradation product of nardostachyne, and a preparation method and application thereof, wherein the degradation product of nardostachyne is 2-deoxynardostachyne M, is obtained by degrading the nardostachyne in water through heating reflux reaction, can enhance vasodilation activity, particularly remarkably dilates vasoconstriction caused by 9, 11-dideoxy-11 alpha, 9 alpha-methylene epoxy prostaglandin F2 alpha, can be used for preparing medicines for preventing and/or treating cardiovascular diseases, particularly hypertension, and has important medicine development value.
Description
Technical Field
The invention relates to the technical field of traditional Chinese medicines, in particular to a degradation product of a novel ketone of lycopodium clavatum as well as a preparation method and application thereof.
Background
Rhizoma Nardostachyos (Nardostachys jatamansi DC) is the dried root and rhizome of Nardostachys chinensis (L.) Nardostachys (L.) Makino of Valerianaceae, and is used for treating cardiovascular diseases and nervous system diseases. The nardostachyne is the only index component downloaded from Chinese pharmacopoeia (first edition 2020 edition) Gan Songxiang, and the content of the nardostachyne in the dry nardostachyne is not less than 0.1%. The nardostachyne is one of main active ingredients of the nardostachys chinensis, but has poor stability. The nardostachyne has the pharmacological activities of protecting myocardial cells, dilating blood vessels, resisting neuroinflammation, promoting neuron differentiation and proliferation, resisting periodontitis, calming, resisting bacteria, killing insects and the like. The chemical structure of the nardostachyne contains a five-membered peroxy ring at the C-7 and C-11 positions, which is easy to generate ring-opening reaction, unstable under acidic and high temperature conditions and easy to generate degradation. In boiling methanol solution, the nardostachyne can be further degraded into a dodecandiol sesquiterpene compound (deoxynardostachyne A and the like) or other pentadecandiol sesquiterpene compounds (nardostachyne diol, isonardostachyne and the like). In view of the instability of the nardostachyne, whether the Chinese herbal medicine taking the nardostachyne as a main component can take the prototype component into blood to play the therapeutic effect of the nardostachyne after oral administration is uncertain, so that the in vivo process and the pharmacokinetics research of the nardostachyne should fully consider the chemical instability of the nardostachyne, and the research on the structure and the activity of the nardostachyne degradation product has important guiding significance for quality control of the nardostachyne and the Chinese patent medicine containing the nardostachyne.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a degradation product of the novel ketone of the nardostachyos.
The invention aims to provide a preparation method of the degradation product of the nardostachyne.
Another technical problem to be solved by the invention is to provide the application of the degradation product of the nardostachyne.
The technical scheme adopted by the invention is as follows:
a degradation product of nardostachyne is 2-deoxynardostachyne M (2-deoxokanshoneM) with a structure shown in a structural formula (I):
preferably, the physical, chemical and spectral properties of the above-mentioned Nardostachyos neoketone degradation product are as follows:
colorless crystals or white amorphous powder, and is easily dissolved in methanol, and has molecular formula of C 12H16O2.
Dark spots exist under a 254nm ultraviolet lamp, fluorescence does not exist under a 365nm ultraviolet lamp, and 10% sulfuric acid ethanol solution is sprayed to heat the ultraviolet lamp to avoid color development. Melting point: 207 ℃; (-) -HRESIMSm/z:193.1205[ M+H ] + and 191.1066[ M-H ] -; (c1.0,MeOH)：+26.0;UV(MeOH)λmax：287、322nm;ECD(c0.125,MeOH)λmax(Δε)：210(-4.33)、278.5(+1.03)、328(-1.05)nm;IR(KBr)νmax：3331、2923、2361、1584、1546、1235cm-1.1H-NMR(600MHz,DMSO-d6)δH：10.83(1H,brs,-OH)、6.49(1H,t,J＝4.0Hz,H-1)、5.23(1H,s,H-8)、2.28(2H,m,H-6)、2.20(2H,m,H-2)、1.62(1H,m,H-4)、1.46(2H,m,H-3)、0.92(3H,s,H-12) And 0.87 (3 h, d, j=6.8 hz, h-11).
13C-NMR(150MHz,DMSO-d6)δC：196.3(C-7)、167.7(C-9)、136.1(C-10)、130.6(C-1)、102.0(C-8)、49.2(C-6)、38.5(C-4)、37.4(C-5)、25.6(C-2)、25.3(C-3)、19.4(C-12) And 15.4 (C-11).
Crystal structure data of 2-deoxyganinidone M by X-ray diffraction analysis: the molecular formula: c 12H16O2, crystal size: 0.16X0.13X0.1 mm 3. The unit cell parameters belong to monoclinic system: α=90°, β= 93.402 (3) °, γ=90°, unit cell volume Number of molecules in unit cell z=2, density calculated D calc＝1.192g/cm3,μ＝0.684mm-1, F (000) =1596.0, fly parameter-0.07 (14), data collection range: 6.628 DEG or more 2 theta or less 155.356 DEG; diffraction finger table range: h is more than or equal to 16 and less than or equal to 15 k is more than or equal to 8 and less than or equal to 9-50.ltoreq.l.ltoreq.50; and (3) reflection collection: 113981; independent diffraction points: 15350[ r int＝0.0855、Rsigma = 0.0776]; data limiting parameters: 15350/1/971; peaks and valleys of residual electron density after finishing are 0.25 and-0.24; r0.0614[ I > 2σ (I) ] and wR 2 0.1781.
The chemical structure of the 2-deoxyganine ketone M is characterized in that: belongs to a novel ketone type sesquiterpene-reducing phenomenon of nardostachys chinensis, and has enol interconversion; the hydroxyl group at the C-9 position on the parent nucleus can be acylated, etherified, amidated by a substituent to form an ester, alcohol ether, phenol ether or to form a nitrogen-containing compound.
The preparation method of the degradation product of the nardostachyne comprises the following specific steps:
(1) Heating and refluxing the nardostachyne with pure water for 2.5 hours, and concentrating under reduced pressure to obtain a hot water degradation product mixture of the nardostachyne;
(2) Subjecting the obtained degradation product mixture to ODS reversed phase column chromatography, and subjecting to gradient elution with methanol-pure water=30:70, 40:60, 50:50, 60:40, 70:30, 85:15, and 100:0 solvent system (30:70 refers to 30% methanol elution, 100:0 refers to 100% methanol elution), to obtain 9 components Fr.1-9;
(3) And (3) eluting the component, namely the component Fr.4, by using a methanol-pure water=50:50 solvent to obtain 2-deoxynardosinone M which is a main degradation product of the nardostachyne.
The application of the degradation product of the nardostachyne in preparing medicaments for enhancing vasodilation activity.
Preferably, the use of the above-mentioned degradation product of nardostachyne, said enhanced vasodilation activity means significant vasodilation of vasoconstriction caused by 9, 11-dideoxy-11 alpha, 9 alpha-methyleneepoxyprostaglandin F2 alpha (U46619).
The application of the degradation product of the nardostachyne in preparing medicaments for preventing and/or treating cardiovascular diseases.
The application of the degradation product of the nardostachyne in preparing the medicine for preventing and/or treating hypertension.
A pharmaceutical composition having the above-mentioned degradation product of ganaxnovel one, comprising a therapeutically and/or prophylactically effective amount of 2-deoxyganine ketone M and optionally a pharmaceutically acceptable excipient.
The pharmaceutically acceptable excipients described above may be any conventional excipient in the pharmaceutical formulation arts, and the choice of a particular excipient will depend on the mode of administration or type and state of the disease being treated for a particular patient, and the method of preparing a suitable pharmaceutical composition for a particular mode of administration is well within the knowledge of one skilled in the pharmaceutical arts. For example, as pharmaceutically acceptable excipients, diluents, carriers, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants and the like which are conventional in the pharmaceutical field may be included, and if necessary, flavoring agents, preservatives, sweeteners and the like may be added to the pharmaceutical composition.
The pharmaceutical composition can be prepared into various forms such as tablets, powder, granules, capsules, oral liquid, ointment, cream, injection emulsion, sterile powder for injection and the like, and the medicaments of various dosage forms can be prepared according to the conventional method in the pharmaceutical field.
The beneficial effects of the invention are as follows:
The degradation product of the nardostachyne is obtained by degradation of the nardostachyne in water through heating reflux reaction, can enhance vasodilation activity, particularly obviously dilate vasoconstriction caused by 9, 11-dideoxy-11 alpha, 9 alpha-methyleneepoxy prostaglandin F2 alpha (U46619), can be used for preparing medicines for preventing and/or treating cardiovascular diseases, particularly hypertension, and has important medicine development value.
Drawings
FIG. 1 shows the molecular structure of 2-deoxyganinidone M as analyzed by X-ray diffraction.
Fig. 2 shows the effect of 2-deoxyganbinone M, ganaxolone and aristolochone on thoracic aortic diastole, mean±sem, n=3, control group added an equal volume of DMSO at a time, without drug, ×p <0.001.
FIG. 3 is a thermal stability study of Nardostachyos, 2-deoxyNardostachyos M and Aristolone based on UHPLC analysis. Wherein, fig. 3a, fig. 3b and fig. 3c are respectively UHPLC chromatograms of nardostachyne, 2-deoxynardostachyne M and aristolenone heated by water reflux for 2 hours, and fig. 3d is a relative content change line diagram of 3 compounds in different time periods in the water reflux heating process.
Detailed Description
To further illustrate the invention, the following examples are provided in connection with:
Example 1
Preparation and structural identification of 2-deoxyganine ketone M
Experimental instrument and reagents: fourier transform nuclear magnetic resonance spectrometer (Bruker company, switzerland, model AV-III 600 MHz); varian 640FT-IR spectrometer (zemoeimer feishi technologies limited, china); AGILENT CARY 60UV-Vis spectrophotometer (China medical group Co., ltd.); UPLC-Q Exactive Orbitrap-MS (Thermo technologies Co., ltd.); SGW X-4 micro-melting point apparatus (Shanghai precision scientific instruments Co., ltd.); JASCO-815 type ECD spectrometer (JASCO Co., tokyo, japan); rudolph AUTOPOL V polarimeter (ruff company, usa); rigaku Xtalab P200 diffractometer (Rigaku Corp., japan); color-developing agent: 10% sulfuric acid-ethanol solution.
The sources of the medicinal materials are as follows: radix Et rhizoma Nardostachyos (100 kg; place of origin: sichuan) was purchased from Baoding Xiande Chinese medicine sales Co.
The nardostachyne is separated from nardostachys chinensis (Nardostachys jatamansi DC.) and has purity of more than 98% by UPLC analysis. The preparation process comprises the following steps:
(1) Extracting: extracting 100kg of radix Et rhizoma Nardostachyos root with 95% ethanol under reflux at a ratio of 1:6 (m/v) for 2 hr for 2 times; concentrating under reduced pressure at 45deg.C to obtain total extract (-15.4 kg).
(2) Dissolving and extracting: dissolving radix Et rhizoma Nardostachyos total extract with dichloromethane-methanol (1:1, v/v), filtering, suspending the residue in 10L water, and extracting with ethyl acetate for 3 times with equal volume; the ethyl acetate layer was combined with dichloromethane-methanol solution and concentrated at 45℃under reduced pressure to give fraction GSG (. About.12 kg).
(3) And (3) separating and purifying: mixing fraction GSG (about 12 kg) with 18kg silica gel (100-200 meshes), and performing silica gel column chromatographic separation on 24kg silica gel column (12 silica gel columns in parallel, each silica gel column 2 kg); sequentially eluting with petroleum ether, dichloromethane and methanol as eluent, and collecting two column volumes at each gradient; combining all fractions through TLC and LC-MS analysis and detection to obtain GSG-1 and GSG-3; GSG-1 (5.7 kg) was sampled with 9kg silica gel (100-200 mesh), and 12kg silica gel column (6 silica gel columns in parallel, 2kg each silica gel column) was subjected to silica gel column chromatography; eluting with petroleum ether/dichloromethane gradient of 100:0, 50:1, 30:1, 10:1, 5:1, 3:1, 1:1 and 0:100 respectively; the fractions were combined by LC-MS analysis into GSG-1-1 (1.8 kg), GSG-1-4 (800 g), GSG-1-17 (360 g) and GSG-1-20 (1.4 kg); placing GSG-1-17 (360 g) in a way of solid precipitation, and filtering to obtain GSG-1-17-LY (245 g) and nardostachyne (114 g); GSG-3 (-2 kg) was sampled with 3kg silica gel (100-200 mesh), and 4kg silica gel column (2 silica gel columns in parallel, 2kg each silica gel column) was subjected to silica gel column chromatography; elution was performed with a petroleum ether/ethyl acetate gradient of 100:0, 50:1, 30:1, 10:1, 5:1, 3:1, 1:1 and 0:100, respectively. The resulting fractions were combined by LC-MS analysis into GSG-3-1 (130 g), GSG-3-3 (300 g), GSG-3-9 (200 g), GSG-3-12 (910 g) and GSG-3-15 (350 g). GSG-3-3 (300 g) was recrystallized from petroleum ether to give the compound ganaxnovel ketone (174.72 g) and filtrate GSG-3-3-LY (120 g).
Dispersing 10.00g of nardostachyne in pure water, heating and refluxing for 2.5 hours, changing the reaction liquid from colorless to light yellow, and concentrating under reduced pressure to obtain 8.13g of a mixture of nardostachyne degradation products; subjecting the obtained degradation product mixture to ODS reversed phase column chromatography, and performing gradient elution by a methanol-pure water (30:70, 40:60, 50:50, 60:40, 70:30, 85:15, 100:0) solvent system (30:70 refers to 30% methanol elution, 100:0 refers to 100% methanol elution) to obtain 9 components Fr.1-Fr.9; wherein methanol-pure water=50:50 solvent elution component Fr.4 (5.773 g), concentrating under reduced pressure to recover solvent to obtain 2-deoxyganine ketone M with yield of 64.23%, which is the main degradation product of hot water reflux of nardostachyne.
According to the measurement, 2-deoxyganine ketone M (2-deoxokanshone M), colorless crystals or white amorphous powder, is easy to dissolve in methanol, and has a molecular formula of C 12H16O2. Dark spots exist under a 254nm ultraviolet lamp, fluorescence does not exist under a 365nm ultraviolet lamp, and 10% sulfuric acid ethanol solution is sprayed to heat the ultraviolet lamp to avoid color development. Melting point: 207 ℃; (-) -HRESIMS m/z:193.1205[ M+H ] + and 191.1066[ M-H ] -; (c1.0,MeOH)：+26.0;UV(MeOH)λmax：287、322nm;ECD(c 0.125,MeOH)λmax(Δε)：210(-4.33)、278.5(+1.03)、328(-1.05)nm;IR(KBr)νmax：3331、2923、2361、1584、1546、1235cm-1.1H-NMR(600MHz,DMSO-d6)δH：10.83(1H,br s,-OH)、6.49(1H,t,J＝4.0Hz,H-1)、5.23(1H,s,H-8)、2.28(2H,m,H-6)、2.20(2H,m,H-2)、1.62(1H,m,H-4)、1.46(2H,m,H-3)、0.92(3H,s,H-12) And 0.87(3H,d,J＝6.8Hz,H-11).13C-NMR(150MHz,DMSO-d6)δC：196.3(C-7)、167.7(C-9)、136.1(C-10)、130.6(C-1)、102.0(C-8)、49.2(C-6)、38.5(C-4)、37.4(C-5)、25.6(C-2)、25.3(C-3)、19.4(C-12) and 15.4 (C-11).
Crystal structure data of 2-deoxyganinidone M by X-ray diffraction analysis: the molecular formula: c 12H16O2, crystal size: 0.16X0.13X0.1 mm 3. The unit cell parameters belong to monoclinic system: α=90°, β= 93.402 (3) °, γ=90°, unit cell volume Number of molecules in unit cell z=2, density calculation dcalc=1.192 g/cm 3,μ＝0.684mm-1, F (000) =1596.0, fly parameter-0.07 (14), data collection range: 6.628 DEG or more 2 theta or less 155.356 DEG; diffraction finger table range: h is more than or equal to 16 and less than or equal to 15, k is more than or equal to-8 and less than or equal to 9, -50.ltoreq.l.ltoreq.50; and (3) reflection collection: 113981; independent diffraction points: 15350[ r int＝0.0855,Rsigma = 0.0776]; data limiting parameters: 15350/1/971; peaks and valleys of residual electron density after finishing are 0.25 and-0.24; r0.0614 [ I > 2σ (I) ] and wR 2 0.1781. The crystallographic data of 2-deoxyganpindone M has been uploaded to the Cambridge crystallographic data center crystal database, british (website: http:// www.ccdc.cam.ac.uk), process number CCDC2215280. After single crystal X-ray diffraction analysis, the chemical structure of 2-deoxyganinidone M was determined (fig. 1).
The 2-deoxidized ganpinacolone M belongs to ganciclone type sesquiterpene, is a main conversion product of ganciclone after heating reflux reaction in water, belongs to ganciclone type sesquiterpene, and has enol interconversion phenomenon; the hydroxyl group at the C-9 position on the parent nucleus can be acylated, etherified, amidated by a substituent to form an ester, alcohol ether, phenol ether or to form a nitrogen-containing compound. The structural formula is as follows:
Example 2
Effect of the Compounds described in example 1 on thoracic aortic diastolic Rate
The vasodilation activity of the nardostachyne and the degradation product 2-deoxynardostachyne M thereof is evaluated by using a mouse in vitro thoracic aortic ring vascular tension test.
1) Experimental instrument and reagent
Experimental instrument:
Multichannel ex vivo vascular tension test system 630AM (denmark DMT a/S company); PL3516 PowerLab biosignal acquisition analysis system (ADInstruments, australia); BST-18 fine scissors/fine tweezers (Shenzhen Ruiword life technologies Co., ltd.); LEICAS6E type microscope (Leica company, germany).
Experimental reagent:
Isoflurane was purchased from Shenzhen Ruiword life technologies Co., ltd; sodium Nitroprusside (SNP), acetylcholine chloride (ACh), dimethyl sulfoxide (dimethyl sulfoxide, DMSO), and 9, 11-dideoxy-11 a, 9 a-methyleneepoxy prostaglandin f2a (U46619) were purchased from Sigma-Aldrich, usa; anhydrous potassium dihydrogen phosphate (KH 2PO 4) and crystalline calcium chloride (CaCl 2·2H2 O) were purchased from bourets biotechnology limited in the Tianjin city; sodium chloride (NaCl), sodium bicarbonate (NaHCO 3) and D-glucose (D-glucose) were purchased from the Tianjin metallocene chemical reagent plant; magnesium sulfate (MgSO 4·7H2 O) was purchased from the light complex technology development limited of the division of the Tianjin; potassium chloride (KCl) was purchased from Tianjin Bo-European industry trade Co.
2) Experimental animal
SPF grade C57BL/6 male mice, 18-22 g, purchased from ston Bei Fu (Beijing) biotechnology Co., ltd, were bred in Tianjin university of traditional Chinese medicine animal center. The raising environment temperature is 25 ℃, the relative humidity is 50%, the ventilation system is good, the light and dark environment interval is 12h alternately circulated, and the mice are fed with normal food and drink water freely. Adaptive feeding was performed for 7 days before the start of the experiment. All experimental animal procedures meet the regulations of the experimental animal management of the people's republic of China.
3) Experimental procedure
The multichannel isolated blood vessel tension measurement system 630AM is used for vasodilation activity test, and the PowerLab biological signal acquisition and analysis system is used for recording blood vessel tension curve. C57BL/6 mice were anesthetized by inhalation of isoflurane. The thoracic cavity of the mice was dissected with tissue scissors, and the thoracic aorta was rapidly removed and placed in a K-H solution (Krebs-Henseleit, composed of NaCl(118),NaHCO3(24.0),KCl(4.7),MgSO4·7H2O(1.2),KH2PO4(1.8),CaCl2·2H2O(11.1),D-glucose(11)(mmol/L)). After carefully separating excess tissue and fat around the thoracic aorta using eye forceps, the blood vessel was cut into 4mm vascular rings with spring scissors. The aortic annulus was placed in a water bath of 5mL K-H solution at 37℃and a mixture of 95% O 2+5％CO2 was continuously injected. Under the microscope, the aortic annulus was screwed onto two parallel steel needles. One steel needle is connected to the pressure sensor and the other to the tension adjustment knob, when no force is applied to the ring. After 15 minutes, the instrument was set to zero, the vascular tension was adjusted to 5mN, and the K-H solution was changed. Thereafter, the K-H solution was changed every 15 minutes, and the vascular tension was maintained at 5mN for 60 minutes. The mouse aortic annulus was pre-contracted with 10 -8 mol/L U46619. After the aortic annulus reached the maximum contraction value about 30 minutes, acetylcholine (10 -9～10-5 mol/L) was added sequentially every 2 minutes. Recording a diastolic curve, and if the maximum diastolic rate reaches 60-80%, completing the aortic annular inner skin; acetylcholine (10 -10～10-6 mol/L) was added sequentially at 1 minute intervals. The diastolic curve is recorded and if the maximum diastolic rate reaches more than 80%, the smooth muscle layer of the aortic annulus is intact. Only if the vascular endothelium and smooth muscle are intact, the next step can be taken. After the aortic annulus is pre-pulled by U46619, solutions of the medicaments to be tested (dissolved by adding a small amount of solvent DMSO) with different concentrations are added cumulatively every 5 minutes, namely 100, 200, 300, 400 mu mol/L of nardostachyne, 25, 75 mu mol/L of 2-deoxynardostachyne M and 50, 100, 150, 200 mu mol/L of aristolochia ketone, and the control group is added with equal volumes of DMSO in sequence. And calculates its diastolic rate using the following formula and draws a diastolic curve.
GU46619: maximum contractile force caused by U46619; GX: contractile force of the drug after 5 minutes of action; g0: resting contractile force.
4) Data analysis:
Experimental results are expressed in mean±sem; data comparison between the two groups data comparison between groups was performed using independent sample T-test using one-way ANOVA. p < 0.05 is considered statistically significant. Statistical analysis was performed using Origin 2021 software.
5) Experimental results
As can be seen from fig. 2, 2-deoxyganisterne M can significantly increase the diastole rate of thoracic aorta of C57BL/6 mice (n=3, compared with the control group), and shows stronger arterial vascular ring diastole effect than that of ganisterne. The vasodilation rate of the nardostachyne at the concentration of 400 mu M is 74.57%, and the vasodilation rate of the 2-deoxynardostachyne M at the concentration of 75 mu M reaches 80.39%. Compared with aristolochic ketone, 2-deoxynardosinone M shows stronger arterial vessel ring relaxation effect than aristolochic ketone. The structural formula of the aristolochone is as follows:
In conclusion, the 2-deoxygandone M is obtained by separating degradation products of the hot water reflux of the ganciclovir, and the test and research of the blood vessel tension of the thoracic aorta of mice are carried out, so that the 2-deoxyganciclovir M can obviously relax the blood vessel contraction caused by U46619, and can be used as a potential therapeutic drug for treating hypertension, preventing and/or treating cardiovascular diseases.
Example 3
Comparison of the thermal stability of the Compounds described in example 1 with Nardostachyos New one and Aristolone
The above 3 compounds were dispersed in a pure water solvent, heated under reflux with boiling water for 2 hours, and examined for thermal stability.
1) Experimental instrument and reagent
Experimental instrument:
ACQUITY H class plus ultra performance liquid chromatograph (waters company, usa); milli-Q ultra-pure water instrument (Millipore Co., U.S.A.); ML 079 bench centrifuge (Eppendorf company, germany); DZTW temperature-regulating electrothermal sleeve (Yongguangming medical instruments Co., ltd. In Beijing).
Experimental reagent:
chromatographic grade acetonitrile and formic acid (sammer feishier technologies limited); drohent's water (haha group limited, child, hangzhou); analytical grade methanol (Kangkode technologies Co., ltd.).
2) Chromatographic conditions
ACQUITYH class plus system, column is ACQUITY UPLCBEH C column (2.1 mm. Times.100 mm,1.7 μm), column temperature: 35 ℃, mobile phase: acetonitrile (a), 0.1% formic acid-water (B). Flow rate: 0.3mL/min, wavelength: 270nm, sample injection amount: 3 μl, gradient elution conditions: 0-22 min, 18-26% (A); 22-30 min and 26-95% (A).
3) Experimental procedure
Respectively taking 5mg of 2-deoxyganarone M, ganaxolone and aristolochic ketone, adding 30mL of pure water, heating and refluxing with boiling water for 2 hours, respectively sucking 500 mu L of reaction liquid in a centrifuge tube at 0, 0.5, 1.0 and 2.0 hours, adding methanol with equal volume, shaking uniformly, centrifuging at 14000rpm for 10min, taking supernatant, and carrying out chromatographic analysis according to the UPLC method.
4) Experimental results
As shown in fig. 3, fig. 3a, fig. 3b and fig. 3c are UHPLC chromatograms of nardostachyne, 2-deoxynardostachyne M and aristolenone, respectively, heated and refluxed in boiling water for 2 hours, and fig. 3d is a plot of the relative content change of these 3 compounds in boiling water for different periods of time. The figure shows that the nardostachyne is unstable and easy to degrade under the high temperature condition; compared with the novel nardostachyne, the 2-deoxynardostachyne M and the aristolenone are more stable in heat, wherein the aristolenone is slightly degraded under the high-temperature condition to generate a small amount of degradation products, and the 2-deoxynardostachyne M has better stability in hot water.
Example 4
Tablet: 2-deoxyganine ketone M10 mg
Lactose 187mg
Corn starch 50mg
Magnesium stearate 3mg
The preparation method comprises the following steps: uniformly mixing 2-deoxyganine ketone M, lactose and starch according to the proportion, sieving with a 200-mesh sieve, uniformly wetting with water, drying the wetted mixture, sieving again, adding magnesium stearate, tabletting the mixture, wherein each tablet weighs 250mg, and the content of active ingredients is 10mg.
Example 5
The capsule comprises the following components: 2-deoxyganine ketone M20 mg
Galactose 188mg
Magnesium stearate 2mg
The preparation method comprises the following steps: uniformly mixing 2-deoxyganine ketone M and galactose according to the proportion, sieving with a 200-mesh sieve, adding magnesium stearate into the obtained mixture, and filling into a No. 2 capsule.
The above examples are only illustrative of the preferred embodiments of the present invention and are not intended to limit the scope of the present invention, and various modifications and improvements made by those skilled in the art to the technical solutions of the present invention should fall within the scope of protection defined by the claims of the present invention without departing from the spirit of the design of the present invention.
Claims (6)
1. A degradation product of a novel ketone of lycopodium clavatum, characterized in that: 2-deoxyganine ketone M has a structure shown in a structural formula (I):
2. the method for preparing the degradation product of the nardostachyne according to claim 1, characterized in that: the method comprises the following specific steps:
(1) Heating and refluxing the nardostachyne with pure water for 2.5 hours, and concentrating under reduced pressure to obtain a hot water degradation product mixture of the nardostachyne;
(2) Subjecting the obtained degradation product mixture to ODS reversed phase column chromatography, and gradient eluting with methanol-pure water=30:70, 40:60, 50:50, 60:40, 70:30, 85:15, 100:0 solvent system to obtain 9 components Fr.1-9;
(3) And (3) eluting the component, namely the component Fr.4, by using a solvent of methanol-pure water=50:50 to obtain 2-deoxynardosinone M which is a degradation product of nardostachyne.
3. Use of the degradation product of nardostachyne according to claim 1 for the preparation of a medicament for the prevention and/or treatment of cardiovascular diseases.
4. Use of the degradation product of nardostachyne according to claim 1 for the preparation of a medicament for the prevention and/or treatment of hypertensive disorders.
5. A pharmaceutical composition having the degradation product of nardostachyne of claim 1, characterized in that: comprising a therapeutically and/or prophylactically effective amount of 2-deoxyganine ketone M and optionally pharmaceutically acceptable excipients.
6. The pharmaceutical composition according to claim 5, wherein: the dosage forms are tablets, powder, granules, capsules, oral liquid, ointment, cream, injection emulsion or sterile powder injection.
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