CN115716812B - Bisabolane sesquiterpene compound in stellera chamaejasme and application thereof - Google Patents
Bisabolane sesquiterpene compound in stellera chamaejasme and application thereof Download PDFInfo
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- 241001263604 Stellera chamaejasme Species 0.000 title claims abstract description 24
- -1 Bisabolane sesquiterpene compound Chemical class 0.000 title claims abstract description 19
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 12
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 10
- 208000036110 Neuroinflammatory disease Diseases 0.000 claims abstract description 8
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 8
- 230000003959 neuroinflammation Effects 0.000 claims abstract description 6
- 238000004440 column chromatography Methods 0.000 claims abstract description 4
- 230000002401 inhibitory effect Effects 0.000 claims abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 229940125904 compound 1 Drugs 0.000 claims description 13
- 229940125782 compound 2 Drugs 0.000 claims description 13
- 206010061218 Inflammation Diseases 0.000 claims description 9
- 241001263603 Stellera Species 0.000 claims description 9
- 230000004054 inflammatory process Effects 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 238000004458 analytical method Methods 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 claims description 3
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 238000004007 reversed phase HPLC Methods 0.000 claims description 3
- 229930004725 sesquiterpene Natural products 0.000 claims description 3
- 238000010828 elution Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 24
- 229940079593 drug Drugs 0.000 abstract description 6
- 238000002481 ethanol extraction Methods 0.000 abstract 1
- 238000003810 ethyl acetate extraction Methods 0.000 abstract 1
- 239000007791 liquid phase Substances 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- 238000005191 phase separation Methods 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
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- 238000010586 diagram Methods 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 238000001052 heteronuclear multiple bond coherence spectrum Methods 0.000 description 4
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- 229910052739 hydrogen Inorganic materials 0.000 description 4
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- 208000015181 infectious disease Diseases 0.000 description 4
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- 238000005481 NMR spectroscopy Methods 0.000 description 3
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- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 3
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 210000005007 innate immune system Anatomy 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
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- 241000196324 Embryophyta Species 0.000 description 2
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 238000001142 circular dichroism spectrum Methods 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
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- 150000002500 ions Chemical class 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
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- 239000002904 solvent Substances 0.000 description 2
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- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 2
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 2
- 235000012141 vanillin Nutrition 0.000 description 2
- 238000005084 2D-nuclear magnetic resonance Methods 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
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- 206010010904 Convulsion Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 244000141359 Malus pumila Species 0.000 description 1
- 235000011430 Malus pumila Nutrition 0.000 description 1
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 1
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 1
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- NOWQRWPUNHMSAF-UHFFFAOYSA-N bisabolane Chemical compound CC(C)CCCC(C)C1CCC(C)CC1 NOWQRWPUNHMSAF-UHFFFAOYSA-N 0.000 description 1
- 229930014717 bisabolane Natural products 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003501 co-culture Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
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- 230000000254 damaging effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 150000004141 diterpene derivatives Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 150000002212 flavone derivatives Chemical class 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
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- 230000036039 immunity Effects 0.000 description 1
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- 238000001802 infusion Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 229930013686 lignan Natural products 0.000 description 1
- 150000005692 lignans Chemical class 0.000 description 1
- 235000009408 lignans Nutrition 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- DYKFCLLONBREIL-KVUCHLLUSA-N minocycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O DYKFCLLONBREIL-KVUCHLLUSA-N 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
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- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
An bisabolane sesquiterpene compound in stellera chamaejasme and application thereof belong to the technical field of medicines, and particularly discloses a novel bisabolane sesquiterpene compound prepared from stellera chamaejasme and application of the novel bisabolane sesquiterpene compound in medicines for treating neurodegenerative diseases caused by neuroinflammation. The compound is obtained through ethanol extraction, ethyl acetate extraction, silica gel column chromatography, HP-20 column and ODS open column chromatography, silica gel column chromatography and preparative high performance liquid phase separation. The compound and the composition containing the compound have the function of inhibiting neuroinflammation and are used for preparing anti-neuroinflammation medicines.
Description
Technical Field
The invention belongs to the technical field of medicines, and in particular relates to a novel bisabolane sesquiterpene compound prepared from stellera chamaejasme and application of the compound in the aspect of nerve treatment of neurodegenerative diseases.
Background
Stellera chamaejasme L is a perennial herb of the genus stellera of the family stelleriaceae. The total number of the stellera plants is 10-12 worldwide, and only 2 plants in China. Wherein stellera chamaejasme is a representative plant of the genus, is also a genuine product of Chinese medicinal stellera chamaejasme, and has the effects of purging water, expelling retained fluid, removing stasis and killing insects. Studies on stellera chamaejasme have shown that the stellera chamaejasme contains various chemical components, including compounds such as daphne diterpene, sesquiterpene, flavone, lignan, coumarin and the like, and has the effects of resisting tumor, inflammation, HIV, bacteria, insects, convulsion, immunity and the like.
Inflammation (infusion): a defensive response of the body to stimulus is manifested by redness, swelling, heat, pain and dysfunction. Inflammation is classified into two types, and may be infectious inflammation caused by infection or non-infectious inflammation caused by infection. Such as attacks on the body's own tissues, inflammation occurring in transparent tissues, etc.
Neurodegenerative diseases (Neurodegenerative diseases) and inflammation: neurodegenerative diseases are an irreversible group of neurological diseases caused by neuronal loss of the brain and spinal cord characterized by delayed onset and dysfunction of selective neurons. The chronic inflammatory environment in the brain is a hallmark of neurodegenerative diseases such as alzheimer's disease and parkinson's disease. Much evidence suggests that inflammation plays an important role in the occurrence of neurodegenerative diseases. The innate immune system is a natural immune defensive function that develops during the development and evolution of the germ line. Compared with another specific immune response of the organism, the novel immune response kit can rapidly respond to various harmful substances to protect the organism. The innate immune system itself is activated by a double sword. The long term and uncontrolled stimulation of harmful substances (e.g., aβ in aggregated form) initiates the innate immune system, which can produce damaging effects on the brain.
Disclosure of Invention
The invention provides 2 new bisabolane sesquiterpene compounds or pharmaceutically acceptable salts thereof extracted and separated from Stellera chamaejasme (Stellera Linn.) belonging to Stellera of Stellera.
The bisabolane sesquiterpene compound is as follows:
the pharmaceutically acceptable salt is a salt formed by the bisabolane sesquiterpene compound and acid; the acid comprises hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, citric acid, tartaric acid, apple tree, benzoic acid and benzenesulfonic acid.
The preparation method of the bisabolane sesquiterpene compound comprises the following steps:
(1) Extracting dried stellera chamaejasme root with ethanol, mixing the extracting solutions, concentrating to obtain an extract, extracting the extract with ethyl acetate, subjecting the obtained fraction to silica gel column chromatography, performing gradient elution with dichloromethane-methanol according to a volume ratio of 100:0-0:100, collecting 6 fractions, and marking as Fr.A-Fr.F;
(2) Subjecting the fraction Fr.B to HP-20 column and ODS open column chromatography, and gradient eluting with methanol-water at volume ratio of 10:90-90:10 to obtain 4 fractions Fr.B1-Fr.B4;
(3) Subjecting the fraction Fr.B3 to silica gel column chromatography to obtain 4 subfractions Fr.B3a-Fr.B3d based on TLC analysis with petroleum ether-dichloromethane at volume ratio of 50:1-1:1;
(4) Separation of fr.b3b on preparative reverse phase high performance liquid chromatography using a methanol-water mobile phase gives compound 1 and compound 2, respectively.
Wherein the Stellera chamaejasme of step (1) is Stellera chamaejasme (Stellera Linn.) belonging to Stellera (Stellera chamaejasme L.).
In the step (1), the ethanol is 70-80% industrial ethanol, and the extraction is ethanol reflux extraction for 2-3 times, each time for 2-4 hours.
The system structure identification results of the compounds 1-2 are as follows, and the corresponding spectrograms are shown in fig. 1-15:
the structure of compounds 1-2 was identified using high resolution mass spectrometry, one-dimensional NMR, two-dimensional NMR, and computational ECD techniques.
Stellerasespene A (1) pale yellow oil (methanol). Is easily dissolved in dichloromethane,In ethyl acetate and methanol solvent, 5% vanillin sulfuric acid turns purple. HRESIMS gives an excimer ion peak [ M+Na ]] + m/z 273.1460(calcd for C 15 H 22 O 3 Na, 273.1461), and the molecular formula of the compound is presumed to be C by combining 1D NMR and HSQC nuclear magnetic data 15 H 22 O 3 The unsaturation was 5.
1 H-NMR(600MHz,DMSO-d 6 ) In the spectrum, delta H 7.22 (1 h, m, h-2), 6.99 (1 h, d, j=7.3 hz, h-4), 7.16 (1 h, t, j=7.5 hz, h-5), 7.21 (1 h, m, h-6) are presumed to be a set of 1, 3-disubstituted benzene ring proton signals; delta H 4.21 (1 h, dtd, j=7.2, 3.6,1.9hz, h-9), 3.70 (1 h, d, j=3.6 hz, h-10) is presumed to be a proton signal on two oxygen carbons; delta H 2.10 (1h, dd, j=12.9, 1.9hz, h-8β), 1.92 (1h, dd, j=12.9, 7.2hz, h-8α) is presumed to be a set of proton signals of magnetically unequal methylene groups; delta H 2.28 (3H, s, H-15), 1.53 (3H, s, H-14), 1.13 (3H, s, H-12) and 1.04 (3H, s, H-13) are presumed to be proton signals of four methyl groups; 13C-NMR (150 MHz, DMSO-d 6 ) Of which 15 carbon signals are given, wherein the low field region has 6 carbon signals, delta C 149.0 (C-1), 137.1 (C-3), 128.1 (C-5), 127.0 (C-4), 125.4 (C-2), 121.9 (C-6) are presumed to be the carbon signals of a set of benzene rings; high field delta C 92.9 (C-10), 84.0 (C-7), 72.1 (C-9), 70.3 (C-11) speculated as the carbon signal of four carbon atoms, δ C 29.3 (C-14), 27.4 (C-13), 25.9 (C-12), 21.7 (C-15) are presumed to be the carbon signal of four methyl groups. Signals of carbon and hydrogen are attributed through an HSQC spectrogram.
In the HMBC spectra, H-4 (delta) H 6.99 And C-2 (delta) C 125.4 Related H-5 (delta) H 7.16 And C-1 (delta) C 149.4),C-3(δ C 137.1 Related H-6 (delta) H 7.21 And C-2 (delta) C 125.4),C-4(δ C 127.0 Related H-15 (delta) H 6.99 And C-2 (delta) C 125.4),C-3(δ C 137.1),C-4(δ C 127.0 Related, and therefore presumably a 3-methylphenyl fragment; h-14 (delta) H 1.53 And C-7 (delta) C 84.0),C-8(δ C 49.2 Related H-8 (delta) H 2.10 And C-10 (delta) C 92.9 Related 9-OH (delta) H 4.94 And C-8 (delta) C 49.2),C-9(δ C 72.1),C-10(δ C 92.9 Related H-10 (delta) H 3.70 And C-7 (delta) C 84.0 Related H-12 (delta) H 1.04)/H-13(δ H 1.13 And C-10 (delta) C 92.9),C-11(δ C 70.3 Related 11-OH (delta) H 4.15 And C-11 (delta) C 70.3),C-12(δ C 25.9),C-13(δ C 27.4 Related, thus speculated as fragment B; h-2 (delta) H 7.22)/H-6(δ H 7.21 And C-7 (delta) C 84.0 Related H-8 (delta) H 1.92)/H-14(δ H 1.53 And C-1 (delta) C 149.4 Related, segment B is presumed to be linked to segment A by C-1-C-7. From the above information, the planar structure of the compound is established.
The relative configuration of the compound was determined by NOESY spectra. H-10 (delta) H 3.70 With H) 3 -14(δ H 1.53),9-OH(δ H 4.94 Related H-9 (delta) H 4.21 With H) 3 -12(δ H 1.04),H 3 -13(δ H 1.13 Related, the relative configuration of the compound is presumed to be 7R,9S,10S.
The absolute configuration of compound 1 was determined by comparing the calculated ECD with the measured ECD. The measured ECD plot of compound 1 shows a better fit to the calculated ECD plot of 7R,9S,10S-1, and therefore, the absolute configuration of compound 1 is 7R,9S,10S.
From the above information, the structure of this compound was determined and designated Stellerasespene A.
Compound 1 1 H (600 MHz) and 13 c (150 MHz) NMR data (DMSO-d 6 )
Stellerasespene B (2) pale yellow oil (dichloromethane) is easily dissolved in methanol, dichloromethane, ethyl acetate, and methanol solvent. 5% vanillin appears blue. HRESIMS gives an excimer ion peak [ M+H ]] + m/z 233.1536(calcd for C 15 H 21 O 2 233.1536), combined with 1 H-NMR, 13 C-NMR and HSQC spectra speculated that the molecular formula was C 15 H 21 O 2 The calculated unsaturation was 6.
1 H-NMR(400MHz,CDCl 3 ) In delta H 4.77 (1H, t, J=1.3 Hz, H-12 a), 4.75 (1H, br s, H-12 b) is presumed to be a hydrogen signal on a set of terminal double bonds, δ H 2.73 (1h, dt, j=13.2, 3.1hz, h-9α), 1.26 (1h, td, j=13.2, 3.6hz, h-9β), 2.20 (1h, d, j=18.9hz, h-2α), 2.46 (1h, d, j=18.9hz, h-2β) are presumed to be two sets of hydrogen signals of magnetically unequal methylene groups, δ H 2.04 (3H, s, H-14), 1.78 (3H, s, H-15), 1.73 (3H, s, H-13) are presumed to be hydrogen signals of three methyl groups. 13 C-NMR(100MHz,CDCl 3 ) Shows 15 carbon signals, and the low field region shows 6 carbon signals, including delta C 207.7 (C-10), 206.3 (C-3), 173.4 (C-5), 148.1 (C-11), 136.5 (C-4), 110.1 (C-12), two ketocarbonyl carbon signals and two sets of double bond carbon signals, including the carbon signal of one set of terminal double bonds, high field delta C 25.4 (C-14), 20.6 (C-13), 8.2 (C-15) are three methyl carbon signals. All hydrocarbon direct correlation signals are subjected to full attribution through an HSQC spectrum.
In HMBC spectra, H 2 -2(δ H 2.46,2.20) and C-1 (delta) C 58.6),C-3(δ C 206.3),C-5(δ C 173.4 Related H3-15 (delta) H 1.78 And C-3 (delta) C 206.3),C-4(δ C 136.5),C-5(δ C 173.4 Related to the fragment A. H-6 (delta) H 2.87 And C-8 (delta) C 28.8 Related H-8 (delta) H 1.80 And C-1 (delta) C 58.6 Related H-9 (delta) H 1.26 And C-1 (delta) C 58.6),C-8(δ C 28.8 Related H-12 (delta) H 4.75 And C-7 (delta) C 46.1),C-11(δ C 148.1),C-13(δ C 20.6 Related H) 3 -13(δ H 1.73 And C-7 (delta) C 46.1),C-11(δ C 148.1),C-12(δ C 110.1 Related, and H-6 (delta) H 2.87 And C-4 (delta) C 136.5 Peak of correlation and H) 2 -2(δ H 2.46,2.20) and C-9 (delta) C 35.4 Indicating that fragments A and B are joined by C-1-C-5. H 3 -14(δ H 2.04 And C-1 (delta) C 58.6),C-10(δ C 207.7 Related H) 2 -2(δ H 2.46,2.20)/H-9(δ H 1.26 And C-10 (delta) C 207.7 Related, presumably an acetyl group attached at the C-1 position. The plane structure of the compound 2 is established according to the related information, and the compound 2 is a sesquiterpene compound.
The relative configuration of the compound was determined by calculation of the nuclear magnetism due to the lack of valuable correlation signals in the NOESY spectrum. Two possible stereoisomers (1R, 7R) -2a and (1S, 7R) -2B were quantum-chemically calculated at the level mPW PW91/6-311+G (d, p)/B3 LYP6-31G (d) and their possible relative configurations were determined using linear correlation and DP4+ analysis. From the calculation, it can be seen that R corresponds to the linear regression equation of the two stereoisomers 2 0.9995 and 0.9986, respectively, while dp4+ statistical analysis gave a probability of (1R, 7R) -2a of 100%, the relative configuration of the compound was thus presumed to be 1R,7R.
The absolute configuration of the compound is obtained by comparing the calculated ECD with the measured ECD. The spectra of the measured ECD and the calculated ECD of (1R, 7R) -2 show a high degree of agreement, and therefore the absolute configuration of the compound is presumed to be 1R,7R.
From the above information, the structure of this compound was determined and designated stellerasespene B.
Compound 2 1 H (400 MHz) and 13 c (100 MHz) NMR data (CDCl) 3 )
The invention also provides a pharmaceutical composition, which comprises the bisabolane sesquiterpene compound, pharmaceutically acceptable salts of the compound, pharmaceutically acceptable excipients or/and carriers.
The invention also provides application of the stellera chamaejasme root extract in medicaments for treating neurodegenerative diseases caused by neuroinflammation.
The invention also provides application of the bisabolane sesquiterpene compound or the pharmaceutically acceptable salt thereof in medicines for treating neurodegenerative diseases caused by neuroinflammation.
The 2 novel bisabolane sesquiterpenoids provided by the invention are subjected to investigation on anti-neuroinflammation effect. The model for in vitro cell testing was Lipopolysaccharide (LPS) -induced mouse microglial BV-2 cells. The results show that the compounds have remarkable inhibition effect on inflammatory response induced by LPS.
The invention has the advantages that:
the bisabolane sesquiterpene compound provided by the invention is a novel compound, is novel in structure, is an optical pure compound with a determined three-dimensional configuration, is strong in nerve cell protection activity, and has further development value.
Drawings
FIG. 1 is the UV spectrum of compound 1 of the present invention;
FIG. 2 is an HR-ESIMS spectrum of Compound 1 of the present invention;
FIG. 3 is a CD spectrum of Compound 1 of the present invention;
FIG. 4 is a diagram of Compound 1 of the present invention 1 H-NMR spectrum (600 MHz, DMSO-d) 6 )；
FIG. 5 is a diagram of Compound 1 of the present invention 13 C-NMR spectrum (150 MHz, DMSO-d 6 )；
FIG. 6 is HSQC spectrum of Compound 1 of the present invention (600 MHz, DMSO-d 6 )；
FIG. 7 is a HMBC spectrum (600 MHz, DMSO-d) 6 )；
FIG. 8 is a NOESY spectrum (600 MHz, DMSO-d) of Compound 1 of the present invention 6 )；
FIG. 9 is a UV spectrum of Compound 2 of the present invention;
FIG. 10 is an HR-ESIMS spectrum of Compound 2 of the present invention;
FIG. 11 is a CD spectrum of Compound 2 of the present invention;
FIG. 12 is a diagram of Compound 2 of the present invention 1 H-NMR spectrum (400 MHz, DMSO);
FIG. 13 is a diagram of Compound 2 of the present invention 13 C-NMR spectrum (100 MHz, DMSO);
FIG. 14 is the HSQC spectrum (600 MHz, DMSO) of compound 2 of the present invention;
FIG. 15 is a HMBC spectrum (600 MHz, DMSO) of Compound 2 of the present invention.
Detailed Description
Example 1: the preparation of the compound 1-2 specifically comprises the following steps:
(1) Reflux-extracting dried radix Euphorbiae Fischerianae (50.0 kg) with 70% ethanol for 2 times, reflux-extracting for 2-4 hr each time, mixing extractive solutions, concentrating to obtain extract, extracting the extract with ethyl acetate, subjecting the obtained fraction to silica gel column chromatography, gradient eluting with dichloromethane-methanol at 100:0,50:1,30:1,20:1,10:1,5:1,3:1,1:1,0:100v/v, and collecting 6 fractions Fr.A-Fr.F.
(2) The fraction Fr.B was subjected to HP-20 column and ODS open column chromatography, and eluted with a gradient of methanol-water at 10:90,30:70,50:50,70:30,90:10v/v to give 4 fractions Fr.B1-Fr.B4.
(3) The fraction Fr.B3 was subjected to silica gel column chromatography with petroleum ether-dichloromethane at 50:1,30:1,20:1,10:1,5:1,3:1,1:1v/v to give 4 subfractions Fr.B3a-Fr.B3d on the basis of TLC analysis.
(4) Fr.B3b was separated on preparative reverse phase high performance liquid chromatography using a methanol-water 85:15v/v mobile phase to give compound 1 (7.0 mg) and compound 2 (20.1 mg).
Example 2
Investigation of the in vitro inhibition of LPS-induced inflammatory action of mouse microglial cells BV-2 by Compounds 1-2.
LPS-induced BV-2 cell NO product content was measured by Griess method. BV-2 cell line was placed in DMEM medium containing 10% fetal bovine serum and 1% diabody at 37℃with 5% CO 2 Is cultured in an incubator of (a). Cells stably subcultured to logarithmic growth were used for the experiment. Taking BV-2 microglioma cells in logarithmic growth phase at 5×10 3 The density of each hole is inoculated in a 96-well plate, 10 mu M of test compound is added when the cells grow to 60%, the cells are observed to grow well after co-culture for 1h, 10 mu g/mL of LPS is added, and the supernatant is taken after 24h and the concentration of NO is detected by using a NO kit. Absorbance was measured at 540nm using an ultraviolet spectrophotometer (Thermo Scientific Multiskan MK, shanghai, china).The results show that compounds 1 and 2 show better anti-inflammatory effect than the positive drug minocycline.
| Comp. | NO product (mu M) |
| 1 | 0.7±0.01*** |
| 2 | 1.1±0.08** |
| Mino | 1.5±0.31** |
| LPS | 5.2±0.02 ### |
NO product concentration in control versus model ### P<0.001; NO product concentration P of experimental group compared to model group<0.1,**P<0.05,***P<0.001。
Claims (9)
1. The bisabolane sesquiterpene compound or the pharmaceutically acceptable salt thereof in the stellera chamaejasme is characterized in that the bisabolane sesquiterpene compound is as follows:
2. the method for preparing the bisabolane-type sesquiterpenoids or pharmaceutically acceptable salts thereof according to claim 1, wherein the method for preparing the bisabolane-type sesquiterpenoids comprises the following steps:
(1) Extracting dried stellera chamaejasme root with ethanol, mixing the extracting solutions, concentrating to obtain an extract, extracting the extract with ethyl acetate, subjecting the obtained fraction to silica gel column chromatography, performing gradient elution with dichloromethane-methanol according to a volume ratio of 100:0-0:100, collecting 6 fractions, and marking as Fr.A-Fr.F;
(2) Subjecting the fraction Fr.B to HP-20 column and ODS open column chromatography, and gradient eluting with methanol-water at volume ratio of 10:90-90:10 to obtain 4 fractions Fr.B1-Fr.B4;
(3) Subjecting the fraction Fr.B3 to silica gel column chromatography to obtain 4 subfractions Fr.B3a-Fr.B3d based on TLC analysis with petroleum ether-dichloromethane at volume ratio of 50:1-1:1;
(4) Separation of fr.b3b on preparative reverse phase high performance liquid chromatography using a methanol-water mobile phase gives compound 1 and compound 2, respectively.
3. The preparation method according to claim 2, wherein the Stellera chamaejasme is Stellera chamaejasme (Stellera Linn.) belonging to Stellera (Stellera chamaejasme L.).
4. The method according to claim 2, wherein in the step (1), the ethanol is 70-80% industrial ethanol, and the extraction is ethanol reflux extraction for 2-3 times each for 2-4 hours.
5. A pharmaceutical composition comprising a bisabolane-type sesquiterpene compound according to claim 1, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, or/and a carrier.
6. The use of a bisabolane-type sesquiterpenoid or a pharmaceutically acceptable salt thereof according to claim 1, for the manufacture of a medicament for the treatment of neurodegenerative diseases caused by neuroinflammation.
7. The use according to claim 6, wherein the use is in the manufacture of a medicament for inhibiting LPS-induced BV-2 cell inflammation.
8. An extract of stellera chamaejasme, wherein the extract of stellera chamaejasme comprises the bisabolane sesquiterpene compound of claim 1.
9. The use of an extract of stellera chamaejasme root as claimed in claim 8, characterized by the use in the preparation of a medicament for the treatment of neurodegenerative diseases caused by neuroinflammation.
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| Jun Pan等.Stelleranoids A–M, guaiane-type sesquiterpenoids based on [5,7] bicyclic system from Stellera chamaejasme and their cytotoxic activity .Bioorganic Chemistry .2021,第115卷105251. * |
| 瑞香狼毒毒性部位的化学成分研究;黄弥娜;曹青青;李云青;费扬;李洋;李盛建;吕磊;赵亮;;环球中医药;9(09);1059-1064 * |
| 瑞香狼毒生物活性成分的提取与分离、纯化方法;张天柱;魏春雁;刘玉峰;;特产研究(01);57-60 * |
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