CN115160390B - Stilbene glucoside dimer compound and preparation method and application thereof - Google Patents
Stilbene glucoside dimer compound and preparation method and application thereof Download PDFInfo
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- CN115160390B CN115160390B CN202210717390.9A CN202210717390A CN115160390B CN 115160390 B CN115160390 B CN 115160390B CN 202210717390 A CN202210717390 A CN 202210717390A CN 115160390 B CN115160390 B CN 115160390B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 136
- -1 Stilbene glucoside Chemical class 0.000 title claims abstract description 96
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 title claims abstract description 95
- 235000021286 stilbenes Nutrition 0.000 title claims abstract description 95
- 239000000539 dimer Substances 0.000 title claims abstract description 91
- 229930182478 glucoside Natural products 0.000 title claims abstract description 79
- 238000002360 preparation method Methods 0.000 title claims abstract description 50
- 238000004440 column chromatography Methods 0.000 claims abstract description 22
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 18
- 230000032683 aging Effects 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 12
- JAYVHSBYKLLDJC-DSNJPTTOSA-N (E)-2,3,5,4'-tetrahydroxystilbene-2-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C(O)C=C(O)C=C1\C=C\C1=CC=C(O)C=C1 JAYVHSBYKLLDJC-DSNJPTTOSA-N 0.000 claims abstract description 10
- 238000000926 separation method Methods 0.000 claims abstract description 8
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 190
- 239000000243 solution Substances 0.000 claims description 38
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 claims description 30
- 238000004811 liquid chromatography Methods 0.000 claims description 28
- 229930182470 glycoside Natural products 0.000 claims description 18
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 229940125782 compound 2 Drugs 0.000 claims description 9
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 claims description 9
- 235000019359 magnesium stearate Nutrition 0.000 claims description 9
- 229940125904 compound 1 Drugs 0.000 claims description 8
- 239000003480 eluent Substances 0.000 claims description 8
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- 239000012507 Sephadex™ Substances 0.000 claims description 7
- 238000010828 elution Methods 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- 239000002798 polar solvent Substances 0.000 claims description 7
- 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 claims description 5
- 229940125898 compound 5 Drugs 0.000 claims description 5
- 239000008101 lactose Substances 0.000 claims description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 4
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000002994 raw material Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 241001289529 Fallopia multiflora Species 0.000 abstract description 2
- 150000008131 glucosides Chemical class 0.000 abstract description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 abstract 1
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical compound C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 description 86
- 239000001257 hydrogen Substances 0.000 description 86
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 44
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 34
- 238000001228 spectrum Methods 0.000 description 29
- 229910052799 carbon Inorganic materials 0.000 description 28
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 26
- 239000000843 powder Substances 0.000 description 16
- 238000012360 testing method Methods 0.000 description 12
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 8
- 239000002775 capsule Substances 0.000 description 8
- 150000002431 hydrogen Chemical class 0.000 description 8
- 238000004262 preparative liquid chromatography Methods 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 241000244206 Nematoda Species 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 3
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
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- 229940126214 compound 3 Drugs 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- 239000000049 pigment Substances 0.000 description 3
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- 150000002338 glycosides Chemical class 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
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- 241000244203 Caenorhabditis elegans Species 0.000 description 1
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- 229920002472 Starch Polymers 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
- 239000004480 active ingredient Substances 0.000 description 1
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- 230000013016 learning Effects 0.000 description 1
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- 210000004185 liver Anatomy 0.000 description 1
- 230000007087 memory ability Effects 0.000 description 1
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- 230000004048 modification Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Toxicology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a stilbene glucoside dimer compound, and a preparation method and application thereof. The stilbene glucoside dimer compound provided by the invention can be used for preparing medicines for preventing and treating aging and diseases caused by the aging. Meanwhile, the polygonum multiflorum stilbene glucoside compound 2,3,5,4' -tetrahydroxy stilbene-2-O-beta-D-glucoside is adopted as a raw material, ferric trichloride is used for carrying out oxidation reaction with the raw material, and a column chromatography separation method is adopted for separation to obtain the stilbene glucoside dimer compound. The invention has the advantages of easily available raw materials, simple preparation method and strong operability.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a stilbene glucoside dimer compound, and a preparation method and application thereof.
Background
The stilbene glucoside compound is a main active ingredient in polygonum multiflorum and has remarkable pharmacological activity. Modern researches have shown that stilbene glycoside compounds can protect nerves, improve learning and memory ability, repair brain injury, prevent and treat parkinsonism and Alzheimer's disease, protect vascular endothelial cells, relax blood vessels, promote proliferation of vascular endothelial cells, reduce cholesterol, inhibit atherosclerosis, resist oxidation, remove free radicals and prevent aging, and have many clinical pharmacological effects of protecting liver, resisting inflammation, resisting tumor, resisting depression, resisting osteoporosis, protecting kidney and the like.
The stilbene glycoside compound in the prior art is composed of a stilbene glycoside group and other substituent groups, and the stilbene glycoside dimer compound and the effect thereof have not been reported yet.
Disclosure of Invention
In view of the above, the invention provides a stilbene glucoside dimer compound, and a preparation method and application thereof. The stilbene glucoside dimer compound provided by the invention can be used for preparing medicines for preventing and treating aging and diseases caused by the aging.
In order to achieve the above object, the present invention provides a stilbene glycoside dimer compound having a structure represented by any one of the formulas I to VI:
in the formula I, 7-substituted hydrogen is alpha-oriented or beta-oriented; the hydrogen substituted at position 8 is in alpha-or beta-orientation; hydrogen substituted at the 7' position is in alpha-or beta-orientation; the hydrogen substituted at the 8' position is alpha-oriented or beta-oriented;
in the formula II, hydrogen substituted at the 7-position is alpha-oriented; hydrogen substituted at position 8 is alpha-oriented; hydrogen substituted at the 7' position is in the alpha-orientation; hydrogen substituted at the 8' position is alpha-oriented;
in the formula III, the hydrogen substituted at the 7' -position is in alpha-orientation or beta-orientation; the hydrogen substituted at the 8' position is alpha-oriented or beta-oriented;
in the formula IV, the hydrogen substituted at the 7-position is alpha-oriented or beta-oriented; the hydrogen substituted at position 8 is in alpha-or beta-orientation; hydrogen substituted at the 7' position is in alpha-or beta-orientation; the hydrogen substituted at the 8' position is alpha-oriented or beta-oriented;
in the formula V, hydrogen substituted at the 7-position is beta-oriented; hydrogen substituted at position 8 is beta-oriented; hydrogen substituted at the 7' position is in alpha-or beta-orientation; the hydrogen substituted at the 8' position is alpha-oriented or beta-oriented;
in the formula VI, the 7-substituted hydrogen is in alpha-orientation or beta-orientation; the hydrogen substituted at position 8 is in alpha-or beta-orientation; hydrogen substituted at the 7' position is in alpha-or beta-orientation; the hydrogen substituted at the 8' position is in the alpha-or beta-orientation.
Preferably, the stilbene glycoside dimer compound is any one of the compounds 1 to 16:
the invention also provides a preparation method of the stilbene glucoside dimer compound, which is characterized by comprising the following steps:
2,3,5,4' -tetrahydroxy stilbene-2-O-beta-D-glucoside and FeCl 3 Mixing with polar solvent, performing oxidation reaction, and performing ODS reversed phase column chromatography separation on the system obtained by the oxidation reaction to obtain a stilbene glucoside dimer compound set;
collecting the stilbene glucoside dimer compounds, performing sephadex column chromatography, eluting by adopting a methylene dichloride-methanol system, separating the obtained eluent by ODS column chromatography, performing gradient elution by adopting 10-100% methanol water solution, and obtaining 7 fractions named PF-1-PF-7 fractions according to the outflow sequence of the components;
purifying the PF-1 fraction by first preparation liquid chromatography, eluting with 8% acetonitrile water solution to obtain stilbene glucoside dimer compound with structure of formula IV;
purifying the PF-2 fraction by a second preparation liquid chromatography, eluting with 10% acetonitrile water solution to obtain stilbene glucoside dimer compound with structure of formula III;
purifying the PF-3 fraction by a third preparation liquid chromatography, eluting with an acetonitrile aqueous solution with a volume concentration of 12% to obtain a stilbene glucoside dimer compound with a structure shown in formula II;
purifying the PF-4 fraction by fourth preparation liquid chromatography, eluting with 12.5% acetonitrile water solution to obtain a first stilbene glucoside dimer compound with the structure shown in formula I; the orientations of the hydrogen substituted at the 7 position, the 8 position, the 7 'position and the 8' position of the first stilbene glucoside dimer compound with the structure shown in the formula I are the same;
purifying the PF-5 fraction by fifth preparation liquid chromatography, eluting with 15% acetonitrile water solution to obtain a second stilbene glucoside dimer compound with the structure shown in formula I;
hydrogen of 7-position, 8-position, 7 '-position and 8' -position substituted hydrogen in the second stilbene glucoside dimer compound with the structure of formula I is different in hydrogen orientation of at least two substitution sites;
purifying the PF-6 fraction by sixth preparation liquid chromatography, eluting with 17.5% acetonitrile water solution to obtain stilbene glucoside dimer compound with structure of formula V;
purifying the PF-7 fraction by seventh preparation liquid chromatography, eluting with 20% acetonitrile water solution to obtain stilbene glucoside dimer compound with structure of formula VI.
Preferably, the volume concentration of the aqueous methanol solution is 10%, 30%, 50%, 70% and 100% in this order.
Preferably, the volume ratio of dichloromethane to methanol in the dichloromethane-methanol system is 1:1.
Preferably, the temperature of the oxidation reaction is 35-40 ℃ and the time is 1-18 h.
The invention also provides application of the stilbene glucoside dimer compound or the stilbene glucoside dimer compound obtained by the preparation method in preparation of medicaments for preventing and treating aging and diseases caused by the aging.
Preferably, the medicament comprises the stilbene glucoside dimer compound and a pharmaceutically acceptable carrier.
Preferably, the carrier comprises a mixture of lactose and magnesium stearate, or a mixture of microcrystalline cellulose and magnesium stearate.
Preferably, the mass concentration of the stilbene glucoside dimer compound in the medicament is 10mg/300mg.
The invention provides a stilbene glucoside dimer compound which has a structure shown in formulas I-VI, and the stilbene glucoside compound can remove DPPH free radical and para-position 1 O 2 The free radical has selective quenching effect, so that the stilbene glucoside dimer compound can be used for preparing medicines for preventing and treating aging and diseases caused by the aging.
The invention also provides a preparation method of the stilbene glucoside dimer compound, which comprises the following steps: 2,3,5,4' -tetrahydroxy stilbene-2-O-beta-D-glucoside and FeCl 3 Mixing with polar solvent, performing oxidation reaction, and performing ODS reversed phase column chromatography separation on the system obtained by the oxidation reaction to obtain a stilbene glucoside dimer compound set; collecting the stilbene glucoside dimer compounds, performing sephadex column chromatography, eluting by adopting a methylene dichloride-methanol system, separating the obtained eluent by ODS column chromatography, performing gradient elution by adopting 10-100% methanol water solution, and obtaining 7 fractions named PF-1-PF-7 fractions according to the outflow sequence of the components; subjecting the PF-1 fraction to a first preparative liquid chromatography purification using a volume concentration of 8%Eluting with acetonitrile water solution to obtain stilbene glucoside dimer compound with structure of formula IV; purifying the PF-2 fraction by a second preparation liquid chromatography, eluting with 10% acetonitrile water solution to obtain stilbene glucoside dimer compound with structure of formula III; purifying the PF-3 fraction by a third preparation liquid chromatography, eluting with an acetonitrile aqueous solution with a volume concentration of 12% to obtain a stilbene glucoside dimer compound with a structure shown in formula II; purifying the PF-4 fraction by fourth preparation liquid chromatography, eluting with 12.5% acetonitrile water solution to obtain a first stilbene glucoside dimer compound with the structure shown in formula I; the orientations of the hydrogen substituted at the 7 position, the 8 position, the 7 'position and the 8' position of the first stilbene glucoside dimer compound with the structure shown in the formula I are the same; purifying the PF-5 fraction by fifth preparation liquid chromatography, eluting with 15% acetonitrile water solution to obtain a second stilbene glucoside dimer compound with the structure shown in formula I; hydrogen of 7-position, 8-position, 7 '-position and 8' -position substituted hydrogen in the second stilbene glucoside dimer compound with the structure of formula I is different in hydrogen orientation of at least two substitution sites; purifying the PF-6 fraction by sixth preparation liquid chromatography, eluting with 17.5% acetonitrile water solution to obtain stilbene glucoside dimer compound with structure of formula V; purifying the PF-7 fraction by seventh preparation liquid chromatography, eluting with 20% acetonitrile water solution to obtain stilbene glucoside dimer compound with structure of formula VI. The invention has the advantages of easily available raw materials, simple preparation method and strong operability.
Detailed Description
The invention provides a stilbene glucoside dimer compound, which has a structure shown in any one of formulas I to VI:
in the formula I, 7-substituted hydrogen is alpha-oriented or beta-oriented; the hydrogen substituted at position 8 is in alpha-or beta-orientation; hydrogen substituted at the 7' position is in alpha-or beta-orientation; the hydrogen substituted at the 8' position is alpha-oriented or beta-oriented;
in the formula II, hydrogen substituted at the 7-position is alpha-oriented; hydrogen substituted at position 8 is alpha-oriented; hydrogen substituted at the 7' position is in the alpha-orientation; hydrogen substituted at the 8' position is alpha-oriented;
in the formula III, the hydrogen substituted at the 7' -position is in alpha-orientation or beta-orientation; the hydrogen substituted at the 8' position is alpha-oriented or beta-oriented;
in the formula IV, the hydrogen substituted at the 7-position is alpha-oriented or beta-oriented; the hydrogen substituted at position 8 is in alpha-or beta-orientation; hydrogen substituted at the 7' position is in alpha-or beta-orientation; the hydrogen substituted at the 8' position is alpha-oriented or beta-oriented;
in the formula V, hydrogen substituted at the 7-position is beta-oriented; hydrogen substituted at position 8 is beta-oriented; hydrogen substituted at the 7' position is in alpha-or beta-orientation; the hydrogen substituted at the 8' position is alpha-oriented or beta-oriented;
in the formula VI, the 7-substituted hydrogen is in alpha-orientation or beta-orientation; the hydrogen substituted at position 8 is in alpha-or beta-orientation; hydrogen substituted at the 7' position is in alpha-or beta-orientation; the hydrogen substituted at the 8' position is in the alpha-or beta-orientation.
Specifically, the stilbene glucoside dimer compound provided by the invention is any one of compounds 1 to 16:
the invention also provides a preparation method of the stilbene glucoside dimer compound, which comprises the following steps:
2,3,5,4' -tetrahydroxy stilbene-2-O-beta-D-glucoside and FeCl 3 Mixing with polar solvent, performing oxidation reaction, and performing ODS reversed phase column chromatography separation on the system obtained by the oxidation reaction to obtain a stilbene glucoside dimer compound set;
collecting the stilbene glucoside dimer compounds, performing sephadex column chromatography, eluting by adopting a methylene dichloride-methanol system, separating the obtained eluent by ODS column chromatography, performing gradient elution by adopting 10-100% methanol water solution, and obtaining 7 fractions named PF-1-PF-7 fractions according to the outflow sequence of the components;
purifying the PF-1 fraction by first preparation liquid chromatography, eluting with 8% acetonitrile water solution to obtain stilbene glucoside dimer compound with structure of formula IV;
purifying the PF-2 fraction by a second preparation liquid chromatography, eluting with 10% acetonitrile water solution to obtain stilbene glucoside dimer compound with structure of formula III;
purifying the PF-3 fraction by a third preparation liquid chromatography, eluting with an acetonitrile aqueous solution with a volume concentration of 12% to obtain a stilbene glucoside dimer compound with a structure shown in formula II;
purifying the PF-4 fraction by fourth preparation liquid chromatography, eluting with 12.5% acetonitrile water solution to obtain a first stilbene glucoside dimer compound with the structure shown in formula I; the orientations of the hydrogen substituted at the 7 position, the 8 position, the 7 'position and the 8' position of the first stilbene glucoside dimer compound with the structure shown in the formula I are the same;
purifying the PF-5 fraction by fifth preparation liquid chromatography, eluting with 15% acetonitrile water solution to obtain a second stilbene glucoside dimer compound with the structure shown in formula I;
hydrogen of 7-position, 8-position, 7 '-position and 8' -position substituted hydrogen in the second stilbene glucoside dimer compound with the structure of formula I is different in hydrogen orientation of at least two substitution sites;
purifying the PF-6 fraction by sixth preparation liquid chromatography, eluting with 17.5% acetonitrile water solution to obtain stilbene glucoside dimer compound with structure of formula V;
purifying the PF-7 fraction by seventh preparation liquid chromatography, eluting with 20% acetonitrile water solution to obtain stilbene glucoside dimer compound with structure of formula VI.
In the present invention, the raw materials used in the present invention are preferably commercially available products unless otherwise specified.
The invention uses 2,3,5,4' -tetrahydroxy stilbene-2-O-beta-D-glucoside and FeCl 3 Mixing with polar solvent, oxidizing reaction, and ODS reversed phase column chromatographic separation to obtain stilbene glycoside dimer compound set.
In the present invention, the polar solvent is preferably an aqueous methanol solution or an aqueous ethanol solution; the volume concentration of the aqueous methanol solution is preferably 20 to 40%, more preferably 25%; the volume concentration of the aqueous ethanol solution is preferably 25 to 50%, more preferably 30%. In the present invention, the mass to polar solvent volume ratio of the 2,3,5,4' -tetrahydroxystilbene-2-O- β -D-glucoside is preferably 4g:40 mL-10 g:40mL; further preferably 5g:40mL. In the present invention, the 2,3,5,4' -tetrahydroxystilbene-2-O-beta-D-glucoside and FeCl 3 The mass ratio of (2) is preferably 6:3 to 10:3, more preferably 5:2.
In the present invention, the temperature of the oxidation reaction is preferably 35 to 40 ℃, and more preferably 36 to 38 ℃. In the present invention, the time of the oxidation reaction is preferably 1 to 18 hours, more preferably 15 hours. In the present invention, the temperature of the oxidation reaction is preferably provided in a water bath, and the oxidation reaction is preferably performed under shaking conditions, and the frequency of the shaking is not particularly limited in the present invention, and may be a frequency well known to those skilled in the art.
In the present invention, the eluent for ODS reversed-phase column chromatography is preferably methanol. In the present invention, the ODS reversed-phase column chromatography separation preferably further comprises eluting with water before eluting with methanol. In the present invention, the water rinse may remove remaining iron ions in the reaction product.
After the ODS reversed-phase column chromatography, the present invention preferably further comprises concentrating the obtained eluent to remove the eluent.
After collecting stilbene glucoside dimer compounds, the invention carries out sephadex column chromatography on the stilbene glucoside dimer compounds, and adopts a methylene dichloride-methanol system for elution, the obtained eluent is separated by ODS column chromatography, and 7 fractions named PF-1-PF-7 fractions are obtained by gradient elution with 10-100% methanol aqueous solution by volume concentration.
In the present invention, the volume ratio of dichloromethane to methanol in the dichloromethane-methanol system is preferably 1:1. In the present invention, the process of sephadex column chromatography separation preferably further comprises obtaining a pigment fraction, and discarding the obtained pigment fraction.
After PF-1-PF-7 fraction is obtained, the PF-1 fraction is subjected to first preparation liquid chromatography purification, and an acetonitrile aqueous solution with the volume concentration of 8% is adopted for elution, so that the stilbene glucoside dimer compound with the structure shown in the formula IV is obtained. In the present invention, the flow rate is preferably 6mL/min when the 8% acetonitrile aqueous solution is eluted. In the embodiment of the invention, the stilbene glucoside dimer compound with the structure shown in the formula IV is specifically compounds 10 to 12.
After PF-1-PF-7 fraction is obtained, the PF-2 fraction is subjected to second preparation liquid chromatography purification, and an acetonitrile aqueous solution with volume concentration of 10% is used for eluting to obtain the stilbene glucoside dimer compound with the structure shown in the formula III. In the present invention, the flow rate is preferably 6mL/min when the 10% acetonitrile aqueous solution is eluted. In the embodiment of the invention, the stilbene glucoside dimer compound with the structure shown in the formula IV is specifically compounds 7 to 9.
After PF-1-PF-7 fraction is obtained, the PF-3 fraction is purified by a third preparation liquid chromatography, and an acetonitrile aqueous solution with the volume concentration of 12% is used for eluting to obtain the stilbene glucoside dimer compound with the structure shown in the formula II. In the present invention, the flow rate is preferably 6mL/min when the 12% acetonitrile aqueous solution is eluted. In the embodiment of the invention, the stilbene glycoside dimer compound with the structure shown in the formula IV is specifically a compound 6.
After PF-1-PF-7 fraction is obtained, the PF-4 fraction is purified by a fourth preparation liquid chromatography, and is eluted by an acetonitrile water solution with the volume concentration of 12.5 percent to obtain a first stilbene glucoside dimer compound with the structure shown in the formula I; the orientations of the hydrogen substituted at the 7 position, the 8 position, the 7 'position and the 8' position of the first stilbene glucoside dimer compound with the structure shown in the formula I are the same. In the present invention, the flow rate is preferably 6mL/min when the 12.5% acetonitrile aqueous solution is eluted. In the embodiment of the invention, the first stilbene glucoside dimer compound with the structure shown in the formula I is specifically compounds 1-2.
After obtaining PF-1-PF-7 fraction, purifying PF-5 fraction by fifth preparation liquid chromatography, eluting with 15% acetonitrile water solution to obtain second stilbene glucoside dimer compound with structure of formula I; the hydrogen of 7-position, 8-position, 7 '-position and 8' -position substituted hydrogen in the second stilbene glucoside dimer compound with the structure of formula I is different in hydrogen orientation of at least two substitution sites. In the present invention, the flow rate is preferably 6mL/min when the 15% acetonitrile aqueous solution is eluted. In the embodiment of the invention, the second distyrene glycoside dimer compound with the structure shown in the formula I is specifically compounds 3-5.
After obtaining PF-1 to PF-7 fractions, purifying the PF-6 fraction by a sixth preparative liquid chromatograph, eluting with an aqueous acetonitrile solution having a volume concentration of 17.5% to obtain a stilbene glycoside dimer compound having a structure of formula V, wherein the flow rate is preferably 6mL/min when eluting with the aqueous 17.5% acetonitrile solution. In the embodiment of the invention, the stilbene glucoside dimer compound with the structure shown in the formula IV is specifically compounds 13 to 14.
After obtaining PF-1-PF-7 fraction, purifying the PF-7 fraction by seventh preparation liquid chromatography, eluting with 20% acetonitrile water solution to obtain stilbene glucoside dimer compound with structure of formula VI; in the present invention, the flow rate is preferably 6mL/min when the 20% acetonitrile aqueous solution is eluted. In the embodiment of the invention, the stilbene glucoside dimer compound with the structure shown in the formula IV is specifically compounds 15-16.
The invention also provides application of the stilbene glucoside dimer compound or the stilbene glucoside dimer compound obtained by the preparation method in preparation of medicaments for preventing and treating aging and diseases caused by the aging.
In the present invention, the drug preferably comprises the stilbene glycoside dimer compound and a pharmaceutically acceptable carrier.
In the present invention, the carrier preferably comprises a mixture of lactose and magnesium stearate, or a mixture of microcrystalline cellulose and magnesium stearate. In the invention, the mass concentration of the stilbene glucoside dimer compound in the medicament is preferably 10mg/300mg.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
5g of 2,3,5,4' -tetrahydroxy stilbene-2-O-beta-D-glucoside is weighed and placed in a 100mL triangular flask, and 40mL of 25% methanol aqueous solution is added to dissolve the glucoside completely. Then, feCl is weighed 3 2g of the mixture is added into 2,3,5,4' -tetrahydroxy stilbene-2-O-beta-D-glucoside solution, and the mixture is shaken in a water bath at 37 ℃ to carry out oxidation reaction for 10 hours.
Transferring the oxidation reaction product obtained by the reaction to an open ODS reversed-phase column chromatography, eluting by using distilled water as a mobile phase, removing residual iron ions in the reaction product, eluting by using methanol as the mobile phase, merging methanol parts, concentrating by using a rotary evaporator, and removing methanol to obtain the stilbene glucoside dimer compound.
Subjecting the stilbene glucoside dimer compound to sephadex column chromatography, eluting with dichloromethane-methanol system (volume ratio of 1:1), removing pigment fraction, subjecting the eluate to ODS column chromatography, and gradient eluting with methanol aqueous solution with methanol volume concentration of 10%, 30%, 50%, 70%, 100% to obtain 7 fractions named PF-1-PF-7 fraction.
Purifying PF-1 fraction by first preparative liquid chromatography, eluting with 8% acetonitrile water as mobile phase at flow rate of 6mL/min to obtain compound 10 (8.2 mg, t) R =22 min), compound 11 (12.4 mg, t R =29 min), compound 12 (21.5 mg, t R ＝44min)；
Purifying PF-2 fraction by second preparative liquid chromatography, eluting with 10% acetonitrile water as mobile phase at flow rate of 6mL/min to obtain compound 7 (13.3 mg, t) R =14 min), compound 8 (9.6 mg, t R =19 min), compound 9 (11.8 mg, t R ＝35min)；
Purifying PF-3 fraction by third preparative liquid chromatography, eluting with acetonitrile water with mobile phase of 12% and flow rate of 6mL/min to obtain compound 6 (16.3 mg, t) R ＝28min)；
Purifying PF-4 fraction by fourth preparative liquid chromatography, eluting with 12.5% acetonitrile water as mobile phase at flow rate of 6mL/min to obtain compound 1 (106.5 mg, t) R =34 min), compound 2 (23.4 mg, t R ＝45min)；
Purifying PF-5 fraction by fifth preparative liquid chromatography, eluting with 15% acetonitrile water as mobile phase at flow rate of 6mL/min to obtain compound 3 (9.5 mg, t) R =47 min), compound 4 (31.5 mg, t R =61 min), compound 5 (23.4 mg, t R ＝74min)；
Purifying PF-6 fraction by sixth preparative liquid chromatography, eluting with 17.5% acetonitrile water as mobile phase at flow rate of 6mL/min to obtain compound 13 (12.2 mg, t) R =27 min), compound 14 (15.5 mg, t R ＝42min)；
Subjecting PF-7 fraction to seventh preparative liquid chromatography, eluting with 20% acetonitrile water as mobile phase at flow rate of 6mL/min to obtain compound 15 (9 mg, t) R =66 min), compound 16 (8 mg, t R ＝69min)。
The physicochemical constants of compounds 1 to 16 are as follows:
compound 1: colorless powder (dissolution solvent: methanol); [ alpha ]]25D+21.9(c0.041,MeOH)；UV(MeOH)λ max (logε):282(3.75)nm；IR(KBr)ν max :3385,1615,1516,1466,1341,1255,1070,1008cm -1 ；HR-ESIMSm/z827.2366[M-H] - (calcdfor C 40 H 43 O 19 827.2399 confirm that compound 1 has the formula C 40 H 44 O 19 The method comprises the steps of carrying out a first treatment on the surface of the The carbon and hydrogen spectrum data are shown in Table 1.
Compound 2: colorless powder (MeOH); [ alpha ]]25D-93.2(c0.044,MeOH)；UV(MeOH)λ max (logε):281(3.77)nm；IR(KBr)ν max :3385,1615,1516,1466,1340,1250,1191,1037cm -1 ；HR-ESIMSm/z827.2366[M-H] - (calcdforC 40 H 43 O 19 827.2399 confirm that compound 2 has the formula C 40 H 44 O 19 The method comprises the steps of carrying out a first treatment on the surface of the The carbon and hydrogen spectrum data are shown in Table 1.
Table 1 carbon and hydrogen spectrum data for compound 1 and compound 2
Note that: the test solvent of the compound 1-2 is deuterated methanol, the hydrogen spectrum test is 600MHz, and the carbon spectrum test is 150MHz.
Compound 3: colorless powder (MeOH); [ alpha ]]25D-22.2(c0.027,MeOH)；UV(MeOH)λ max (logε):280(3.68)nm；IR(KBr)ν max :3363,1615,1516,1464,1224,1035cm -1 ；HR-ESIMSm/z827.2366[M-H] - (calcdforC 40 H 43 O 19 827.2399 confirm that compound 3 has the formula C 40 H 44 O 19 ； 13 C and C 1 The H data are shown in Table 2.
Compound 4: black powder (MeOH); [ alpha ]]25D-46.5(c0.043,MeOH)；UV(MeOH)λ max (logε):282(3.76)nm；IR(KBr)ν max :3393,1616,1598,1517,1466,1348,1251,1066cm -1 ；HR-ESIMSm/z827.2366[M-H] - (calcdforC 40 H 43 O 19 827.2399 confirm that compound 4 has the formula C 40 H 44 O 19 The method comprises the steps of carrying out a first treatment on the surface of the The carbon and hydrogen spectrum data are shown in Table 2.
Compound 5: black powder (MeOH); [ alpha ]]25D-35.3(c0.034,MeOH)；UV(MeOH)λ max (logε):281(3.74)nm；IR(KBr)ν max :3355,1616,1595,1517,1467,1345,1247,1069cm -1 ；HR-ESIMSm/z827.2366[M-H] - (calcdforC 40 H 43 O 19 827.2399 confirm that compound 5 has the formula C 40 H 44 O 19 The method comprises the steps of carrying out a first treatment on the surface of the The carbon and hydrogen spectrum data are shown in Table 2.
Table 2 carbon and Hydrogen Spectrum data for Compounds 3 to 5
Note that: the test solvent of the compounds 3-5 is deuterated methanol, the hydrogen spectrum test is 600MHz, and the carbon spectrum test is 150MHz.
Compound 6: colorless powder (MeOH); [ alpha ]]25D-2.94(c0.034,MeOH)；UV(MeOH)λ max (logε):284(4.01)nm；IR(KBr)ν max :3347,1611,1511,1457,1350,1261,1235,1069cm -1 ；HR-ESIMSm/z809.2325[M-H] - (calcdforC 40 H 41 O 18 809.2293 confirm that compound 6 has the formula C 40 H 42 O 18 The method comprises the steps of carrying out a first treatment on the surface of the The carbon and hydrogen spectrum data are shown in Table 3.
TABLE 3 carbon and hydrogen Spectrometry data for Compound 6
Compound 7: black powder (MeOH); [ alpha ]]25D+85.7(c0.0175,MeOH)；UV(MeOH)λ max (logε):320(4.26)nm；IR(KBr)ν max :3336,1608,1515,1457,1340,1255,1066cm -1 ；HR-ESIMSm/z809.2325[M-H] - (calcdforC 40 H 41 O 18 809.2293 confirm that compound 7 has the formula C 40 H 42 O 18 The method comprises the steps of carrying out a first treatment on the surface of the The carbon and hydrogen spectrum data are shown in Table 4.
Compound 8: black powder (MeOH); [ alpha ]]25D-57.1(c0.035,MeOH)；UV(MeOH)λ max (logε):320(4.25)nm；IR(KBr)ν max :3362,1607,1514,1452,1346,1258,1067cm -1 ；HR-ESIMSm/z809.2325[M-H] - (calcdforC 40 H 41 O 18 809.2293 confirm that compound 8 has the formula C 40 H 42 O 18 The method comprises the steps of carrying out a first treatment on the surface of the The carbon and hydrogen spectrum data are shown in Table 4.
Compound 9: black powder (MeOH); [ alpha ]]25D-16.3(c0.043,MeOH)；UV(MeOH)λ max (logε):319(4.18)nm；IR(KBr)ν max :3374,1608,1515,1454,1348,1243,1066cm -1 ；HR-ESIMSm/z809.2325[M-H] - (calcdforC 40 H 41 O 18 809.2293 confirm that compound 9 has the formula C 40 H 42 O 18 The method comprises the steps of carrying out a first treatment on the surface of the The carbon and hydrogen spectrum data are shown in Table 4.
Table 4 carbon and Hydrogen Spectrum data for Compounds 7 to 8
Compound 10: black powder (MeOH); [ alpha ]]25D-19.6(c0.051,MeOH)；UV(MeOH)λ max (logε):284(3.82)nm；IR(KBr)ν max :3316,1613,1514,1462,1344,1240,1069cm -1 ；HR-ESIMSm/z827.2366[M-H] - (calcdforC 40 H 43 O 19 827.2399 confirm that compound 10 has formula C 40 H 44 O 19 The method comprises the steps of carrying out a first treatment on the surface of the The carbon and hydrogen spectrum data are shown in Table 5.
Compound 11: black powder (MeOH); [ alpha ]]25D-31.1(c0.045,MeOH)；UV(MeOH)λ max (logε):283(3.90)nm；IR(KBr)ν max :3374,1613,1514,1462,1344,1242,1069cm -1 ；HR-ESIMSm/z827.2366[M-H] - (calcdforC 40 H 43 O 19 827.2399 confirm that compound 11 has the formula C 40 H 44 O 19 The method comprises the steps of carrying out a first treatment on the surface of the The carbon and hydrogen spectrum data are shown in Table 5.
Compound 12: black powder (MeOH); [ alpha ]]25D-16.7(c0.042,MeOH)；UV(MeOH)λ max (logε):283(3.85)nm；IR(KBr)ν max :3354,1613,1514,1464,1346,1243,1069cm -1 ；HR-ESIMSm/z827.2366[M-H] - (calcdforC 40 H 43 O 19 827.2399 confirm that compound 12 has the formula C 40 H 44 O 19 The method comprises the steps of carrying out a first treatment on the surface of the The carbon and hydrogen spectrum data are shown in Table 5.
TABLE 5 carbon and Hydrogen Spectrum data for Compounds 10 to 12
Compound 13: black powder (MeOH); [ alpha ]]25D+46.2(c0.039,MeOH)；UV(MeOH)λ max (logε):286(3.84)nm；IR(KBr)ν max :3339,1613,1514,1455,1341,1255,1067cm -1 ；HR-ESIMSm/z809.2325[M-H] - (calcdforC 40 H 41 O 18 809.2293 confirm that compound 13 has the formula C 40 H 42 O 18 The method comprises the steps of carrying out a first treatment on the surface of the The carbon and hydrogen spectrum data are shown in Table 6.
Compound 14: black powder (MeOH); [ alpha ]]25D-11.8(c0.034,MeOH)；UV(MeOH)λ max (logε):285(3.84)nm；IR(KBr)ν max :3370,1613,1514,1455,1341,1254,1068cm -1 ；HR-ESIMSm/z809.2325[M-H] - (calcdforC 40 H 41 O 18 809.2293 confirm that compound 14 has the formula C 40 H 42 O 18 The method comprises the steps of carrying out a first treatment on the surface of the The carbon and hydrogen spectrum data are shown in Table 6.
TABLE 6 carbon and Hydrogen Spectrum data for Compounds 13 to 14
Note that: the test solvent of the compounds 13-14 is deuterated methanol, the hydrogen spectrum test is 600MHz, and the carbon spectrum test is 150MHz.
Compound 15: black powder (MeOH); [ alpha ]]25D+5.3(c0.038,MeOH)；UV(MeOH)λ max (logε):284(3.84)nm；IR(KBr)ν max :3045,1613,1515,1461,1344,1239,1069cm -1 ；HR-ESIMSm/z809.2325[M-H] - (calcdforC 40 H 41 O 18 809.2293 confirm that compound 15 has the formula C 40 H 42 O 18 The method comprises the steps of carrying out a first treatment on the surface of the The carbon and hydrogen spectrum data are shown in Table 7.
Compound 16: black powder (MeOH); [ alpha ]]25D+17.6(c0.034,MeOH)；UV(MeOH)λ max (logε):283(3.84)nm；IR(KBr)ν max :3393,1613,1515,1461,1343,1242,1069cm -1 ；HR-ESIMSm/z809.2325[M-H] - (calcdforC 40 H 41 O 18 809.2293 confirm that compound 16 has the formula C 40 H 42 O 18 The method comprises the steps of carrying out a first treatment on the surface of the The carbon and hydrogen spectrum data are shown in Table 7.
TABLE 7 Hydrogen and carbon Spectrum data for Compounds 15 to 16
Note that: the test solvent of the compounds 15-16 is deuterated methanol, the hydrogen spectrum test is 600MHz, and the carbon spectrum test is 150MHz.
Example 2
Activity experiment of stilbene glycoside dimer compound for prolonging life of caenorhabditis elegans
Preparation of the culture medium: autoclaving the prepared NGM medium (120deg.C, 20 min), cooling to 50deg.C, adding 1MMgSO per 500mL of medium 4 Salt buffer 500. Mu.L, 1MCaCl 2 500. Mu.L, 750. Mu.L of 1M potassium phosphate buffer and 500. Mu.L of 5M-g/mL cholesterol. And (3) carrying out a plating experiment in an ultra-clean workbench by adopting a sterile operation technology, pouring the mixture into a culture dish after uniform mixing, and storing the mixture in a refrigerator at 4 ℃ for standby.
Sample preparation: the sample adhered to the tube wall is dissolved by 5 mu LDMSO and then transferred to a new EP tube, the weight change of the original EP tube is called, the mass of the sample is calculated, the sample dissolved in DMSO is centrifugally evaporated to dryness, DMSO is added again to prepare mother solution of 100mM/L and 200mg/ml, and the mother solution is preserved at-20 ℃.
The experimental concentrations of the compounds 1 to 16 are respectively 100 mu m/L, 450 mu m of culture solution is prepared for each sample, 12 holes are formed for each sample, 30 mu m of culture solution is added for each hole, 2-3 nematodes in L4 stage are picked into each hole, the body of the nematodes is touched by a needle point every 24 hours for observation, if the body of the nematodes does not move, the body of the nematodes is judged to be dead, the observed number of each sample is not less than 20, and the experimental results are shown in Table 8.
Table 8 Experimental results of Compounds 1-16 for prolonging the longevity of C.elegans
Note that: * p <0.05, < p <0.01, < p <0.001.
Example 3
Mixing 1g of the stilbene glycoside dimer compound with the structure shown in the formulas I-VI obtained in the example 1 with 29g of starch, adding water to prepare a soft material, sieving with a 12-mesh sieve, granulating, and drying to obtain granules.
In the granule, every 300mg of the granule contains 10mg of the mixture of the distyrene glycoside dimer compounds with the structures of the formulas I to VI.
Example 4
Preparation of compound 1 tablet:
1g of compound 1 was mixed with 27g of microcrystalline cellulose and 2g of magnesium stearate, and the mixture was pressed into tablets with a diameter of 6mm and a weight of 300mg using single punched tablets. Each tablet contains 10mg of Compound 1.
Example 5
Preparation of compound 6 capsules:
1g of Compound 6 was mixed with 27g of lactose and 2g of magnesium stearate, and the capsule was filled every 300mg. In the present capsule, each capsule contains 10mg of Compound 6.
Example 5:
preparation of compound 2 and compound 7 mixed capsules:
each of compound 2 and compound 7 was mixed with 26g of lactose and 3g of magnesium stearate, and the capsule was filled every 300mg. In the present capsule, each capsule contained 10mg of a mixture of compound 2 and compound 7.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which is also intended to be within the scope of the present invention.
Claims (7)
1. A stilbene glycoside dimer compound characterized by having a structure represented by compound 1, compound 2, compound 4 or compound 5:
2. the method for preparing the stilbene glucoside dimer compound as claimed in claim 1, which is characterized by comprising the following steps:
2,3,5,4' -tetrahydroxy stilbene-2-O-beta-D-glucoside and FeCl 3 Mixing with polar solvent, performing oxidation reaction, and performing ODS reversed phase column chromatography separation on the system obtained by the oxidation reaction to obtain a stilbene glucoside dimer compound set;
collecting the stilbene glucoside dimer compounds, performing sephadex column chromatography, eluting by adopting a methylene dichloride-methanol system, separating the obtained eluent by ODS column chromatography, performing gradient elution by adopting a methanol water solution with the volume concentration of 10-100%, and obtaining 7 fractions named PF-1-PF-7 fractions according to the outflow sequence of the components; the volume concentration of the methanol aqueous solution is 10%, 30%, 50%, 70% and 100% in sequence; the volume ratio of dichloromethane to methanol in the dichloromethane-methanol system is 1:1;
purifying the PF-4 fraction by fourth preparation liquid chromatography, eluting with 12.5% acetonitrile water solution to obtain compound 1 and compound 2;
purifying the PF-5 fraction by fifth preparation liquid chromatography, eluting with 15% acetonitrile water solution to obtain compound 4 and compound 5.
3. The preparation method according to claim 2, wherein the temperature of the oxidation reaction is 35-40 ℃ for 1-18 hours.
4. The use of a stilbene glycoside dimer compound according to claim 1 or a stilbene glycoside dimer compound obtained by the preparation method according to any of claims 2 to 3 in the preparation of a medicament for preventing or treating aging and diseases caused thereby.
5. The use according to claim 4, wherein the medicament comprises the stilbene glycoside dimer compound and a pharmaceutically acceptable carrier.
6. The use according to claim 5, wherein the carrier comprises a mixture of lactose and magnesium stearate, or a mixture of microcrystalline cellulose and magnesium stearate.
7. The use according to any one of claims 4 to 6, wherein the mass concentration of the stilbene glycoside dimer compound in the medicament is 10mg/300mg.
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Non-Patent Citations (4)
| Title |
|---|
| 中药何首乌的化学成分研究;张静娴;崔艳梅;;中国中药杂志(第17期);全文 * |
| 何首乌中二苯乙烯苷清除DPPH自由基机理研究;吕丽爽;汤坚;Chi-Tang Ho;;食品与机械(第05期);全文 * |
| 何首乌化学成分与药理作用研究进展;王浩;杨健;周良云;罗碧;程轩轩;张春荣;唐晓敏;潘利明;刘露;杨全;;中国实验方剂学杂志(第13期);全文 * |
| 大孔吸附树脂纯化何首乌中二苯乙烯苷的工艺研究;相聪坤;吴海燕;;河北中医(第03期);全文 * |
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