CN107496433A - A kind of biphenyl compound is in the application for preparing oxidative stress and inducing an illness in medicine - Google Patents
A kind of biphenyl compound is in the application for preparing oxidative stress and inducing an illness in medicine Download PDFInfo
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- CN107496433A CN107496433A CN201710735302.7A CN201710735302A CN107496433A CN 107496433 A CN107496433 A CN 107496433A CN 201710735302 A CN201710735302 A CN 201710735302A CN 107496433 A CN107496433 A CN 107496433A
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- Prior art keywords
- biphenyl
- application
- tetrahydroxybiphenyls
- biphenyl compound
- cells
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title claims abstract description 75
- 235000010290 biphenyl Nutrition 0.000 title claims abstract description 51
- 239000004305 biphenyl Substances 0.000 title claims abstract description 51
- -1 biphenyl compound Chemical class 0.000 title claims abstract description 42
- 239000003814 drug Substances 0.000 title claims abstract description 28
- 230000036542 oxidative stress Effects 0.000 title claims abstract description 14
- 230000001939 inductive effect Effects 0.000 title abstract description 6
- 210000005036 nerve Anatomy 0.000 claims abstract description 13
- 239000000126 substance Substances 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 10
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 206010061218 Inflammation Diseases 0.000 claims description 8
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- 208000015122 neurodegenerative disease Diseases 0.000 claims description 8
- 241000723346 Cinnamomum camphora Species 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 208000020832 chronic kidney disease Diseases 0.000 claims description 7
- 206010012601 diabetes mellitus Diseases 0.000 claims description 7
- RQKYHDHLEMEVDR-UHFFFAOYSA-N oxo-bis(phenylmethoxy)phosphanium Chemical compound C=1C=CC=CC=1CO[P+](=O)OCC1=CC=CC=C1 RQKYHDHLEMEVDR-UHFFFAOYSA-N 0.000 claims description 7
- 230000000241 respiratory effect Effects 0.000 claims description 7
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 6
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
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- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 claims description 6
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
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- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
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- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 3
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- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 claims description 3
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- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 claims description 3
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 claims description 3
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- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
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- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 claims description 2
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- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 1
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- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 claims 1
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- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 claims 1
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- UVYVLBIGDKGWPX-UHFFFAOYSA-N digitonine Natural products CC1C(C2(CCC3C4(C)CC(O)C(OC5C(C(O)C(OC6C(C(OC7C(C(O)C(O)CO7)O)C(O)C(CO)O6)OC6C(C(OC7C(C(O)C(O)C(CO)O7)O)C(O)C(CO)O6)O)C(CO)O5)O)CC4CCC3C2C2O)C)C2OC11CCC(C)CO1 UVYVLBIGDKGWPX-UHFFFAOYSA-N 0.000 description 1
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- 210000000969 egg white Anatomy 0.000 description 1
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- AZHSSKPUVBVXLK-UHFFFAOYSA-N ethane-1,1-diol Chemical compound CC(O)O AZHSSKPUVBVXLK-UHFFFAOYSA-N 0.000 description 1
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- 150000002207 flavanone derivatives Chemical class 0.000 description 1
- 235000011981 flavanones Nutrition 0.000 description 1
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- 229940093632 flavin-adenine dinucleotide Drugs 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
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- 239000012535 impurity Substances 0.000 description 1
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- 150000002632 lipids Chemical class 0.000 description 1
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- 238000011068 loading method Methods 0.000 description 1
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- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
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- 235000002577 monoterpenes Nutrition 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
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- 230000007398 protein translocation Effects 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- 229930183339 qinghaosu Natural products 0.000 description 1
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- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
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- 239000010865 sewage Substances 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical class [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- NCPXQVVMIXIKTN-UHFFFAOYSA-N trisodium;phosphite Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])[O-] NCPXQVVMIXIKTN-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 235000012711 vitamin K3 Nutrition 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C301/00—Esters of sulfurous acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/04—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups
- C07C303/08—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups by reaction with halogenosulfonic acids
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- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/07—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing oxygen atoms bound to the carbon skeleton
- C07C309/09—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing oxygen atoms bound to the carbon skeleton containing etherified hydroxy groups bound to the carbon skeleton
- C07C309/11—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing oxygen atoms bound to the carbon skeleton containing etherified hydroxy groups bound to the carbon skeleton with the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
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Abstract
It is in the application for preparing oxidative stress and inducing an illness in medicine, the chemical formula of the biphenyl compound the invention discloses a kind of biphenyl compound：Wherein, R1For H, CH3、R2For H, CH3、X1For H, Na+、K+Or NH4 +, X2For H, Na+、K+Or NH4 +, X3For H, Na+、K+Or NH4 +.The biphenyl compound can raise Nrf2 and its regulation and control antioxidase γ GCS, II phase detoxification enzyme NQO1 protein levels；Endogenous cellular antioxidant agent GSH levels can be increased, suppress arsenic induction Beas 2B cellular damages and apoptosis；It is horizontal to go out similar cytoprotection increase endogenous cellular antioxidant agent GSH to glomerulus membrane system cell SV40MES13 cells, people nerve SHSY5Y cells, the cells shows of human breast carcinoma MDA MB 231, suppresses arsenic induction Beas 2B cellular damages and apoptosis；Similar cytoprotection is gone out to glomerulus membrane system cell SV40MES13 cells, people nerve SHSY5Y cells, the cells shows of human breast carcinoma MDA MB 231.
Description
Technical field
The invention belongs to field of medicaments, is related to the application of biphenyl compound, and in particular to prepared by biphenyl compound
The application that prevention or treatment oxidative stress induce an illness in medicine or health products.
Background technology
The industrialized fast development of society, causes air, water source, soil, food pollution serious, such as carbon sulphur nitrogen oxides
(CO、SO2、NO2Deng), heavy metal (lead, chromium, arsenic etc.), building Mineral Dust formed haze；Water caused by industry and sanitary sewage
Source is polluted and soil pollution, and grain contamination caused by entering.These pollutants attack human tissue organ, cause human body to be lived
Property oxygen, active nitrogen increase, cause human body nucleotides, albumen, lipid mechanism harm, induce COPD, chronic kidney disease, exhale
Inhale the generation of road inflammation, diabetes, nerve degenerative diseases and tumor disease.
Nuclear factor Nrf2 (Nuclear factor-erythroid 2-related factor 2) signal path is
Regulate and control the critical path of human body oxidative stress, be the target spot of chemopreventive agent (medicine) effect.Nrf2 is to adjust cellular oxidation also
Yuanping City weighing apparatus important transcription factor, by with antioxidase and II phase detoxication enzyme promoter region Antioxidation reaction original papers (ARE)
With reference to regulating cell redox equilibrium, II phase detoxication enzyme of its target gene including encoding GST, UGT, NQO1, and γ GCS,
The endogenous anti-oxidative albumen such as HO-1.When body is exposed to the environmental pollution of electrophilicity foreign matter, chemical carcinogen equivalent damage body
During thing, Nrf2 will activate antioxidase and II phases detoxication enzyme removes noxious pollutant, prevent its infringement to cell tissue, protect
Protect harm of the body from environmental contaminants.
Under damage and oxidative stress status caused by pollutant, human body device is raised using exogenous Nrf2 activators
Official and tissue Nrf2 are horizontal, can strengthen body self-defense ability, for prevention COPD, chronic kidney disease,
Respiratory inflammation, diabetes, the generation of nerve degenerative diseases and tumor disease are significant.Activation Nrf2 signals lead to
Road, II phases can be raised and detoxified enzyme level, clearing the pollution off middle carcinogenic substance or reduces its toxicity, suppresses the DNA of carcinogenic substance induction
Damage, gene mutation, so as to the generation of pre- preventing tumor.Raise Nrf2 expression, by increasing capacitance it is possible to increase glutathione levels, enhancing
Activities of antioxidant enzymes, active oxygen in scavenger-cell, suppress cytolipin peroxidating, reduce COPD, chronic renal
The incidence of disease of the diseases such as disease, respiratory inflammation, diabetes, nerve degenerative diseases.
Natural products is the important sources of lead compound, and significant contribution is made that to human medicine development history.Mesh
Before, many clinical applications are for natural products or from natural products, such as qinghaosu, taxol, ET743 etc., from natural production
The lead compound with preventive and therapeutic action is found in thing, is the important channel of medicament research and development.Wherein, hard leaf Cinnomomum Sps. Extract
With Nrf2 agonisms, the potentiality with the medicine that induced an illness as preventing and treating oxidative stress.But contain fat in hard leaf camphor tree
Compounds of group, monoterpenes compound, sesquiterpenoids, phenolic acid compound, aromatic compound, biphenyl compound,
Naphthane ketone compounds, benzopyrans compounds, Lignanoids compounds, chromogen ketone compounds, flavone compound,
The compounds such as flavonoid drugs, flavanone kind composition, the various complexity of its composition, and do not have document in hard leaf camphor tree
Chemical composition carry out Activity determination.
The content of the invention
In order to solve the deficiencies in the prior art, an object of the present invention is to provide a kind of biphenyl compound and prepared in advance
Anti- or treatment oxidative stress induces an illness the application in medicine or health products, can prevent and treat COPD,
Chronic kidney disease, respiratory inflammation, diabetes, nerve degenerative diseases and tumor disease.
To achieve these goals, the technical scheme is that：
A kind of application of biphenyl compound in preparation prevention or treatment oxidative stress induce an illness medicine or health products,
The chemical formula of the biphenyl compound is：
Wherein, R1For-H ,-CH3、R2For-H ,-CH3、X1For
Na+、K+Or NH4 +, X2For Na+、K+Or NH4 +, X3For Na+、K+Or NH4 +。
The present inventor has found 3,3' by studying, and 4,4'- tetrahydroxybiphenyls can raise Nrf2 and its regulation and control
Antioxidase γ GCS, II phase detoxification enzyme NQO1 protein levels, its activation mechanism are suppressed by increasing Nrf2 protein stabilities
What Nrf2 protein degradations were realized；Using the pulmonary branches tracheal epithelium Beas-2B cellular damage model evaluations 3,3' of arsenic induction, 4,
The cytoprotection of 4'- tetrahydroxybiphenyls, the results showed that the compound can increase endogenous cellular antioxidant agent GSH water
It is flat, suppress arsenic induction Beas-2B cellular damages and apoptosis；To glomerulus membrane system cell SV40MES13 cells, people's nerve SHSY5Y
Cell, human breast carcinoma MDA-MB-231 cells shows go out similar cytoprotection；Further determine that o-phenol for activity
Essential group, by the way that its derivatization obtained into its phosphate and sulfate, keep Nrf2 agonisms while can to improve its molten
Xie Du increases druggability.It is above-mentioned test result indicates that, biphenyl compound of the present invention have preventing and treating chronic obstructive pulmonary
The effect of disease, chronic kidney disease, respiratory inflammation, diabetes, nerve degenerative diseases and tumor disease.
The second object of the present invention is to provide a kind of pharmaceutical composition for realizing above-mentioned application, including above-mentioned biphenyl class chemical combination
Thing.
The third object of the present invention is to provide a kind of medicament for realizing above-mentioned application, including above-mentioned biphenyl compound and auxiliary
Material.
The fourth object of the present invention is to provide a kind of preparation method of above-mentioned medicament, by above-mentioned biphenyl compound, starch
And sieved after dextrin mixing, sodium carboxymethylcellulose granulation is added, tabletting after magnesium stearate mixes then is added and produces tablet.
Beneficial effects of the present invention are：
The present inventor has found 3,3' by studying, and 4,4'- tetrahydroxybiphenyls can raise Nrf2 and its regulation and control
Antioxidase γ GCS, II phase detoxification enzyme NQO1 protein levels, its activation mechanism are suppressed by increasing Nrf2 protein stabilities
What Nrf2 protein degradations were realized；Using the pulmonary branches tracheal epithelium Beas-2B cellular damage model evaluations 3,3' of arsenic induction, 4,
The cytoprotection of 4'- tetrahydroxybiphenyls, the results showed that the compound can increase endogenous cellular antioxidant agent GSH water
It is flat, suppress arsenic induction Beas-2B cellular damages and apoptosis；To glomerulus membrane system cell SV40MES13 cells, people's nerve SHSY5Y
Cell, human breast carcinoma MDA-MB-231 cells shows go out similar cytoprotection.
Brief description of the drawings
The Figure of description for forming the part of the application is used for providing further understanding of the present application, and the application's shows
Meaning property embodiment and its illustrate be used for explain the application, do not form the improper restriction to the application.
The block diagram that the induced activity that Fig. 1 is NQO1 is tested, shows 3,3', 4,4'- tetrahydroxybiphenyls to that can induce
Hepa1c1c7 cell II phase detoxication enzymes NQO1 expression simultaneously strengthens its activity, 3,3', 4,4'- tetrahydroxybiphenyl concentration in figure
Unit for μM, 2.0 μM of sulforaphen is positive control；
Fig. 2 is the immunoblotting assay figure of the tetrahydroxybiphenyl of various concentrations 3,3', 4,4'-, shows 3,3', 4,4'- tetra- hydroxyls
Base biphenyl can raise Nrf2 and anti-oxidant γ GCS downstream and II phases and detoxify zymoprotein NQO1 protein levels, wherein, 3,3',
4,4'- tetrahydroxybiphenyls concentration unit is μM；
Fig. 3 is the fluorescence micrograph of cellular immunity, shows that 3,3', 4,4'- tetrahydroxybiphenyls can promote Nrf2 indexable
Enter core, 2.0 μM of sulforaphen is positive control in figure, and 3,3', 4,4'- tetrahydroxybiphenyl concentration are 12.5 μM；
Fig. 4 is the immunoblotting assay figure of the tetrahydroxybiphenyl of different time 3,3', 4,4'-, shows 3,3', 4,4'- tetra- hydroxyls
Base biphenyl can extend Nrf2 protein half-lifes, wherein, 3,3', 4,4'- tetrahydroxybiphenyl concentration are 12.5 μM；
Fig. 5 is the block diagram of influence of the different material to glutathione, shows that 3,3', 4,4'- tetrahydroxybiphenyls can increase
Add human bronchial epithelial Beas-2B endogenous cellular antioxidant agent glutathione levels, wherein, 2.5 μM of sulforaphen is positive right
According to 3,3', 4,4'- tetrahydroxybiphenyl concentration units are μM；
Fig. 6 is the block diagram of the cell survival amount of cell toxicity test, shows that 3,3', 4,4'- tetrahydroxybiphenyls can drop
The cytotoxicity of low arsenic induction, wherein, A is the tetrahydroxybiphenyl of various concentrations 3,3', 4,4'- to 10 μM of arsenic inducing cytotoxics
Protective effect, B are 1.56 μM 3,3', protective effect of 4, the 4'- tetrahydroxybiphenyls to various concentrations arsenic inducing cytotoxic；
Fig. 7 is the fluorescence micrograph of natural death of cerebral cells, and AO/EB dyeing shows that 3,3', 4,4'- tetrahydroxybiphenyls can suppress
The Apoptosis of arsenic induction, wherein, 3,3', 4,4'- tetrahydroxybiphenyl concentration are 1.56 μM, and the concentration of arsenic is 5 μM.
Embodiment
It is noted that described further below is all exemplary, it is intended to provides further instruction to the application.It is unless another
Indicate, all technologies used herein and scientific terminology are with usual with the application person of an ordinary skill in the technical field
The identical meanings of understanding.
It should be noted that term used herein above is merely to describe embodiment, and be not intended to restricted root
According to the illustrative embodiments of the application.As used herein, unless the context clearly indicates otherwise, otherwise singulative
It is also intended to include plural form, additionally, it should be understood that, when in this manual using term "comprising" and/or " bag
Include " when, it indicates existing characteristics, step, operation, device, component and/or combinations thereof.
As background technology is introduced, it is various complicated and do not have document to heavily fortified point to there is hard leaf camphor tree composition in the prior art
Chemical composition in leaf camphor tree carries out the deficiency of Activity determination, and in order to solve technical problem as above, present applicant proposes one kind to join
Benzene-like compounds are in the application for preparing oxidative stress and inducing an illness in medicine.
A kind of exemplary embodiment of the application, there is provided a kind of biphenyl compound should in preparation prevention or treatment oxidation
Swash the application in induce an illness medicine or health products, the chemical formula of the biphenyl compound is：
Wherein, R1For-H ,-CH3、R2For-H ,-CH3、X1
For-H, Na+、K+Or NH4 +, X2For-H, Na+、K+Or NH4 +, X3For-H, Na+、K+Or NH4 +。
Present inventor has found 3,3' by studying, and 4,4'- tetrahydroxybiphenyls can raise Nrf2 and its regulation and control
Antioxidase γ GCS, II phase detoxification enzyme NQO1 protein levels, its activation mechanism are suppressed by increasing Nrf2 protein stabilities
What Nrf2 protein degradations were realized；Using the pulmonary branches tracheal epithelium Beas-2B cellular damage model evaluations 3,3' of arsenic induction, 4,
The cytoprotection of 4'- tetrahydroxybiphenyls, the results showed that the compound can increase endogenous cellular antioxidant agent GSH water
It is flat, suppress arsenic induction Beas-2B cellular damages and apoptosis；To glomerulus membrane system cell SV40MES13 cells, people's nerve SHSY5Y
Cell, human breast carcinoma MDA-MB-231 cells shows go out similar cytoprotection；Further determine that o-phenol for activity
Essential group, by the way that its derivatization obtained into its phosphate and sulfate, keep Nrf2 agonisms while can to improve its molten
Xie Du increases druggability.It is above-mentioned test result indicates that, biphenyl compound of the present invention have preventing and treating chronic obstructive pulmonary
The effect of disease, chronic kidney disease, respiratory inflammation, diabetes, nerve degenerative diseases and tumor disease.
Preferably, the oxidative stress induces an illness as COPD, chronic kidney disease, respiratory inflammation, sugar
Urine disease, nerve degenerative diseases or tumor disease.
Preferably, the concentration of the biphenyl compound is 0.78~3.12 μM.More preferable protect is produced under the concentration to cell
Shield acts on.It is further preferred that the concentration of the biphenyl compound is 1.56 μM.Best protection is produced to cell under the concentration
Effect.
Preferably, 3,3', the preparation method of 4,4'- tetrahydroxybiphenyls is that the aerial part of hard leaf camphor tree is carried out using extractant
Extraction obtains extract, and extract is extracted using petroleum ether and ethyl acetate successively, and the part of ethyl acetate extraction is carried out
Petroleum ether-ethyl acetate system gradient elution obtains 19 parts, and the 14th part is obtained through sephadex lh-20 chromatogram post separation
3,3', 4,4'- tetrahydroxybiphenyl.The chemical formula of the 3,3', 4,4'- tetrahydroxybiphenyl is
It is further preferred that the ethanol solution that it is 95% that the extractant, which is volume fraction,.
Preferably, 3,3', the preparation method of the derivative of 4,4'- tetrahydroxybiphenyls is, in 0 DEG C and inert gas shielding
Under, triethylamine is added dropwise in the anhydrous acetonitrile of 3,3', 4,4'- tetrahydroxybiphenyls, carbon tetrabromide and dibenzyl phosphite,
Reacted in room temperature, remove solvent after reaction, then gains are dissolved in ethyl acetate, and with hydrochloric acid, the saturated common salt aqueous solution
Wash successively, after organic phase is dried, remove solvent and obtain the dibenzyl phosphite intermediate of biphenyl；In -5 DEG C and inert gas
Under protection, bromotrimethylsilane is added dropwise in the anhydrous acetonitrile of dibenzyl phosphite intermediate of biphenyl, then by temperature
0 DEG C is risen to, solvent is removed after stirring a period of time, then gains are cleaned with n-hexane and dichloromethane mixed solution, is obtained
The phosphorous acid of biphenyl.
The chemical formula of the phosphorous acid of the biphenyl is
It is further preferred that methoxide or ammoniacal liquor are added separately in the methanol solution of the phosphorous acid of biphenyl, pH value is adjusted
For alkalescence, the phosphite of biphenyl is obtained after removing solvent.
The chemical formula of the phosphite of the biphenyl is
Wherein, M Na+、K+Or NH4 +。
Preferably, 3,3', the preparation method of the derivative of 4,4'- tetrahydroxybiphenyls is that chlorosulfonic acid is added dropwise under the conditions of 0 DEG C
Into the anhydrous pyridine solution of 3,3', 4,4'- tetrahydroxybiphenyls, then temperature is warmed to room temperature, reacted, after reaction terminates
Solvent is removed, then gains are soluble in water, hydrogenation sodium oxide molybdena, potassium hydroxide or ammoniacal liquor adjust pH value to produce biphenyl to alkalescence
Sulphite.The room temperature is 15~30 DEG C.
The chemical formula of the sulphite of the biphenyl is
Wherein, M' Na+、K+Or NH4 +。
Carry out biphenyl compound activation Nrf2 as representative compound using 3,3', 4,4'- tetrahydroxybiphenyls below
Signal path acts on and pollutant is induced cellular damage protective effect research：
Using mouse hepa 1c1c7 liver cancer cell lines, induction of the biphenyl compound to II phase detoxification enzymes NQO1 have rated
Effect, the results showed that 3,3', 4,4'- tetrahydroxybiphenyls, which have, raises NQO1 activity, i.e., and 3,3', 4,4'- tetrahydroxybiphenyls have
Suppress the effect (Fig. 1) of oxidative stress.
Using the normal pulmonary epithelial cells Beas-2B cells of people, biphenyl compound is have rated to cell Nrf2 signal paths
Effect.Western blot shows that 3,3', 4,4'- tetrahydroxybiphenyls can raise the expression of Nrf2 albumen, and energy
The anti-oxidant γ GCS in downstream and II phases is promoted to detoxify zymoprotein NQO1 expression (Fig. 2).Cellular immunofluorescence, which is tested, to be shown, 3,3',
4,4'- tetrahydroxybiphenyls can promote Nrf2 indexings to enter core (Fig. 3), one-step activation downstream gene of going forward side by side.Further study showed that
3,3', 4,4'- tetrahydroxybiphenyls can extend Nrf2 protein half-lifes, suppress Nrf2 protein degradations, increase its stability (figure
4)。
The cytotoxicity model of arsenic induction is selected, 3,3', 4,4'- tetrahydroxybiphenyls of evaluation are to the normal pulmonary epithelial cells of people
Beas-2B protective effect.Research it has proven convenient that arsenic by increase intracellular reactive oxygen level, induce cellular oxidation stress, cause
Cellular damage and death.As a result show, through 3,3', 4,4'- tetrahydroxybiphenyls processing cell, its survival rate is significantly higher than non-dosing
Treatment group, it was demonstrated that the compound can significantly inhibit the cytotoxicity of arsenic induction, and producing best protection to cell at 1.56 μM makees
With (Fig. 6)；In addition, 3,3', 4,4'- tetrahydroxybiphenyls can suppress the Apoptosis of arsenic induction.The result proves, 3,3', 4,
4'- tetrahydroxybiphenyls can be used for the prevention and treatment for preventing and treating tumour as medicine or health products.
The another embodiment of the application, there is provided a kind of pharmaceutical composition for realizing above-mentioned application, including it is above-mentioned
Benzene-like compounds.
Embodiment there is provided a kind of medicament for realizing above-mentioned application, including above-mentioned biphenyl class for the third of the application
Compound and auxiliary material.The auxiliary material is medically acceptable auxiliary material.
Preferably, the medicament is capsule, tablet, powder, granule, injection, oral liquid, vina, pill, mixture
Or tincture.
The 4th kind of the application is embodiment there is provided a kind of preparation method of above-mentioned medicament, by above-mentioned biphenyl class chemical combination
Sieved after thing, starch and dextrin mixing, add sodium carboxymethylcellulose granulation, then adding tabletting after magnesium stearate mixes is
Obtain tablet.
Preferably, the biphenyl compound, starch and dextrin mass ratio are 1~2:1~2:2~4.
In order that the technical scheme of the application can clearly be understood by obtaining those skilled in the art, below with reference to tool
The embodiment of body describes the technical scheme of the application in detail.
Embodiment 1：The preparation of 3,3', 4,4'- tetrahydroxybiphenyl and structural identification
The preparation method of 3,3', 4,4'- tetrahydroxybiphenyl is as follows：Hard leaf camphor tree aerial part, second is extracted to obtain with 95% ethanol
Alcohol extracting thing, then extracted successively using petroleum ether and ethyl acetate.Ethyl acetate portion uses petroleum ether-ethyl acetate system
Gradient elution, obtain 19 parts (A-S).N section obtains 3,3', 4,4'- tetrahydroxys connection through sephadex lh-20 chromatogram post separation
Benzene.
With 3,3', 4, the 4'- tetrahydroxybiphenyls that are prepared for raw material, under 0 DEG C and nitrogen protective condition, by triethylamine
(4mmol) is slowly added dropwise to 3,3', 4,4'- tetrahydroxybiphenyls (1mmol), carbon tetrabromide (4.4mmol) and dibenzyl phosphite
In the anhydrous acetonitrile of (5mmol), then it is stirred at room temperature 2 hours, after reaction terminates, removes solvent under reduced pressure, gains are dissolved in
Ethyl acetate, and washed respectively three times with 0.1M aqueous hydrochloric acid solution, the saturated common salt aqueous solution, organic phase is dried with sodium sulphate, with
After filter, solvent is evaporated off and obtains the dibenzyl phosphite intermediate of biphenyl.Under -5 DEG C and nitrogen protective condition, by front three bromide
Silane is slowly added dropwise in the anhydrous acetonitrile of intermediate, is then slowly recovered to 0 DEG C, and stirs 1h, and solvent is then evaporated off,
Gains are with 1:1 n-hexane and dichloromethane mixed solution cleaning, obtains the phosphorous acid product of biphenyl.By sodium methoxide, methanol
Potassium or ammoniacal liquor are added separately in the methanol solution of the product, adjust pH value that after solvent is evaporated off, gained crude product is placed in for alkalescence
Recrystallized in the mixed solution of water and acetonitrile, finally give corresponding phosphorous acid sodium salt, sylvite and ammonium salt product.
Chlorosulfonic acid (2mmol) is slowly added dropwise to 3,3' under the conditions of 0 DEG C, 4,4'- tetrahydroxybiphenyls (0.5mmol) it is anhydrous
In pyridine solution, then recover to room temperature, be stirred overnight.After reaction terminates, divide exactly solvent, gains are soluble in water, hydrogenation
Sodium oxide molybdena, potassium hydroxide or ammoniacal liquor adjust pH value to alkalescence, subsequent reversed phase chromatography post of crossing to remove organic impurities, and after further treatment
Obtain corresponding sulfonate sodium, sylvite and ammonium salt.
Method：With DMSO-d6For solvent, TMS is internal standard, and determining its hydrogen using nuclear magnetic resonance chemical analyser composes and carry out structure
Parsing.
As a result：Compound1H-NMR signals are δH:8.92(2H,s,3,3'or 4,4'-OH)；8.85(2H,s,3,3'
or4,4'-OH)；6.88 (2H, d, J=1.8Hz, H-2,2')；6.77 (2H, dd, J=1.8,8.4Hz, H-6,6')；6.74
(2H, d, J=7.8Hz, H-5,5').It is 3,3' through structural identification, 4,4'- tetrahydroxybiphenyls.
Embodiment 2：The NQO1 induced activitys evaluation of 3,3', 4,4'- tetrahydroxybiphenyl
(1) culture of murine hepatocarcinoma cell hepa 1c1c cell lines
Murine hepatocarcinoma cell hepa 1c1c cell lines are purchased from American Type Culture collection warehousing (ATCC), using containing 10%
The MEM culture mediums of hyclone (FBS), are placed in 37 DEG C, 5%CO2Cultivated in incubator.
(2) NQO induced activitys are tested
Hepa 1c1c cells are inoculated on 96 orifice plates, 3,3', 4,4'- tetra- hydroxyls of various concentrations are added after cell attachment
Base biphenyl (embodiment 1 is confirmed), handle 24 hours, using 0.8% digitonin solution cell lysis, add detection liquid
(1.0mL0.5M trishydroxymethylaminomethanes-hydrochloric acid (Tris-HCl), 15mg bovine serum albumin(BSA)s, 6mg MTT, 150 μ L tweens-
20,150 μ L 150mM D-Glucose -6- phosphoric acid, 15 μ L 7.5mM flavin adenine dinucleotide (FAD)s, 27 μ L 50mM nicotinoyl amine glands
Purine dinucleotides phosphoric acid, 20 μ L 50mM menadiones), place 3 minutes, luminous intensity is determined in 630nm.
As a result：As shown in figure 1,3,3', 4,4'- tetrahydroxybiphenyls can activate NQO1 activity in hepa 1c1c7 cells,
Its maximum induced activity is 2.19 times (100 μM), and positive control medicine sulforaphen (2.0 μM) is 2.80 times of blank control group.
The above results show that 3,3', 4,4'- tetrahydroxybiphenyls can activate II phase detoxification enzymes, have protective effect to human body cell.
Embodiment 3：3,3', 4,4'- tetrahydroxybiphenyl can raise Nrf2, γ GCS and NQO1 protein levels
Method：The change of protein level in western blot analysis (Western blot) detection cell
Beas-2B cells are inoculated in diameter 35mm culture dishes, cultivated after reaching 70%-80% to density, are added not
Testing compound with concentration handles 16h, and PBS is washed 2 times, adds cell pyrolysis liquid (50 μ g/ml Aprotinins, 0.5mM benzyls
Sulfuryl fluoride, 1mM sodium vanadates, 10mM sodium fluorides, 10mM β-phosphoglycerol), collect albumen and using Bradford methods measure egg
White concentration.Sample protein (100 μ g) loading is respectively taken, SDS-PAGE protein isolates component is simultaneously turned protein band using electrotransfer method
Move on cellulose nitrate film.Film through TBS prepare 5% skimmed milk power solution room temperature closing 1h after, respectively with it is each to be measured
4 DEG C of overnight incubations of protein antibodies.After the secondary antibody incubation 1h of horseradish peroxidase is separately added into after TBS is washed, with increasing
Strong type ECL chemiluminescences carry out analysis of protein.
As a result：As shown in Fig. 2 after cell handles 16h through 3,3', 4,4'- tetrahydroxybiphenyls, Nrf2 and anti-oxidant downstream
With II phases detoxify zymoprotein NQO1 and γ GCS protein levels present dose dependent increase, Keap1 protein levels are unchanged, card
The real compound can activate Nrf2 signal paths on protein level.
Embodiment 4：3,3', 4,4'- tetrahydroxybiphenyl promote Nrf2 protein translocations to enter core
Method：Immuno-fluorescence assay Nrf2 intracellular locations
Cell climbing sheet is positioned in 24 orifice plates, Beas-2B cells is inoculated with, 3,3', 4,4'- tetra- is added after cell attachment
Xenol is handled 8 hours, and PBS is washed 2 times, is added methanol and is fixed 4 hours, and PBS is washed 2 times, and it is small to add Nrf2 antibody incubations 1
When, PBS is washed 3 times, adds DAPI and fluorescence secondary antibody is incubated 50 minutes, using fluorescence microscope and take pictures.
As a result：Immunofluorescence results are shown (Fig. 3), and under cell normal condition, Nrf2 is located in cytoplasm, add 3,3',
After 4,4'- tetrahydroxybiphenyls and positive control sulforaphen are handled 8 hours, Nrf2 indexings enter nucleus.
Embodiment 5：3,3', 4,4'- tetrahydroxybiphenyl increase Nrf2 protein stabilities
Method：Western blot analysis detect Nrf2 protein half-lifes
Beas-2B cells are inoculated in diameter 35mm culture dishes, cultivated after reaching 70%-80% to density, add 3,
3', 4,4'- tetrahydroxybiphenyl 8h, cycloheximide is then added, timing, albumen was collected at 0,10,20,30,40 minute respectively, enters
Row western blot analysis detect, and are quantified using Image J softwares.
As a result：As shown in figure 4, blank group Beas-2B cell Nrf2 protein half-lifes are 14.6 minutes, through 3,3', 4,4'-
After tetrahydroxybiphenyl processing 8h, Nrf2 protein half-lifes extend to 31.7 minutes, show that 3,3', 4,4'- tetrahydroxybiphenyls can
Extend Nrf2 protein half-lifes.
Embodiment 6：3,3', 4,4'- tetrahydroxybiphenyl can increase endogenous cellular antioxidant agent glutathione level
(1) culture of people's normal epidermis Beas-2B cells
People normal lung bronchiolar epithelium Beas-2B cells are purchased from American Type Culture collection warehousing (ATCC), using 1640
Culture medium, and 10% hyclone (FBS) is added thereto, 5% glutamine, 37 DEG C are placed in, 5%CO2Cultivated in incubator.
(2) measure of glutathion inside cell content
Beas-2B cells are inoculated in diameter 35mm culture dishes, cultivated after reaching 70%-80% to density, are added not
Handled 24 hours with the 3,3' of concentration, 4,4'- tetrahydroxybiphenyls (embodiment 1 is confirmed), PBS is washed 2 times, adds 0.5mL 50mM
Sodium phosphate and 1mM edta buffers liquid receive cell, and ultrasonic 1min, 10000g are centrifuged 15 minutes, supernatant are taken, according to glutathione
Kit specification operation is determined, 412nm measure absorbances simultaneously calculate glutathione content.
As a result：As shown in figure 5,3,3', 4,4'- tetrahydroxybiphenyls can dramatically increase glutathione levels, increase
Strong intracellular reducing power.
Embodiment 7：The guarantor for the human bronchial epithelial Beas-2B cellular damages that 3,3', 4,4'- tetrahydroxybiphenyl are induced arsenic
Shield acts on
Method：The protective effect for the cytotoxicity that mtt assay measure Chinese medicine composition is induced arsenic
Beas-2B cells are inoculated on 96 orifice plates, after cell attachment, joined using the tetrahydroxy of concentration 3,3', 4,4'- to be measured
Benzene pretreatment cell 8 hours, add the arsenic and the tetrahydroxybiphenyl of concentration to be measured 3,3', 4,4'- of various concentrations (embodiment 1 is confirmed)
Processing 48 hours, or MTT is added after 3 hours, 590nm measure absorbances simultaneously calculate cells survival rate.
As a result：As shown in Figure 6A, using 3,3', 4,4'- tetrahydroxybiphenyl pretreatment cell 8 hours, can significantly inhibit
The cytotoxicity that 10 μM of arsenic induces, increase cells survival rate, wherein 1.56 μM of tetrahydroxybiphenyl activity of concentration 3,3', 4,4'- are most
It is good.As shown in Figure 6B, using 1.56 μM of tetrahydroxybiphenyls of concentration 3,3', 4,4'- as protection medicines, can significantly inhibit 5,
10th, the cytotoxicity that 20 μM of arsenic induces, cells survival rate is increased.As a result prove, 3,3', 4,4'- tetrahydroxybiphenyls can press down
The toxicity of carcinogenic substance arsenic induction processed.
Embodiment 8：3,3', 4,4'- tetrahydroxybiphenyl can suppress the natural death of cerebral cells of arsenic induction
Beas-2B cells are inoculated in 35mm culture dishes, 5 μM of arsenic or 1.56 μM 3,3', 4,4'- tetra- hydroxyls are added after adherent
Base biphenyl handles 12h, is separately added into acridine orange (AO)/ethidium bromide (EB) and is dyed, and uses fluorescence microscope cell
State.
As a result：As shown in fig. 7, using arsenic or 3,3', 4,4'- tetrahydroxybiphenyl coprocessing 12 hours, can significantly inhibit
The Apoptosis of arsenic induction.
Embodiment 9：The preparation of tablet
3,3', 4,4'- tetrahydroxybiphenyls (embodiment 1 is confirmed) 1g, starch 1g, dextrin 2g are added, sieving, adds carboxymethyl
Appropriate sodium cellulosate, granulation.Magnesium Stearate proper quantity is added, mixes, tabletting, produces.
The preferred embodiment of the application is the foregoing is only, is not limited to the application, for the skill of this area
For art personnel, the application can have various modifications and variations.It is all within spirit herein and principle, made any repair
Change, equivalent substitution, improvement etc., should be included within the protection domain of the application.
Claims (10)
1. a kind of application of biphenyl compound in preparation prevention or treatment oxidative stress induce an illness medicine or health products, its
It is characterized in, the chemical formula of the biphenyl compound is：
Wherein, R1For-H ,-CH3、Or, R2For-H ,-CH3、X1For-H, Na+、K+Or NH4 +, X2For-H, Na+、K+Or NH4 +, X3For-H, Na+、K+Or NH4 +。
2. application as claimed in claim 1, it is characterized in that, the oxidative stress induce an illness for COPD,
Chronic kidney disease, respiratory inflammation, diabetes, nerve degenerative diseases or tumor disease.
3. application as claimed in claim 1, it is characterized in that, the concentration of the biphenyl compound is 0.78~3.12 μM.
4. application as claimed in claim 1, it is characterized in that, the preparation method of 3,3', 4,4'- tetrahydroxybiphenyls is, using carrying
Take agent to carry out extraction to the aerial part of hard leaf camphor tree and obtain extract, extract is carried out using petroleum ether and ethyl acetate successively
Extraction, the part of ethyl acetate extraction is subjected to petroleum ether-ethyl acetate system gradient elution and obtains 19 parts, by the 14th
Lease making sephadex lh-20 chromatogram post separation obtains 3,3', 4,4'- tetrahydroxybiphenyls.
5. application as claimed in claim 1, it is characterized in that, the preparation method of the derivative of 3,3', 4,4'- tetrahydroxybiphenyls
For under 0 DEG C and inert gas shielding, triethylamine is added dropwise into 3,3', 4,4'- tetrahydroxybiphenyls, carbon tetrabromide and phosphorous acid
In the anhydrous acetonitrile of dibenzyl ester, reacted in room temperature, solvent removed after reaction, then gains are dissolved in ethyl acetate,
And washed successively with hydrochloric acid, the saturated common salt aqueous solution, after organic phase is dried, remove solvent and obtain the dibenzyl phosphite of biphenyl
Intermediate；Under -5 DEG C and inert gas shielding, bromotrimethylsilane is added dropwise to the dibenzyl phosphite intermediate of biphenyl
In anhydrous acetonitrile, then temperature risen to 0 DEG C, stir and solvent is removed after a period of time, then by gains n-hexane and two
Chloromethanes mixed solution cleans, and obtains the phosphorous acid of biphenyl；Preferably, methoxide or ammoniacal liquor are added separately to the phosphorous of biphenyl
In the methanol solution of acid, pH value is adjusted to obtain the phosphite of biphenyl after removing solvent for alkalescence；
Or, chlorosulfonic acid is added dropwise in the anhydrous pyridine solution of 3,3', 4,4'- tetrahydroxybiphenyls under the conditions of 0 DEG C, then by temperature
Be warmed to room temperature, reacted, reaction removes solvent after terminating, then gains are soluble in water, hydrogenation sodium oxide molybdena, potassium hydroxide or
Ammoniacal liquor adjusts pH value to produce the sulphite of biphenyl to alkalescence.The room temperature is 15~30 DEG C.
6. a kind of pharmaceutical composition for realizing any described application of Claims 1 to 5, it is characterized in that, including claim 1~
The biphenyl compound used in 3 any applications.
7. a kind of medicament for realizing any described application of Claims 1 to 5, it is characterized in that, including claims 1 to 3 is any
The biphenyl compound and auxiliary material used in the application.
8. medicament as claimed in claim 7, it is characterized in that, the medicament is capsule, tablet, powder, granule, injection
Agent, oral liquid, vina, pill, mixture or tincture.
9. a kind of preparation method of medicament as claimed in claim 7, it is characterized in that, by any application of Claims 1 to 5
Biphenyl compound, starch and the dextrin of middle use sieve after mixing, and add sodium carboxymethylcellulose granulation, then add hard
Tabletting produces tablet after fatty acid magnesium mixing.
10. preparation method as claimed in claim 9, it is characterized in that, the biphenyl compound, starch and dextrin mass ratio are
1~2:1~2:2~4.
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| CN109045017A (en) * | 2018-07-10 | 2018-12-21 | 济南市妇幼保健院 | A kind of Polymethoxylated flavanones is preparing the application in anti-oxidation stress medicine |
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