KR100320787B1 - Hispidin-series chemical compound capable of removing active oxygen and process for prepration thereof - Google Patents
Hispidin-series chemical compound capable of removing active oxygen and process for prepration thereof Download PDFInfo
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- KR100320787B1 KR100320787B1 KR1019990026761A KR19990026761A KR100320787B1 KR 100320787 B1 KR100320787 B1 KR 100320787B1 KR 1019990026761 A KR1019990026761 A KR 1019990026761A KR 19990026761 A KR19990026761 A KR 19990026761A KR 100320787 B1 KR100320787 B1 KR 100320787B1
- Authority
- KR
- South Korea
- Prior art keywords
- compound
- methanol
- hispidine
- active oxygen
- present
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims description 38
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 title abstract description 12
- 229910052760 oxygen Inorganic materials 0.000 title abstract description 12
- 239000001301 oxygen Substances 0.000 title abstract description 12
- 238000000034 method Methods 0.000 title description 6
- SGJNQVTUYXCBKH-HNQUOIGGSA-N hispidin Chemical compound O1C(=O)C=C(O)C=C1\C=C\C1=CC=C(O)C(O)=C1 SGJNQVTUYXCBKH-HNQUOIGGSA-N 0.000 claims abstract description 28
- -1 butylperoxy Chemical group 0.000 claims abstract description 22
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 49
- ZICIMKCNGGNJIZ-UHFFFAOYSA-N Hispidine Natural products C1=CC(OC)=CC=C1C(C1)=C(C=2C=C(OC)C(OC)=CC=2)CN2C1CCC2 ZICIMKCNGGNJIZ-UHFFFAOYSA-N 0.000 claims description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 229940123973 Oxygen scavenger Drugs 0.000 claims description 13
- 230000003859 lipid peroxidation Effects 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 230000003078 antioxidant effect Effects 0.000 claims description 7
- 238000004440 column chromatography Methods 0.000 claims description 7
- 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
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 2
- 230000002441 reversible effect Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 claims 1
- 238000004587 chromatography analysis Methods 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- 239000000741 silica gel Substances 0.000 claims 1
- 229910002027 silica gel Inorganic materials 0.000 claims 1
- 230000002292 Radical scavenging effect Effects 0.000 abstract description 27
- 230000002000 scavenging effect Effects 0.000 abstract description 15
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 abstract description 12
- 239000000463 material Substances 0.000 abstract description 8
- 235000001674 Agaricus brunnescens Nutrition 0.000 abstract description 7
- HHEAADYXPMHMCT-UHFFFAOYSA-N dpph Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC([N+]([O-])=O)=C1[N]N(C=1C=CC=CC=1)C1=CC=CC=C1 HHEAADYXPMHMCT-UHFFFAOYSA-N 0.000 abstract description 6
- 241001026513 Phellinus xeranticus Species 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 5
- SGJNQVTUYXCBKH-UHFFFAOYSA-N hispidin Natural products O1C(=O)C=C(O)C=C1C=CC1=CC=C(O)C(O)=C1 SGJNQVTUYXCBKH-UHFFFAOYSA-N 0.000 abstract description 4
- 239000008280 blood Substances 0.000 abstract description 3
- 210000004369 blood Anatomy 0.000 abstract description 3
- 230000001590 oxidative effect Effects 0.000 abstract 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 22
- 238000002835 absorbance Methods 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 15
- 229930003427 Vitamin E Natural products 0.000 description 11
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 11
- 150000003254 radicals Chemical class 0.000 description 11
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- 229940046009 vitamin E Drugs 0.000 description 11
- 239000011709 vitamin E Substances 0.000 description 11
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 10
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- 230000002401 inhibitory effect Effects 0.000 description 9
- MGJZITXUQXWAKY-UHFFFAOYSA-N diphenyl-(2,4,6-trinitrophenyl)iminoazanium Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC([N+]([O-])=O)=C1N=[N+](C=1C=CC=CC=1)C1=CC=CC=C1 MGJZITXUQXWAKY-UHFFFAOYSA-N 0.000 description 7
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 7
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 5
- 239000003963 antioxidant agent Substances 0.000 description 5
- 235000006708 antioxidants Nutrition 0.000 description 5
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
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- 229960003531 phenolsulfonphthalein Drugs 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 210000000170 cell membrane Anatomy 0.000 description 4
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- 239000003112 inhibitor Substances 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- RVBUGGBMJDPOST-UHFFFAOYSA-N 2-thiobarbituric acid Chemical compound O=C1CC(=O)NC(=S)N1 RVBUGGBMJDPOST-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 3
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 3
- 241000191967 Staphylococcus aureus Species 0.000 description 3
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 3
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000002537 cosmetic Substances 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000001554 Hemoglobins Human genes 0.000 description 2
- 108010054147 Hemoglobins Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 108010093894 Xanthine oxidase Proteins 0.000 description 2
- 102100033220 Xanthine oxidase Human genes 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 2
- 239000000490 cosmetic additive Substances 0.000 description 2
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
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- 239000002778 food additive Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
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- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 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 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000005502 peroxidation Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 2
- 229960003912 probucol Drugs 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 229940075420 xanthine Drugs 0.000 description 2
- YKTNISGZEGZHIS-UHFFFAOYSA-N 2-$l^{1}-oxidanyloxy-2-methylpropane Chemical group CC(C)(C)O[O] YKTNISGZEGZHIS-UHFFFAOYSA-N 0.000 description 1
- 241000221198 Basidiomycota Species 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 208000013600 Diabetic vascular disease Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
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- 206010019728 Hepatitis alcoholic Diseases 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
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- 241000191940 Staphylococcus Species 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
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- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
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- 239000000287 crude extract Substances 0.000 description 1
- 201000009101 diabetic angiopathy Diseases 0.000 description 1
- 201000002249 diabetic peripheral angiopathy Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 150000007955 flavonoid glycosides Chemical class 0.000 description 1
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- 238000009472 formulation Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 230000007760 free radical scavenging Effects 0.000 description 1
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- 238000001802 infusion Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
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- 208000019423 liver disease Diseases 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- 230000036244 malformation Effects 0.000 description 1
- 239000000401 methanolic extract Substances 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- JPXMTWWFLBLUCD-UHFFFAOYSA-N nitro blue tetrazolium(2+) Chemical compound COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC(=CC=2)[N+]([O-])=O)=CC=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=C([N+]([O-])=O)C=C1 JPXMTWWFLBLUCD-UHFFFAOYSA-N 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000005424 photoluminescence Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
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- 108090000623 proteins and genes Proteins 0.000 description 1
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- 238000011282 treatment Methods 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/06—Fungi, e.g. yeasts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Mycology (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Engineering & Computer Science (AREA)
- Alternative & Traditional Medicine (AREA)
- Biotechnology (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Microbiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
본 발명은 신규한 히스피딘(hispidin)계 활성산소소거물질 및 그 제조방법에 관한 것으로 찔레꽃버섯(Inonotus xeranticus)으로부터 추출분리하여 정제한 본 발명 히스피딘계 활성산소소거물질은 하기 식(I)으로 표시되며 흰쥐의 간에서 추출한 마이크로좀의 지질과산화를 강하게 억제하는 항산화활성이 있고 수퍼옥사이드 라디칼 소거능, 삼차부틸퍼옥시라디칼 소거능 및 1,1-디페닐-2-피크릴하이드라질(DPPH) 소거능이 있는 뛰어난 효과가 있다.The present invention is a novel Heath pidin (hispidin) based active oxygen scavenging material and a method of manufacturing jjilrekkot mushroom invention Heath blood dingye active oxygen scavenging materials are the formula (I) is purified by separating extracted from (Inonotus xeranticus) it relates to Oxidative activity of superoxide radical scavenging activity, tertiary butylperoxy radical scavenging activity and 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging activity. That has an outstanding effect.
Description
본 발명은 신규한 히스피딘(hispidin)계 활성산소소거물질 및 그 제조방법에 관한 것이다. 더욱 상세하게는, 본 발명은 찔레꽃버섯(Inonotus xeranticus) 추출물로부터 분리한 활성산소를 강력하게 소거하는 신규한 히스피딘계 스피로 타입 화합물 및 그 제조방법에 관한 것이다.The present invention relates to a novel hispidin-based active oxygen scavenging substance and a method for producing the same. More specifically, the present invention relates to a novel hispidine -based spiro type compound for strongly scavenging free radicals isolated from an extract of Inonotus xeranticus , and a method for preparing the same.
활성산소와 유리라디칼은 여러 가지 산화반응에 의하여 생성되며 세포에 산화적 손상을 가하여 각종 질환을 야기한다. 즉 각종 산화반응, 화학약품, 식품, 인체질환 및 방사선 등에 의해 슈퍼옥사이드(superoxide, O2), 하이드록실라디칼(hydroxyl radical, ·OH) 및 과산화수소(H2O2) 등과 같은 반응성이 큰 활성산소와 유리라디칼(free radical) 등이 생체내에 생성되면 이들에 의해서 불포화 지방산이 다량 함유된 세포막의 지질이 산화되어 세포막에 지질 과산화물이 생성되게 된다. 세포막에 지질과산화물이 축적하게되면 세포막의 유동성과 기능성이 저하되어 세포의 전체적인 기능이 억제되고 세포의 구조도 변화하는 등 조직상에 국소적인 장해가 생기면서 각종 질환이 유발되는 것이다. 또한 활성산소와 유리라디칼은 세포 구성성분인 핵산, 당 등을 변형 또는 파괴함으로써 암을 비롯하여 알콜성 간염 등의 간장질환, 뇌혈관 장해로 인한 뇌졸중, 심근경색, 당뇨병성 혈관장애, 고지혈증, 급성염증, 류마치스 질환 등 각종 인체 질환을 일으키게 된다. 따라서 강력하면서도 독성이 없는 활성산소소거물질의 발견은 각종 질병의 치료제 개발이나 노화방지용 화장품첨가제 및 식품첨가제 등으로 매우 유용하게 활용될 것이다. 지금까지 지질과산화저해제로는 부틸 하이드록시 톨루엔(butylated hydroxy toluene:BHT) 및 부틸 하이드록시 아니솔(butylated hydroxy anisol:BHA) 등과 같은 합성 항산화제가 사용되어 왔으나, 이들 BHT나 BHA는 항산화활성은 우수하나 암 또는 기형을 유발할 수 있는 가능성이 매우 높아 계속적으로 사용할 수 없는 단점이 있었다. 따라서 천연물로부터 새로운 활성산소소거물질을 창출하여 독성이나 부작용이 전혀 없는 항산화제를 개발하는 것이 필요하다.Free radicals and free radicals are produced by various oxidation reactions, causing oxidative damage to cells and causing various diseases. That is, highly reactive free radicals such as superoxide (O 2 ), hydroxyl radical (OH) and hydrogen peroxide (H 2 O 2 ) due to various oxidation reactions, chemicals, food, human diseases and radiation When free radicals and the like are generated in vivo, lipids of cell membranes containing a large amount of unsaturated fatty acids are oxidized, thereby producing lipid peroxides on the cell membranes. Accumulation of lipid peroxides in the cell membrane reduces the fluidity and functionality of the cell membrane, thereby inhibiting the overall function of the cell and changing the structure of the cell. In addition, free radicals and free radicals modify or destroy cell constituents such as nucleic acids and sugars, resulting in cancer, liver disease such as alcoholic hepatitis, stroke due to cerebrovascular disorders, myocardial infarction, diabetic vascular disorders, hyperlipidemia, and acute inflammation. And various human diseases such as rheumatoid disease. Therefore, the discovery of a powerful but non-toxic reactive oxygen scavenger will be very useful as a therapeutic agent for various diseases, anti-aging cosmetic additives and food additives. Until now, synthetic antioxidants such as butylated hydroxy toluene (BHT) and butylated hydroxy anisol (BHA) have been used as lipid peroxidant inhibitors, but these BHT and BHA have excellent antioxidant activity. The possibility of causing cancer or malformation was very high, there was a disadvantage that can not be used continuously. Therefore, it is necessary to create an antioxidant that has no toxicity or side effects by creating a new active oxygen scavenger from natural products.
미생물 및 천연물로부터 신규 활성산소 소거작용을 나타내는 생리활성물질의 탐색연구는 비교적 최근에 이루어 졌다. 즉 유칼리나무 추출물로부터 화장품 및 의약품으로 이용가능한 신규 후라보노이드 배당체(일본특허 특개평6-65278, 1994.3.8), 활성산소 소거활성을 나타내는 항산화제(JP 05186768, 1993.7.27), 식품 및 화장품에 사용할수 있는 항산화제(JP 05186769, 1993년.7.27) 등이 알려져 있으나 이들보다 더 강력하면서도 독성이 없는 활성산소 소거활성을 갖는 새로운 물질이 요구되고 있으며 이러한 물질이 발견된다면 각종 질병의 치료제 개발이나 노화방지용 화장품첨가제 및 식품첨가제 등으로 매우 유용하게 활용될 것이다.The search for physiologically active substances exhibiting new active oxygen scavenging activity from microorganisms and natural products has been relatively recent. New Flavonoid Glycosides Available in Cosmetics and Medicines from Eucalyptus Extracts (Japanese Patent Laid-Open No. Hei 6-65278, 1994.3.8), Antioxidants Showing Active Oxygen Scavenging Activity (JP 05186768, July 27, 1993) A number of known antioxidants (JP 05186769, July 27, 1993) are known, but newer substances that have more powerful and non-toxic free radical scavenging activity are required.If such substances are found, they are used to develop treatments for various diseases or to prevent aging. It will be very useful as a cosmetic additive and food additive.
본 발명자들은 미생물, 버섯류 또는 약용식물 등 각종 천연물로부터 새로운 활성산소소거물질을 탐색하던 중, 찔레꽃버섯(Inonotus xeranticus)의 추출물로부터 새로운 히스피딘 골격을 가지며 우수한 활성산소 소거능을 갖는 스피로타입의 화합물을 발견하고 그 물질의 이화학적 특성을 규명함과 동시에 그 제조방법을 확립하고 약리활성을 확인함으로써 본 발명을 완성하였다.The inventors of the present invention, while searching for new active oxygen scavengers from various natural products such as microorganisms, mushrooms or medicinal plants, found a spiro type compound having a new hispidine skeleton from the extract of the brier mushroom ( Inonotus xeranticus ) and having excellent active oxygen scavenging ability The present invention was completed by identifying the physicochemical properties of the substance, establishing the preparation method and confirming the pharmacological activity.
따라서, 본 발명의 목적은 찔레꽃버섯(Inonotus xeranticus) 추출물로부터활성산소 소거작용이 우수한 히스피딘계 화합물을 분리하여 제공함에 있다. 본 발명의 다른 목적은 상기 히스피딘계 화합물의 추출분리 및 정제방법을 제공함에 있다.Accordingly, an object of the present invention is to isolate and provide a histidine -based compound having excellent active oxygen scavenging action from the extract of Inertus xeranticus . Another object of the present invention is to provide a method for extracting and separating the hispidine-based compound.
본 발명의 상기 목적은 찔레꽃 버섯 자실체로부터 추출한 추출물을 정제하여 얻은 순수한 화합물을 질량스펙트럼, 자외선 흡수 스펙트럼, 적외선 흡수 스펙트럼, 수소 핵자기 공명 스펙트럼, 탄소핵자기 공명 스펙트럼으로 조사하여 히스피딘계 화합물로 동정하고 그 구조를 결정한 후 상기 본 발명 히스피딘계 화합물의 생체막 과산화 억제능, 수퍼옥사이드 라디칼 소거능, 삼차부틸퍼옥시 라디칼 소거능 및 1-1-디페닐-2-피크릴하이드라질(1,1-Diphenyl-2-picrylhydrazyl:DPPH) 라디칼 소거능을 각각 측정하여 본 발명 히스피딘계 화합물의 탁월한 활성산소 소거활성과 안전성을 확인함으로써 달성하였다.The object of the present invention is to identify the pure compound obtained by purifying the extract extracted from the staple fruiting fruit body by mass spectrum, ultraviolet absorption spectrum, infrared absorption spectrum, hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum to identify as hispidine-based compound After determining the structure thereof, the biofilm peroxidation inhibitory activity, superoxide radical scavenging activity, tertiary butylperoxy radical scavenging activity and 1-1-diphenyl-2-picrylhydrazyl (1,1-Diphenyl- 2-picrylhydrazyl: DPPH) radical scavenging ability was measured to determine the excellent active oxygen scavenging activity and safety of the hispidine-based compound of the present invention.
이하, 본 발명의 구성 및 작용을 설명한다.Hereinafter, the configuration and operation of the present invention.
도 1은 본 발명 히스피딘계 활성산소소거물질의 고속 원자 충격 질량스펙트럼을 나타낸다.Figure 1 shows the high-speed atomic impact mass spectrum of the hispidine-based active oxygen scavenging material of the present invention.
도 2는 본 발명 히스피딘계 활성산소소거물질의 자외선 흡수 스펙트럼을 나타낸다Figure 2 shows the ultraviolet absorption spectrum of the hispidine-based active oxygen scavenger of the present invention
도 3은 본 발명 히스피딘계 활성산소소거물질의 적외선 스펙트럼을 나타낸다.Figure 3 shows the infrared spectrum of the hispidine-based active oxygen scavenger of the present invention.
도 4는 본 발명 히스피딘계 활성산소소거물질의 수소핵자기공명 스펙트럼을 나타낸다.Figure 4 shows the hydrogen nuclear magnetic resonance spectrum of the histidine-based active oxygen scavenger of the present invention.
도 5는 본 발명 히스피딘계 활성산소소거물질의 탄소핵자기공명 스펙트럼을 나타낸다.Figure 5 shows the carbon nuclear magnetic resonance spectrum of the hispidine-based active oxygen scavenging material of the present invention.
본 발명은 찔레꽃 버섯 자실체로부터 메탄올 추출 및 에틸아세테이트 추출한 추출물을 실리카겔 컬럼 크로마토그라피, 세파덱스 LH-20 컬럼크로마토그라피, 역상 컬럼크로마토그라피로 순차적으로 정제하여 본 발명 히스피딘계 활성산소소거물질을 제조하는 단계; 상기 추출 정제한 본 발명 히스피딘계 활성산소소거물질의 질량스펙트럼, 자외선 흡수 스펙트럼, 적외선 흡수 스펙트럼, 수소핵자기 공명 스펙트럼, 탄소핵자기 공명 스펙트럼을 조사하여 이화학적 성질을 조사하고 화학구조식을 결정하는 단계; 흰쥐의 간으로부터 분리한 마이크로좀을 생체막 지질원으로 사용하여 본 발명 히스피딘계 활성산소소거물질과 FeSO4용액을 반응시킨 후 트리크로로초산으로 반응을 정지시키고 이 반응액을 원심분리하여 얻은 상징액에 치오바비추릭산(thiobarbituric acid)을 첨가하여 반응시킨 후 분광광도계를 사용하여 반응양성물질의 양을 측정하고 상기와 같은 방법으로 대조물질을 처리하고 역시 같은 방법으로 반응양성물질의 양을 측정하여 생체막 지질과산화 억제능을 비교조사하는 단계; 크산틴(xanthine)과 니트로블루테트라졸리움(nitroblueterazolium)을 용해시킨 인산칼리완충용액, 본 발명 히스피딘계 활성산소소거물질 및 잔틴옥시다제(xanthine oxidase)를 반응시키면서 흡광도를 측정하여 수퍼옥사이드 라디칼 소거능을 측정하는 단계; 스타필로코쿠스 아우레우스 209(Staphylococcus aureus209) 균 현탁액 및 헤모글로빈을 본 발명 히스피딘계 활성산소소거물질 및 대조물질과 각각 섞은 후 삼차부틸퍼옥시드를 첨가하여 반응시킨 다음 이 반응액을 마니톨페놀레드 배지에 분주하고 하룻밤 배양시키면서 라디칼의 살균작용을 완전억제하는 시료의 최소농도를 측정하여 삼차부틸퍼옥시 라디칼 소거능을 조사하는 단계 및; DPPH 용액과 메탄올에 녹인 본 발명 히스피딘계 활성산소소거물질을 섞은 후 광흡수도를 측정하고 같은 방법으로 대조물질의 광흡수도를 측정하여 DPPH 라디칼 소거능을 비교조사하는 단계로 구성된다.The present invention is to extract the methanol extract and ethyl acetate extract from the staple mushroom fruiting body sequentially silica gel column chromatography, Sephadex LH-20 column chromatography, reverse phase column chromatography to prepare the histidine-based active oxygen scavenger step; Investigation of physicochemical properties and determination of chemical structural formulas by investigating the mass spectrum, ultraviolet absorption spectrum, infrared absorption spectrum, hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum of the extracted histidine-based active oxygen scavenger step; Using the microsomes isolated from the liver of rats as a biofilm lipid source, the reaction solution of the present invention hispidine-based active oxygen scavenger and FeSO 4 solution was terminated with trichloroacetic acid and the supernatant obtained by centrifugation of the reaction solution. After reacting with thiobarbituric acid, the reaction is measured using a spectrophotometer, the control material is treated in the same manner as above, and the amount of the reaction positive material is measured in the same manner. Comparing and investigating the biological membrane lipid peroxidation inhibitory ability; Superoxide radical scavenging ability was measured by measuring absorbance while reacting a phosphate-buffered solution in which xanthine and nitroblueterazolium were dissolved, the present hisidine-based active oxygen scavenger, and xanthine oxidase. Measuring; Staphylococcus aureus 209 ( Staphylococcus aureus 209) bacteria suspension and hemoglobin were mixed with the histidine-based active oxygen scavenger and the control of the present invention, respectively, and then reacted by adding tert-butyl peroxide, followed by mannitol Investigating tertiary butylperoxy radical scavenging ability by measuring the minimum concentration of the sample to disinfect the phenol red medium and completely inhibit the sterilization of radicals while overnight culture; After mixing the DPPH solution and the present invention hispidine-based active oxygen scavenger dissolved in methanol, the light absorbance is measured and the light absorbance of the control compound is measured in the same manner to compare the DPPH radical scavenging ability.
본 발명 히스피딘(hispidin)계 화합물은 하기 식(I)으로 표시되는 바와 같이 스피로타입의 골격을 함유하며 담자균류에 속하는 버섯으로부터 물이나 유기용매(알콜, 에텔, 아세톤 등)에 의한 추출, 초산에틸 그밖의 유기용매, 각종 칼럼 크로마토그라피 등, 버섯성분의 분리 추출에 이용할 수 있는 공지의 방법을 단독 또는 적당히 혼용하여 얻을 수가 있고 조추출물은 필요에 따라서 상법에 의해 더욱 순수하게 정제할 수 있다.The hispidine compound of the present invention contains a spirotype skeleton and is extracted by water or an organic solvent (alcohol, ether, acetone, etc.) from mushrooms belonging to basidiomycete as shown by the following formula (I): A well-known method which can be used for isolation | extraction extraction of mushroom components, such as ethyl and other organic solvents and various column chromatography, can be obtained individually or in mixture suitably, and crude extract can be refine | purified more purely by a conventional method as needed.
본 발명의 스피로타입 골격을 함유한 히스피딘(hispidin)계 화합물은 활성산소나 유리라디칼을 소거하는 작용을 가지고 있으며, 상기 본 발명 화합물과 유사한 공지의 다른 화합물 보다도 더욱 강한 항산화활성을 나타내 생체내 항산화제 분야 이외에도 생체막 지질의 과산화 반응과 관련되는 생리활성분야에서 매우 유용하게 이용할 수 있다.Hispidin-based compounds containing the spirotype skeleton of the present invention have the action of scavenging free radicals and free radicals and exhibit stronger antioxidant activity than other known compounds similar to the compounds of the present invention. In addition to the first field can be very useful in the field of physiological activity associated with the peroxidation reaction of biological membrane lipids.
본 발명의 스피로타입 골격을 함유한 히스피딘계 화합물은 탁월한 활성산소 소거활성을 나타냄과 동시에 안전성도 매우 높아 항산화제로서 식품이나 화장품 등에 첨가하는 경우 이외에도 탁월한 생체내 항산화 활성을 이용한 각종 의약품으로서 사용 가능하다. 의약품으로 사용할 경우에는 본 발명에서 명시한 각 화합물들을 유효성분으로 하며 그에 상응하는 무기 또는 유기 담체를 가하여, 고체, 반고체 또는 액체의 형태로 제제화하고 경구 투여제 뿐만 아니라 외상용 등 비경구투여제로 제제화 할 수 있다. 경구투여를 위한 제제화에는 정제, 환제, 과립제, 캡슐제, 펠렛제, 산제, 세립제, 분제, 유탁제, 현탁제, 시럽제 등을 열거할 수 있으며 , 비경구투여제로는 주사제, 점적제, 수액, 연고, 스프레이제, 현탁제, 유제, 좌제 등을 들 수 있다.The hispidine-based compound containing the spirotype skeleton of the present invention exhibits excellent active oxygen scavenging activity and is also very safe, and can be used as various medicines using excellent in vivo antioxidant activity in addition to food or cosmetics as an antioxidant. Do. When used as a medicament, each compound specified in the present invention is used as an active ingredient, and the corresponding inorganic or organic carrier is added to form a solid, semi-solid or liquid form, and to be formulated not only for oral administration but also for parenteral administration such as trauma. Can be. Formulations for oral administration may include tablets, pills, granules, capsules, pellets, powders, granules, powders, emulsions, suspensions, syrups, and the like. Parenteral dosages include injections, drops, sap, Ointments, sprays, suspensions, emulsions, suppositories, and the like.
본 발명의 유효성분을 제제화하기 위하여 상법에 따르면 비교적 쉽게 제제화할 수 있으며 계면활성제, 부형제, 착색제, 착향제, 보존제, 안정제, 완충제, 현탁제 등도 상법에 따라 적당히 선별하여 사용할 수 있다.In order to formulate the active ingredient of the present invention can be formulated relatively easily according to the conventional method, surfactants, excipients, colorants, flavoring agents, preservatives, stabilizers, buffers, suspending agents and the like can also be appropriately selected according to the conventional method.
이하, 본 발명의 구체적인 방법을 실시예를 들어 상세히 설명하고자 하지만 본 발명의 권리범위는 이들 실시예에만 한정되는 것은 아니다.Hereinafter, the specific method of the present invention will be described in detail with reference to Examples, but the scope of the present invention is not limited only to these Examples.
실시예 1: 본 발명 히스피딘계 화합물의 제조Example 1 Preparation of the Hispidine Compound of the Invention
풍건한 찔레꽃버섯(Inonotus xeranticus) 자실체 500g을 분쇄기로 잘게 마쇄한 후 8L의 80% 메탄올로 추출한 다음 감압농축한 후 재차 에틸아세테이트로 추출하여 에틸아세테이트 층과 물층으로 나누었다. 에틸아세테이트 층은 크로로포름-메탄올 60:1, 20:1, 10:1 혼합용매를 사용하며 농도구배 실리카겔 컬럼 크로마토그라피를 실시한 후 활성분획을 재차 세파덱스 LH-20 컬럼 크로마토그라피, 역상 (ODS) 컬럼 크로마토그라피를 순차적으로 실시한 다음 물 33g에 메탄올 67g을 섞은 67% 메탄올을 용매로하여 ODS TLC를 실시하고, 활성분획은 물 40g에 메탄올 60g을 섞은 60% 메탄올을 사용하여 HPLC를 실시함으로써 순수하게 정제된 노란색 화합물 10.3mg을 얻을 수 있었다.500 g of the dried brier ( Inonotus xeranticus ) fruiting body was finely crushed with a grinder, extracted with 8 L of 80% methanol, concentrated under reduced pressure, and extracted again with ethyl acetate, and then divided into an ethyl acetate layer and a water layer. The ethyl acetate layer was mixed with chromoform-methanol 60: 1, 20: 1, 10: 1, and subjected to concentration gradient silica gel column chromatography, followed by active fractionation. Sephadex LH-20 column chromatography, reversed phase (ODS) ) Column chromatography was performed sequentially, followed by ODS TLC using 67% methanol mixed with 67 g of methanol in 33 g of water as a solvent, and the active fraction was purified by HPLC using 60% methanol mixed with 60 g of methanol in 40 g of water. To obtain 10.3 mg of a purely purified yellow compound.
실시예 2: 본 발명 히스피딘계 화합물의 동정 및 이화학적 성질Example 2: Identification and Physicochemical Properties of Hispidine Compounds of the Invention
상기 실시예 1에서 추출분리 정제한 노란색 화합물의 성상, 분자량, 분자식, 질량분석치, 선광도, 자외선 흡수 스펙트럼, 적외선 흡수 스펙트럼, 수소 핵자기 공명 스펙트럼, 탄소핵자기 공명 스펙트럼을 조사하여 동정하고 그 이화학적 특성을 조사하였다. 실험결과는 하기에 나타낸 바와 같으며 이 결과로부터 본 발명의 화합물은 스피로타입의 골격을 함유하는 히스피딘계 화합물로 확인되었다.Characterization, molecular weight, molecular formula, mass spectrometry, photoluminescence, ultraviolet absorption spectrum, infrared absorption spectrum, hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum of the yellow compound extracted and purified in Example 1 were identified and catabolized The chemical properties were investigated. Experimental results are as shown below, and from this result, the compound of the present invention was identified as a hispidine-based compound containing a spirotype skeleton.
물질의 성상: 황색분말 Form of material : Yellow powder
분자량: 462 Molecular Weight: 462
분자식: C25H18O9 Molecular Formula : C 25 H 18 O 9
질량분석치(도 1): HRFAB-MS〔(M+H)+,m/z실측치 463.1045, 계산치 463.1029〕 Mass spectrometry (FIG. 1) : HRFAB-MS ((M + H) + , m / z found 463.1045, calculated 463.1029]
선광도: 〔α〕D= 0 (c=9.0, CH3OH) Luminous intensity : [α] D = 0 (c = 9.0, CH 3 OH)
자외선 흡수 스펙트럼(도 2)(UVλmax nm (ε) in MeOH) UV absorption spectrum (FIG. 2) (UVλmax nm (ε) in MeOH)
262(11,822), 389(11,568)262 (11,822), 389 (11,568)
적외선 흡수 스펙트럼(도 3)( IRυmax in KBr ) Infrared absorption spectrum (FIG. 3) (IRυmax in KBr)
3430, 1700, 1695, 1593, 1549, 1384, 1276, 1127 cm-1 3430, 1700, 1695, 1593, 1549, 1384, 1276, 1127 cm -1
수소 핵자기공명 스펙트럼(도 4): δppm ( 600MHz, CD3OD) Hydrogen Nuclear Magnetic Resonance Spectrum (Fig. 4) : δ ppm (600 MHz, CD 3 OD)
1.98 (s, Me-1'), 5.57 (s, H-2'), 5.65 (s, H-5'), 6.50 (s, H-4), 6.59 (dd, J=8.1, 1.6, H-11'), 6.71 (d, J=1.6, H-7'), 6.72 (d, J=15.9, H-6), 6.75 (d, J=8.1, H-10'), 6.79 (d, J=8.2, H-12), 7.00 (dd, J=8.2, 1.8, H-13), 7.08 (d, J=1.8, H-9), 7.44 (d, J=15.9, H-7)1.98 (s, Me-1 '), 5.57 (s, H-2'), 5.65 (s, H-5 '), 6.50 (s, H-4), 6.59 (dd, J = 8.1, 1.6, H -11 '), 6.71 (d, J = 1.6, H-7'), 6.72 (d, J = 15.9, H-6), 6.75 (d, J = 8.1, H-10 '), 6.79 (d, J = 8.2, H-12), 7.00 (dd, J = 8.2, 1.8, H-13), 7.08 (d, J = 1.8, H-9), 7.44 (d, J = 15.9, H-7)
탄소 핵자기공명 스펙트럼(도 5): δppm ( 150MHz, CD3OD) Carbon nuclear magnetic resonance spectrum (FIG. 5) : δ ppm (150 MHz, CD 3 OD)
20.0 (Me-1'), 94.5 (C-4'), 95.5 (C-4), 95.9 (C-5'), 99.5 (C-2), 105.1 (C-2'), 115.0 (C-9), 115.1 (C-7'), 115.5 (C-10'), 115.8 (C-12), 116.6 (C-6), 120.2 (C-11'), 122.7 (C-13), 123.2 (C-6'), 128.5 (C-8), 139.9 (C-7), 146.3 (C-8'), 147.0 (C-10), 147.8 (C-9'), 149.5 (C-11), 160.6 (C-1), 167.0 (C-5), 176.8 (C-3), 192.9 (C-1'), 203.1 (C-3')20.0 (Me-1 '), 94.5 (C-4'), 95.5 (C-4), 95.9 (C-5 '), 99.5 (C-2), 105.1 (C-2'), 115.0 (C- 9), 115.1 (C-7 '), 115.5 (C-10'), 115.8 (C-12), 116.6 (C-6), 120.2 (C-11 '), 122.7 (C-13), 123.2 ( C-6 '), 128.5 (C-8), 139.9 (C-7), 146.3 (C-8'), 147.0 (C-10), 147.8 (C-9 '), 149.5 (C-11), 160.6 (C-1), 167.0 (C-5), 176.8 (C-3), 192.9 (C-1 '), 203.1 (C-3')
화학구조식Chemical structure
실시예 3: 본 발명 히스피딘계 화합물의 생체막 지질과산화 억제능Example 3 Inhibition of Biofilm Lipid Peroxidation of the Hispidine Compound of the Present Invention
본 실시예에서는 본 발명 히스피딘계 화합물의 지질 과산화 억제능을 측정하기 위해 흰쥐의 간으로부터 분리한 마이크로좀을 생체막으로 사용하였다. 마이크로좀의 분리는 분별원심분리법으로 실시하였다. 즉, 흰쥐의 간을 적출한 후 4℃의 0.25 M 수크로오스 용액에 넣어 2∼3회 세척한 후 세절한 다음 간 무게의 8배 용량의 수크로오스 용액, 5 mM 트리스-염산 완충용액 (pH 7.4) 및 0.1 mM EDTA 혼합용액을 가하여 조직분쇄기로 마쇄하였다. 이것을 7,000g에서 10분간 원심분리한 다음 상징액을 취하여 77,000g에서 60분간 초원심분리한 후 침전물을 취하여 트리스-염산 완충용액으로 3회 세척하였다. 이것을 트리스-염산 완충용액으로 현탁 희석하고 로우리방법으로 단백질을 정량하여 1 mg/mL로 만들었다. 상기와 같이 분리한 흰쥐의 간 마이크로좀을 생체막 지질원으로하여 시료의 지질 과산화 억제능을 측정하였다. 시험관에 마이크로좀용액 10 ㎕, 메탄올에 녹인 각 농도의 시료 10 ㎕, 100 mM 트리스-염산 완충용액 (pH 7.5) 0.5 mL, 증류수 450 ㎕를 넣고 4mM FeSO4용액 30 ㎕를 첨가하여 반응을 개시하였다. 반응은 37℃의 수욕상에서 30분간 행하였고 3M 트리크로로초산- 2 N 염산 1:1 혼합액 0.3 mL를 첨가하여 반응을 정지시켰다. 이것을 3000g에서 10분간 원심분리한 다음 상징액 1mL을 취한 후 0.67치오바비추릭산 (thiobarbituric acid, TBA) 0.3 mL을 첨가하여 끓는 수욕상에서 10분간 반응시키고 이때 생성된 TBA에 대한 반응양성물질의 양을 분광광도계를 사용하여 파장 530 nm에서의 흡광도를 측정하여 하기 식에 따라 지질 과산화 억제 활성()을 산출하였다. 양성 대조군으로는 비타민 E와 부틸하이드록시아니솔(Butylated hydroxy anisole;BHA)를 사용하였다.In this example, microsomes isolated from livers of rats were used as biological membranes in order to measure the lipid peroxidation inhibitory activity of the inventive hispidine-based compounds. Microsomes were separated by fractional centrifugation. That is, the livers of the rats were extracted, washed 2 to 3 times in a 0.25 M sucrose solution at 4 ° C, and then chopped. 0.1 mM EDTA mixed solution was added and ground using a tissue grinder. This was centrifuged at 7,000g for 10 minutes, the supernatant was taken, ultracentrifuged at 77,000g for 60 minutes, and the precipitate was taken out and washed three times with Tris-HCl buffer. This was suspended in tris-hydrochloric acid buffer and the protein was quantified by Lowry method to make 1 mg / mL. The liver microsomes of rats isolated as above were used as biological membrane lipid sources to measure lipid peroxidation inhibitory activity of the samples. The reaction was initiated by adding 10 μl of microsomal solution, 10 μl of sample in each concentration dissolved in methanol, 0.5 mL of 100 mM Tris-hydrochloric acid buffer (pH 7.5), 450 μl of distilled water, and 30 μl of 4mM FeSO 4 solution. . The reaction was carried out for 30 minutes in a 37 DEG C water bath and the reaction was stopped by adding 0.3 mL of 3M trichloroacetic acid-2N hydrochloric acid 1: 1 mixture. After centrifugation at 3000g for 10 minutes, 1 mL of the supernatant was added, and 0.3 mL of 0.67 thiobarbituric acid (TBA) was added to react for 10 minutes in a boiling water bath. Absorbance at wavelength 530 nm was measured using a photometer to calculate lipid peroxidation inhibitory activity () according to the following formula. As a positive control, vitamin E and butylated hydroxy anisole (BHA) were used.
A: 저해제를 넣지 않은 것의 흡광도A: absorbance without the inhibitor
B: 저해제와 마이크로좀을 넣지 않은 것의 흡광도B: Absorbance of Without Inhibitors and Microsomes
C: 저해제를 넣은 것의 흡광도C: absorbance of the inhibitor
실험결과, 쥐의 간에서 추출한 마이크로좀의 지질과산화를 50억제하는 농도(IC50)를 지표로 하여 하기 표 1에 본 발명 히스피딘계 화합물의 지질과산화 저해활성을 나타냈다. 본 발명 화합물이 대조화합물 1보다는 생체막 지질 과산화 억제능이 약간 높았고 대조화합물 2보다는 월등하게 높음을 알 수 있었다.As a result of the experiment, the lipid peroxidation inhibitory activity of the histodine-based compound of the present invention is shown in Table 1 below with the concentration (IC 50 ) of inhibiting lipid peroxidation of microsomes extracted from rat liver. The compound of the present invention was slightly higher than the control compound 1 in biofilm lipid peroxidation inhibition and was found to be significantly higher than the control compound 2.
실시예 4: 본 발명 히스피딘계 화합물의 수퍼옥사이드 라디칼 소거능Example 4 Superoxide Radical Scavenging Activity of the Hispidine Compounds of the Present Invention
본 발명 히스피딘계 화합물의 수퍼옥사이드 라디칼 소거능을 조사하기 위하여, 96-well 마이크로플레이트의 웰 당 50mM, pH7.8 인산칼리완충용액 (potassiumphosphate buffer)에 용해시킨 크산틴(xanthine)(2 mM)과 니트로블루테트라졸리움 [nitroblueterazolium, NBT (0.1 mM)] 혼합용액 100 ㎕, 메탄올에 녹인 본 발명 히스피딘을 비롯한 대조물질 각 농도의 시료 5 ㎕를 넣은 후 4 units/mL의 잔틴옥시다제 (xanthine oxidase) 30 ㎕를 첨가하여 반응을 개시한 후 즉시 마이크로플레이트 리더(microplate reader)로 570 nm에서의 흡광도를 측정하고 20분간 반응시킨 다음 다시 흡광도를 측정하였다. 수퍼옥사이드 라디칼 소거활성은 20분간 반응시킨 후의 흡광도(A20)로부터 반응개시 직후 (A0)의 흡광도값을 뺌으로써 흡광도 변화 (A20-A0)를 계산하여 산출하였으며, 활성의 단위는 시료를 넣지 않은 대조구에 비하여 흡광도 변화를 50감소시키는 시료의 농도를 IC50으로 하였다. 양성 대조군으로는 비타민 E와 부틸하이드록시아니솔(BHA)를 사용하였다.In order to investigate the superoxide radical scavenging ability of the hisidine compound of the present invention, xanthine (2 mM) dissolved in 50 mM, pH7.8 potassium phosphate buffer per well of a 96-well microplate, and Nitrobluetetrazolium [nitroblueterazolium, NBT (0.1 mM)] 100 μl of the mixed solution, 5 μl of the sample of each concentration of the control material including the present invention hispidine dissolved in methanol were added and then 4 units / mL of After initiating the reaction by adding 30 μl of xanthine oxidase, the absorbance at 570 nm was immediately measured using a microplate reader, the reaction was performed for 20 minutes, and then the absorbance was again measured. Superoxide radical scavenging activity was measured for absorbance after reaction for 20 minutes (A20Immediately after the reaction starts from0Change in absorbance by subtracting the absorbance value of20-A0), And the unit of activity is the concentration of the sample that reduces the change in absorbance by 50 compared to the control without the sample.50It was made. As a positive control, vitamin E and butylhydroxyanisole (BHA) were used.
A: 시료를 넣지 않은 것의 흡광도 변화A: Change in absorbance without the sample
B: 시료를 넣은 것의 흡광도 변화B: Absorbance change of the sample
실험결과, 본 발명 히스피딘계 화합물의 수퍼옥사이드 라디칼 소거능을 IC50으로 환산하여 하기 표 2에 나타낸 바와 같이 본 발명 히스피딘계 화합물의 수퍼옥사이드 라디칼 소거능이 대조물질에 비해 월등이 우수함을 알 수 있었다.Result, the superoxide radical scavenging activity of the present invention Heath blood as to, in terms of the superoxide radical scavenging activity of dingye compound with IC 50 shown in Table 2, the present invention Heath blood dingye compound showed a superior is superior compared to the control substance .
실시예 5: 본 발명 히스피딘계 화합물의삼차부틸퍼옥시 라디칼(Example 5: Tertiary butyl peroxy radical of the hispidine-based compound of the present invention ( tt -butylperoxy radical,-butylperoxy radical, tt -BOO·) 소거능-BOO ·) erasure
스타필로코쿠스 아우레우스 209(Staphylococcus aureus209) 균주를 브레인-하아트 인푸젼(brain-heart infusion) 배지 5 mL에 접종한 후 37℃에서 하룻밤 배양한 다음, 균체를 원심분리 (1,000 × g)하여 PBS (pH 7.2)로 3회 세정하였다. PBS에 균을 현탁하여 1×107CFU/mL로 조제하였다. 96-well 마이크로플레이트의 각 well당 균현탁 70㎕, 본 발명 히스피딘계 화합물과 대조물질인 각 농도의 시료 10㎕, 1 mg/mL 헤모글로빈 30㎕를 넣고 잘 섞은 후 50mM 삼차부틸퍼옥시드(t-BOOH)를 40㎕ 첨가하고 곧바로 섞어 반응을 개시하고 반응액을 37℃에서 30분간 배양하였다. 마니톨페놀레드 배지 (beef extract 6 g, 펩톤 20 g, 소금 10 g, 마니톨 20 g, 페놀레드 0.07 g, 물 1L, pH 7.4) 5㎕를 가하여 반응을 정지시켰다. 96-well 마이크로플레이트에 마니톨페놀레드 배지를 100㎕/well로 분주한 다음 전술한 살균반응액 50㎕ 첨가하고 37℃에서 하룻밤 배양하였다. 플레이트상에서 본 발명 화합물에 의하여 삼차부틸퍼옥시 라디칼이 소거됨으로써 생존균을 함유하게된 well 중의 배지는 균의 증식에 의해 pH가 낮아져 배지중의 페놀레드의 색깔이 적색에서 황색으로 변화하였다. 화합물의 삼차부틸퍼옥시 라디칼 소거능은 라디칼의 살균작용을 완전 억제하는 시료의 최소농도(MIC)로 나타내었으며, 양성 대조군으로는 비타민 E, BHA 및 프로부콜(probucol)을 사용하였다. 실험결과, 본 발명 화합물의 삼차부틸퍼옥시 라디칼 소거능을 MIC로 하여 하기 표 3에 나타낸 바와 같이 본 발명 화합물의 MIC의 양이 가장 적음을 알 수 있었다.Staphylococcus aureus 209(Staphylococcus aureus209) The strain was inoculated in 5 mL of brain-heart infusion medium and incubated overnight at 37 ° C., followed by centrifugation (1,000 × g) of the cells and washing three times with PBS (pH 7.2). It was. Suspension of bacteria in PBS 1 × 107Prepared at CFU / mL. 70 µl of bacterial suspension per well of 96-well microplate, 10 µl of sample of each concentration of the invention hispidine-based compound and control, 1 mg / mL Add 30 μl of hemoglobin, mix well, and add 50 mM tert-butyl peroxide (t-BOOH) was added and the mixture was immediately mixed to start the reaction, and the reaction solution was incubated at 37 ° C for 30 minutes. The reaction was stopped by adding 5 µl of mannitol phenol red medium (6 g of beep extract, 20 g of peptone, 10 g of salt, 20 g of mannitol, 0.07 g of phenol red, 1 L of water, pH 7.4). The mannitol phenol red medium was dispensed into 100 µl / well in a 96-well microplate, and then 50 µl of the above-described sterilization reaction solution was incubated at 37 ° C overnight. The medium in the well containing the viable bacteria by eliminating the tertiary butyl peroxy radical by the compound of the present invention on the plate, the pH was lowered by the growth of the bacteria, the color of the phenol red in the medium was changed from red to yellow. The tertiary butylperoxy radical scavenging ability of the compound was expressed as the minimum concentration (MIC) of the sample to completely inhibit the sterilization action of the radical, and vitamin E, BHA and probucol were used as a positive control. As a result, the tertiary butyl peroxy radical scavenging ability of the compound of the present invention was determined to be MIC, as shown in Table 3 below.
실시예 6: 본 발명 히스피딘계 화합물의 1,1-디페닐-2-피크릴하이드라질 라디칼 소거능Example 6: 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity of the hispidine-based compound of the present invention
에탄올에 녹인 0.15mM 1,1-디페닐-2-피크릴하이드라질(1,1-Diphenyl-2-picrylhydrazyl; DPPH) 용액 1 mL과 메탄올에 녹인 본 발명 히스피딘계 화합물과 대조물질 각 농도의 시료 0.1 mL를 섞은 후 30분간 방치한 다음 517 nm에서의 광흡수도와 시료를 넣지 않고 메탄올만을 넣은 대조구의 광흡수도를 측정하여 하기 식에 따라 DPPH 라디칼 소거능을 산출하였다. 양성 대조군으로는 비타민 E와 BHA를 사용하였다.1 mL of a solution of 0.15 mM 1,1-diphenyl-2-picrylhydrazyl (DPPH) dissolved in ethanol and the concentrations of the inventive hispidine-based compound and the reference compound dissolved in methanol After mixing 0.1 mL of the sample, the mixture was left for 30 minutes, and then the absorbance at 517 nm and the absorbance of the control group containing only methanol without the sample were measured to calculate DPPH radical scavenging ability according to the following formula. As a positive control, vitamin E and BHA were used.
A: 시료를 넣지 않은 것의 흡광도A: absorbance without sample
B: 시료를 넣은 것의 흡광도B: absorbance of the sample
실험결과, DPPH 라디칼 50소거하는 농도(IC50)를 지표로 나타낸 본 발명 히스피딘계 화합물의 DPPH 라디칼 소거능은 표 4에 나타낸 바와 같으며 본 발명 히스피딘계 화합물의 DPPH 라디칼 소거능이 대조화합물에 비해 우수함을 알 수 있었다.As a result, the DPPH radical scavenging ability of the histidine-based compound of the present invention, the concentration of which eliminates DPPH radical 50 (IC 50 ), is as shown in Table 4, and the DPPH radical scavenging ability of the histidine-based compound of the present invention was higher than that of the control compound. It was found to be excellent.
상기 실시예를 통하여 설명한 바와 같이 찔레꽃버섯(Inonotus xeranticus)으로부터 추출분리한 본 발명 히스피딘(hispidin)계 화합물은 쥐의 간에서 추출한 마이크로좀의 지질과산화를 강하게 억제하는 항산화활성이 있고 수퍼옥사이드 라디칼 소거능, 삼차부틸옥시라디칼 소거능 및 1,1-디페닐-2-피크릴하이드라질(DPPH) 소거능이 있는 뛰어난 효과가 있고 또 본 발명 히스피딘계 화합물의 화학구조식을 결정함으로써 상기 화학구조식을 변화시켜 신규한 화합물을 얻을 수 있는 효과가 있으므로 식품, 화장품 및 의약품산업상 매우 유용한 발명인 것이다.As described through the above examples, the present invention hispidin-based compound extracted from a staple mushroom ( Inonotus xeranticus ) has an antioxidant activity that strongly inhibits lipid peroxidation of microsomes extracted from rat liver and has a superoxide radical scavenging ability. , Tertiary butyloxy radical scavenging ability and 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging effect has an excellent effect, and by changing the chemical formula of the present invention hispidine-based compound by changing the chemical formula Since one compound has the effect of obtaining a very useful invention in the food, cosmetics and pharmaceutical industries.
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