CN116655711A - New isoliquiritigenin from carob, and preparation method and application thereof - Google Patents
New isoliquiritigenin from carob, and preparation method and application thereof Download PDFInfo
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- CN116655711A CN116655711A CN202310690608.0A CN202310690608A CN116655711A CN 116655711 A CN116655711 A CN 116655711A CN 202310690608 A CN202310690608 A CN 202310690608A CN 116655711 A CN116655711 A CN 116655711A
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- Prior art keywords
- isoliquiritigenin
- carob
- liver
- pod
- methanol
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- JBQATDIMBVLPRB-UHFFFAOYSA-N isoliquiritigenin Natural products OC1=CC(O)=CC=C1C1OC2=CC(O)=CC=C2C(=O)C1 JBQATDIMBVLPRB-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 235000008718 isoliquiritigenin Nutrition 0.000 title claims abstract description 39
- 235000013912 Ceratonia siliqua Nutrition 0.000 title claims abstract description 38
- 240000008886 Ceratonia siliqua Species 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- DXDRHHKMWQZJHT-FPYGCLRLSA-N isoliquiritigenin Chemical compound C1=CC(O)=CC=C1\C=C\C(=O)C1=CC=C(O)C=C1O DXDRHHKMWQZJHT-FPYGCLRLSA-N 0.000 title abstract description 27
- -1 flavonoid glycoside compound Chemical class 0.000 claims abstract description 22
- 210000004185 liver Anatomy 0.000 claims abstract description 21
- 206010067125 Liver injury Diseases 0.000 claims abstract description 15
- 231100000753 hepatic injury Toxicity 0.000 claims abstract description 12
- 208000019425 cirrhosis of liver Diseases 0.000 claims abstract description 8
- 201000007270 liver cancer Diseases 0.000 claims abstract description 8
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 8
- 206010061218 Inflammation Diseases 0.000 claims abstract description 7
- 230000000903 blocking effect Effects 0.000 claims abstract description 7
- 230000004054 inflammatory process Effects 0.000 claims abstract description 7
- 230000006870 function Effects 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 23
- 238000000605 extraction Methods 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- 239000000284 extract Substances 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 239000003208 petroleum Substances 0.000 claims description 10
- 239000007791 liquid phase Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 claims description 7
- 239000003480 eluent Substances 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- 238000004587 chromatography analysis Methods 0.000 claims description 4
- 239000012153 distilled water Substances 0.000 claims description 4
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 claims description 4
- 235000013305 food Nutrition 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 4
- 239000011347 resin Substances 0.000 claims description 4
- 229920005989 resin Polymers 0.000 claims description 4
- 238000010898 silica gel chromatography Methods 0.000 claims description 4
- 238000010521 absorption reaction Methods 0.000 claims description 3
- 150000001720 carbohydrates Chemical class 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 239000012535 impurity Substances 0.000 claims description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 239000008213 purified water Substances 0.000 claims description 3
- 238000001179 sorption measurement Methods 0.000 claims description 3
- 239000003463 adsorbent Substances 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims description 2
- 230000036541 health Effects 0.000 claims description 2
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims 1
- 238000005191 phase separation Methods 0.000 claims 1
- 239000000741 silica gel Substances 0.000 claims 1
- 229910002027 silica gel Inorganic materials 0.000 claims 1
- 229930182486 flavonoid glycoside Natural products 0.000 abstract description 5
- 241000220485 Fabaceae Species 0.000 abstract description 3
- 235000013913 Ceratonia Nutrition 0.000 abstract 1
- 241001060815 Ceratonia Species 0.000 abstract 1
- 229940043431 ceratonia Drugs 0.000 abstract 1
- 235000013399 edible fruits Nutrition 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 17
- 230000000694 effects Effects 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 239000008187 granular material Substances 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 239000000853 adhesive Substances 0.000 description 6
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- 239000000314 lubricant Substances 0.000 description 6
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 5
- 102000019197 Superoxide Dismutase Human genes 0.000 description 5
- 108010012715 Superoxide dismutase Proteins 0.000 description 5
- 208000019423 liver disease Diseases 0.000 description 5
- 229940118019 malondialdehyde Drugs 0.000 description 5
- 238000011160 research Methods 0.000 description 5
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- 235000013373 food additive Nutrition 0.000 description 4
- 239000002778 food additive Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 3
- 235000017367 Guainella Nutrition 0.000 description 3
- 244000046052 Phaseolus vulgaris Species 0.000 description 3
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 3
- 208000029618 autoimmune pulmonary alveolar proteinosis Diseases 0.000 description 3
- 230000036952 cancer formation Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229930003935 flavonoid Natural products 0.000 description 3
- 235000017173 flavonoids Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 2
- 108010082126 Alanine transaminase Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 108090000340 Transaminases Proteins 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 231100000439 acute liver injury Toxicity 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 150000002215 flavonoids Chemical class 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 2
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 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 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000003440 toxic substance Substances 0.000 description 2
- 102000014898 transaminase activity proteins Human genes 0.000 description 2
- 208000030090 Acute Disease Diseases 0.000 description 1
- XOJVHLIYNSOZOO-SWOBOCGESA-N Arctiin Chemical compound C1=C(OC)C(OC)=CC=C1C[C@@H]1[C@@H](CC=2C=C(OC)C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)=CC=2)C(=O)OC1 XOJVHLIYNSOZOO-SWOBOCGESA-N 0.000 description 1
- 240000005528 Arctium lappa Species 0.000 description 1
- 235000003130 Arctium lappa Nutrition 0.000 description 1
- 235000008078 Arctium minus Nutrition 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010008479 Chest Pain Diseases 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 244000303040 Glycyrrhiza glabra Species 0.000 description 1
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 231100000481 chemical toxicant Toxicity 0.000 description 1
- 231100000012 chronic liver injury Toxicity 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
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- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 235000011477 liquorice Nutrition 0.000 description 1
- 230000005976 liver dysfunction Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- JMZOMFYRADAWOG-UHFFFAOYSA-N methyl 7-methoxy-4-(7-methoxy-5-methoxycarbonyl-1,3-benzodioxol-4-yl)-1,3-benzodioxole-5-carboxylate Chemical compound COC(=O)C1=CC(OC)=C2OCOC2=C1C1=C2OCOC2=C(OC)C=C1C(=O)OC JMZOMFYRADAWOG-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
- C07H1/08—Separation; Purification from natural products
-
- 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
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Botany (AREA)
- Mycology (AREA)
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- Polymers & Plastics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The application relates to a flavonoid glycoside compound new isoliquiritigenin and a preparation method and application thereof, in particular to a flavonoid glycoside compound which is separated from Ceratonia siliquaLinn. Dry fruit pods of carob of the genus carob of the family Leguminosae and has the functions of protecting liver, repairing liver injury, reducing liver inflammatory reaction, blocking liver cirrhosis and liver cancer, and a preparation method and application thereof. The flavonoid glycoside compound provided by the application is novel isoliquiritigenin, and the purity of the flavonoid glycoside compound is more than or equal to 99.5%.
Description
Technical Field
The application relates to the field of medicines and health-care foods, in particular to a flavonoid glycoside compound new isoliquiritigenin which is separated from Ceratonia siliqua Linn dried pods of carob beans of the genus carob of the family Leguminosae, has the effects of protecting liver, repairing liver injury, reducing liver inflammatory reaction, blocking liver cirrhosis and liver cancer, and provides a preparation method and application of the compound.
Background
Liver is an important organ for maintaining life activities of organism, and participates in the metabolic processes of substances such as oxidation, reduction, hydrolysis, combination and the like in organism, and secretion of bile participates in digestion process of organism. During the metabolism and digestion, toxic substances are converted and detoxified. It should be noted that the liver is a fragile organ and that once a large amount of toxic chemicals is taken in a short period of time beyond the tolerance range of the liver, acute and chronic liver injury to the liver may occur. Liver dysfunction caused by liver injury is a common pathological basis of various liver lesions, and is the cause of occurrence, development and final trend of various severe liver diseases. Therefore, the composition has important significance in repairing liver injury and researching prevention and treatment of acute and chronic liver diseases, hepatitis, liver cirrhosis and liver cancer.
In China, which is a high incidence area of hepatitis, no specific medicine for treating the diseases exists in modern chemical medicines and can be taken for a long time, and side effects after medicine use cannot be avoided in most medicines in the prior art, such as: after bifendate is taken, reactions such as dry mouth, nausea, rash and the like can occur, and transaminase rebound can also occur after medicine withdrawal; chest distress, edema, and mild elevated blood pressure may be caused after the administration of Qiangling Ning. The traditional advantages of the traditional Chinese medicine are developed, and the development of the traditional Chinese medicine preparation with stable preparation, safe administration, accurate dosage, controllable quality and reliable curative effect has important significance. At present, the technology of using some Chinese patent medicines for treating liver diseases is not few, but no matter what medicinal material extraction method is used, the obtained total extract of medicinal materials contains effective components such as volatile oils, flavonoids and other ineffective components, which inevitably leads to larger dosage of the medicines, and the action mechanism of various components is also not clear, so that the limitation of the medicines in the market is precisely the fact that the medicines are applied. Furthermore, the dosage ratio of the various active ingredients is not clear. This would not guarantee the quality of such pharmaceutical products, and would not be beneficial to the efficacy of the traditional Chinese medicine.
The carob pod is a dried pod of Ceratonia siliqua Linn. Of the genus carob of the family Leguminosae grown in Mediterranean, and its mature pod is 10-25 cm long and mainly contains polysaccharides, cellulose, minerals, small amount of proteins and small amount of non-saccharide small molecular compounds. Modern researches have shown that the water extract of carob pod, flavonoid and polyphenol compounds have remarkable anti-inflammatory and antioxidant activities, but the specific drug effect substance basis is not clear. The carob pod is used as raw material, and has feasibility of developing active ingredients with the effects of protecting liver, repairing liver injury, reducing liver inflammatory reaction, and blocking liver cirrhosis and liver cancer formation. The plant source has specific functions, is small in amount and high in efficiency, can be added into food as a daily food additive to achieve the effect of preventing and treating liver diseases, and has almost no toxic or side effect due to the plant source.
Disclosure of Invention
In one aspect, the application provides a novel isoliquiritigenin derived from carob, which has the effects of protecting liver, repairing liver injury, reducing liver inflammatory reaction, and blocking liver cirrhosis and liver cancer formation. In another aspect, the application provides a process for the preparation of the compound.
The application provides novel isoliquiritigenin which is a flavonoid compound derived from carob, and is extracted from dried pods of carob (Latin brand name: ceratonia siliqua Linn.) which is a plant of the genus carob of the family of the beans for seed removal.
New isoliquiritigenin is a known compound, natural source of new isoliquiritigenin is mainly extracted from Glycyrrhrizae radix and radix Arctii, but new isoliquiritigenin from carob is not involved in the existing study. In addition, the prior researches suggest that the extracts of liquorice and burdock root are applied to the effects of antioxidation, anti-inflammatory and the like, and the extracts are obtained by component research and analysis to contain the novel isoliquiritigenin, so that the integral effect of the extract is reflected. The application separates and purifies the new isoliquiritigenin from the carob by the technical means, the extraction rate of the extraction process is very high, and the purity can reach more than 99.50 percent. After research, the new isoliquiritigenin from carob has the functions of protecting liver, repairing liver injury, reducing liver inflammatory reaction, and blocking liver cirrhosis and liver cancer formation.
The preparation method of the novel isoliquiritigenin compound from carob beans comprises the following specific steps:
the pod of the carob seed is crushed, preferably the pod of the carob seed is crushed to 60-120 mesh.
Then reflux-extracting for several times by 2-10 times of ethanol solution with different concentrations, mixing the extractive solutions, and concentrating into extract. Preferably, the reflux extraction is performed with ethanol 1-4 times, the concentration of the ethanol solution used each time is 60% -100%, further preferably, the reflux extraction is performed in two times, the first reflux extraction ethanol concentration is 80-100% for 2-3 times, and the second reflux extraction ethanol concentration is preferably 60-80% for 1-2 times.
Then diluting and dispersing with 1-5 times of purified water, adsorbing with macroporous adsorption resin D101, eluting with distilled water and ethanol solution, and recovering non-sugar small molecules in the solvent. Preferably, the distilled water is used for washing 1 to 3 times, and then 80 to 100 percent ethanol solution is used for washing 1 to 3 times, and each time is used for washing 0.5 to 2.0 hours.
Then dispersing the non-saccharide small molecules by using 35% -65% methanol solution, extracting for 4-6 times by petroleum ether and ethyl acetate respectively, and recovering to obtain ethyl acetate parts. The extract fractions were analyzed by HPLC.
Preferably, the chromatographic column is an ACE 5C18 column (4.6X250 mm,5 μm); the mobile phase system is water (A) -methanol (B); the flow rate is 1.0mL/min; the column temperature is 30 ℃, the sample injection amount is 10 mu L, and the detection wavelength is 254nm; gradient elution procedure was 0-10min:10-30% B, 10-40min 30-60% B, 40-50min 60-95% B.
The ethyl acetate part is eluted by silica gel column chromatography gradient, preferably, 200-300 mesh silica gel column chromatography is adopted, the eluent is petroleum ether-ethyl acetate and methylene dichloride-methanol, the volume ratio of petroleum ether-ethyl acetate is 50:50-0:100, and the volume ratio of methylene dichloride-methanol is 88:12-0:100.TLC identification, combining similar fractions and repeating the procedure 1-3 times.
The above elution fraction is separated again by ODS chromatography, preferably, the mobile phase is methanol-water 15:85-100:0.
Then separating by Sephadex LH-20 column chromatography, preferably with dichloromethane-methanol (volume ratio of 1:1) as eluent.
Separating and purifying the semi-prepared liquid phase to obtain the novel isoliquiritigenin. Preferably, the semi-preparative liquid phase is prepared using se:Sup>A YMC-Pack ODS-A column.
According to the application, the research shows that the extraction and separation of the compounds from the plants often results in very low extraction rate and high purification difficulty due to the fact that the impurities are more and most of the compounds are unstable. The extraction method for extracting the novel isoliquiritigenin compound from the carob pods has high extraction rate and high purity, and can reach 99.50-99.99%.
The application also provides a tablet prepared from the novel isoliquiritigenin compound from the pod of carob.
Specifically, the novel isoliquiritigenin compound from the pod of carob contains active drugs, adhesive, diluent, disintegrating agent and lubricant.
The application also provides application of the novel isoliquiritigenin compound extracted from the carob pods.
Such applications include at least one of the following fields, in particular food, pharmaceutical or health care products.
The novel isoliquiritigenin compound prepared by the application has the functions of protecting liver, repairing liver injury, reducing liver inflammatory reaction and blocking liver cirrhosis and liver cancer.
Drawings
FIG. 1 shows the level of glutamic-pyruvic transaminase (ALT) activity.
FIG. 2 shows the level of glutamate oxaloacetic transaminase (AST) activity.
FIG. 3 shows superoxide dismutase (SOD) levels.
Fig. 4 is Malondialdehyde (MDA) activity levels.
FIG. 5 is a structural view
FIG. 6 shows a hydrogen nuclear magnetic resonance spectrum.
FIG. 7 is a nuclear magnetic resonance carbon spectrum.
Detailed Description
The following examples are illustrative of the application but are not intended to limit the scope of the application.
The semi-preparative liquid phase used in the examples below was se:Sup>A YMC-Pack ODS-A column having an inner diameter of 20mm for column I and an inner diameter of 10mm for column II.
Example 1 preparation method
The present example provides a new isoliquiritigenin from carob, its preparation method is as follows:
(1) Removing 200g of seed pods of the dried carob, and crushing to obtain coarse powder with the particle size smaller than 2 mm; adding 2L of 95% ethanol solution into the carob seed-removed pod coarse powder, reflux-extracting for 5 times (1.5 h each time) with 1L of 70% ethanol, mixing the extractive solutions, recovering solvent, and concentrating to obtain 200mL extract.
(2) Purified water was added to 1000mL to disperse the extract. Adsorbing with macroporous adsorbent resin D101, eluting with distilled water for 3 column volumes to remove impurities such as saccharide, eluting with 95% ethanol for 3 column volumes, and recovering solvent to obtain 5g of non-saccharide small molecule part.
(3) Dispersing the obtained non-saccharide small molecule part with 2 times of 50% methanol, sequentially extracting with petroleum ether and ethyl acetate for 5 times, and recovering solvent to obtain petroleum ether part 0.31 weight part, ethyl acetate part 1.52 weight part and water part 3.17 weight part.
(4) Separating the ethyl acetate part by 200 mesh silica gel column chromatography, and gradient eluting with petroleum ether-ethyl acetate and dichloromethane-methanol eluting system. The volume ratio of the petroleum ether to the ethyl acetate of the eluent is 50:50, 30:70, 0:100, the volume ratio of eluent methylene dichloride to methanol is 88:12, 50:50 and 0:100.TLC thin layer identification, combining similar fractions, labeled fr.a-J according to polarity from small to large.
(5) Subjecting the fraction Fr.I to ODS reverse chromatography column, gradient eluting with methanol-water (volume ratio of 15:85, 45:55, 75:25, 100:0), TLC thin layer chromatography, mixing similar fractions,the sign from small to large polarity is I 1 -I 5 。
(6) Mixing the above components I 4 Separating by Sephadex LH-20 column chromatography, eluting with dichloromethane-methanol (volume ratio of 1:1) to obtain fractions 4a-4c.
(7) Separating the above fraction 4c via semi-preparative liquid phase (column i, methanol: water=48:52, absorption wavelength 210 nm), and purifying the fraction via semi-preparative liquid phase (column ii, methanol: water=48:52, absorption wavelength 210 nm) to obtain new isoliquiritigenin (t) R =31.57 min). The structural formula is shown in figure 5. The nuclear magnetic resonance detection spectrum is shown in the accompanying figures 6-7: FIG. 6 is a diagram of 1 An H NMR spectrum, FIG. 7 is 13 C NMR spectrum.
The content of the novel isoliquiritigenin after separation and purification reaches a higher level, and the purity reaches 99.95 percent.
Example 2
Using the new isoliquiritigenin obtained in example 1 as raw material, adding food additive, and making into tablet;
the specific composition is shown in table 1:
| active pharmaceutical | New isoliquiritigenin | 40mg |
| Adhesive agent | Sodium hydroxymethyl cellulose | 13mg |
| Diluent agent | Microcrystalline cellulose | 35mg |
| Disintegrating agent | Dry starch | 25.5mg |
| Lubricant | Magnesium stearate | 1.5mg |
The preparation method of the tablet comprises the following steps: mixing the active medicine and the adhesive through an equivalent incremental method, and adding the mixture into an acetone solution with the concentration of 10% to be uniformly mixed; uniformly mixing a diluent and a disintegrating agent, and then adding the mixture into the solution to uniformly mix to prepare wet granules; drying the wet granules at 60 ℃ until the solvent is completely removed, and then finishing the granules; adding lubricant, mixing, and tabletting.
Example 3
Using the new isoliquiritigenin obtained in example 1 as raw material, adding food additive, and making into tablet;
the specific composition is shown in table 2:
the preparation method of the tablet comprises the following steps: mixing the active medicine and the adhesive through an equivalent incremental method, and adding the mixture into an acetone solution with the concentration of 10% to be uniformly mixed; uniformly mixing a diluent and a disintegrating agent, and then adding the mixture into the solution to uniformly mix to prepare wet granules; drying the wet granules at 60 ℃ until the solvent is completely removed, and then finishing the granules; adding lubricant, mixing, and tabletting.
Example 4
Using the new isoliquiritigenin obtained in example 1 as raw material, adding food additive, and making into tablet;
the specific composition is shown in table 3:
| active pharmaceutical | New isoliquiritigenin | 10mg |
| Adhesive agent | Sodium hydroxymethyl cellulose | 8mg |
| Diluent agent | Microcrystalline cellulose | 35mg |
| Disintegrating agent | Dry starch | 25.5mg |
| Lubricant | Magnesium stearate | 1mg |
The preparation method of the tablet comprises the following steps: mixing the active medicine and the adhesive through an equivalent incremental method, and adding the mixture into an acetone solution with the concentration of 10% to be uniformly mixed; uniformly mixing a diluent and a disintegrating agent, and then adding the mixture into the solution to uniformly mix to prepare wet granules; drying the wet granules at 60 ℃ until the solvent is completely removed, and then finishing the granules; adding lubricant, mixing, and tabletting.
Comparative example
This comparative example provides a tablet which differs from example 2 in that it does not contain an active agent and other ingredients and preparation methods are the same as in example 1.
Experimental example repair and protection against liver injury
42 8-week-old mice were selected and divided into 7 groups of 6 mice each, including a blank group, a model group, examples 1-4, and a comparative group. And (3) adopting APAP in vitro induction to the mice of the groups except the blank control group to establish an APAP induced acute liver injury model.
The blank group and the model group were perfused with an equal amount of physiological saline, the new isoliquiritigenin (200 mg/kg) prepared in example 1 was perfused in example 1, examples 2-4, and the tablets (1 tablet) prepared in examples 2, 3, and 4 and the comparative example were administered with standard feed, free water, once daily, and for 7 consecutive days, respectively. After the last administration for 2 hours, the rest groups except the blank group are intraperitoneally injected with 350mg/kg of APAP solution (the solvent is normal saline) in a standard tank, and the blank group is intraperitoneally injected with the same volume of normal saline.
After 12h of no water forbidden after fasting, the orbit is used for taking blood, the physiological and biochemical indexes in serum are detected by centrifugation, and the contents of glutamic pyruvic transaminase (ALT) and glutamic oxaloacetic transaminase (AST) in the blood are detected. Mice were then sacrificed and superoxide dismutase (SOD) and Malondialdehyde (MDA) levels in liver assays were removed.
The results are shown in figures 1, 2, 3 and 4, and the model group is very significantly different from the blank control group, so that the successful modeling is demonstrated. The novel isoliquiritigenin prepared in example 1 and the tablet containing the novel isoliquiritigenin prepared in example 1 significantly reduce the AST, ALT, MDA activity of mice and significantly improve the SOD level of the mice. The new isoliquiritigenin extracted from pod of carob has effects of improving liver injury and protecting liver.
While the application has been described in detail in the general context and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the application and are intended to be within the scope of the application as claimed.
Claims (7)
1. The extraction method of the new isoliquiritigenin compound from the pod of carob is characterized by comprising the steps of reflux extraction by an alcohol extraction method, adsorption by macroporous adsorption resin D101, separation by a silica gel chromatographic column, separation by an ODS reverse chromatographic column, separation by a SephadexLH-20 column and semi-preparative liquid phase separation and purification.
2. The extraction method of the novel isoliquiritigenin compound from the pod of carob is characterized by comprising the following specific steps:
(1) Reflux-extracting with 2-10 times of 60-100% ethanol solution for 1-4 times, mixing extractive solutions, and concentrating to obtain extract.
(2) Diluting and dispersing with 1-5 times of purified water, adsorbing with macroporous adsorbent resin D101, eluting with distilled water and 80-100% ethanol solution sequentially, and removing impurities such as saccharide.
(3) Dispersing the non-saccharide small molecules with 35% -65% methanol solution, extracting with petroleum ether and ethyl acetate for 4-6 times, and recovering to obtain ethyl acetate. The extract fractions were analyzed by HPLC.
(4) The ethyl acetate part is eluted by 200-300 mesh silica gel column chromatography gradient, preferably, the eluent is petroleum ether-ethyl acetate and methylene dichloride-methanol.
(5) The mixture is separated again by ODS chromatography, preferably with a mobile phase of 15:85-100:0 methanol-water.
(6) The eluent is preferably methylene chloride-methanol (volume ratio 1:1) by SephadexLH-20 column chromatography.
(7) The semi-preparative liquid phase is separated and purified, preferably by YMC-Pack ODS-A chromatography.
3. In the step (4) of the extraction method of the new isoliquiritigenin compound from the pod of carob, the volume ratio of petroleum ether to ethyl acetate as eluent is 50:50-0:100, and the volume ratio of dichloromethane to methanol is 88:12-0:100.
4. The extraction method of a new isoliquiritigenin compound from carob pod of claim 2, wherein in the step (7), the semi-prepared liquid phase mobile phase volume ratio is methanol: water=48:52, absorption wavelength 210nm.
5. A tablet comprising a novel isoliquiritigenin compound derived from pod of carob.
6. A product characterized by comprising a novel isoliquiritigenin compound derived from carob pod obtained by the process of any one of claims 1 to 5, preferably the product is a pharmaceutical, health product or food product.
7. The novel isoliquiritigenin compound of pod source of carob obtained by the preparation method of any one of claims 1 to 5 has at least the functions of protecting liver, repairing liver injury, reducing liver inflammatory reaction, and blocking one or more of liver cirrhosis and liver cancer.
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