CN117586214A - Linderane type sesquiterpene dimer and preparation method and application thereof - Google Patents
Linderane type sesquiterpene dimer and preparation method and application thereof Download PDFInfo
- Publication number
- CN117586214A CN117586214A CN202311583836.4A CN202311583836A CN117586214A CN 117586214 A CN117586214 A CN 117586214A CN 202311583836 A CN202311583836 A CN 202311583836A CN 117586214 A CN117586214 A CN 117586214A
- Authority
- CN
- China
- Prior art keywords
- column chromatography
- chloranthus
- methanol
- linderane
- volume ratio
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229930003839 sesquiterpene dimer Natural products 0.000 title claims abstract description 33
- KBMSVODXFLAQNJ-DXGHHDSJSA-N Linderane Chemical compound C1=2C(C)=COC=2C\C(C)=C\CC[C@@]23C(=O)O[C@@H]1[C@@H]2O3 KBMSVODXFLAQNJ-DXGHHDSJSA-N 0.000 title claims abstract description 18
- KBMSVODXFLAQNJ-ZEBDJQDSSA-N Linderane Natural products O=C1O[C@@H]2[C@@H]3O[C@]13CC/C=C(/C)\Cc1occ(C)c21 KBMSVODXFLAQNJ-ZEBDJQDSSA-N 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title abstract description 13
- UCIMZKYTYXUXCC-PVTJBWNLSA-N chlorajaponilide E Natural products COC(=O)C(=C1C(=O)[C@H](O)[C@@]2(C)[C@@H]3C[C@@H]3[C@]4(C[C@H]5[C@@]6(C)[C@@H]7C[C@@H]7[C@@](O)(COC(=O)C(=CC)C)[C@@H]6CC8=C(CO)C(=O)O[C@]58C1=C24)OO)C UCIMZKYTYXUXCC-PVTJBWNLSA-N 0.000 claims abstract description 51
- 229930187341 chlorahololide Natural products 0.000 claims abstract description 45
- 239000003814 drug Substances 0.000 claims abstract description 25
- 208000037976 chronic inflammation Diseases 0.000 claims abstract description 18
- 208000037893 chronic inflammatory disorder Diseases 0.000 claims abstract description 18
- 239000000203 mixture Substances 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 99
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- 241000721167 Chloranthus Species 0.000 claims description 29
- 238000004440 column chromatography Methods 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
- 239000003960 organic solvent Substances 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000000463 material Substances 0.000 claims description 17
- 239000000499 gel Substances 0.000 claims description 16
- 238000010898 silica gel chromatography Methods 0.000 claims description 16
- 238000011894 semi-preparative HPLC Methods 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 238000010828 elution Methods 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 241000196324 Embryophyta Species 0.000 claims description 11
- 239000000284 extract Substances 0.000 claims description 11
- 239000003208 petroleum Substances 0.000 claims description 11
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 10
- 239000011347 resin Substances 0.000 claims description 8
- 229920005989 resin Polymers 0.000 claims description 8
- 230000002441 reversible effect Effects 0.000 claims description 6
- 239000003480 eluent Substances 0.000 claims description 5
- 238000010298 pulverizing process Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 239000010425 asbestos Substances 0.000 claims description 2
- 238000013375 chromatographic separation Methods 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 229910052895 riebeckite Inorganic materials 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 241001310037 Chloranthus henryi Species 0.000 claims 1
- 102000000874 Pyrin Domain-Containing 3 Protein NLR Family Human genes 0.000 abstract description 28
- 108010001946 Pyrin Domain-Containing 3 Protein NLR Family Proteins 0.000 abstract description 28
- 230000005764 inhibitory process Effects 0.000 abstract description 9
- 206010061218 Inflammation Diseases 0.000 abstract description 7
- 230000004054 inflammatory process Effects 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000001404 mediated effect Effects 0.000 abstract description 3
- 230000002757 inflammatory effect Effects 0.000 description 25
- 239000012071 phase Substances 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 23
- 239000002609 medium Substances 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 229910052739 hydrogen Inorganic materials 0.000 description 15
- 230000004913 activation Effects 0.000 description 13
- 239000012124 Opti-MEM Substances 0.000 description 11
- 239000002158 endotoxin Substances 0.000 description 10
- DANUORFCFTYTSZ-UHFFFAOYSA-N epinigericin Natural products O1C2(C(CC(C)(O2)C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)C)C(C)C(OC)CC1CC1CCC(C)C(C(C)C(O)=O)O1 DANUORFCFTYTSZ-UHFFFAOYSA-N 0.000 description 10
- 229920006008 lipopolysaccharide Polymers 0.000 description 10
- DANUORFCFTYTSZ-BIBFWWMMSA-N nigericin Chemical compound C([C@@H]1C[C@H]([C@H]([C@]2([C@@H](C[C@](C)(O2)C2O[C@@](C)(CC2)C2[C@H](CC(O2)[C@@H]2[C@H](C[C@@H](C)[C@](O)(CO)O2)C)C)C)O1)C)OC)[C@H]1CC[C@H](C)C([C@@H](C)C(O)=O)O1 DANUORFCFTYTSZ-BIBFWWMMSA-N 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 238000010829 isocratic elution Methods 0.000 description 8
- 210000002540 macrophage Anatomy 0.000 description 8
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 7
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 7
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 7
- 230000006907 apoptotic process Effects 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 108090000426 Caspase-1 Proteins 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 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 5
- 239000011734 sodium Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 108091008099 NLRP3 inflammasome Proteins 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- -1 but not limited to Substances 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 description 4
- 230000003595 spectral effect Effects 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102100035904 Caspase-1 Human genes 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-N 0.000 description 2
- OOJGVMFNPNJNFV-HXUWFJFHSA-N (4aR)-4-[2-(furan-3-yl)ethyl]-1-hydroxy-3,4a,8,8-tetramethyl-6,7-dihydro-5H-naphthalen-2-one Chemical compound O=C1C(C)=C(CCc2cocc2)[C@]2(C)C(=C1O)C(C)(C)CCC2 OOJGVMFNPNJNFV-HXUWFJFHSA-N 0.000 description 2
- HUUSXLKCTQDPGL-UHFFFAOYSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonylurea Chemical compound CC(C)(O)C1=COC(S(=O)(=O)NC(=O)NC=2C=3CCCC=3C=C3CCCC3=2)=C1 HUUSXLKCTQDPGL-UHFFFAOYSA-N 0.000 description 2
- PRDFBSVERLRRMY-UHFFFAOYSA-N 2'-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-2,5'-bibenzimidazole Chemical compound C1=CC(OCC)=CC=C1C1=NC2=CC=C(C=3NC4=CC(=CC=C4N=3)N3CCN(C)CC3)C=C2N1 PRDFBSVERLRRMY-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 2
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 206010018634 Gouty Arthritis Diseases 0.000 description 2
- 102000003777 Interleukin-1 beta Human genes 0.000 description 2
- 108090000193 Interleukin-1 beta Proteins 0.000 description 2
- 102000003810 Interleukin-18 Human genes 0.000 description 2
- 108090000171 Interleukin-18 Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- OOJGVMFNPNJNFV-UHFFFAOYSA-N Leojaponin Natural products CC1=C(CCc2cocc2)C3(C)CCCC(C)(C)C3=C(O)C1=O OOJGVMFNPNJNFV-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- 102000012064 NLR Proteins Human genes 0.000 description 2
- 108091005686 NOD-like receptors Proteins 0.000 description 2
- 208000012902 Nervous system disease Diseases 0.000 description 2
- 208000025966 Neurological disease Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 240000004274 Sarcandra glabra Species 0.000 description 2
- 235000010842 Sarcandra glabra Nutrition 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 230000004900 autophagic degradation Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 208000029028 brain injury Diseases 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000012930 cell culture fluid Substances 0.000 description 2
- 230000005779 cell damage Effects 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000002519 electronic circular dichroism spectroscopy Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- ROAYSRAUMPWBQX-UHFFFAOYSA-N ethanol;sulfuric acid Chemical compound CCO.OS(O)(=O)=O ROAYSRAUMPWBQX-UHFFFAOYSA-N 0.000 description 2
- 239000000469 ethanolic extract Substances 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 238000004896 high resolution mass spectrometry Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000401 methanolic extract Substances 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
- 238000002156 mixing Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 2
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 235000011837 pasties Nutrition 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000002137 ultrasound extraction Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- WBDGLSGKTWAWHK-UHFFFAOYSA-N 2,3-dibutylbenzoic acid Chemical compound CCCCC1=CC=CC(C(O)=O)=C1CCCC WBDGLSGKTWAWHK-UHFFFAOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 108010076667 Caspases Proteins 0.000 description 1
- 102000011727 Caspases Human genes 0.000 description 1
- 240000002064 Castanea henryi Species 0.000 description 1
- 241000721153 Chloranthus japonicus Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- TULNGKSILXCZQT-UHFFFAOYSA-N Cysteinyl-Aspartate Chemical compound SCC(N)C(=O)NC(C(O)=O)CC(O)=O TULNGKSILXCZQT-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 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 1
- 231100000416 LDH assay Toxicity 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- 108010085220 Multiprotein Complexes Proteins 0.000 description 1
- 102000007474 Multiprotein Complexes Human genes 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 239000003911 antiadherent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 238000002983 circular dichroism Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000000571 coke Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000006353 environmental stress Effects 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 238000002843 lactate dehydrogenase assay Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000007056 liver toxicity Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000004065 mitochondrial dysfunction Effects 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 229940088417 precipitated calcium carbonate Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
-
- 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]
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
Abstract
The invention belongs to the field of phytochemistry and medicines, relates to a linderane type sesquiterpene dimer, a preparation method and application thereof, and also relates to a medicine or a medicine composition containing the linderane type sesquiterpene dimer. The linderane sesquiterpene dimers chlorahololides H, J, L and chlorajaponilide E have remarkable NLRP3 inflammation corpuscle inhibition activity and can be used for treating chronic inflammatory diseases mediated by NLRP3 inflammation corpuscles.
Description
Technical Field
The invention belongs to the technical field of phytochemistry and medicines, and particularly relates to a linderane type sesquiterpene dimer chlorahololides H, J, L and chlorajaponilide E, a medicine or a medicine composition containing the linderane type sesquiterpene dimer, a preparation method of the linderane type sesquiterpene dimer and application of the linderane type sesquiterpene dimer in preparation of a medicine or a medicine composition for treating chronic inflammatory diseases.
Background
Inflammatory corpuscles are a class of protein complexes that play an important role in immunomodulation and in the inflammatory process. Inflammatory bodies act as intracellular signaling platforms capable of sensing and responding to intracellular and extracellular stimuli, including microbial infection, cellular injury, and environmental stress. Among them, the NLRP3 inflammatory body is a member of the NOD-like receptor (NLR) family, which plays an important role in sensing and modulating endogenous and exogenous signals within host cells. NLRP3 inflammatory corpuscles consist of a number of components, including NLRP3 protein, apoptosis-related spotted protein (ASC) and caspase-1 precursor (pro-cysteinyl aspartate specific proteinase-1, pro-caspase-1). NLRP3 inflammatory corpuscles are activated when stimulated by microorganisms, cell damage or other stresses. Activation of NLRP3 inflammatory body signals usually involves disorders of the intracellular and extracellular environment, such as intracellular K + Ion loss, ca 2+ Signal, accumulation of reactive oxygen species (reactive oxygen species, ROS), mitochondrial dysfunction, lysosomal disruption, etc. After activation of the NLRP3 inflammatory body, caspase precursor-1 (pro-caspase-1) is sheared to generate bioactive caspase-1 (caspase-1) which further promotes maturation and release of pro-inflammatory cytokines such as IL-1β (interleukin-1β) and IL-18 (interleukin-18), thereby triggering inflammatory effects.
Abnormal activation of NLRP3 inflammatory bodies is associated with the occurrence and progression of a variety of inflammation-related disorders, including rheumatoid arthritis, inflammatory bowel disease, type II diabetes, and the like. Thus, modulation of NLRP3 inflammatory bodies is a potential therapeutic strategy for the treatment of these chronic inflammatory diseases. Development of inhibitors of NLRP3 inflammatory body activation assembly provides a new treatment for related diseases. MCC950 has been widely studied as a small molecule inhibitor specific to NLRP3inflammasome, and its potential application in treating inflammatory diseases such as rheumatoid arthritis has attracted much attention and even entered phase II clinical trial. However, due to the problem of liver toxicity it eventually fails clinical trials.
Natural products are important sources for development of lead compounds of medicaments and are indispensable in medicament development. The method for searching the NLRP3 inflammation small molecule inhibitor with low toxicity and high activity from natural products has important significance. The Chloranthus (Chloranthus) is a Chinese herbal medicine with important clinical value, and has great potential in searching natural products with the treatment effect on chronic inflammatory diseases.
Disclosure of Invention
In view of the above, an object of the present invention is to provide linderane-type sesquiterpene dimers having NLRP3 inflammation-small-body inhibitory activity, namely, compounds chlorahololides H, J, L and chlorajaponilide E; medicaments or pharmaceutical compositions containing these compounds; the application of the compounds in preparing medicines or medicine compositions for treating chronic inflammatory diseases and the preparation method of the compounds provide new options for developing NLRP3 inflammation corpuscle inhibitors.
The object of the invention can be achieved by the following technical scheme.
In a first aspect, the present invention provides a linderane-type sesquiterpene dimer or a pharmaceutically acceptable derivative thereof represented by the following structural formulas I, II, III and IV,
in a second aspect, the present invention provides a medicament or pharmaceutical composition for the treatment of chronic inflammatory diseases comprising at least one linderane-type sesquiterpene dimer of formulae I, II, iii and IV or a pharmaceutically acceptable derivative thereof.
In a third aspect, the invention relates to the use of linderane-type sesquiterpene dimers chlorahololides H, J, L and chlorajaponilide E or pharmaceutically acceptable derivatives thereof for the preparation of a medicament or pharmaceutical composition for the treatment of chronic inflammatory diseases.
In embodiments of the invention, the chronic inflammatory disease is a NLRP3 inflammatory body-mediated chronic inflammatory disease including, but not limited to, arthritis such as rheumatoid arthritis, gouty arthritis; type II diabetes; non-alcoholic steatohepatitis; inflammatory bowel disease; neurological diseases and brain injuries including multiple sclerosis, alzheimer's disease, etc.
In a fourth aspect, the present invention provides a method of preparing linderane-type sesquiterpene dimers chlorahololides H, J, L and chlorajaponilide E, comprising the steps of:
1) Drying Chloranthus plant material, pulverizing, extracting with organic solvent, and desolventizing to obtain Chloranthus plant material extract; and
2) Subjecting the chloranthus plant material extract to column chromatography to obtain linderane type sesquiterpene dimers chlorahololides H, J, L and chlorajaponilide E.
In an embodiment of the process of the present invention, the organic solvent used in step 1) may be at least one of petroleum ether, chloroform, methylene chloride, ethyl acetate, acetone, ethanol, methanol, n-butanol and acetonitrile; preferably, the organic solvent is ethyl acetate, methanol, 95% ethanol or a mixture thereof.
Compared with the prior art, the invention has obvious beneficial effects. Specifically, the linderane sesquiterpene dimers chlorahololides H, J, L and chlorajaponilide E have remarkable NLRP3 inflammation corpuscle inhibition activity and can be used for treating chronic inflammatory diseases.
Drawings
FIG. 1 is a chemical formula of linderane-type sesquiterpene dimers chlorahololides H, J, L and chlorajaponilide E of the present invention.
FIG. 2 is a graph of chlorajaponilide E inhibiting apoptosis of mononuclear macrophages J774A.1.
FIG. 3 is a graph of the quantification of chlorajaponilide E inhibition of mononuclear macrophage J774A.1 pyro-apoptosis.
Detailed Description
The present invention will be described more fully hereinafter in order to facilitate an understanding of the present invention, and preferred embodiments of the present invention are set forth. This invention may, however, be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the scope of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
According to a first aspect, the present invention provides linderane-type sesquiterpene dimers chlorahololides H, J, L and chlorajaponilide E having NLRP3inflammasome inhibitory activity, having the structural formulae shown in formulas I, II, iii and IV below, respectively, or pharmaceutically acceptable derivatives, such as pharmaceutically acceptable salts, esters or prodrugs thereof:
according to a second aspect of the present invention there is provided a medicament or pharmaceutical composition for the treatment of chronic inflammatory diseases comprising as an active pharmaceutical ingredient at least one of the linderane sesquiterpene dimers chlorahololides H, J, L and chlorajaponilide E or pharmaceutically acceptable derivatives thereof. It will be appreciated by those skilled in the art that the medicament or pharmaceutical composition for treating chronic inflammatory diseases of the invention herein may further comprise a pharmaceutically acceptable carrier, adjuvant or excipient. Thus, in a more specific embodiment, a medicament or pharmaceutical composition for treating chronic inflammatory diseases comprises as active pharmaceutical ingredient at least one of linderane-type sesquiterpene dimers chlorahololides H, J, L and chlorajaponilide E or pharmaceutically acceptable derivatives thereof, and a pharmaceutically acceptable carrier, adjuvant or excipient.
In an embodiment of the medicament or pharmaceutical composition of the invention, the linderane-type sesquiterpene dimer as an active ingredient may be any one of chlorahololides H, J, L and chlorajaponilide E or any combination thereof.
It will be appreciated by those skilled in the art that pharmaceutically acceptable derivatives of the compounds chlorahololides H, J, L or chlorajaponilide E of the present invention, such as pharmaceutically acceptable salts, esters, solvates or hydrates or prodrugs of these compounds, may also be used as active ingredients in the medicaments or pharmaceutical compositions of the present invention. Thus, in yet another embodiment of the medicament or pharmaceutical composition of the invention, the active ingredient may be a pharmaceutically acceptable derivative of chlorahololides H, J, L or chlorajaponilide E, for example a pharmaceutically acceptable salt, ester, solvate or hydrate or prodrug of these compounds.
As is well known to those skilled in the art, the pharmaceutically acceptable salt may be, for example, a pharmaceutically acceptable base addition salt. Pharmaceutically acceptable base addition salts include salts derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary and tertiary amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine and triethanolamine.
The pharmaceutically acceptable esters may be esters of the linderane sesquiterpene dimers of the invention with pharmaceutically acceptable non-toxic organic acids, such as acetic acid, propionic acid, malic acid, citric acid, oxalic acid and palmitic acid.
Thus, in embodiments of the pharmaceutical compositions of the present invention, the active pharmaceutical ingredient may be any one, two, three or four of chlorahololides H, J, L or chlorajaponilide E, or an esterified, solvated, hydrated or other derivative thereof.
Pharmaceutically acceptable carriers, adjuvants or excipients are well known to those skilled in the art. Pharmaceutically acceptable carriers or excipients are one or more solid, semi-solid and liquid diluents, fillers and pharmaceutical product adjuvants including, but not limited to, fillers (diluents), lubricants (glidants or anti-adherents), dispersants, wetting agents, binders, solubilizing agents, antioxidants, bacteriostats, emulsifiers, disintegrants and the like. The binder comprises syrup, acacia, gelatin, sorbitol, tragacanth, cellulose and its derivatives (such as microcrystalline cellulose, sodium carboxymethylcellulose, ethylcellulose or hydroxypropyl methylcellulose), gelatin slurry, syrup, starch slurry or polyvinylpyrrolidone; the filler comprises lactose, sugar powder, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salt (such as calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, etc.), sorbitol or glycine, etc.; the lubricant comprises aerosil, magnesium stearate, talcum powder, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol and the like; disintegrants include starch and its derivatives (e.g., sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, corn starch, etc.), polyvinylpyrrolidone, microcrystalline cellulose, etc.; the wetting agent comprises sodium dodecyl sulfate, water or alcohol, etc.; the antioxidant comprises sodium sulfite, sodium bisulphite, sodium metabisulfite, dibutyl benzoic acid and the like; the bacteriostat comprises 0.5% phenol, 0.3% cresol, 0.5% chlorobutanol and the like; the emulsifier comprises polysorbate-80, sorbitan without acid, lecithin, soybean lecithin, etc.; the solubilizer comprises Tween-80, bile, glycerol, etc.
When the linderane sesquiterpene dimer of the present invention is used as a medicine, it may be administered directly or in the form of a pharmaceutical composition. In the pharmaceutical composition of the present invention, the pharmaceutical composition may contain from 0.1 to 99% by weight of chlorahololides H, J, L or chlorajaponilide E, preferably from 0.5 to 50% by weight of the total pharmaceutical composition.
An "effective amount" of a linderane-type sesquiterpene dimer chlorahololides H, J, L or chlorajaponilide E or a pharmaceutically acceptable derivative thereof, e.g., an ester, refers to an amount sufficient to achieve the desired biological effect. It will be appreciated that the effective dose will depend on the age, sex, health condition and weight of the recipient. Typically, the effective amount is determined by the person administering the treatment, e.g., a treating physician.
The pharmaceutical composition of the present invention may be administered in the form of a unit weight dose. All pharmaceutical compositions containing the linderane sesquiterpene dimers chlorahololides H, J, L or chlorajaponilide E or pharmaceutically acceptable derivatives thereof such as esterified substances as active ingredients are prepared into various dosage forms such as liquid preparations (injections, suspensions, emulsions, solutions, syrups and the like), solid preparations (tablets, capsules, granules, medicinal granules and the like), sprays, aerosols and the like by methods accepted in the pharmaceutical and food fields. The pharmaceutical composition of the present invention can be used for the treatment of inflammatory diseases by injection (intravenous injection, intravenous drip, intramuscular injection, intraperitoneal injection, subcutaneous injection), oral administration, sublingual administration, mucosal dialysis and other administration routes.
According to a third aspect, the present invention provides the use of a linderane-type sesquiterpene dimer chlorahololides H, J, L or chlorajaponilide E or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament or pharmaceutical composition for the treatment of chronic inflammatory diseases.
In embodiments of the invention, the chronic inflammatory disease is a NLRP3 inflammatory body-mediated chronic inflammatory disease including, but not limited to, arthritis such as rheumatoid arthritis, gouty arthritis; type II diabetes; non-alcoholic steatohepatitis; inflammatory bowel disease; neurological diseases and brain injuries including multiple sclerosis, alzheimer's disease, etc.
According to a fourth aspect, the present invention provides a process for preparing linderane-type sesquiterpene dimers chlorahololides H, J, L and chlorajaponilide E, comprising the steps of:
1) Drying and pulverizing chloranthus plant material, leaching with organic solvent, and desolventizing to obtain chloranthus plant extract; and
2) Subjecting the chloranthus extract to column chromatography to obtain chlorahololides H, J, L and chlorajaponilide E.
In embodiments of the invention, the chloranthus material may be various parts of chloranthus, such as roots, stems, branches and leaves, or whole plants. In an embodiment of the invention, the chloranthus plant is a plant of the genus chloranthus, preferably chloranthus serrulatum (C.halostegius), chloranthus latifolia (C.henryi) or chloranthus serrulatum (C.halostegius var. Shimianensis).
In an embodiment of the present invention, in step 1), the organic solvent may be at least one of petroleum ether, chloroform, methylene chloride, ethyl acetate, acetone, ethanol, methanol, n-butanol, and acetonitrile; preferably, the organic solvent is ethyl acetate, methanol, 95% ethanol or a mixture thereof.
In an embodiment of the present invention, in step 1), the extraction method may be organic solvent cold leaching extraction, heating reflux extraction, organic solvent ultrasonic extraction, or the like.
In an embodiment of the invention, the chloranthus material is extracted at least 1 time, for example 2, 3, 4 times, preferably 3 times, with an organic solvent.
In embodiments of the invention, the volume ratio of organic solvent to dried chloranthus material may be from 1:1 to 5:1, for example 1:1, 2:1, 3:1, 4:1, 5:1, and ratios between any two of the foregoing, for example 1.5:1, 2.5:1, 3.5:1, 4.5:1, etc., preferably 3:1.
In a specific embodiment of the present invention, in step 2), the column chromatography includes normal phase silica gel column chromatography, reverse phase silica gel column chromatography (e.g., RP-18 column chromatography), resin column chromatography (e.g., D101 macroporous resin), gel column chromatography (e.g., sephadex LH-20), medium pressure chromatography separation gel (e.g., MCI gel), and semi-preparative high performance liquid chromatography (hereinafter referred to as semi-preparative HPLC).
In a specific embodiment of the present invention, in step 2), the eluent used in the column chromatography is at least one of petroleum ether, methylene chloride, chloroform, ethyl acetate, acetone, ethanol, methanol, n-butanol, acetonitrile, water and formic acid, such as a combination of any two of the above organic solvents, a combination of any three, a combination of any four, and the like. In a more specific embodiment of the invention, for normal phase silica gel column chromatography, petroleum ether and acetone may be used in a gradient elution from 1:0 to 0:1 by volume, such as 1:0, 50:1, 20:1, 10:1, 5:1, 1:1, 1:5, 0:1. In more specific embodiments of the invention, for normal phase silica gel column chromatography, dichloromethane and methanol may also be used in a gradient elution from 1:0 to 1:1 by volume, such as 1:0, 200:1, 100:1, 50:1, 20:1, 10:1, 1:1. In a more specific embodiment of the invention, for reverse phase silica gel column chromatography, such as reverse phase RP-18 column chromatography, methanol and water may be used in a gradient from 2:8 to 10:0 by volume, for example, the methanol to water volume ratio may be 2:8,5:5,8:2, 10:0. In a more specific embodiment of the invention, for resin column chromatography, such as D101 macroporous resin column chromatography, gradient elution of methanol and water may be employed in a volume ratio from 2:8 to 10:0, e.g., the volume ratio of methanol to water may be 2:8,5:5,8:2, 10:0. In a more specific embodiment of the invention, for gel column chromatography, such as Sephadex LH-20 gel column chromatography, methanol or chloroform-methanol (1:1, v: v) elution may be employed. In a more specific embodiment of the invention, for medium pressure chromatographic separation gels, such as MCI gels, ethanol and water may be used to elute in a gradient from 2:8 to 10:0 volume ratio, e.g., the volume ratio of ethanol to water may be 2:8,5:5,8:2, 10:0. In a more specific embodiment of the invention, for semi-preparative HPLC, an isocratic elution with acetonitrile and water, e.g. with 50% acetonitrile-water as mobile phase, may be used. In a more specific embodiment of the invention, for semi-preparative HPLC, it is also possible to use acetonitrile and water gradient elution, for example from 2:8 to 8:2 by volume.
Preferred embodiments of the present invention will be described in detail with reference to examples. It should be understood that the following examples are given for illustrative purposes only and are not intended to limit the scope of the present invention. Various modifications and substitutions may be made by those skilled in the art without departing from the spirit and scope of the invention, all such modifications and substitutions being within the scope of the invention as set forth in the appended claims.
The experimental methods used in the following examples are conventional methods unless otherwise specified. Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
In the examples described below, optical rotation was measured using an Autopol VI polarimeter. Electronic Circular Dichroism (ECD) was measured using a Applied Photophysics circular dichroism spectrometer. Ultraviolet (UV) spectra were measured using a Shimadzu UV2700 UV spectrometer. 1 H NMR, 13 C NMR and 2DNMR spectra were recorded using Bruker AM-500 or AM-600 nuclear magnetic resonance apparatus. High resolution mass spectrometry (HR-ESI-MS) was determined using an Agilent 1290UPLC/6540Q-TOF mass spectrometer. Semi-preparative HPLC used Agilent 1260 liquid phase, chromatographic column Zorbax SB-C18 preparative column at flow rates of 3.0mL/min. Column chromatography involves the use of silica gel (200-300 mesh, qingdao ocean chemical Co., ltd., china), RP-18 (40-60 μm, merk), D101 macroporous resin (Shanghai Mikroorganism Biochemical Co., ltd., china), MCI gel (75-150 μm, mitsubishi chemical Co., ltd., japan) and Sephadex LH-20 (GE Healthcare, USA). Thin Layer Chromatography (TLC) was performed on silica gel GF254 plates (peninsula ocean chemical company, china) and spots were observed by 10% sulfuric acid-ethanol solution. Absorbance values were measured using a Biotek ELX800 multifunctional microplate reader. Fluorescence pictures were taken using an inverted microscope (Axio Observer3, zeiss; oberkochen, germany).
Example 1: preparation method one of Compounds chlorahololides H, J, L and chlorajaponilide E
Drying whole plant of the variety of chloranthus glaber asbestos (20 kg), pulverizing, adding 60L methanol (volume ratio of organic solvent to plant material is 3:1), reflux-extracting at 65deg.C for 3 times and 3 h/time, mixing extractive solutions, and distilling under reduced pressure to obtain methanol extract (1.8 kg). The methanol extract is passed through a D101 macroporous resin column, eluted by methanol-water gradient (2:8, 5:5,8:2, 10:0, v/v), the volume of each gradient is 4-6, the eluted part (162.4 g) of methanol and water with the volume ratio of 8:2 is taken to pass through a normal phase silica gel column for chromatography, and the eluted part is eluted by dichloromethane-methanol gradient (1:0, 200:1, 100:1, 50:1, 20:1, 10:1, 1:1, v/v), the volume of each gradient is 4-6, and 7 components are obtained after the color development of 10% sulfuric acid-ethanol solution according to thin layer chromatography, which are Fr.1-Fr.7 respectively. Fr.5 (22.6 g) was subjected to RP-18 reverse phase silica gel column chromatography eluting with methanol-water gradients (2:8, 3:7, 5:5, 7:3, 8:2, 10:0, v/v) with 4-6 column volumes per gradient to give 6 fractions Fr.5.1-Fr.5.6, respectively. Fr.5.3 (2.9 g) was chromatographed on normal phase silica gel column eluting with petroleum ether-acetone gradients (20:1, 10:1, 5:1, 1:1, 1:5, v/v), 4-6 column volumes per gradient, to give 5 fractions Fr.5.3.1-Fr.5.3.5, respectively. Fr.5.3.2 (675.2 mg) was prepared by semi-preparative HPLC using isocratic elution with 50% acetonitrile-water as the mobile phase to give 7.8mg chlorahololide H (yield: 0.000039%) and 4.0mg chlorajaponilide E (yield: 0.00002%). Fr.5.4 (3.6 g) was subjected to normal phase silica gel column chromatography, and isocratic elution with methylene chloride-methanol (100:1, v/v) gave 6 fractions Fr.5.4.1-Fr.5.4.6, respectively. Fr.5.4.3 (573.3 mg) was prepared by semi-preparative HPLC using isocratic elution with 60% acetonitrile-water as mobile phase to give 10.0mg chlorahololide J (yield: 0.00005%) and 14.0mg chlorahololide L (yield: 0.00007%).
Physical constants and spectral data for chlorihole H: white powder;(c0.14,MeOH)；UV(MeOH)λ max (logε)223(3.18)nm；CD(MeOH)λ max (Δε)208(-14.1),251(+9.75),335(-1.33)nm； 1 HNMR(500MHz)δ1.59(1H,m,H-1),0.93(1H,td,J＝7.6,4.5Hz,H-2α),0.34(1H,q,J＝4.2Hz,H-2β),1.86(1H,m,H-3),3.88(1H,d,J＝3.4Hz,H-6),2.69(1H,d,J＝19.1Hz,H-9α),2.53(1H,m,H-9β),1.83(3H,s,H 3 -13),1.17(3H,s,H 3 -14),2.74(1H,dd,J＝16.1,1.5Hz,H-15α),2.53(1H,m,H-15β),1.39(1H,td,J＝8.4,3.9Hz,H-1′),0.71(1H,td,J＝8.4,5.6Hz,H-2′α),1.78(1H,m,H-2′β),1.19(1H,m,H-3′),1.62(1H,m,H-5′),2.38(2H,m,H-6),1.92(1H,dd,J＝5.9,1.8Hz,H-9′),4.35(2H,m,H-13′),0.62(3H,s,H 3 -14′),3.53(1H,dd,J＝11.4,6.1Hz,H-15′a),3.57(1H,dd,J＝11.4,5.0Hz,H-15′b),3.72(3H,s,MeO-12)； 13 CNMR(CDCl 3 ,125MHz)δ28.4(C-1,d),16.2(C-2,t),24.9(C-3,d),138.8(C-4,s),134.1(C-5,s),41.2(C-6,d),137.3(C-7,s),204.9(C-8,s),52.2(C-9,t),45.2(C-10,s),142.9(C-11,s),170.8(C-12,s),19.4(C-13,q),22.8(C-14,q),25.5(C-15,t),24.1(C-1′,d),16.7(C-2′,t),21.3(C-3′,d),47.2(C-4′,d),57.8(C-5′,d),24.9(C-6′,t),169.3(C-7′,s),93.3(C-8′,s),54.4(C-9′,d),44.0(C-10′,s),126.1(C-11′,s),172.8(C-12′,s),55.1(C-13′,t),24.4(C-14′,q),63.2(C-15′,t),52.8(MeO-12,q).HRESIMS m/z 543.2360[M+Na] + (calcd forC 31 H 36 NaO 7 + ,543.2359)。
physical constants and spectral data for chlorsholide J: yellow gum;(c 0.14,MeOH)；UV(MeOH)λ max (logε)219(3.42)nm；CD(MeOH)λ max (Δε)209(-21.9),253(+18.6),333(-3.02)nm； 1 HNMR(CDCl 3 ,600MHz)δ1.60(1H,o,H-1),0.95(1H,td,J＝7.7,4.7Hz,H-2α),0.36(1H,q,J＝4.1Hz,H-2β),1.84(1H,o,H-3),3.88(1H,d,J＝3.7Hz,H-6),2.36(1H,d,J＝18.5Hz,H-9α),2.56(1H,d,J＝18.5Hz,H-9β),1.81(3H,s,H 3 -13),1.15(3H,s,H 3 -14),2.75(1H,d,J＝16.6Hz,H-15α),2.55(1H,o,H-15β),1.60(1H,o,H-1′),0.71(1H,td,J＝8.7,5.8Hz,H-2′α),1.31(1H,qJ＝4.0Hz,H-2′β),1.39(1H,td,J＝8.8,3.5Hz,H-3′),1.70(1H,dd,J＝13.6,6.2Hz,H-5′),2.46(1H,dd,J＝18.5,6.1Hz,H-6′α),2.73(1H,dd,J＝18.5,13.6Hz,H-6′β),1.84(1H,m,H-9′),4.65(1H,d,J＝12.4Hz,H-13′a),4.98(1H,d,J＝12.5Hz,H-13′b),0.82(3H,s,H 3 -14′),3.69(1H,d,J＝11.6Hz,H-15′a),4.53(1H,d,J＝11.7,Hz,H-15′b),6.89(1H,m,H-3″),4.35(1H,m,H-4″a),4.42(1H,dd,J＝15.7,4.8Hz,H-4″b),1.87(3H,s,H 3 -5″),2.12(3H,s,H-2″′),3.65(3H,s,MeO-12)； 13 C NMR(CDCl 3 ,150MHz)δ28.6(C-1,d),16.3(C-2,t),24.8(C-3,d),138.5(C-4,s),134.7(C-5,s),41.2(C-6,d),136.5(C-7,s),201.0(C-8,s),52.2(C-9,t),45.2(C-10,s),143.0(C-11,s),171.0(C-12,s),19.1(C-13,q),22.8(C-14,q),25.3(C-15,t),25.3(C-1′,d),11.7(C-2′,t),27.9(C-3′,d),77.7(C-4′,s),61.2(C-5′,d),23.1(C-6′,t),173.3(C-7′,s),93.2(C-8′,s),55.6(C-9′,d),45.0(C-10′,s),123.0(C-11′,s),171.9(C-12′,s),54.7(C-13′,t),26.5(C-14′,q),71.8(C-15′,t),168.1(C-1″,s),127.2(C-2″,d),142.5(C-3″,d),60.1(C-4″,t),12.8(C-5″,q),171.4(C-1″′,s),20.7(Me-2″′,q),53.0(MeO-12,q).HRESIMS m/z 699.2781[M+Na] + (calcd for C 38 H 44 NaO 11 + ,699.2781)。
physical constants and spectral data for chlorsholide L: yellow gum;(c 0.11,MeOH)；UV(MeOH)λ max (logε)220(3.29)nm；CD(MeOH)λ max (Δε)209(-21.5),259(+34.2),330(-6.69)nm； 1 H NMR(CDCl 3 ,600MHz)δ1.56(1H,o,H-1),0.92(1H,m,H-2α),1.33(1H,m,H-2β),1.87(1H,o,H-3),2.25(1H,d,J＝17.8Hz,H-9α),2.55(1H,d,J＝17.8Hz,H-9β),1.70(3H,s,H 3 -13),1.23(3H,s,H 3 -14),3.00(1H,dd,J＝14.1,7.1Hz,H-15α),1.52(1H,o,H-15β),1.52(1H,o,H-1′),0.58(1H,td,J＝8.9,5.6Hz,H-2′α),1.18(1H,m,H-2′β),1.59(1H,m,H-3′),1.44(1H,dd,J＝13.0,6.7Hz,H-5′),2.31(1H,dd,J＝17.5,6.5Hz,H-6′α),2.83(1H,dd,J＝17.5,13.1Hz,H-6′β),2.57(1H,d,J＝17.2Hz,H-9′),4.38(1H,d,J＝13.8Hz,H-13′a),4.44(1H,d,J＝13.6Hz,H-13′b),0.97(3H,s,H 3 -14′),3.89(1H,d,J＝11.6Hz,H-15′a),4.25(1H,d,J＝11.5,Hz,H-15′b),6.90(1H,m,H-3″),1.83(3H,d,J＝7.2Hz,H-4″),1.86(3H,s,H 3 -5″),3.70(3H,s,MeO-12)； 13 C NMR(CDCl 3 ,150MHz)δ28.7(C-1,d),8.4(C-2,t),29.4(C-3,d),90.4(C-4,s),160.7(C-5,s),126.6(C-6,s),136.5(C-7,s),201.4(C-8,s),48.6(C-9,t),44.5(C-10,s),135.2(C-11,s),169.6(C-12,s),20.0(C-13,q),22.1(C-14,q),37.1(C-15,t),27.2(C-1′,d),10.5(C-2′,t),29.4(C-3′,d),77.8(C-4′,s),54.6(C-5′,d),21.7(C-6′,t),166.4(C-7′,s),87.6(C-8′,s),51.8(C-9′,d),45.2(C-10′,s),127.8(C-11′,s),173.0(C-12′,s),55.4(C-13′,t),24.3(C-14′,q),70.8(C-15′,t),168.4(C-1″,s),128.4(C-2″,d),138.6(C-3″,d),14.7(C-4″,q),12.3(C-5″,q),52.7(MeO-12,q).HRESIMS m/z 673.2626[M+Na] + (calcd for C 36 H 42 NaO 11 + ,673.2625)。
physical constants and spectral data of Chlorajaponilide E: white powder; 1 H NMR(500MHz,Chloroform-d)δ2.00(1H,m,H-1),1.23(1H,m,H-2α),0.95(1H,m,H-2β),1.85(1H,m,H-3),3.75(1H,s,H-9),1.78(3H,s,H 3 -13),1.02(3H,s,H 3 -14),3.07(1H,dd,J＝14.3,7.1Hz,H-15α),1.60(1H,m,H-15β),1.58(1H,m,H-1′),1.18(1H,m,H-2′α),0.60(1H,td,J＝9.0,5.5Hz,,H-2′β),1.60(1H,m,H-3′),1.60(1H,m,H-5′),2.88(1H,dd,J＝17.5,13.1Hz,H-6′α),2.25(1H,dd,J＝17.5,6.7Hz,H-6′β),2.59(1H,dd,J＝10.0,7.1Hz,H-9′),4.43(1H,d,J＝13.7Hz,H-13′a),4.36(1H,d,J＝13.9Hz,H-13′b),0.98(3H,s,H 3 -14′),4.15(1H,d,J＝11.4Hz,H-15′a),3.93(1H,d,J＝11.5Hz,H-15′b),6.84(1H,m,H-3″),1.84(3H,s,H-4″),1.85(3H,s,H 3 -5″),3.78(3H,s,MeO-12)； 13 C NMR(125MHz,Chloroform-d)δ26.1(C-1,d),8.4(C-2,t),27.8(C-3,d),90.6(C-4,s),158.7(C-5,s),127.1(C-6,s),143.0(C-7,s),198.9(C-8,s),77.9(C-9,d),50.3(C-10,d),129.2(C-11,s),170.3(C-12,s),21.3(C-13,q),15.4(C-14.q),36.8(C-15,t),27.4(C-1′,d),10.5(C-2′,t),29.3(C-3′,d),77.7(C-4′,s),54.8(C-5′,d),21.9(C-6′,t),166.5(C-7′,s),87.6(C-8′,s),52.5(C-9′,d),45.2(C-10′,s),128.5(C-11′,s),173.1(C-12′,s),55.1(C-13′,t),24.4(C-14′,q),70.6(C-15′,t),168.3(C-1″,s),128.2(C-2″,s),139.0(C-3″,d),14.7(C-4″,q),12.3(C-5″,q),52.9(MeO-12,q)。
example 2: preparation method two of compounds chlorahololides H, J, L and chlorajaponilide E
Pulverizing dried root (20 kg) of the whole plant of chloranthus glaber, adding 100L ethyl acetate (volume ratio of organic solvent to plant material is 5:1), cold soaking and extracting for 4 times (3 days/time), mixing extractive solutions, and vacuum distilling to obtain pasty extract (1.1 kg). Subjecting the extract to normal phase silica gel column chromatography, and eluting with petroleum ether-acetone gradient (1:0, 50:1, 10:1, 1:1, 1:5, 0:1, v/v), wherein each gradient has 4-6 column volumes to obtain 6 components, which are Fr.1-Fr.6 respectively. Fr.4 (88.2 g) was subjected to MCI gel column chromatography eluting with ethanol-water gradients (2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2, 10:0, v/v), 4-6 column volumes per gradient, yielding 8 fractions Fr.4.1-Fr.4.8, respectively. Fr.4.3 (7.8 g) was chromatographed on normal phase silica gel using chloroform-methanol gradients (200:1, 50:1, 20:1, 10:1, 1:1, v/v), 4-6 column volumes per gradient, yielding 5 fractions Fr.4.3.1-Fr.4.3.5, respectively. Fr.4.3.3 (267.9 mg) was prepared by semi-preparative HPLC using isocratic elution with 55% acetonitrile-water as the mobile phase to give 12.0mg chlorahololide H (yield: 0.00006%) and 6.0mg chlorajaponilide E (yield: 0.00003%). Fr.4.3.4 (437.2 mg) was prepared by semi-preparative HPLC using gradient elution (0-30 min, acetonitrile concentration from 30% -80%, v/v) to give 16.0mg chlorahololide J (yield: 0.00008%) and 4.0mg chlorahololide L (yield: 0.00002%).
Example 3: preparation method three of compounds chlorahololides H, J, L and chlorajaponilide E
The whole plant (15 kg) of chloranthus japonicus is dried and crushed, 45L of 95% ethanol (the volume ratio of organic solvent to plant material is 3:1) is used for heating and reflux extraction for 2 times and 3 hours/time at 70 ℃, and the ethanol extract (1.4 kg) is obtained by vacuum distillation after the extraction liquid is combined. The ethanol extract was suspended in 6L of purified water, and then extracted 3 times with 6L of ethyl acetate, and the extracts were combined and the solvent was recovered to give ethyl acetate extract (763.5 g). Ethyl acetate extract was purified by medium MCI gel column chromatography eluting with methanol-water gradients (2:8, 3:7, 5:5, 7:3, 8:2, 10:0, v/v), 4-6 column volumes per gradient, yielding 6 fractions fr.1-fr.6, respectively. Fr.3 (146.7 g) was subjected to gradient elution (200:1, 100:1, 50:1, 10:1, 1:1, v/v) using normal phase silica gel column chromatography with dichloromethane-methanol as eluent, with each gradient ranging from 4 to 6 column volumes, yielding 5 fractions Fr.3.1-Fr.3.5, respectively. Fr.3.2 (24.3 g) was prepared by semi-preparative HPLC using Sephadex LH-20 gel column chromatography with methanol as eluent and acetonitrile-water as mobile phase using isocratic elution (acetonitrile concentration 55%) to give 4.5mg chlorahololide H (yield: 0.00003%) and 15.0mg chlorajaponilide E (yield: 0.0001%). Fr.3.3 (16.4 g) was prepared by semi-preparative HPLC using Sephadex LH-20 gel column chromatography with chloroform-methanol (1:1, v:v) as eluent and then with acetonitrile-water as mobile phase by isocratic elution (acetonitrile concentration 60%) to give 18mg chlorahololide J (yield: 0.00012%) and 13.5mg chlorahololide L (yield: 0.00009%).
Example 4: preparation method four of Compounds chlorahololides H, J, L and chlorajaponilide E
The whole chloranthus latifolia (20 kg) is dried and crushed, 20L of methanol (the volume ratio of the organic solvent to the plant material is 1:1) is used for ultrasonic extraction for 3 times at room temperature, and the extract is combined and distilled under reduced pressure to obtain a pasty extract (1.3 kg). Subjecting the extract to normal phase silica gel column chromatography, eluting with dichloromethane-methanol gradient (1:0, 200:1, 100:1, 50:1, 20:1, 10:1, 1:1, v/v), and collecting 7 components (Fr.1-Fr.7) with each gradient of 4-6 column volumes. Fr.5 (127.4 g) was subjected to RP-18 reverse phase silica gel column chromatography eluting with methanol-water gradients (2:8, 5:5,8:2, 10:0, v/v) with 4-6 column volumes per gradient to give 4 fractions Fr.5.1-Fr.5.4, respectively. Fr.5.3 (16.4 g) was eluted with petroleum ether-acetone gradients (10:1, 1:1, 1:5, 0:1, v/v) using normal phase silica gel column chromatography, with 4-6 column volumes per gradient, yielding 4 fractions Fr.5.3.1-Fr.5.3.4, respectively. Fr.5.3.2 (478.6 mg) was prepared by semi-preparative HPLC using isocratic elution with 50% acetonitrile-water as the mobile phase to give 10.0mg chlorahololide H (yield: 0.00005%) and 16.0mg chlorajaponilide E (yield: 0.00008%). Fr.5.4 (23.3 g) was eluted with a normal phase silica gel column with petroleum ether-acetone gradient (20:1, 10:1, 1:1, 1:5, 0:1, v/v), each gradient 4-6 column volumes, yielding 5 fractions Fr.5.4.1-Fr.5.4.5, respectively. Fr.5.4.2 (898.4 mg) was prepared by semi-preparative HPLC using gradient elution (0-30 min, acetonitrile concentration from 30% -70%, v/v) to give 8.0mg chlorahololide J (yield: 0.00004%) and 12.0mg chlorahololide L (yield: 0.00006%).
Example 5: NLRP3 inflammatory corpuscle inhibitory Activity of chlorahololides H, J, L and chlorajaponilide E
Lactate Dehydrogenase (LDH) is a stable cytoplasmic enzyme that is present in all cells and is rapidly released into cell culture when the cell membrane is damaged. Activation of NLRP3 inflammatory bodies eventually leads to cell scorch and rupture of cell membranes, leading to release of LDH into the cell culture fluid, which can be monitored by measuring the LDH content in the cell culture fluid. Thus, in this example, a model of NLRP3 inflammatory body activation was constructed using mouse mononuclear macrophages j774a.1, which together induced NLRP3 inflammatory body activation by Lipopolysaccharide (LPS) and Nigericin (Nigericin). Specific methods can be found in Xing, jie Zhang, et al 2021,Leojaponin inhibits NLRP3inflammasome activation through restoration of autophagy via upregulating RAPTOR phosphorylation,Journal of Ethnopharmacology 278 (2021) 114322.
Specific experiments were as follows, mouse mononuclear macrophage J774A.1 (purchased from Kunming animal institute, national academy of sciences) was used at 2X 10 5 Density of cells per well was seeded in 24 well plates, each well containing 500. Mu.L of Dulbecco's Modified Eagle Medium (DMEM, gibco) supplemented with 8% heat-inactivated fetal bovine serum (FBS, gibco) and placed in a well containing 5% CO 2 The cells were cultured overnight in a CO2 incubator (Thermo Scientific) at a constant temperature of 37 ℃. After overnight incubation, the medium was removed. Subsequently, 500. Mu.L of 200ng/mL LPS (Shanghai Biyun Biotechnology Co., ltd.) in Opti-MEM medium (Thermo Scientific, eugene, OR, USA) was added to each well to stimulate the cells for 3.5 hours. Then, the medium was aspirated, 500. Mu.L of 10. Mu.M compounds chlorahololides H, J, L and chlorajaponilide E in Opti-MEM medium was added, 500. Mu.L of 0.1. Mu.M MC CC950 (Shanghai Ala Biochemical Co., ltd.) in Opti-MEM medium was added as a positive control, 500. Mu.L of 1. Mu.L/mL DMSO in Opti-MEM medium was added as a negative control, and cells were incubated in a CO2 incubator for 30min. Finally, the medium was aspirated, and 500. Mu.L of 10. Mu.M Nigericin (Albumin Biotechnology Co., shanghai) dissolved in Opti-MEM medium was added to each well to stimulate the cells for 1 hour. After activation of inflammatory bodies and treatment with compounds, the cell culture supernatant was taken down120 μl) was collected in 96-well plates, and 60 μl of LDH assay working solution (Shanghai Biyun biotechnology limited) was added, mixed well, and incubated at room temperature for 30min in the absence of light. The absorbance was measured at 490nm, and the LDH release inhibition rate was calculated as follows, i.e., LDH release inhibition rate (%) = (DMSO-treated group OD 490 nm Sample set OD 490 nm ) DMSO-treated group OD 490 nm X 100%. Compounds chlorahololides H, J, L and chlorajaponilide E semi-inhibitory concentration on NLRP3 inflammatory body activation (Halfmaximal inhibitory concentration, IC 50 ) The test method of (2) is as follows: each compound was set up with different concentration gradients (10. Mu.M, 5. Mu.M, 2.5. Mu.M, 1.25. Mu.M and 0.625. Mu.M), the compounds were tested for their inhibition of LDH release at different concentrations, and nonlinear regression analysis was performed using GraphPad prism7.0 software to calculate the IC of the compound 50 Values. Cell viability was examined using the MTT method, excluding toxic effects of compounds chlorahololides H, J, L and chlorajaponilide E on cells, as described in Xing, jie Zhang 2021 (supra). All experiments were repeated at least 3 times and experimental data were calculated analytically using GraphPad prism 7.0.
Experimental results as shown in tables 1 and 2, chlorahololides H, J, L and chlorajaponilide E had significant NLRP3 inflammatory body inhibitory activity at a concentration of 10 μm, and the IC of these compounds was further tested 50 Values were 8.73. Mu.M, 6.15. Mu.M, 3.03. Mu.M, and 2.99. Mu.M, respectively.
Tables 1.Chlorahololides H, J, L and chlorajaponilide E show inhibition of NLRP3 inflammatory corpuscles (%)
a MCC950 as positive control
Tables 2.Chlorahololides H, J, L and chlorajaponilide E IC for NLRP3 inflammatory corpuscle inhibition 50 Value of
a CC 50 The values represent the concentration of the compound that induces 50% cytotoxicity
Example 6: chlorajaponilide E significantly reduces the pyro-death of j774a.1 macrophages
This example discusses the effect of linderane-type sesquiterpene dimer chlorajaponilide E, which has significant inhibitory activity on NLRP3 inflammatory bodies, on j774a.1 macrophage coke death. Specific methods can be found in Xing, jie Zhang, et al, 2021,Leojaponin inhibits NLRP3inflammasome activation through restoration of autophagy via upregulating RAPTOR phosphorylation,Journal of Ethnopharmacology 278 (2021) 114322.
Specific experiments were as follows, mouse mononuclear macrophage J774A.1 (purchased from Kunming animal institute, national academy of sciences) was isolated at 4X 10 4 Density of cells per well was seeded in 96-well plates, each well containing 200. Mu.L of Dulbecco's Modified Eagle Medium (DMEM, gibco) supplemented with 8% heat-inactivated fetal bovine serum (FBS, gibco) and placed in a well containing 5% CO 2 The cells were cultured overnight in a CO2 incubator (Thermo Scientific) at a constant temperature of 37 ℃. After one night of incubation, three different experiments were set up. The LPS and nigericin treatment groups were operated as follows: the medium was removed, 200. Mu.L of 200ng/mL LPS in Opti-MEM medium was added to each well, the cells were stimulated for 3.5 hours, then the medium was aspirated, and 200. Mu.L of compound chlorajaponilide E (1. Mu.M, 3. Mu.M and 9. Mu.M) in Opti-MEM medium, and DMSO (negative control, 1. Mu.L/mL) were added to each well, and the cells were washed in CO 2 Incubate in incubator for 30min. Finally, the medium was removed and 200. Mu.L of 10. Mu.M Nigericin in Opti-MEM medium was added to each well and the cells were stimulated for 1 hour. Untreated groups operate as follows: the medium was removed and 200. Mu.L of Opti-MEM medium was added to each well. Treatment groups with chlorajaponilide E (9 μm) alone were operated as follows: the medium was removed and 200. Mu.L of Opti-MEM medium was added to each well. After 3.5 hours, the medium was aspirated and 200. Mu.L of 9. Mu.M compound chlorajaponilide E in Opti-MEM medium was added to each well.
After activation of NLRP3 inflammatory bodies, LPS and Nigericin treated group cells were removed from the supernatant, 100. Mu.L of 3. Mu.g/mL PBS-formulated Propidium iodide (Propidium iodate, PI, shanghai Biyun Biotechnology Co., ltd.) and 0.5. Mu.g/mL Hoechst 33342 (Shanghai Biyun Biotechnology Co., ltd.) were added as dyes to stain macrophages J774A.1, stained at room temperature for 15min, and photographed with a fluorescent inverted microscope (Axio Olerver 3, zeiss; oberkochen, germany). PI stained the scorched cells red and Hoechst 33342 stained the nuclei blue. The other two groups of experimental cells used the same procedure. All experiments were repeated at least 3 times. Experimental data were calculated analytically using GraphPad prism 7.0. Differences between groups were analyzed using One-way analysis of variance (One-way analysis). * P <0.05, < P <0.01, < P <0.001, there are significant differences when P <0.05 is statistically significant.
The results are shown in FIGS. 2 and 3. From figure 2 it can be seen that the LPS and nigericin treated groups significantly increased the proportion of PI staining compared to the untreated groups, indicating a significantly increased number of apoptotic cells. While cells from the treated group were indistinguishable from untreated groups with chlorajaponilide E (9. Mu.M) alone, indicating that compound chlorajaponilide E did not cause j774A.1 cells to undergo focal death. In addition, chlorajaponilide E reduced the proportion of j774a.1 apoptosis in the LPS and nigericin treated groups in a concentration-dependent manner compared to the negative control DMSO, indicating that the compound was effective in inhibiting apoptosis induced by NLRP3 inflammatory body activation. Fig. 3 is a graph of chlorajaponilide E quantification of inhibition of j774a.1 cell apoptosis, in the LPS and nigericin treated groups, of j774a.1 cell apoptosis was inhibited following administration of chlorajaponilide E (1 μm, 3 μm and 9 μm) compared to the negative control DMSO, P <0.001, indicating that chlorajaponilide E can significantly inhibit j774a.1 cell apoptosis induced by LPS and nigericin.
Claims (9)
1. The linderane type sesquiterpene dimer or a pharmaceutically acceptable derivative thereof is characterized in that the linderane type sesquiterpene dimer has any one of the following structural formulas I-IV:
2. a medicament or pharmaceutical composition for the treatment of chronic inflammatory diseases, characterized in that it comprises at least one of the linderane sesquiterpene dimers or pharmaceutically acceptable derivatives thereof according to claim 1.
3. Use of a linderane-type sesquiterpene dimer or a pharmaceutically acceptable derivative thereof according to claim 1 in the manufacture of a medicament for the treatment of chronic inflammatory diseases.
4. A process for preparing the linderane-type sesquiterpene dimer according to claim 1, characterized by comprising the steps of:
1) Drying and pulverizing Chloranthus (Chloranthus) plant material, extracting with organic solvent, and desolventizing to obtain Chloranthus plant material extract; and
2) Subjecting the chloranthus material extract to column chromatography to obtain chlorahololides H, J, L and chlorajaponilide E.
5. The method according to claim 4, wherein the chloranthus material is the root, stem, branch, whole plant or a mixture thereof of chloranthus, preferably the chloranthus is chloranthus gracilis (c.holosticus), chloranthus latifolia (c.henryi) or chloranthus gracilis asbestos variety (c.holosticus var. Shimianensis).
6. The process according to claim 4, characterized in that the volume ratio of the organic solvent to the chloranthus material is from 1:1 to 5:1, preferably 3:1.
7. The method according to claim 4, wherein in step 1), the organic solvent is at least one of petroleum ether, chloroform, methylene chloride, ethyl acetate, acetone, ethanol, methanol, n-butanol, and acetonitrile; preferably, the organic solvent is ethyl acetate, methanol, 95% ethanol or a mixture thereof.
8. The method according to claim 4, wherein in step 2), the column chromatography includes normal phase silica gel column chromatography, reverse phase silica gel column chromatography, resin column chromatography, gel column chromatography, medium pressure chromatography separation gel and semi-preparative HPLC.
9. The method according to claim 8, wherein in step 2), the eluent used for the column chromatography is at least one of petroleum ether, methylene chloride, chloroform, ethyl acetate, acetone, ethanol, methanol, n-butanol, acetonitrile, water and formic acid; preferably, the normal phase silica gel column chromatography adopts petroleum ether and acetone to perform gradient elution according to the volume ratio of 1:0 to 0:1, or adopts methylene dichloride and methanol to perform gradient elution according to the volume ratio of 1:0 to 1:1; the reversed-phase silica gel column chromatography adopts methanol and water to carry out gradient elution according to the volume ratio of 2:8 to 10:0; the resin column chromatography adopts methanol and water to carry out gradient elution according to the volume ratio of 2:8 to 10:0; the gel column chromatography adopts methanol or methanol and chloroform to elute according to the volume ratio of 1:1; the medium-pressure chromatographic separation gel adopts methanol or ethanol and water to carry out gradient elution according to the volume ratio of 2:8 to 10:0; the semi-preparative HPLC is eluted with acetonitrile and water isocratically, or the semi-preparative HPLC is eluted with acetonitrile and water in a volume ratio from 2:8 to 8:2 gradient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311583836.4A CN117586214A (en) | 2023-11-24 | 2023-11-24 | Linderane type sesquiterpene dimer and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311583836.4A CN117586214A (en) | 2023-11-24 | 2023-11-24 | Linderane type sesquiterpene dimer and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117586214A true CN117586214A (en) | 2024-02-23 |
Family
ID=89909498
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311583836.4A Pending CN117586214A (en) | 2023-11-24 | 2023-11-24 | Linderane type sesquiterpene dimer and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117586214A (en) |
-
2023
- 2023-11-24 CN CN202311583836.4A patent/CN117586214A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6531505B2 (en) | Immunosuppressive agents | |
| EP2415749B1 (en) | New salvianolic acid compound l, preparation method and use thereof | |
| TWI648257B (en) | Compounds from antrodia camphorata, method for preparing the same and use thereof | |
| KR19990035847A (en) | Use of Calendula Glycoside for Psoriasis Treatment | |
| CN108689851B (en) | Tiglic alkane type diterpene compound and preparation method and application thereof | |
| CN113912482A (en) | Guaiane type sesquiterpenoids, preparation and application thereof | |
| CN110452110B (en) | Phloroglucinol natural medicine and preparation method and application thereof | |
| CN114057764B (en) | Linderane type dimeric sesquiterpene with anti-inflammatory activity and preparation method and application thereof | |
| CN117586214A (en) | Linderane type sesquiterpene dimer and preparation method and application thereof | |
| CN100434419C (en) | Compound of monocyclic polysubstitution saturated cyclohexanones, prepartion method and usage | |
| CN105837592B (en) | Phloroglucin a pair of horses going side by side abietane diterpene-kind compound and preparation method thereof and medicinal usage | |
| WO2012144711A2 (en) | Composition containing caryopteris incana extracts or a compound isolated therefrom for preventing and treating hepatotoxicity | |
| CN110638822A (en) | Albizzia julibrissin glycoside compound for promoting endothelial cell proliferation and application thereof | |
| CN110204477B (en) | Diterpene alkaloid with antioxidant effect and application thereof in preparation of medicines | |
| CN111978309B (en) | Tripterygium wilfordii source compound, application and preparation method thereof, pharmaceutical composition and pesticide | |
| CN111909119B (en) | Tripterygium wilfordii source compound and application and preparation method thereof, pharmaceutical composition and pesticide | |
| CN115160332B (en) | Phloroglucinol compound and preparation method and application thereof | |
| CN114805382B (en) | Sesquiterpene chromone compound, separation thereof and application thereof in preparation of pancreatic cancer resisting drugs | |
| KR102612269B1 (en) | Compound extracspted from the leave of Viburnum erosum Thunb and tyrosinase activity inhibitory ability composition comprising the same | |
| KR100569086B1 (en) | Acer mono leaf extracts and Phenolic compounds isolated thereof having hepatoprotective activity | |
| CN100582110C (en) | Cyclohexanone analog saturated triring(bridge)compound and its preparation method and uses | |
| CN115403650A (en) | Ypsilandoside G with platelet aggregation inducing activity and preparation method and application thereof | |
| JPS62207213A (en) | Anticancer agent | |
| CN1872828B (en) | Monocyclic polysubstitution cyclohexenol, and compound of ketones, and preparation method, and usage | |
| CN103739658B (en) | A kind of compound, its extracting method, it prepares the antineoplastic of application and the preparation thereof of antineoplastic |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |