CN102174083B - Compositae cyclopeptide, immunosuppressive medicine using compositae cyclopeptide as active ingredient and preparation method and application of compositae cyclopeptide - Google Patents
Compositae cyclopeptide, immunosuppressive medicine using compositae cyclopeptide as active ingredient and preparation method and application of compositae cyclopeptide Download PDFInfo
- Publication number
- CN102174083B CN102174083B CN201110039063.4A CN201110039063A CN102174083B CN 102174083 B CN102174083 B CN 102174083B CN 201110039063 A CN201110039063 A CN 201110039063A CN 102174083 B CN102174083 B CN 102174083B
- Authority
- CN
- China
- Prior art keywords
- astin
- cyclic peptide
- cyclopeptide
- compositae
- methanol
- 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.)
- Expired - Fee Related
Links
- 108010069514 Cyclic Peptides Proteins 0.000 title claims abstract description 79
- 102000001189 Cyclic Peptides Human genes 0.000 title claims abstract description 79
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000003814 drug Substances 0.000 title description 9
- 230000001506 immunosuppresive effect Effects 0.000 title description 3
- 241000208838 Asteraceae Species 0.000 title 3
- 239000004480 active ingredient Substances 0.000 title 1
- 239000002131 composite material Substances 0.000 claims abstract description 35
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 239000003018 immunosuppressive agent Substances 0.000 claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims description 15
- 239000000470 constituent Substances 0.000 claims description 7
- 229940124589 immunosuppressive drug Drugs 0.000 abstract description 9
- UJOYFRCOTPUKAK-MRVPVSSYSA-N (R)-3-ammonio-3-phenylpropanoate Chemical compound OC(=O)C[C@@H](N)C1=CC=CC=C1 UJOYFRCOTPUKAK-MRVPVSSYSA-N 0.000 abstract description 4
- 125000000217 alkyl group Chemical group 0.000 abstract description 4
- 125000003118 aryl group Chemical group 0.000 abstract description 4
- 125000005843 halogen group Chemical group 0.000 abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 4
- 229920006395 saturated elastomer Polymers 0.000 abstract description 4
- 150000001413 amino acids Chemical class 0.000 abstract description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical class OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 abstract description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 99
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 238000010898 silica gel chromatography Methods 0.000 description 24
- 238000010828 elution Methods 0.000 description 22
- 239000003480 eluent Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 238000000034 method Methods 0.000 description 18
- 238000000926 separation method Methods 0.000 description 17
- 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 16
- 239000002904 solvent Substances 0.000 description 16
- NHJVRSWLHSJWIN-UHFFFAOYSA-N 2,4,6-trinitrobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O NHJVRSWLHSJWIN-UHFFFAOYSA-N 0.000 description 15
- 210000001744 T-lymphocyte Anatomy 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000000284 extract Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 241000132092 Aster Species 0.000 description 11
- 206010009887 colitis Diseases 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 210000001072 colon Anatomy 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 229960001866 silicon dioxide Drugs 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 230000002757 inflammatory effect Effects 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 208000023275 Autoimmune disease Diseases 0.000 description 5
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 5
- 230000003213 activating effect Effects 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 230000000452 restraining effect Effects 0.000 description 5
- 108010062580 Concanavalin A Proteins 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000006052 T cell proliferation Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 230000028993 immune response Effects 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000000401 methanolic extract Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- MZSAMHOCTRNOIZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylaniline Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(NC2=CC=CC=C2)C=CC=1 MZSAMHOCTRNOIZ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 229920002472 Starch Polymers 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229960003444 immunosuppressant agent Drugs 0.000 description 3
- 230000001861 immunosuppressant effect Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- 238000012856 packing Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 150000003505 terpenes Chemical group 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 241001662414 Aster tataricus Species 0.000 description 2
- 229930182670 Astin Natural products 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229930105110 Cyclosporin A Natural products 0.000 description 2
- 108010036949 Cyclosporine Proteins 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229960001265 ciclosporin Drugs 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- -1 polyoxyethylene Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 208000037816 tissue injury Diseases 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 102000006306 Antigen Receptors Human genes 0.000 description 1
- 108010083359 Antigen Receptors Proteins 0.000 description 1
- YWGAKIGNXGAAQR-UHFFFAOYSA-N Astin C Natural products N1C(=O)C(CO)NC(=O)C(CC)NC(=O)C2C(Cl)C(Cl)CN2C(=O)C(CC)NC(=O)CC1C1=CC=CC=C1 YWGAKIGNXGAAQR-UHFFFAOYSA-N 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- YWGAKIGNXGAAQR-DLPAQYCSSA-N C1([C@H]2CC(=O)N[C@@H](CC)C(=O)N3C[C@@H](Cl)[C@@H](Cl)[C@H]3C(=O)N[C@H](C(N[C@@H](CO)C(=O)N2)=O)CC)=CC=CC=C1 Chemical compound C1([C@H]2CC(=O)N[C@@H](CC)C(=O)N3C[C@@H](Cl)[C@@H](Cl)[C@H]3C(=O)N[C@H](C(N[C@@H](CO)C(=O)N2)=O)CC)=CC=CC=C1 YWGAKIGNXGAAQR-DLPAQYCSSA-N 0.000 description 1
- 241000252983 Caecum Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 235000008495 Chrysanthemum leucanthemum Nutrition 0.000 description 1
- 235000000604 Chrysanthemum parthenium Nutrition 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000035186 Hemolytic Autoimmune Anemia Diseases 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
- 206010062016 Immunosuppression Diseases 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
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 240000004460 Tanacetum coccineum Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000002474 Tinea Diseases 0.000 description 1
- 241000130764 Tinea Species 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000005377 adsorption chromatography Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003409 anti-rejection Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 108010069923 astin C Proteins 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000004534 cecum Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000000039 congener Substances 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000011082 depyrogenation Methods 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
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 235000008384 feverfew Nutrition 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000003284 homeostatic effect Effects 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000007233 immunological mechanism Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000003808 methanol extraction Methods 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 150000008130 triterpenoid saponins Chemical class 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Composite family type cyclic peptide compounds refer to that skeleton contains β-phenylalanine, and are connected directly the equal pentapeptide compound of the monocycle to be formed with normal amino acid peptide bond; Typically contain a L- β-phenylalanine, a Serine, a L-PROLINE derivative and two other amino acid derivativges. Wherein structural formula is amp; amp; lt; b/ amp; gt; AstinC(1 composite family type cyclic peptide) is the immunosuppressor in novel plant source. The preparation method of such compound is provided and is preparing the application in immunosuppressive drug.
R1, R2=aryl or alkyl, R3, R4, R5=hydroxyl or halogen atom, X, Y=unsaturated bond or saturated bond.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, relate to particularly a class composite family type cyclic peptide, as immunosuppressor, the pharmaceutical composition take it as effective constituent, its preparation method and the application in the preparation immunosuppressive drug thereof.
Background technology
Immunomodulatory is that body is kept homeostatic key factor.If the function of immune system imbalance, body produces excessive immune response to autoantigen and causes tissue injury, will cause autoimmune disorder or anaphylaxis etc.Immunosuppressor refers to can be by suppressing cell and humoral immune reaction, the class material that tissue injury is alleviated.It is inhibited to the immune response of body, can suppress the proliferation and function with immune response cells involved (scavenger cells such as T cell and B cell), reduces organism immune response.Immunosuppressor is widely used in the anti-rejection of organ transplantation and autoimmune disease such as rheumatoid arthritis, lupus erythematosus, tinea, film kidney ball ephritis, inflammatory bowel and autoimmune hemolytic anemia etc. at present.At present existing many immunosuppressor are found, mainly be divided into chemical synthesis preparation, hormone, microbial metabolites, Chinese medicine and effective constituent thereof and biological technology products (cytokine, albumen, antibody) etc., the listing of a lot of successful medicines is wherein also arranged and produce huge economic benefit, as derive from S-Neoral, the chemicals endoxan of microbial metabolites, the prednisone of hormones etc.But in the existing immunosuppressive drug, there are the shortcomings such as poor specificity, toxic side effect is obvious, the treatment window is narrow and expensive, so the immunosuppression new drug of anxious high-efficiency low-toxicity to be developed more.Chinese medicine is the rarity of the Chinese nation, and the Chinese medicine immunosuppressor now becomes the main flow in market together because of advantages such as composition is diversified, pharmacological action is extensive, few side effects, no dependences with neotype immunosuppressant.Have very important academic significance and good application prospect so from motherland's traditional Chinese medicine material, find neotype immunosuppressant.
The T lymphocyte accounts for leading role in the pathologic process of various autoimmune diseases and transplant rejection etc., suppressor T cell is one of main mechanism of playing a role of immunosuppressive drug.Most of T cells are experiencing the destiny of tranquillization, activation, effect, apoptosis in the immunne response process.Ripe T cells is activated by its antigen receptor after antigen recognition, the T cell of activation carries out clonal expansion with exponential speed, next be divided into the effector cell, secrete cytokines or direct killing target cell enter apoptosis at last to keep the homeostasis of T cell population.Immunosuppressor cyclosporin A (the Cyclosporin A of relative low toxicity, CsA) can optionally act on the t cell activation stage, stop its activation and proliferation, be widely used in clinically suppressing the rejection that organ transplantation causes, but unsatisfactory to the curative effect of autoimmune disease.This is likely that the pathologic reaction that unable prevention has started is to the damage of autologous tissue because they are not strong to the effector T cell restraining effect that activated.Many researchs also show in the pathogenic process of autoimmune disorder, and autoreactive T cell is in the continuous activation state that stimulated by autoantigen, constantly discharges inflammatory cytokine, and can assist the B cell to produce a large amount of autoantibodies.In order to suppress ongoing pathologic immunne response, the T cell of activation is the good targets of immunosuppressive drug selectively acting.
In the prior art there are no the report of composite family type cyclic peptide as immunosuppressor.
Composite family type cyclic peptide exists kind few in feverfew, only separates at present obtaining 9 from composite family Aster aster.Cyclic peptide is because of the difficult separation of the reasons such as the bad content of its solvability is lower.In the prior art, the separating ring peptide constituents has been published following method from aster: aster dry root methanol extraction, n-butanol extraction gets two positions of propyl carbinol and water.N-butanol portion is through Diaion HP-20 column chromatography, (1:0-0:1) methanol/water is eluent, 80%(methanol/water wherein) component is through silica gel column chromatography, (1:0-0:1) methylene chloride/methanol is eluent, wherein 10% (ethanol/methylene) component is through the separation and purification of ODS HPLC semipreparative column, acetonitrile/water is eluent, obtains compd A stin C.Referring to: Morita, H.; Nagashima, S.; Takeya, K.; Itokawa, H.; Iitaka, Y., Structures and conformation of antitumour cyclic pentapeptides, astins A, B and C, from
Aster tataricus.
Tetrahedron 1995, 51(4), 1121-1132.Its shortcoming is repeatedly to use the mixed solvent system of organic solvent and water in the separation and purification, and this mixed solvent recovered temperature is high, is unfavorable for the recovery of solvent; All solvents are expensive in the HPLC method, make extraction cost too high, and the HPLC technology also is unfavorable for industrial mass production simultaneously.
Summary of the invention
For prior art above shortcomings part, the object of the present invention is to provide a class composite family type cyclic peptide compounds; The method of this compounds of preparation is provided, this extraction and separation method controllability and favorable reproducibility, sample loss is few, and cost is lower, and is easy to operate, can more easily separatedly obtain cyclic peptide, and solvent can be recycled repeatedly, also is applicable to industrial production.The present invention also aims to provide the pharmaceutical composition take composite family type cyclic peptide compounds as effective constituent; The application in the preparation immunosuppressive drug of this compounds and composition thereof.
In order to realize above-mentioned purpose of the present invention, the invention provides following technical scheme:
Composite family type cyclic peptide compounds is that a class skeleton contains
β-phenylalanine, and the equal pentapeptide compound of monocycle that directly link to each other to form with normal amino acid peptide bond; Generally contain a L
-β-phenylalanine, a Serine, a L-PROLINE derivative and two other amino acid derivative.
Cyclic peptide of the present invention, the compd A stin C(that preferably has following structural formula
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5).
R
1, R
2=aryl or alkyl
R
3, R
4, R
5=hydroxyl or halogen atom
X, Y=unsaturated link(age) or saturated bond
The method for preparing the above-mentioned composite family type of the present invention cyclic peptide compounds is got the rhizome of composite family aster, drying, pulverize after, fully extract with methanol eddy; After methanol extract added the water suspendible, fully extract with ethyl acetate and propyl carbinol successively; Ethyl acetate part and propyl carbinol part are used silica gel, the various chromatography column separation and purification of Sephadex LH-20, RP-18 repeatedly, and the TLC detection method in conjunction with cyclic peptide namely obtains composite family type cyclic peptide again.
Be prepared as follows the type of composite family shown in structural formula cyclic peptide compounds Astin C(
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5) method, get the aster rhizome, drying, shatter after, extract 3 times with methanol eddy, the time is each 1-3 hour, extracting solution gets methanol extract through concentrating under reduced pressure; After methanol extract added the water suspendible, fully extract with ethyl acetate and propyl carbinol successively, equal-volume respectively extracts three times, reclaims solvent and obtains ethyl acetate part, propyl carbinol part and water section; Ethyl acetate part through silica gel column chromatography, use 100:0,9:1,8:2,7:3, the chloroform/methanol gradient elution of 0:100, thin-layer chromatography is in conjunction with cyclic peptide TLC detection method merging 9:1 and the 8:1 part that contains cyclic peptide wherein; Each following step all must be carried out separation and purification in conjunction with cyclic peptide TLC detection method; Medicinal extract after the merging is used 20:1 again through silica gel column chromatography, 10:1, and 85:15,8:2, the chloroform/methanol gradient elution of 0:1 is merged into eight component Fr.1-Fr.8 according to the difference of cyclic peptide point; The Fr.2 component is through silica gel column chromatography, and the sherwood oil of 2:1-1:2/acetone gradient elution merges and obtains six subfraction Fr.2-1 – Fr.2-6; Fr.2-5 is again through silica gel column chromatography, 20:1, and 15:1,10:1, the chloroform/methanol gradient elution of 5:1 merges and obtains five subfraction Fr.2-5-1 – Fr.2-5-5; Component Fr.2-5-1 reclaims solvent, obtains compd A stin D(behind the evaporate to dryness
3); The Fr.3 component is that the eluent separation obtains two subfraction Fr.3-1 – Fr.3-2 through silica gel column chromatography with 1:1-1:2 sherwood oil/acetone; Wherein the Fr.3-2 component is that the eluent separation obtains two component Fr.3-2-1 and Fr.3-2-2 again through silica gel column chromatography with 1:3-1:5 chloroform/ethyl acetate; Fr.3-2-2 is through Sephadex LH-20 chromatography, and the chloroform/methanol of 1:1 is eluent, obtains the part of enrichment cyclic peptide.This part obtains compd A stin C(through recrystallization
1); The Fr.4 component is through silica gel column chromatography, and 1:1-1:2 sherwood oil/acetone carries out gradient elution, merges similar cyclic peptide point part, obtains two subfraction Fr.4-1 – Fr.4-2; Subfraction Fr.4-2 is again through silica gel column chromatography, 2:1, and 1:1,1:2 sherwood oil/acetone carries out gradient elution, merges to obtain three subfraction Fr.4-2-1 – Fr.4-2-3; Wherein Fr.4-2-2 carries out the cyclic peptide enrichment through Sephadex LH-20, and the 1:1 chloroform/methanol is eluent, again through RP-18 column chromatography enrichment cyclic peptide, 30:70-80:20 methanol/water gradient elution; Behind Sephadex LH-20 and RP-18 enrichment cyclic peptide, component Fr.4-2-2 is again through silica gel column chromatography, 20:1, and 10:1, the 5:1 chloroform/methanol is that eluent carries out gradient elution, obtains four subfraction Fr.4-2-2-1 – Fr.4-2-2-4; Wherein Fr.4-2-2-2 is again through silica gel column chromatography 20:1,10:1, and the 5:1 chloroform/methanol is that eluent carries out gradient elution, obtains five subfraction Fr.4-2-2-2-1 – Fr.4-2-2-2-5; Wherein directly through Sephadex LH-20 purification enrichment cyclic peptide part, the 1:1 chloroform/methanol is eluent to Fr.4-2-2-2-4, merges the cyclic peptide part, reclaims solvent, and evaporate to dryness obtains compd A stin H(
4); Component Fr.4-2-2-4 is through Sephadex LH-20 purification enrichment cyclic peptide part, and the 1:1 chloroform/methanol is eluent, obtains two component Fr.4-2-2-4-1 – Fr.4-2-2-4-2; Component Fr.4-2-2-4-1 reclaims solvent, obtains compound Tataricin A(behind the evaporate to dryness
5); The Fr.5 component is through silica gel column chromatography, 1:3-1:9 chloroform/ethyl acetate gradient elution, and with the enrichment of cyclic peptide part, this part is through Sephadex LH-20, and the 1:1 chloroform/methanol is eluent, obtains two component Fr.5-1 – Fr.5-2; Wherein component Fr.5-2 is through silica gel column chromatography, and the 15:1-3:1 chloroform/methanol is carried out gradient elution, obtains two component Fr.5-2-1 – Fr.5-2-2; Component Fr.5-2-1 reclaims solvent, obtains compd A stin B(behind the evaporate to dryness
2).
R
1, R
2=aryl or alkyl
R
3, R
4, R
5=hydroxyl or halogen atom
X, Y=unsaturated link(age) or saturated bond
The salt of allowing on above-mentioned composite family type cyclic peptide of the present invention or its pharmacology is the immunosuppressor of effective constituent.
Be used for the immunosuppressive drug compositions, wherein contain salt and the pharmaceutically acceptable carrier of allowing on the of the present invention above-mentioned composite family type cyclic peptide for the treatment of significant quantity or its pharmacology.
The present invention also provides the composite family type cyclic peptide compounds Astin that contains shown in the said structure formula for the treatment of significant quantity C(
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5) or its pharmacology on the salt of allowing and the pharmaceutical composition of pharmaceutically acceptable carrier.
The present invention provides the application of the salt of allowing on composite family type cyclic peptide of the present invention or its pharmacology in the preparation immunosuppressor simultaneously.
With compd A stin C(
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5) or its pharmacology on the salt of allowing be the immunosuppressor of effective constituent.
Compd A stin C(
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5) in the application of preparation in the immunosuppressor.
Compd A stin C(
1) for the preparation of immunosuppressor.
The present invention carries out the cyclic peptide chemical constitution study of system to composite family aster aster, utilize multiple separation and purification means, comprises positive reversed-phase silica gel column chromatography, Sephadex LH-20 gel chromatography, and recrystallizations etc. have therefrom obtained a series of composite family type cyclic peptide.Afterwards, to main Cyclopeptides Astin C(
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5) in its restraining effect of activating T cell proliferation experiment detection that Con A induces, reach the mouse immune colitis experimental model that causes at trinitro-benzene-sulfonic acid and detect its therapeutic action.Find Astin C(
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5) all showing in vivo and in vitro certain immunosuppressive activity, the immunosuppressor for the novel plant source can be used for preparing immunosuppressive drug.
The salt of allowing on described composite family type cyclic peptide of the present invention or its pharmacology, can enumerate such as with the mineral acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, Hydrogen bromide, perhaps organic acids such as toxilic acid, fumaric acid, tartrate, lactic acid, citric acid, acetic acid, methylsulfonic acid, p-benzene methanesulfonic acid, hexanodioic acid, palmitinic acid, Weibull, lithium, the basic metal such as sodium, potassium, the alkaline-earth metal such as calcium, magnesium, the salt that the basic aminoacidss such as Methionin become.
The pharmaceutical composition for the treatment of immunity system relative disease of the present invention, by the pharmaceutical dosage form of composite family type cyclic peptide compounds and pharmaceutically acceptable carrier preparation comprise tablet, capsule, oral liquid, injection, injection is freeze-dried or powder injection etc.Because composite family type cyclic peptide can extract separation from aster and congener, and tablet, capsule, oral liquid, injection, injection is freeze-dried or the preparation of the pharmaceutical dosage form such as powder injection also is the conventional knowledge of this area.Therefore.Various pharmaceutical dosage forms by composite family type cyclic peptide compounds and respective carrier preparation also can be realized by those skilled in the art.
Above described pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, such as: thinner, vehicle such as water etc., weighting agent such as starch, sucrose etc.; Tamanori such as derivatived cellulose, alginate, gelatin and polyvinylpyrrolidone; Wetting agent such as glycerine; Disintegrating agent such as agar, calcium carbonate and sodium bicarbonate; Absorption enhancer such as quaternary ammonium compound; Tensio-active agent such as cetyl alcohol; Absorption carrier such as kaolin and soap clay; Lubricant such as talcum powder, calcium stearate and Magnesium Stearate and polyoxyethylene glycol etc.Can also in composition, add other assistant agent such as flavouring agent, sweeting agent etc. in addition.
The compounds of this invention can with the form of composition by oral, snuffing enters, the mode of rectum or administered parenterally is applied to the patient who needs this treatment.Be used for to be made into conventional solid preparation such as tablet, pulvis, granula, capsule etc. when oral, make liquid preparation such as water or oil-suspending agent or other liquid preparations such as syrup, elixir etc.; When being used for administered parenterally, can be made into solution, water or the oiliness suspension agent etc. of injection.The various formulations of pharmaceutical composition of the present invention can be according to the conventional production method preparation of pharmaceutical field.Activeconstituents is mixed with one or more carriers, then be made into required formulation.
It is 0.1%～99.5% activeconstituents that pharmaceutical composition of the present invention preferably contains weight ratio, most preferably contains weight ratio and be 0.5%～95% activeconstituents.
The amount of application of the compounds of this invention can be according to variations such as the type of age of route of administration, patient, body weight, the disease for the treatment of and severity, and its per daily dose can be 0.01～10 mg/kg body weight, preferred 0.1～5 mg/kg body weight.Can use by one or many.
The excellent benefit of composite family type cyclic peptide extracting method of the present invention is, at first extract the separation thinking and have novelty, successfully utilize the chromatography technology that other small molecules are separated with composite family type cyclic peptide, obtain the comparatively cyclic peptide of purifying, the technical points such as recycling recrystallization are from the cyclic peptide that obtains purifying.Put it briefly, because the main chemical compositions of aster is terpene and glycoside thereof, in the cyclic peptide sepn process, have a large amount of terpenoids to disturb, especially triterpenoid saponin is usually mixed in together not easily separated with cyclic peptide.So at first utilize the molecular sieve principle of Sephadex LH-20, can separate the ter penoids that a part and cyclic peptide molecular weight differ greatly, the adsorption chromatography principle of recycling normal phase column chromatographic column, the success separation obtains containing the less cyclic peptide part of pigment, comprise that in conjunction with various chromatographic materials RP-18 and multiple separation means comprise recrystallization etc. again, separation and purification is to the cyclic peptide sterling.Secondly, only utilize the chromatographic material of laboratory or industrial routine, comprise positive reverse phase silica gel, Sephadex LH-20 etc., needn't use special chromatographic material such as aminopropyl key and silica gel, also avoid using the chromatographic materials such as the stronger activated carbon of adsorptivity and aluminum oxide; At last, in the sepn process of cyclic peptide must in conjunction with the TLC detection method of cyclic peptide (referring to Zhou Jun, Tan Ninghua, Science Bulletin, 2000,45(10), 1047-1051).In a word, extraction and separation method controllability of the present invention and favorable reproducibility, sample loss is few, and cost is lower, and is easy to operate, separablely obtains micro-cyclic peptide, and solvent can be recycled repeatedly, also is applicable to industrial production.
Description of drawings:
Fig. 1 is preparation method's schema of composite family type cyclic peptide compounds of the present invention;
Fig. 2 a is that composite family type cyclic peptide compounds Astin C of the present invention is to the effect of normal T cell proliferation; Fig. 2 b is that composite family type cyclic peptide compounds Astin C of the present invention is to the effect of activating T cell propagation;
The therapeutic action of Fig. 3 a, Fig. 3 b, Fig. 3 c mouse immune colitis experimental model that to be composite family type cyclic peptide compounds Astin C of the present invention cause trinitro-benzene-sulfonic acid.
Embodiment:
Below in conjunction with accompanying drawing, further specify essentiality content of the present invention with embodiments of the invention, but do not limit the present invention with this.Essence according to the present invention all belongs to scope of the present invention to the improvement that the present invention carries out.
Embodiment 1:
Composite family type cyclic peptide compounds Astin C(
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5) preparation and Tataricin A(
5) Structural Identification:
Get aster (
Aster tataricus. L) dry root and rhizome 50 Kg, after pulverizing with the first cold soaking of 90% industrial methanol 5 hours, post-heating refluxing extraction (temperature=65 ℃), extract altogether three times, 3 hours for the first time, 2 hours for the second time, 2 hours for the third time, united extraction liquid, underpressure distillation gets methanol extract totally 23 Kg after concentrating and removing organic solvent, and this crude extract is allocated in the water, fully extracts with ethyl acetate, propyl carbinol successively, equal-volume respectively extracts three times, reclaims solvent and obtains ethyl acetate part (2Kg), propyl carbinol part (5L) and water section; Ethyl acetate is partly used dissolve with methanol, and 2.5 Kg 100-200 order silica gel mixed samples are after sample drying is mixed by institute, sieve respectively with sieve aperture 40 orders and 80 purpose sieves, sieving on the rear sample, (the 200-300 order 10Kg), is used 100:0 to silicagel column, 9:1,8:2,7:3, the chloroform/methanol gradient elution of 0:100, thin-layer chromatography detects with the specific coloration method of cyclic peptide-triketohydrindene hydrate in-situ chemical reaction method.According to the result of cyclic peptide colour developing, merge the part that 9:1 and 8:1 contain cyclic peptide, altogether 1063g.Each following step all must be carried out separation and purification in conjunction with cyclic peptide TLC detection method.Medicinal extract after the merging is again through silica gel column chromatography, and 950g 100-200 order silica gel mixed sample with (20:1,10:1,85:15,8:2,0:1) chloroform/methanol gradient elution, is merged into eight components (Fr.1-Fr.8) according to the difference of cyclic peptide point; Fr.2(75 g) component is through silica gel column chromatography, and the sherwood oil of 2:1-1:2/acetone gradient elution merges and obtains six subfraction Fr.2-1 – Fr.2-6; Fr.2-5(4 g) again through silica gel column layer, 20:1,15:1,10:1, the chloroform/methanol gradient elution of 5:1, merging obtains five subfraction Fr.2-5-1 – Fr.2-5-5; Component Fr.2-5-1(1.5 g) reclaims solvent, obtain compd A stin D(behind the evaporate to dryness
3) (1 g).
Component Fr.3(55 g) through silica gel column chromatography, be that the eluent separation obtains two subfraction Fr.3-1 – Fr.3-2 with 1:1-1:2 sherwood oil/acetone; Fr.3-2(40 g wherein) component is again through silica gel column chromatography, is that eluent separates and obtains two component Fr.3-2-1 and Fr.3-2-2 with 1:3-1:5 chloroform/ethyl acetate; Fr.3-2-2(24 g) through Sephadex LH-20 chromatography, the chloroform/methanol of 1:1 is eluent, obtains the part of enrichment cyclic peptide.This part obtains compd A stin C(through recrystallizing methanol
1) (8 g).
Component Fr.4(85 g) through silica gel column chromatography, 1:1-1:2 sherwood oil/acetone carries out gradient elution, merges similar cyclic peptide point part, obtains two subfraction Fr.4-1 – Fr.4-2; Subfraction Fr.4-2(60 g) again through silica gel column chromatography, 2:1,1:1,1:2 sherwood oil/acetone carries out gradient elution, merges to obtain three subfraction Fr.4-2-1 – Fr.4-2-3; Fr.4-2-2(14 g wherein) carry out the cyclic peptide enrichment through Sephadex LH-20, the 1:1 chloroform/methanol is eluent, again through RP-18 column chromatography enrichment cyclic peptide, 30:70-80:20 methanol/water gradient elution; Behind Sephadex LH-20 and RP-18 enrichment cyclic peptide, component Fr.4-2-2 is again through silica gel column chromatography, 20:1, and 10:1, the 5:1 chloroform/methanol is that eluent carries out gradient elution, obtains four subfraction Fr.4-2-2-1 – Fr.4-2-2-4; Fr.4-2-2-2(4 g wherein) again through silica gel column chromatography 20:1,10:1, the 5:1 chloroform/methanol is that eluent carries out gradient elution, obtains five subfraction Fr.4-2-2-2-1 – Fr.4-2-2-2-5; Fr.4-2-2-2-4(210mg wherein) directly through Sephadex LH-20 purification enrichment cyclic peptide part, the 1:1 chloroform/methanol is eluent, merges the cyclic peptide part, reclaims solvent, and evaporate to dryness obtains compd A stin H(
4) (120 mg); Component Fr.4-2-2-4(1.5 g) through Sephadex LH-20 purification enrichment cyclic peptide part, the 1:1 chloroform/methanol is eluent, obtains two component Fr.4-2-2-4-1 – Fr.4-2-2-4-2; Component Fr.4-2-2-4-1(55 mg) reclaims solvent, obtain compound Tataricin A(behind the evaporate to dryness
5) (40 mg);
Fr.5(146 g) component is through silica gel column chromatography, 1:3-1:9 chloroform/ethyl acetate gradient elution, and with the enrichment of cyclic peptide part, this part is through Sephadex LH-20, and the 1:1 chloroform/methanol is eluent, obtains two component Fr.5-1 – Fr.5-2; Component Fr.5-2(50 g wherein) through silica gel column chromatography, the 15:1-3:1 chloroform/methanol is carried out gradient elution, obtains two component Fr.5-2-1 – Fr.5-2-2; Component Fr.5-2-1(17 g) reclaims solvent, obtain compd A stin B(behind the evaporate to dryness
2) (15 g).
R
1, R
2=aryl or alkyl
R
3, R
4, R
5=hydroxyl or halogen atom
X, Y=unsaturated link(age) or saturated bond
Tataricin A(
5) the Structural Identification data be:
Tataricin A(
5): clear crystal;
-23.2 (
c0.19, C
5H
5N); UV (MeOH)
λ Max(log e) 204 (4.26), 268 (4.20) nm; IR (KBr)
n Max3423,1660,1533,1409,1305,1149,1075,752,578 cm
-1;
1H NMR (DMSO-
d 6 , 600 MHz) and and
13C NMR (DMSO-
d 6 , 150 MHz), data see Table 1; Positive ESIMS
M/z514 (30) [M+H]
+; Positive HRESIMS
M/z[514.2295 M+H]
+(cacld for C
25H
32N
5O
7,514.2301).
Embodiment 2:
Composite family type cyclic peptide compounds Astin C(of the present invention
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5) the activating T cell proliferation experiment of inducing at Con A shows and suppress active.Experimental principle, method and result are as follows:
Experimental principle: the T lymphocyte of normal body is subject to specific antigens or mitotic division primary stimuli in Process of in vitro, a series of variations can occur for the metabolism of cell and form.Main manifestations is the change of electric charge, and cell volume increases, and metabolism is vigorous, and intracellular protein and nucleic acid are synthetic to increase (and can divide), and cellular form can be converted into lymphoblast, is the lymphocyte transformation phenomenon.For this reason, utilize various stimulants to excite lymphocyte external, can measure the lymphocytic answering of T (height of lymphocyte transformation rate can reflect the Cellular Immunity level) according to its transforming degree.This experimental applications Con A stimulates the T lymphocyte, then measures the cell survival amount with mtt assay.
Experimental technique: get 5 * 10
5The C57BL/6 mouse lymph nodal cell of cells/well places 96 well culture plates, and it is the Con A solution of 5 μ g/ml that medicine group and Control group add final concentration, puts 37 ℃, 5% CO
2In the incubator, cultivate 24 h.Adopt MTT to survey cell survival rate behind 24 h.The record result, take concentration as X-coordinate, the T cell survival rate is the ordinate zou curve plotting, the IC of computerized compound
50Value.
Experimental result:
Astin C(
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5) to normal T cell proliferation all without remarkable restraining effect, compd A stin C demonstrates certain restraining effect to activating T cell propagation, concrete IC
50See Table 1.
Experimental result shows: aster type cyclic peptide Astin C demonstrates certain restraining effect, IC to activating T cell propagation
50=12 μ M.When 20 μ M, inhibiting rate is near S-Neoral (CsA).Because the low cytotoxicity of aster cyclic peptide Astin C, thereby possesses the prospect that becomes new cyclic peptide immunosuppressor.
Embodiment 3:
Composite family type cyclic peptide compounds Astin C(of the present invention
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5) therapeutic action of mouse immune colitis that trinitro-benzene-sulfonic acid (TNBS) is caused.Experimental principle, method and result are as follows:
Experimental principle: inflammatory bowel mainly comprises ulcerative colitis and Crohn's disease, is a kind of repeatedly chronic nonspecific enteritis disease of outbreak, and the cause of disease that it is definite and pathogenesis are not clear so far, also lack safely and effectively medicine in the treatment.The mouse colitis that trinitro-benzene-sulfonic acid is induced is short because of its cycle, and method is easy, is the immunologic mechanism of the human inflammatory bowel of research and the ideal model of research and development anti-inflammatory new drug.
Experimental technique: got for 6 ~ 8 ages in week, the C57BL/6 female mice of 18 ~ 22 g carefully inserts colon with 3.5 F flexible pipes via anus, and depth of penetration is 4 cm approximately.With 1 mL disposable sterilized injector TNBS is injected colon through flexible pipe, every injected in mice TNBS dosage is 100 mg/kg, and solvent is 40% ethanol PBS solution, after the injection, mouse was stood upside down 30 seconds, spill to prevent TNBS, and make it to be distributed in whole colon, comprise caecum and appendix.The blank group is injected 100 μ L solvents (40% ethanol PBS solution) with identical method.From modeling same day, every day oral administration once, continue ten days, until experiment finishes.From modeling same day, weighing every day Mouse Weight, diarrhoea situation and the death condition of every group of mouse are observed and recorded to record compare increase or the reduction of modeling body weight on same day value simultaneously.After experiment finishes, put to death mouse and get colon, record each treated animal colon length and add up and observe its tissue pathologies change, get animal serum, measure the level of serum inflammatory cytokine.
Experimental result: Astin C(
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5) can alleviate alleviating of colitis mice body weight that TNBS induces; Improve the colitis mice survival rate that TNBS induces; Alleviate the colitis mice diarrhoea that TNBS induces; The oedema that alleviates TNBS colitis mice colon shortens; Reduce the lesion degree of TNBS colitis mice colon; The level that suppresses Th1 cytokine TNF-α in the TNBS colitis mice serum.
Experimental result shows, Astin C(
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5) mouse colitis tool that trinitro-benzene-sulfonic acid is caused has some improvement, and proves Astin C(
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5) can become a kind of neotype immunosuppressant for the treatment of inflammatory bowel.
Embodiment 4:
Embodiment 1 gained compd A stin C(
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5), the ethanol solution of sulfuric acid of adding 4%, PH=4 filters, and drying is made sulphate cpd
1-5
Embodiment 5:
Embodiment 1 gained compd A stin C(
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5), the hydrochloric acid soln of adding 4%, PH=4 filters, and drying is made hydrochloride compound
1-5
Embodiment 6:
Embodiment 1 gained compd A stin C(
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5), the tartaric acid solution of adding 4%, PH=4 filters, and drying is made the tartrate compound
1-5
Embodiment 7:
Embodiment 1 gained compd A stin C(
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5), the citric acid solution of adding 4%, PH=4 filters, and drying is made the Citrate trianion compound
1-5
Embodiment 8:
Tablet: with embodiment 1 gained compd A stin C(
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5) or salt 10 mg of embodiment 4-7 gained, lactose 180 mg, starch 55 mg, Magnesium Stearate 5 mg, lactose and starch are mixed, water evenly moistening, the mixture after moistening is sieved and drying, after sieve, add Magnesium Stearate, then with the mixture compressing tablet, every heavy 250 mg, compounds content is 10 mg.
Embodiment 9:
Ampulla: with embodiment 1 gained compd A stin C(
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5) or salt 2 mg of embodiment 4-7 gained, sodium-chlor 10 mg are dissolved in an amount of water for injection, filter gained solution, in the ampoule of packing under aseptic condition.
Embodiment 10:
Injection is freeze-dried: embodiment 1 gained compd A stin C(
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5) or salt 10 mg of embodiment 4-7 gained, sodium bicarbonate 2 mg, N.F,USP MANNITOL 252 mg.Preparation method: with sodium bicarbonate, N.F,USP MANNITOL, be dissolved in water for injection, add activated carbon adsorption 30 min depyrogenations, remove by filter activated carbon, add compound or its salt in filtrate, supersound process makes dissolving, regulating PH with 1 N hydrochloric acid is 5.0-7.0, millipore filtration filters, and injects water, packing, lyophilize, top plug rolls lid, and get final product.
Embodiment 11:
Capsule: embodiment 1 gained compd A stin C(
1), Astin B(
2), Astin D(
3), Astin H(
4), Tataricin A(
5) or the salt 10mg of embodiment 4-7 gained, lactose 187 mg, Magnesium Stearate 3mg; The preparation method: compound or its salt and solubility promoter is mixed, sieve, evenly mix, the mixture that the obtains hard gelatin capsule of packing into, each capsule weighs 200 mg, and active component content is 10 mg.
Claims (2)
1. take the composite family type cyclic peptide compounds Astin C(1 of following structural formula) or its pharmacology on the salt of allowing be the immunosuppressor of effective constituent,
The composite family type cyclic peptide compounds Astin C(1 in the claim 1) or the application of the salt of allowing on its pharmacology in the preparation immunosuppressor 2..
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110039063.4A CN102174083B (en) | 2011-02-16 | 2011-02-16 | Compositae cyclopeptide, immunosuppressive medicine using compositae cyclopeptide as active ingredient and preparation method and application of compositae cyclopeptide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110039063.4A CN102174083B (en) | 2011-02-16 | 2011-02-16 | Compositae cyclopeptide, immunosuppressive medicine using compositae cyclopeptide as active ingredient and preparation method and application of compositae cyclopeptide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102174083A CN102174083A (en) | 2011-09-07 |
| CN102174083B true CN102174083B (en) | 2013-03-06 |
Family
ID=44517368
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110039063.4A Expired - Fee Related CN102174083B (en) | 2011-02-16 | 2011-02-16 | Compositae cyclopeptide, immunosuppressive medicine using compositae cyclopeptide as active ingredient and preparation method and application of compositae cyclopeptide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102174083B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107335049B (en) * | 2017-08-18 | 2019-10-18 | 中国药科大学 | Application of the composite family type cyclic peptide compounds as cGAS-STING signal pathway inhibitor |
| CN110054665B (en) * | 2019-04-29 | 2022-08-26 | 湖南新汇制药股份有限公司 | Application of cyclic pentapeptide compound in preparation of immunosuppressant drug |
| CN110357864B (en) * | 2019-05-22 | 2022-06-14 | 中国科学院昆明植物研究所 | Pyrrole sesquiterpenoid compound and preparation method and application thereof |
-
2011
- 2011-02-16 CN CN201110039063.4A patent/CN102174083B/en not_active Expired - Fee Related
Non-Patent Citations (16)
| Title |
|---|
| Astins A and B, antitumor cyclic pentapeptides from Aster tataricus;Morita et al;《Chemical & Pharmaceutical Bulletin》;19931231;全文 * |
| Isolation and Structure of Asterin,A New Halogenated Cyclic Penta-Peptide from Aster tataricus;Seiji KOSEMURA;《Tetrahedron Letters》;19931231;第1291页第二段 * |
| Morita et al.Structure of a new peptide, astin J, from Aster tataricus..《Chemical & Pharmaceutical Bulletin》.1995, |
| Morita et al.Thionation of an antitumor cyclic pentapeptide, astin B, from Aster tataricus.《Bioorganic & Medicinal Chemistry Letters 》.1995, |
| Morita et al.Three novel cyclic pentapeptides, astins F, G and H from Aster tataricus.《Heterocycles 》.1994, |
| Morita et al.Two novel monochlorinated cyclic pentapeptides, astins D and E, from Aster tataricus.《Chemistry Letters》.1993, |
| Morita, Hiroshi.Structures and conformation of antitumor cyclic pentapeptides, astins A, B and C, from Aster tataricus.《Tetrahedron》.1995, |
| Moritaetal.AstinsAandB antitumor cyclic pentapeptides from Aster tataricus.《Chemical & Pharmaceutical Bulletin》.1993 |
| Ning-Hua Tan et al.Plant Cyclopeptides.《Chem.Rev.》.2006, |
| Plant Cyclopeptides;Ning-Hua Tan et al;《Chem.Rev.》;20060214;第858页 * |
| SeijiKOSEMURA.IsolationandStructureofAsterin A New Halogenated Cyclic Penta-Peptide from Aster tataricus.《Tetrahedron Letters》.1993 |
| Structure of a new peptide, astin J, from Aster tataricus.;Morita et al;《Chemical & Pharmaceutical Bulletin》;19951231;全文 * |
| Structures and conformation of antitumor cyclic pentapeptides, astins A, B and C, from Aster tataricus;Morita, Hiroshi;《Tetrahedron》;19951231;全文 * |
| Thionation of an antitumor cyclic pentapeptide, astin B, from Aster tataricus;Morita et al;《Bioorganic & Medicinal Chemistry Letters 》;19951231;全文 * |
| Three novel cyclic pentapeptides, astins F, G and H from Aster tataricus;Morita et al;《Heterocycles 》;19941231;全文 * |
| Two novel monochlorinated cyclic pentapeptides, astins D and E, from Aster tataricus;Morita et al;《Chemistry Letters》;19931231;全文 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102174083A (en) | 2011-09-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107335049B (en) | Application of the composite family type cyclic peptide compounds as cGAS-STING signal pathway inhibitor | |
| CN102174083B (en) | Compositae cyclopeptide, immunosuppressive medicine using compositae cyclopeptide as active ingredient and preparation method and application of compositae cyclopeptide | |
| CN104262465B (en) | Rubiaceae cyclopeptides used as TAK1 inhibitor and preparation method thereof | |
| CN103360456B (en) | Triterpene compound and Synthesis and applications | |
| CN111202737B (en) | Application of tripterine amide derivative in preparation of medicine for treating autoimmune diseases | |
| JP3128823B2 (en) | Anticancer compound and method for producing the same | |
| CN108659089B (en) | Sterol compound with antioxidant effect and application thereof in preparation of medicines | |
| CN108785316B (en) | Use of cortex Periplocae Radicis C21 steroids in preparation of IDO inhibitor | |
| JP2000154151A (en) | Immunosuppressant | |
| CN103145792A (en) | Shionone triterpenes as well as pharmaceutical compositions, preparation methods and applications of shionone triterpenes | |
| CN108635352A (en) | Magnoflorine is in the Use and preparation method for preparing prevention insomnia antidepressant agents | |
| CN108785322A (en) | Purposes of the Heiguteng exract C21 steroids in preparing IDO inhibitor | |
| CN108785317B (en) | Use of cortex Periplocae Radicis C21 steroid compound in preparation of IDO inhibitor | |
| CN102451220A (en) | Erythrophleum fordii Oliver extract, preparation method and pharmaceutical composition thereof and application | |
| CN108785319B (en) | Application of phenylpropanoid glycosides in preparation of IDO inhibitor | |
| CN103288914A (en) | Preparation method of traditional Chinese medicine manyflower tickclove herb extract and application in anti-senile dementia medicaments | |
| CN114394931B (en) | Monoterpene alkaloid with vasodilation activity and extraction method and application thereof | |
| JP7393457B2 (en) | Furan aspidospermine dimer or its pharmaceutically acceptable salt, its production method and application, and pharmaceutical composition | |
| CN108785321A (en) | Purposes of the Heiguteng exract C21 steroids in preparing IDO inhibitor | |
| CN115073463B (en) | Matrine type dimer alkaloid compound, pharmaceutical composition and application thereof | |
| CN110204477B (en) | Diterpene alkaloid with antioxidant effect and application thereof in preparation of medicines | |
| CN108785350B (en) | Use of cortex Periplocae Radicis extract in preparing IDO inhibitor | |
| JPH07179348A (en) | Cerebral function improver comprising sucrose acryl compound as active ingredient | |
| CN103450323A (en) | Radix ophiopogonis nerve growth factor activity simulating component and compound and preparation | |
| CN117682988A (en) | Wangzaozi B derivative, and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130306 Termination date: 20160216 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |