KR20220064719A - Novel lipopeptide compound, a preparing method, and a use thereof - Google Patents
Novel lipopeptide compound, a preparing method, and a use thereof Download PDFInfo
- Publication number
- KR20220064719A KR20220064719A KR1020200151116A KR20200151116A KR20220064719A KR 20220064719 A KR20220064719 A KR 20220064719A KR 1020200151116 A KR1020200151116 A KR 1020200151116A KR 20200151116 A KR20200151116 A KR 20200151116A KR 20220064719 A KR20220064719 A KR 20220064719A
- Authority
- KR
- South Korea
- Prior art keywords
- cancer
- solvate
- stereoisomer
- formula
- pharmaceutically acceptable
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 63
- 238000000034 method Methods 0.000 title claims description 14
- 108010028921 Lipopeptides Proteins 0.000 title abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 44
- 239000012453 solvate Substances 0.000 claims abstract description 40
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 23
- 201000011510 cancer Diseases 0.000 claims abstract description 23
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 241000187180 Streptomyces sp. Species 0.000 claims description 11
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 150000002430 hydrocarbons Chemical group 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- PMDCZENCAXMSOU-UHFFFAOYSA-N N-ethylacetamide Chemical group CCNC(C)=O PMDCZENCAXMSOU-UHFFFAOYSA-N 0.000 claims description 6
- 238000012258 culturing Methods 0.000 claims description 6
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 239000004471 Glycine Substances 0.000 claims description 5
- 206010017758 gastric cancer Diseases 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 229930195734 saturated hydrocarbon Natural products 0.000 claims description 5
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- QNJMAPUHMGDDBE-UHFFFAOYSA-N 9-methyldec-1-ene Chemical compound CC(C)CCCCCCC=C QNJMAPUHMGDDBE-UHFFFAOYSA-N 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims description 2
- 201000005787 hematologic cancer Diseases 0.000 claims description 2
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 2
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims 2
- 230000001093 anti-cancer Effects 0.000 abstract description 4
- 230000003013 cytotoxicity Effects 0.000 abstract description 3
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 16
- -1 antifungals Substances 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 13
- 239000002609 medium Substances 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- 239000004215 Carbon black (E152) Substances 0.000 description 8
- 229930195733 hydrocarbon Natural products 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 244000005700 microbiome Species 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 241000187747 Streptomyces Species 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 230000010261 cell growth Effects 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 208000003174 Brain Neoplasms Diseases 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 3
- 229960005420 etoposide Drugs 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000000366 juvenile effect Effects 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000012669 liquid formulation Substances 0.000 description 3
- SXQCTESRRZBPHJ-UHFFFAOYSA-M lissamine rhodamine Chemical compound [Na+].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S([O-])(=O)=O)C=C1S([O-])(=O)=O SXQCTESRRZBPHJ-UHFFFAOYSA-M 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 description 3
- 239000008158 vegetable oil Substances 0.000 description 3
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 2
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108010006654 Bleomycin Proteins 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- 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 2
- 101710204212 Neocarzinostatin Proteins 0.000 description 2
- 108010038807 Oligopeptides Proteins 0.000 description 2
- 102000015636 Oligopeptides Human genes 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 2
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- 229960001561 bleomycin Drugs 0.000 description 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 229930013356 epothilone Natural products 0.000 description 2
- 150000003883 epothilone derivatives Chemical class 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012091 fetal bovine serum 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
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000007857 hydrazones Chemical class 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 229960002340 pentostatin Drugs 0.000 description 2
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- JUJWROOIHBZHMG-RALIUCGRSA-N pyridine-d5 Chemical compound [2H]C1=NC([2H])=C([2H])C([2H])=C1[2H] JUJWROOIHBZHMG-RALIUCGRSA-N 0.000 description 2
- 206010038038 rectal cancer Diseases 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 125000000542 sulfonic acid group Chemical group 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 229950009268 zinostatin Drugs 0.000 description 2
- 108020004465 16S ribosomal RNA Proteins 0.000 description 1
- 125000003562 2,2-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003660 2,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 238000005084 2D-nuclear magnetic resonance Methods 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000186361 Actinobacteria <class> Species 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 229930183010 Amphotericin Natural products 0.000 description 1
- QGGFZZLFKABGNL-UHFFFAOYSA-N Amphotericin A Natural products OC1C(N)C(O)C(C)OC1OC1C=CC=CC=CC=CCCC=CC=CC(C)C(O)C(C)C(C)OC(=O)CC(O)CC(O)CCC(O)C(O)CC(O)CC(O)(CC(O)C2C(O)=O)OC2C1 QGGFZZLFKABGNL-UHFFFAOYSA-N 0.000 description 1
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 208000007860 Anus Neoplasms Diseases 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 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
- 229920002261 Corn starch Polymers 0.000 description 1
- 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 1
- 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 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
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 108010013198 Daptomycin Proteins 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 235000019733 Fish meal Nutrition 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical group [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 206010023825 Laryngeal cancer Diseases 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 208000004059 Male Breast Neoplasms Diseases 0.000 description 1
- 208000030070 Malignant epithelial tumor of ovary Diseases 0.000 description 1
- 208000032271 Malignant tumor of penis Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 208000007571 Ovarian Epithelial Carcinoma Diseases 0.000 description 1
- 206010061328 Ovarian epithelial cancer Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000000821 Parathyroid Neoplasms Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Natural products N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000004107 Penicillin G sodium Substances 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 description 1
- 206010034811 Pharyngeal cancer Diseases 0.000 description 1
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 1
- 201000005746 Pituitary adenoma Diseases 0.000 description 1
- 206010061538 Pituitary tumour benign Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 235000019764 Soybean Meal Nutrition 0.000 description 1
- 241000204060 Streptomycetaceae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 1
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 206010062129 Tongue neoplasm Diseases 0.000 description 1
- 206010044002 Tonsil cancer Diseases 0.000 description 1
- 208000006842 Tonsillar Neoplasms Diseases 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 208000023915 Ureteral Neoplasms Diseases 0.000 description 1
- 206010046392 Ureteric cancer Diseases 0.000 description 1
- 206010046431 Urethral cancer Diseases 0.000 description 1
- 206010046458 Urethral neoplasms Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 206010047741 Vulval cancer Diseases 0.000 description 1
- 208000004354 Vulvar Neoplasms Diseases 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 208000004064 acoustic neuroma Diseases 0.000 description 1
- 201000005188 adrenal gland cancer Diseases 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000004279 alanine Nutrition 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
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 229940009444 amphotericin Drugs 0.000 description 1
- 229960003942 amphotericin b Drugs 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000003926 antimycobacterial agent Substances 0.000 description 1
- 201000011165 anus cancer Diseases 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- FCPVYOBCFFNJFS-LQDWTQKMSA-M benzylpenicillin sodium Chemical compound [Na+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 FCPVYOBCFFNJFS-LQDWTQKMSA-M 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 201000009036 biliary tract cancer Diseases 0.000 description 1
- 208000020790 biliary tract neoplasm Diseases 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-M bromate Inorganic materials [O-]Br(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-M 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 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
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004113 cell culture Methods 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
- 238000005119 centrifugation Methods 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- MYPYJXKWCTUITO-KIIOPKALSA-N chembl3301825 Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)C(O)[C@H](C)O1 MYPYJXKWCTUITO-KIIOPKALSA-N 0.000 description 1
- 239000002962 chemical mutagen Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical compound C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 description 1
- 229960005484 daptomycin Drugs 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- VFNGKCDDZUSWLR-UHFFFAOYSA-L disulfate(2-) Chemical compound [O-]S(=O)(=O)OS([O-])(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-L 0.000 description 1
- 229950005627 embonate Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 208000024519 eye neoplasm Diseases 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000004467 fishmeal Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 208000010749 gastric carcinoma Diseases 0.000 description 1
- 201000011587 gastric lymphoma Diseases 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 150000002333 glycines Chemical group 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910001867 inorganic solvent Inorganic materials 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 201000007450 intrahepatic cholangiocarcinoma Diseases 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- VMPHSYLJUKZBJJ-UHFFFAOYSA-N lauric acid triglyceride Natural products CCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC)COC(=O)CCCCCCCCCCC VMPHSYLJUKZBJJ-UHFFFAOYSA-N 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 1
- 201000003175 male breast cancer Diseases 0.000 description 1
- 208000010907 male breast carcinoma Diseases 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
- 230000036210 malignancy Effects 0.000 description 1
- 208000006178 malignant mesothelioma Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 208000021644 malignant soft tissue neoplasm Diseases 0.000 description 1
- 208000026045 malignant tumor of parathyroid gland Diseases 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 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 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 235000013379 molasses Nutrition 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 239000003471 mutagenic agent Substances 0.000 description 1
- 231100000707 mutagenic chemical Toxicity 0.000 description 1
- 201000005962 mycosis fungoides Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 208000021284 ovarian germ cell tumor Diseases 0.000 description 1
- 229940039748 oxalate Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 238000004816 paper chromatography Methods 0.000 description 1
- 235000019369 penicillin G sodium Nutrition 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 201000002628 peritoneum cancer Diseases 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 208000021310 pituitary gland adenoma Diseases 0.000 description 1
- 238000001292 planar chromatography Methods 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 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
- 239000013641 positive control Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 208000020615 rectal carcinoma Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 201000002314 small intestine cancer Diseases 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000004455 soybean meal Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 206010062261 spinal cord neoplasm Diseases 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 159000000008 strontium salts Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 201000006134 tongue cancer Diseases 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
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 241001446247 uncultured actinomycete Species 0.000 description 1
- 201000011294 ureter cancer Diseases 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 208000037965 uterine sarcoma Diseases 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 201000005102 vulva cancer Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P21/00—Preparation of peptides or proteins
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
- C12R2001/465—Streptomyces
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biophysics (AREA)
- Tropical Medicine & Parasitology (AREA)
- Virology (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
신규한 지질펩티드 화합물, 이를 생산하는 방법, 및 이의 항암 용도에 관한 것이다.It relates to novel lipopeptide compounds, methods for their production, and their anti-cancer uses.
미생물로부터 유래한 생리 활성 물질은 대체로 항생제, 항진균, 항암제의 원천이었으며 이를 비롯한 다양한 질병 치료를 위한 신약으로 개발되거나 신약 개발의 바탕(template)이 되어 왔다. 미생물로부터 유래한 항생제는 예를 들면, 암포테리신(amphotericin), 에리트로마이신(erythromycin), 스트렙토마이신(streptomycin), 테트라사이클린(tetracycline), 및 반코마이신(vancomycin)이 대표적이다. 또한, 2003년에는 방선균인 스트렙토마이세스(Streptomyces)에서 분리된 댑토마이신(daptomycin)이 차세대 항생제로서 미국 식품의약안전청(FDA)의 승인을 받은 바 있다. 한편, 세균으로부터 유래한 항암제는 예를 들면, 독소루비신(doxorubicin), 블레오마이신(bleomycin), 미스라마이신(mithramycin), 네오카르지노스타틴(neocarzinostatin), 펜토스타틴(pentostatin), 및 에포틸론(epothilone)이 있다. 이와 같이, 세균 유래 생리 활성 물질의 연구는 항균제, 항진균제, 및 항암제 개발에서 매우 중요하다.Physiologically active substances derived from microorganisms have generally been the source of antibiotics, antifungals, and anticancer drugs, and have been developed as new drugs for the treatment of various diseases including these, or as a template for the development of new drugs. Antibiotics derived from microorganisms are representative of, for example, amphotericin, erythromycin, streptomycin, tetracycline, and vancomycin. Also, in 2003, daptomycin isolated from the actinomycete Streptomyces was approved by the US Food and Drug Administration (FDA) as a next-generation antibiotic. On the other hand, anticancer agents derived from bacteria, for example, doxorubicin (doxorubicin), bleomycin (bleomycin), misramycin (mithramycin), neocarzinostatin (neocarzinostatin), pentostatin (pentostatin), and epothilone (epothilone) There is this. As such, the study of bioactive substances derived from bacteria is very important in the development of antibacterial agents, antifungal agents, and anticancer agents.
구조적으로 기존의 물질과는 판이하게 다른 생리활성물질을 탐색하기 위하여 최근 천연물 연구 중 하나의 전략은 지리적, 계통분류학적으로 특이한 환경에서 천연물을 연구하는 것이다. 손쉽게 접근이 가능한 토양 서식 미생물이나 육상식물들은 오랜 기간에 걸쳐서 천연물 획득을 위하여 깊게 연구되었지만, 해양 기원의 미생물에 대한 연구는 상대적으로 활발하게 이루어지지 않았다. 해양은 지구 표면의 70%를 차지하고 있고 그 자체가 대부분 탐사되지 않은 기회의 공간으로 제시되고 있다. 해양 미생물은 그 다양성에 대하여 정확하게 파악되지 않고 있지만 현재까지 해양 미생물 중 단지 1%만이 배양되거나 동정된 것으로 추정될 정도로 이 분야의 연구가 미진한 상황이다.In order to search for physiologically active substances that are structurally different from existing substances, one of the recent natural product research strategies is to study natural products in a geographically and phylogenetically unique environment. Although easily accessible soil-dwelling microorganisms and terrestrial plants have been studied in depth to acquire natural products over a long period of time, studies on microorganisms of marine origin have not been conducted relatively actively. The ocean occupies 70% of the Earth's surface and is presented as a space of opportunity that is largely unexplored. Although the diversity of marine microorganisms is not accurately understood, research in this field is insufficient so far that only 1% of marine microorganisms have been cultured or identified.
따라서, 구조적으로 새로운 항생제 및 항암제의 개발을 위하여, 유용한 생리 활성 물질을 생산하는 해양 미생물을 선별하고, 이들이 생산하는 신규 화합물을 탐색, 발굴하는 것이 필요하다.Therefore, for the development of structurally novel antibiotics and anticancer drugs, it is necessary to select marine microorganisms that produce useful physiologically active substances, and to search for and discover new compounds produced by them.
지질펩티드 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 제공한다.Provided are lipopeptide compounds, stereoisomers, solvates, or pharmaceutically acceptable salts thereof.
지질펩티드 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 생산하는 세균을 제공한다.Bacteria that produce lipopeptide compounds, stereoisomers, solvates, or pharmaceutically acceptable salts thereof are provided.
지질펩티드 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 생한하는 방법을 제공한다.A method for producing a lipopeptide compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof is provided.
지질펩티드 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 포함하는 암 예방 또는 치료용 약학적 조성물을 제공한다.Provided is a pharmaceutical composition for preventing or treating cancer comprising a lipopeptide compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
지질펩티드 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 이용하여 암을 예방 또는 치료하는 방법을 제공한다.Provided is a method for preventing or treating cancer using a lipopeptide compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
일 양상은 식 1로 표시되는 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 제공한다:One aspect provides a compound represented by Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof:
[식 1][Equation 1]
R1-(C=O)-Ser-Thr-Ala-Thr-Pro-Gly-X-Ala-Leu-Ser-R2.R 1 -(C=O)-Ser-Thr-Ala-Thr-Pro-Gly-X-Ala-Leu-Ser-R 2 .
상기 식 1에서, C=O는 1개의 산소 원자에 이중결합된 1개의 탄소원자로 이루어진 기능기 즉, 카르보닐(carbonyl)기를 의미한다.In Formula 1, C=O means a functional group consisting of one carbon atom double bonded to one oxygen atom, that is, a carbonyl group.
상기 식 1에서, Ser은 세린(Serine: S)을 의미한다. Thr은 트레오닌(Shreonine: T)을 의미한다. Ala은 알라닌(Alanine: A)을 의미한다. Pro은 프롤린(Proline: P)을 의미한다. Gly은 글리신(Glycine: G)을 의미한다. Leu은 류신(Leucine: L)을 의미한다.In Formula 1, Ser means serine (S). Thr stands for threonine (T). Ala means Alanine (A). Pro stands for Proline (P). Gly means glycine (G). Leu means leucine (L).
상기 식 1에서, X는 C1 내지 C10 알킬아세트아미드로 치환된 글리신(Glyine; Gly 또는 G)일 수 있다. 상기 C1 내지 C10 알킬아세트아미드는 C1 내지 C5 알킬아세트아미드일 수 있다. 상기 C1 내지 C10 알킬아세트아미드는 n-에틸아세트아미드(ethylacetmaide)일 수 있다. 상기 X는 n-에틸아세트아미드로 치환된 글리신일 수 있다.In Formula 1, X may be glycine (Glyine; Gly or G) substituted with C 1 to C 10 alkylacetamide. The C 1 to C 10 alkylacetamide may be a C 1 to C 5 alkylacetamide. The C 1 to C 10 alkylacetamide may be n-ethylacetamide (ethylacetmaide). X may be glycine substituted with n-ethylacetamide.
상기 식 1에서, R1은 포화 또는 불포화된 탄화수소 사슬일 수 있다. 용어 "탄화수소(hydrocarbon)"는 탄소와 수소로 이루어진 유기 화합물을 말한다. 상기 탄화수소는 지방족 포화 탄화수소, 지방족 불포화 탄화수소, 지방족 고리 탄화수소, 또는 방향족 탄화수소일 수 있다. 상기 포화 탄화수소는 단일 결합으로 구성된 탄화수소를 말한다. 상기 불포화 탄화수소는 하나 이상의 이중결합 또는 삼중 결합을 포함하는 탄화수소를 말한다. 상기 R1은 치환 또는 비치환된 C1 내지 C30의 알킬기, 치환 또는 비치환된 C2 내지 C30의 알케닐기, 치환 또는 비치환된 C2 내지 C30의 알키닐기, 또는 이들의 조합으로부터 선택될 수 있다. 상기 R1은 C1 내지 C10의 알킬기(예, 메틸기)로 치환된(즉, 분지된) 것일 수 있다. 상기 R1은 1개 이상의 알케닐기를 포함하는 C1 내지 C30의 알킬기일 수 있다. 상기 R1은 9-메틸-1-데센(9-methyl-1-decene)일 수 있다.In Formula 1, R 1 may be a saturated or unsaturated hydrocarbon chain. The term “hydrocarbon” refers to an organic compound composed of carbon and hydrogen. The hydrocarbon may be an aliphatic saturated hydrocarbon, an aliphatic unsaturated hydrocarbon, an alicyclic hydrocarbon, or an aromatic hydrocarbon. The saturated hydrocarbon refers to a hydrocarbon composed of a single bond. The unsaturated hydrocarbon refers to a hydrocarbon containing one or more double bonds or triple bonds. Wherein R 1 is a substituted or unsubstituted C 1 to C 30 alkyl group, a substituted or unsubstituted C 2 to C 30 alkenyl group, a substituted or unsubstituted C 2 to C 30 alkynyl group, or a combination thereof can be selected. The R 1 may be substituted (ie, branched) with a C 1 to C 10 alkyl group (eg, a methyl group). The R 1 may be a C 1 to C 30 alkyl group including one or more alkenyl groups. The R 1 may be 9-methyl-1-decene.
상기 식 1에서, R2는 없거나, 또는 치환 또는 비치환된 C1 내지 C20 알킬기, 치환 또는 비치환된 C1 내지 C20 알케닐기, 또는 치환 또는 비치환된 C1 내지 C20 알키닐기일 수 있다. 상기 R2가 없는 경우, 식 1 중 Ser-R2는 세린일 수 있다. 상기 R2는 치환 또는 비치환된 C1 내지 C20 알킬기일 수 있다. 상기 R2는 메틸기일 수 있다.In Formula 1, R 2 is absent, or a substituted or unsubstituted C 1 to C 20 alkyl group, a substituted or unsubstituted C 1 to C 20 alkenyl group, or a substituted or unsubstituted C 1 to C 20 alkynyl group can In the absence of R 2 , Ser-R 2 in Formula 1 may be serine. The R 2 may be a substituted or unsubstituted C 1 to C 20 alkyl group. The R 2 may be a methyl group.
상기 화합물은 지질펩티드(lipopeptide) 화합물 또는 리포펩티드로 불릴 수 있다. 용어 "지질펩티드(lipopeptide)"는 펩티드에 접합된 지질을 포함하는 물질을 말한다. 상기 지질펩티드의 지질은 포화 또는 불포화된 탄화수소일 수 있다. 상기 지질은 아실(acyl) 기 또는 아실 사슬일 수 있다. 상기 지질펩티드의 펩티드는 펩티드(peptide)는 두개 이상의 아미노산이 카르복시기와 아미노기 간의 펩티드 결합으로 연결된 형태의 화합물이다. 구성 아미노산의 수에 따라 디펩티드(dipeptide), 트리펩티드(tripeptide), 테트라펩티드(tetrapeptide) 등이라 하고, 약 10개 이하의 펩티드 결합이 있는 것을 올리고펩티드(oligopeptide), 다수의 펩티드 결합이 있는 것을 폴리펩티드(polypeptide)라고 한다. 상기 펩티드는 2개 내지 50개, 2개 내지 40개, 2개 내지 30개, 2개 내지 20개, 또는 2개 내지 10개의 아미노산을 포함할 수 있다. 상기 아미노산은 할로겐 원자, 히드록시기, 니트로기, 시아노기, 아민기, 아미디노기, 아세트아미노기, 히드라진, 히드라존, 카르복실기, 술포닐기, 술파모일(sulfamoyl)기, 술폰산기, 인산, C1 내지 C10의 알킬기, C1 내지 C10의 알콕시기, C2 내지 C10의 알케닐기, C2 내지 C10의 알키닐기, C3 내지 C10의 시클로알킬기, C6 내지 C10의 아릴기, C6 내지 C10의 헤테로아릴기, C6 내지 C20의 아릴알킬기, C6 내지 C20의 헤테로아릴알킬기, 또는 이들의 조합으로 치환될 수 있다.The compound may be referred to as a lipopeptide compound or a lipopeptide. The term “lipopeptide” refers to a substance comprising a lipid conjugated to a peptide. The lipid of the lipopeptide may be a saturated or unsaturated hydrocarbon. The lipid may be an acyl group or an acyl chain. The peptide of the lipopeptide is a compound in which two or more amino acids are linked by a peptide bond between a carboxyl group and an amino group. Depending on the number of constituent amino acids, they are called dipeptide, tripeptide, tetrapeptide, etc., and those with about 10 or less peptide bonds are called oligopeptides, and those with multiple peptide bonds are called oligopeptides. It is called a polypeptide. The peptide may comprise 2 to 50, 2 to 40, 2 to 30, 2 to 20, or 2 to 10 amino acids. The amino acid is a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amine group, an amidino group, an acetamino group, hydrazine, hydrazone, a carboxyl group, a sulfonyl group, a sulfamoyl group, a sulfonic acid group, phosphoric acid, C 1 to C 10 Alkyl group, C 1 To C 10 Alkoxy group, C 2 To C 10 Alkenyl group, C 2 To C 10 Alkynyl group, C 3 To C 10 Cycloalkyl group, C 6 To C 10 Aryl group, C It may be substituted with a 6 to C 10 heteroaryl group, a C 6 to C 20 arylalkyl group, a C 6 to C 20 heteroarylalkyl group, or a combination thereof.
상기 화합물은 상기 식 1로 표시되는 화합물의 유도체를 포함한다. 용어 "유도체(derivative)"는 상기 화합물의 구조 일부를 다른 원자나 원자단으로 치환하여 얻어지는 화합물을 말한다.The compound includes a derivative of the compound represented by Formula 1 above. The term "derivative" refers to a compound obtained by substituting another atom or group of atoms for a part of the structure of the compound.
상기 식 1로 표시되는 화합물은 식 2 또는 식 3으로 표시되는 화합물 일 수 있다:The compound represented by Formula 1 may be a compound represented by Formula 2 or Formula 3:
[식 2][Equation 2]
; 및 ; and
[식 3][Equation 3]
. .
상기 식 1로 표시되는 화합물은 식 4 또는 식 5로 표시되는 화합물 일 수 있다:The compound represented by Formula 1 may be a compound represented by Formula 4 or Formula 5:
[식 4][Equation 4]
; 및 ; and
[식 5][Equation 5]
. .
상기 "비치환" 또는 "치환"에서의 용어 "치환"은 유기 화합물 중의 하나 이상의 수소 원자를 다른 원자단으로 치환하여 유도체를 형성한 경우 수소 원자 대신에 도입되는 것을 말하고, 치환기는 도입된 원자단을 말한다. 상기 치환기는 할로겐 원자, 히드록시기, 니트로기, 시아노기, 아민기, 아미디노기, 아세트아미노기, 히드라진, 히드라존, 카르복실기, 술포닐기, 술파모일(sulfamoyl)기, 술폰산기, 인산, C1 내지 C10의 알킬기, C1 내지 C10의 알콕시기, C2 내지 C10의 알케닐기, C2 내지 C10의 알키닐기, C3 내지 C10의 시클로알킬기, C6 내지 C10의 아릴기, C6 내지 C10의 헤테로아릴기, C6 내지 C20의 아릴알킬기, C6 내지 C20의 헤테로아릴알킬기, 또는 이들의 조합일 수 있다.The term "substitution" in the above "unsubstituted" or "substituted" refers to introduced instead of a hydrogen atom when a derivative is formed by substituting one or more hydrogen atoms in an organic compound with another atomic group, and the substituent refers to an introduced atomic group . The substituent is a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amine group, an amidino group, an acetamino group, hydrazine, hydrazone, a carboxyl group, a sulfonyl group, a sulfamoyl group, a sulfonic acid group, phosphoric acid, C 1 to C 10 Alkyl group, C 1 To C 10 Alkoxy group, C 2 To C 10 Alkenyl group, C 2 To C 10 Alkynyl group, C 3 To C 10 Cycloalkyl group, C 6 To C 10 Aryl group, C It may be a 6 to C 10 heteroaryl group, a C 6 to C 20 arylalkyl group, a C 6 to C 20 heteroarylalkyl group, or a combination thereof.
용어 "알킬(alkyl)"은 완전 포화된 분지형 또는 비분지형 (또는, 직쇄 또는 선형) 탄화수소를 말한다. 상기 알킬은 C1 내지 C30, C1 내지 C20, C1 내지 C15, C1 내지 C10, 또는 C1 내지 C5인 알킬기일 수 있다. 상기 알킬은 예를 들어, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, 2차 부틸(sec-butyl), n-펜틸, 이소펜틸, 네오펜틸, iso-아밀, n-헥실, 3-메틸헥실, 2,2-디메틸펜틸, 2,3-디메틸펜틸, 또는 n-헵틸이다.The term “alkyl” refers to a fully saturated branched or unbranched (or straight chain or linear) hydrocarbon. The alkyl is C 1 to C 30 , C 1 to C 20 , C 1 to C 15 , C 1 to C 10 , or C 1 to C 5 It may be an alkyl group. The alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, iso-amyl, n- hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, or n-heptyl.
용어 "알케닐(alkenyl)"은 하나 이상의 탄소-탄소 이중결합을 갖는 분지형 또는 비분지형 탄화수소를 말한다. 상기 알케닐기는 C2 내지 C30, C2 내지 C20, C2 내지 C15, C2 내지 C10, 또는 C2 내지 C5인 알케닐기일 수 있다. 상기 알케닐기는 예를 들어, 비닐, 알릴, 부테닐, 이소프로페닐, 또는 이소부테닐이다.The term “alkenyl” refers to a branched or unbranched hydrocarbon having one or more carbon-carbon double bonds. The alkenyl group may be a C 2 to C 30 , C 2 to C 20 , C 2 to C 15 , C 2 to C 10 , or C 2 to C 5 alkenyl group. The alkenyl group is, for example, vinyl, allyl, butenyl, isopropenyl, or isobutenyl.
용어 "알키닐(alkynyl)"은 적어도 하나의 탄소-탄소 삼중결합을 갖는 분지형 또는 비분지형 탄화수소를 말한다. 상기 알키닐기는 C2 내지 C30, C2 내지 C20, C2 내지 C15, C2 내지 C10, 또는 C2 내지 C5인 알키닐기일 수 있다. 상기 알키닐은 예를 들어, 에티닐, 부티닐, 이소부티닐, 또는 이소프로피닐이다.The term "alkynyl" refers to a branched or unbranched hydrocarbon having at least one carbon-carbon triple bond. The alkynyl group may be a C 2 to C 30 , C 2 to C 20 , C 2 to C 15 , C 2 to C 10 , or C 2 to C 5 alkynyl group. The alkynyl is, for example, ethynyl, butynyl, isobutynyl, or isopropynyl.
상기 알킬아세트아미드 중 아세트아미드(acetamide)는 에탄아미드(ethanamide)로도 불릴 수 있다. 상기 아세트아미드는 CH3CONH-일 수 있다.Among the alkylacetamides, acetamide may also be referred to as ethanamide. The acetamide may be CH 3 CONH-.
용어 "할로겐(halogen)" 원자는 주기율표의 17족에 속하는 원자를 말한다. 할로겐 원자는 불소, 브롬, 염소, 요오드 등을 포함한다.The term "halogen" atom refers to an atom belonging to group 17 of the periodic table. Halogen atoms include fluorine, bromine, chlorine, iodine and the like.
용어 "히드록시(hydroxy)"는 -OH 기능기(수산기)를 말한다. 상기 히드록시알킬기는 히드록시기로 치환된 알킬기일 수 있다.The term "hydroxy" refers to a -OH functional group (hydroxyl group). The hydroxyalkyl group may be an alkyl group substituted with a hydroxy group.
용어 "시아노(cyano)"는 탄소 원자와 질소 원자 사이에 삼중결합으로 이루어진 기능기를 말한다.The term "cyano" refers to a functional group consisting of a triple bond between a carbon atom and a nitrogen atom.
용어 "아민(amine)"은 암모니아(NH3)에서 하나 이상의 수소가 알킬 또는 방향족 고리로 치환된 기능기를 말한다. 상기 아민기는 예를 들어, 아미노기(-NH2) 및 알킬아민기(alkylamine)일 수 있다.The term “amine” refers to a functional group in which one or more hydrogens are substituted with an alkyl or aromatic ring in ammonia (NH 3 ). The amine group may be, for example, an amino group (—NH 2 ) and an alkylamine group.
용어 "알콕시(alkoxy)"는 산소 원자에 단일 결합된 알킬을 말한다. 상기 알콕시는 예를 들어 메톡시, 에톡시, 또는 부톡시이다.The term “alkoxy” refers to an alkyl single bonded to an oxygen atom. Said alkoxy is, for example, methoxy, ethoxy, or butoxy.
용어 "시클로알킬(cycloalkyl)"는 포화 또는 부분적으로 불포화된 비방향족(non-aromatic) 모노시클릭, 바이시클릭 또는 트리시클릭 탄화수소기를 말한다.The term “cycloalkyl” refers to a saturated or partially unsaturated non-aromatic monocyclic, bicyclic or tricyclic hydrocarbon group.
용어 "아릴(aryl)"은 단독 또는 조합하여 사용되어, 하나 이상의 고리를 포함하는 방향족 시스템을 말하고, 방향족 고리가 하나 이상의 탄소 고리에 융합된 그룹도 포함한다. 상기 C6 내지 C30의 아릴기는 C6 내지 C15, 또는 C6 내지 C10인 아릴기일 수 있다. 상기 아릴은 예를 들어, 페닐, 나프틸, 또는 테트라히드로나프틸이다.The term "aryl", used alone or in combination, refers to an aromatic system comprising one or more rings, including groups in which the aromatic ring is fused to one or more carbon rings. The C 6 to C 30 aryl group may be a C 6 to C 15 , or C 6 to C 10 aryl group. The aryl is, for example, phenyl, naphthyl, or tetrahydronaphthyl.
용어 "헤테로아릴(heteroaryl)"은 N, O, P 및 S로 이루어진 군으로부터 선택된 하나 이상의 헤테로원자를 포함하고, 나머지 고리원자가 탄소인 모노시클릭(monocyclic) 또는 바이시클릭(bicyclic) 유기 화합물을 말한다. 상기 헤테로아릴기는 1 내지 5개의 헤테로원자를 포함할 수 있고, 5 내지 10 고리 멤버(ring member)를 포함할 수 있다. 상기 S 또는 N은 산화되어 여러 산화 상태를 가질 수 있다.The term "heteroaryl" refers to a monocyclic or bicyclic organic compound containing one or more heteroatoms selected from the group consisting of N, O, P and S, and the remaining ring atoms are carbon. say The heteroaryl group may include 1 to 5 heteroatoms, and 5 to 10 ring members. The S or N may be oxidized to have several oxidation states.
용어 "입체이성질체"의 "이성질체(isomer)"는 분자식은 같지만 분자 내에 있는 구성 원자의 연결 방식이나 공간 배열이 동일하지 않은 화합물을 말한다. 이성질체는 예를 들면, 구조 이성질체(structural isomers), 및 입체이성질체(stereoisomer)를 포함한다. 상기 입체이성질체는 부분입체 이성질체(diasteromer) 또는 거울상이성질체(enantiomer)일 수 있다. 거울상이성질체는 왼손과 오른손의 관계처럼 그 거울상과 겹쳐지지 않는 이성질체를 말하고, 광학 이성질체(optical isomer)라고도 한다. 거울상 이성질체는 키랄 중심 탄소에 4개 이상의 치환기가 서로 다른 경우 R(Rectus: 시계 방향) 및 S(Sinister: 반시계 방향)로 구분한다. 부분입체이성질체는 거울상 관계가 아닌 입체 이성질체를 말하고, 원자의 공간 배열이 달라 생기는 이성질체이다. 상기 부분입체이성질체는 시스(cis)-트랜스(trans) 이성질체 및 형태 이성질체(conformational isomer 또는 conformer) 로 나뉠 수 있다.The term "isomer" of the term "stereoisomer" refers to a compound that has the same molecular formula but does not have the same spatial arrangement or connection mode of constituent atoms in the molecule. Isomers include, for example, structural isomers, and stereoisomers. The stereoisomer may be a diasteromer or an enantiomer. An enantiomer refers to an isomer that does not overlap its mirror image as in the relationship between the left hand and the right hand, and is also called an optical isomer. Enantiomers are divided into R (Rectus: clockwise) and S (Sinister: counterclockwise) when four or more substituents differ from each other at the chiral central carbon. Diastereomers refer to stereoisomers that are not in a mirror image relationship, and are isomers resulting from a different spatial arrangement of atoms. The diastereomers may be divided into cis-trans isomers and conformational isomers or conformers.
용어 "용매화물(solvate)"은 유기 또는 무기 용매에 용매화된 화합물을 말한다. 상기 용매화물은 예를 들어 수화물이다.The term “solvate” refers to a compound solvated in an organic or inorganic solvent. The solvate is, for example, a hydrate.
용어 "염(salt)"은 화합물의 무기 및 유기산 부가염을 말한다. 상기 약학적으로 허용가능한 염은 화합물이 투여되는 유기체에 심각한 자극을 유발하지 않고 화합물의 생물학적 활성과 물성들을 손상시키지 않는 염일 수 있다. 상기 무기산염은 염산염, 브롬산염, 인산염, 황산염, 또는 이황산염일 수 있다. 상기 유기산염은 포름산염, 아세트산염, 프로피온산염, 젖산염, 옥살산염, 주석산염, 말산염, 말레인산염, 구연산염, 푸마르산염, 베실산염, 캠실산염, 에디실염, 트리클로로아세트산, 트리플루오로아세트산염, 벤조산염, 글루콘산염, 메탄술폰산염, 글리콜산염, 숙신산염, 4-톨루엔술폰산염, 갈룩투론산염, 엠본산염, 글루탐산염, 에탄술폰산염, 벤젠술폰산염, p-톨루엔술폰산염, 또는 아스파르트산염일 수 있다. 상기 금속염은 칼슘염, 나트륨염, 마그네슘염, 스트론튬염, 또는 칼륨염일 수 있다.The term "salt" refers to the inorganic and organic acid addition salts of compounds. The pharmaceutically acceptable salt may be a salt that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound. The inorganic acid salt may be hydrochloride, bromate, phosphate, sulfate, or disulfate. The organic acid salt is formate, acetate, propionate, lactate, oxalate, tartrate, malate, maleate, citrate, fumarate, besylate, camsylate, edicyl salt, trichloroacetic acid, trifluoroacetate , benzoate, gluconate, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, galacturonate, embonate, glutamate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or aspartate It may be an acid. The metal salt may be a calcium salt, a sodium salt, a magnesium salt, a strontium salt, or a potassium salt.
다른 양상은 일 양상에 따른 식 1로 표시되는 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 생산하는 스트렙토마이세스 속(Streptomyces sp.) AMD43 균주(수탁번호: KCTC14317BP)를 제공한다.Another aspect provides a Streptomyces sp. AMD43 strain (Accession No.: KCTC14317BP) for producing a compound represented by Formula 1 according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof do.
식 1로 표시되는 화합물, 입체이성질체, 용매화물, 및 염은 전술한 바와 같다.The compound, stereoisomer, solvate, and salt represented by Formula 1 are as described above.
스트렙토마이세스 속(Streptomyces sp.) AMD43 균주(수탁번호: KCTC14317BP)는 해양 유래 세균일 수 있다. 상기 스트렙토마이세스 속(Streptomyces sp.) 세균은 방선균과(Streptomycetaceae)에 속하는 그람양성(Gram-positive) 세균이다. Streptomyces sp. AMD43 strain (accession number: KCTC14317BP) may be a marine-derived bacterium. The Streptomyces genus ( Streptomyces sp.) bacteria are Gram-positive bacteria belonging to the Actinomycetes family (Streptomycetaceae).
상기 균주는 일 양상에 따른 식 1로 표시되는 화합물, 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 생산할 수 있다.The strain may produce a compound represented by Formula 1 according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt.
상기 균주는 그의 변이체를 포함한다. 변이체는 예를 들면, 자연 돌연변이 또는 인위적 돌연변이에 의해 생긴 변이체일 수 있다. 인위적 돌연변이는 자외선 등 물리적 돌연변이원, 또는 염기 화합물 등 화학적 돌연변이원에 의해 발생할 수 있다.The strain includes variants thereof. A variant may be, for example, a variant caused by natural mutation or artificial mutation. Artificial mutations may be caused by physical mutagens such as ultraviolet rays, or chemical mutagens such as basic compounds.
상기 균주는 균주의 포자, 균체, 또는 이것의 배양물을 포함한다.The strain includes spores, cells, or cultures of the strain.
다른 양상은 스트렙토마이세스 속(Streptomyces sp.) AMD43 균주(수탁번호: KCTC14317BP)를 배양하는 단계; 및Another aspect is Streptomyces genus ( Streptomyces sp.) culturing the AMD43 strain (Accession Number: KCTC14317BP); and
상기 균주를 배양한 배양액으로부터 일 양상에 따른 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 분리하는 단계를 포함하는, 일 양상에 따른 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 생산하는 방법을 제공한다.A compound according to an aspect, comprising the step of isolating a compound according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof from the culture medium in which the strain is cultured, a stereoisomer thereof, a solvate, or a pharmaceutical Provided is a method for producing a chemically acceptable salt.
스트렙토마이세스 속(Streptomyces sp.) AMD43 균주, 식 1로 표시되는 화합물, 입체이성질체, 용매화물, 및 염은 전술한 바와 같다. Streptomyces sp. AMD43 strain, the compound represented by Formula 1, stereoisomers, solvates, and salts are as described above.
상기 방법은 스트렙토마이세스 속(Streptomyces sp.) AMD43 균주(수탁번호: KCTC14317BP)를 배양하는 단계를 포함한다. 배양하는 단계는 액체 배지 또는 고체 배지에서 균주를 배양하는 것일 수 있다. 배지는 탄소원으로서 예를 들면, 포도당, 물엿, 덱스트린, 전분, 당밀, 동물유, 또는 식물유를 포함할 수 있다. 배지는 질소원으로서 예를 들면, 밀기울, 대두박, 소맥, 맥아, 면실박, 어박, 콘스팁리커, 육즙, 효모 추출물, 맥아 추출물, 황산암모늄, 질산소다, 또는 요소를 포함할 수 있다.The method includes the step of culturing Streptomyces sp. AMD43 strain (accession number: KCTC14317BP). The culturing step may be culturing the strain in a liquid medium or a solid medium. The medium may contain, for example, glucose, starch syrup, dextrin, starch, molasses, animal oil, or vegetable oil as a carbon source. The medium may contain, for example, bran, soybean meal, wheat, malt, cottonseed meal, fish meal, cornstarch, broth, yeast extract, malt extract, ammonium sulfate, sodium nitrate, or urea as a nitrogen source.
배양은 호기성 조건에서 진탕 또는 정치하면서 배양하는 것일 수 있다. 배양 온도는 예를 들어 약 20℃ 내지 약 40℃, 약 25℃ 내지 약 37℃, 약 28℃ 내지 약 35℃, 또는 약 30℃일 수 있다. 배양 시간은 예를 들어 약 1일 내지 약 4개월, 약 1일 내지 약 2개월, 약 1일 내지 약 6주, 약 1일 내지 약 1개월, 약 1일 내지 약 2주, 또는 약 1일 내지 약 1주일 수 있다.The culture may be cultured while shaking or standing still under aerobic conditions. The incubation temperature may be, for example, from about 20°C to about 40°C, from about 25°C to about 37°C, from about 28°C to about 35°C, or about 30°C. The incubation time may be, for example, from about 1 day to about 4 months, from about 1 day to about 2 months, from about 1 day to about 6 weeks, from about 1 day to about 1 month, from about 1 day to about 2 weeks, or about 1 day. to about 1 week.
상기 방법은 배양액으로부터 식 1로 표시되는 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 분리하는 단계를 포함한다.The method includes isolating the compound represented by Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof from the culture solution.
분리하는 단계는 배양액을 농축, 원심분리, 여과, 또는 크로마토그래피를 수행하는 단계를 포함할 수 있다. 크로마토그래피는 예를 들면, 정지상의 형태에 따라 컬럼 크로마토그래피, 평판 크로마토그래피(planar chromatography), 종이 크로마토그래피 또는 얇은 막 크로마토그래피일 수 있다. 크로마토그래피는 예를 들면, 이동상의 물리적 특성에 따라, 기체 크로마토그래피, 액체 크로마토그래피, 또는 친화 크로마토그래피일 수 있다. 액체 크로마토그래피는 예를 들면 고성능 액체 크로마토그래피(HPLC)일 수 있다. 크로마토그래피는 예를 들면, 분리 방법에 따라, 이온 교환 크로마토그래피, 크기-배제 크로마토그래피일 수 있다. 크로마토그래피는 예를 들면, 정상 크로마토그래피 또는 역상 크로마토그래피일 수 있다.Separation may include performing concentration, centrifugation, filtration, or chromatography of the culture solution. The chromatography may be, for example, column chromatography, planar chromatography, paper chromatography or thin film chromatography depending on the type of stationary phase. The chromatography may be, for example, gas chromatography, liquid chromatography, or affinity chromatography, depending on the physical properties of the mobile phase. The liquid chromatography may be, for example, high performance liquid chromatography (HPLC). The chromatography may be, for example, ion exchange chromatography, size-exclusion chromatography, depending on the separation method. The chromatography may be, for example, normal phase chromatography or reverse phase chromatography.
다른 양상은 일 양상에 따른 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 포함하는 암 예방 또는 치료용 약학적 조성물을 제공한다.Another aspect provides a pharmaceutical composition for preventing or treating cancer, comprising the compound according to the aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
식 1로 표시되는 화합물, 입체이성질체, 용매화물, 및 염은 전술한 바와 같다.The compound, stereoisomer, solvate, and salt represented by Formula 1 are as described above.
상기 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염은 암세포에 대해 세포독성을 가질 수 있다. 상기 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염은 항암제로 사용될 수 있다.The compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof may be cytotoxic to cancer cells. The compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof may be used as an anticancer agent.
상기 암은 예를 들면 간내 담관암, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 균상식육종, 급성 골수성 백혈병, 만성 골수성 백혈병, 급성 림프구성 백혈병, 만성 림프구 백혈병, 기저세포암, 난소 상피암, 난소 생식 세포 종양, 남성 유방암, 뇌종양, 뇌하수체선종, 다발성 골수종, 담낭암, 담도암, 대장암, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아 뇌종양, 소아 림프종, 소아 백혈병, 소장암, 수막종, 식도암, 신경교종, 신경모세포종, 신우요관암, 신장암, 악성 연부 조직 종양, 악성 골종양, 악성 림프종, 악성 중피종, 악성 흑색종, 안종양, 외음부암, 요도암, 원발부위 불명암, 위림프종, 위암, 위유암종, 위장관 간질 종양, 윌름 종양, 유방암, 육종, 음경암, 인두암, 임신 융모 질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 뇌종양, 직장암, 직장유암종, 질암, 척수종양, 청신경초종, 췌장암, 침샘암, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 후두암 또는 이들의 조합일 수 있다. 상기 암은 폐암, 대장암, 위암, 혈액암, 간암, 또는 유방암일 수 있다.The cancer is, for example, intrahepatic cholangiocarcinoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, mycosis fungoides, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, basal cell carcinoma , ovarian epithelial cancer, ovarian germ cell tumor, male breast cancer, brain tumor, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, Non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, juvenile brain tumor, juvenile lymphoma, juvenile leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, neuroblastoma, pelvic ureter cancer, renal cancer, malignant soft tissue tumor, malignant bone tumor, malignancy Lymphoma, malignant mesothelioma, malignant melanoma, eye tumor, vulvar cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal tumor, Wilms tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, pregnancy villi Disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic brain tumor, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord tumor, acoustic schwannoma, pancreatic cancer, salivary gland cancer, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung It may be squamous cell carcinoma, skin cancer, anal cancer, laryngeal cancer, or a combination thereof. The cancer may be lung cancer, colon cancer, stomach cancer, blood cancer, liver cancer, or breast cancer.
용어 "예방"은 조성물의 투여에 의해 질병을 억제시키거나 발병을 지연시키는 모든 행위를 말한다. 용어 "치료"는 조성물의 투여에 의해 질병의 증세가 호전되거나 이롭게 변경하는 모든 행위를 말한다.The term "prevention" refers to any action that suppresses or delays the onset of a disease by administration of the composition. The term "treatment" refers to any act of improving or beneficially changing the symptoms of a disease by administering the composition.
상기 약학적 조성물은 식 1로 표시되는 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 유효 성분으로 포함할 수 있다. 상기 약학적 조성물은 항암 활성을 갖는 공지의 유효 성분을 더 포함할 수 있다.The pharmaceutical composition may include the compound represented by Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition may further include a known active ingredient having anticancer activity.
상기 약학적 조성물은 담체, 부형제 또는 희석제를 더 포함할 수 있다. 담체, 부형제 및 희석제는 예를 들면, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로스, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트, 또는 광물유를 포함할 수 있다.The pharmaceutical composition may further include a carrier, excipient or diluent. Carriers, excipients and diluents include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil.
상기 약학적 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화될 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다.The pharmaceutical composition may be formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, or sterile injection solutions according to conventional methods, respectively. In the case of formulation, it can be prepared using a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, surfactant, etc. commonly used.
상기 약학적 조성물에 있어서, 경구 투여를 위한 고형 제제는 정제, 환제, 산제, 과립제, 또는 캡슐제일 수 있다. 상기 고형 제제는 부형제를 더 포함할 수 있다. 부형제는 예를 들면, 전분, 칼슘 카르보네이트(calcium carbonate), 수크로스(sucrose), 락토오스(lactose), 또는 젤라틴일 수 있다. 또한, 상기 고형 제제는 마그네슘 스테아레이트, 또는 탈크와 같은 윤활제를 더 포함할 수 있다. 상기 약학적 조성물에 있어서, 경구를 위한 액상 제제는 현탁제, 내용액제, 유제, 또는 시럽제일 수 있다. 상기 액상 제제는 물, 또는 리퀴드 파라핀을 포함할 수 있다. 상기 액상 제제는 부형제, 예를 들면 습윤제, 감미제, 방향제, 또는 보존제를 포함할 수 있다. 상기 약학적 조성물에 있어서, 비경구 투여를 위한 제제는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 또는 및 좌제일 수 있다. 비수성용제 또는 현탁제는 식물성 기름 또는 에스테르를 포함할 수 있다. 식물성 기름은 예를 들면, 프로필렌 글리콜(propylene glycol), 폴리에틸렌 글리콜, 또는 올리브 오일일 수 있다. 에스테르는 예를 들면 에틸올레이트일 수 있다. 좌제의 기제는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 또는 글리세로젤라틴일 수 있다.In the pharmaceutical composition, the solid preparation for oral administration may be a tablet, pill, powder, granule, or capsule. The solid formulation may further include an excipient. The excipient may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatin. In addition, the solid formulation may further include a lubricant such as magnesium stearate or talc. In the pharmaceutical composition, the oral liquid formulation may be a suspension, an oral solution, an emulsion, or a syrup. The liquid formulation may contain water or liquid paraffin. The liquid formulation may contain excipients, for example, wetting agents, sweetening agents, perfuming agents, or preservatives. In the pharmaceutical composition, the preparation for parenteral administration may be a sterile aqueous solution, non-aqueous solution, suspension, emulsion, freeze-dried or suppository. The non-aqueous solvent or suspending agent may include vegetable oil or ester. The vegetable oil may be, for example, propylene glycol, polyethylene glycol, or olive oil. The ester may be, for example, ethyl oleate. The base of the suppository may be witepsol, macrogol, tween 61, cacao butter, laurin, or glycerogelatin.
상기 약학적 조성물의 바람직한 투여량은 개체의 상태 및 체중, 질병의 정도, 약물 형태, 투여 경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 상기 화합물, 이의 이성질체, 유도체, 용매화물, 또는 약학적으로 허용가능한 염은 예를 들면, 약 0.0001 ㎎/㎏ 내지 약 100 ㎎/㎏, 또는 약 0.001 ㎎/㎏ 내지 약 100 ㎎/㎏의 양을 일일 1회 내지 24회, 2일 내지 1주에 1 내지 7회, 또는 1개월 내지 12개월에 1 내지 24회로 나누어 투여할 수 있다. 상기 약학적 조성물에서 화합물, 이의 이성질체, 유도체, 용매화물, 또는 약학적으로 허용가능한 염은 전체 조성물 총 중량에 대하여 약 0.0001 중량% 내지 약 10 중량%, 또는 약 0.001 중량% 내지 약 1 중량%로 포함될 수 있다.The preferred dosage of the pharmaceutical composition varies depending on the condition and weight of the individual, the degree of disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art. However, the compound, isomer, derivative, solvate, or pharmaceutically acceptable salt thereof may be, for example, from about 0.0001 mg/kg to about 100 mg/kg, or from about 0.001 mg/kg to about 100 mg/kg. The amount may be administered in divided doses from 1 to 24 times a day, 1 to 7 times per 2 days to 1 week, or 1 to 24 times per 1 month to 12 months. In the pharmaceutical composition, the compound, isomer, derivative, solvate, or pharmaceutically acceptable salt thereof is present in an amount of from about 0.0001% to about 10% by weight, or from about 0.001% to about 1% by weight, based on the total weight of the composition. may be included.
투여 방법은 경구, 또는 비경구 투여일 수 있다. 투여 방법은 예를 들어, 경구, 경피, 피하, 직장, 정맥내, 동맥내, 복강내, 근육내, 흉골내, 국소, 코안(intranasal), 기관내(intratracheal), 또는 피내 경로일 수 있다. 상기 조성물은 전신적으로 또는 국부적으로 투여될 수 있고, 단독으로 또는 다른 약학적 활성 화합물과 함께 투여될 수 있다.The administration method may be oral or parenteral administration. The method of administration can be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal routes. The compositions may be administered systemically or locally, alone or in combination with other pharmaceutically active compounds.
다른 양상은 일 양상에 따른 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 포함하는 암 예방 또는 치료용 약학적 조성물을 개체에게 투여하는 단계를 포함하는 암을 예방 또는 치료하는 방법을 제공한다.Another aspect is a method for preventing or treating cancer, comprising administering to an individual a pharmaceutical composition for preventing or treating cancer comprising a compound according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof provides
식 1로 표시되는 화합물, 입체이성질체, 용매화물, 염, 암, 예방, 치료, 및 약학적 조성물은 전술한 바와 같다.The compound, stereoisomer, solvate, salt, cancer, prevention, treatment, and pharmaceutical composition represented by Formula 1 are as described above.
상기 개체는 포유동물, 예를 들면, 인간, 마우스, 래트, 소, 말, 돼지, 개, 원숭이, 양, 염소 또는 고양이일 수 있다. 상기 개체는 암을 앓고 있거나, 앓을 가능성이 큰 개체일 수 있다.The subject may be a mammal, such as a human, mouse, rat, cow, horse, pig, dog, monkey, sheep, goat or cat. The subject may be suffering from, or likely to have, cancer.
투여 방법은 경구, 또는 비경구 투여일 수 있다. 투여 방법은 예를 들어, 경구, 경피, 피하, 직장, 정맥내, 동맥내, 복강내, 근육내, 흉골내, 국소, 코안(intranasal), 기관내(intratracheal), 또는 피내 경로일 수 있다. 상기 약학적 조성물은 전신적으로 또는 국부적으로 투여될 수 있고, 단독으로 또는 다른 약학적 활성 화합물과 함께 투여될 수 있다.The administration method may be oral or parenteral administration. The method of administration can be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal routes. The pharmaceutical composition may be administered systemically or locally, alone or in combination with other pharmaceutically active compounds.
상기 약학적 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물 형태, 투여 경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 상기 투여량은 예를 들어, 성인 기준으로 약 0.001 ㎎/kg 내지 약 100 ㎎/kg, 약 0.01 ㎎/kg 내지 약 10 ㎎/kg, 또는 약 0.1 ㎎/kg 내지 약 1 ㎎/kg의 범위 내 일 수 있다. 상기 투여는 1일 1회, 1일 다회, 또는 1주일에 1회, 2주일에 1회, 3주일에 1회, 또는 4주일에 1회 내지 1년에 1회 투여될 수 있다.The preferred dosage of the pharmaceutical composition varies depending on the condition and weight of the patient, the degree of disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art. The dosage is, for example, in the range of from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, or from about 0.1 mg/kg to about 1 mg/kg on an adult basis. can be The administration may be administered once a day, multiple times a day, or once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks to once a year.
신규한 지질펩티드 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염은 암세포에 대해 세포독성을 가지므로, 다양한 종류의 암을 예방 또는 치료하는데 사용할 수 있다.Since the novel lipopeptide compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof has cytotoxicity to cancer cells, it can be used to prevent or treat various types of cancer.
도 1은 스트렙토마이세스 속(Streptomyces sp.) AMD43 균주를 고체 배지에서 배양한 균주의 사진이다.1 is a photograph of a strain of Streptomyces sp. AMD43 cultured in a solid medium.
이하 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, it will be described in more detail through examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.
실시예 1. 태안아미드의 분리 및 구조의 확인Example 1. Isolation of Taeanamide and Confirmation of Structure
1-1. 태안아미드 생산 균주의 분리1-1. Isolation of Taeanamide-producing strain
2019년 한국 안면도에서 채집한 갯벌 시료의 침전물로부터 AMD43 균주를 분리하였다. AMD43 균주는 YEME 고체 배지(물 1L 당 맥아 추출물 10 g, 효모 4 g, 포도당 4 g, 및 한천 18 g)에 접종하여 28℃에서 약 7일 동안 배양하여 분리하였다(도 1).AMD43 strain was isolated from the sediments of tidal flat samples collected in Anmyeondo, Korea in 2019. AMD43 strain was isolated by inoculating the YEME solid medium (10 g of malt extract per 1 L of water, 4 g of yeast, 4 g of glucose, and 18 g of agar) and culturing at 28° C. for about 7 days (FIG. 1).
16S rDNA 염기서열 분석 결과에 기반하여, AMD43 균주는 스트렙토마이세스 속(Streptomyces sp.)인 것으로 동정되었다. 이 균주를 스트렙토마이세스 속(Streptomyces sp.) AMD43 균주로 명명하고, 상기 균주를 2020년 9월 21일자로 한국생명공학연구원에 기탁하였다(수탁번호: KCTC14317BP).Based on the results of 16S rDNA sequencing, the AMD43 strain was identified as being of the genus Streptomyces sp. This strain was named Streptomyces sp. AMD43 strain, and the strain was deposited with the Korea Research Institute of Bioscience and Biotechnology on September 21, 2020 (accession number: KCTC14317BP).
1-2. 스트렙토마이세스 속 AMD43 균주의 배양1-2. Culture of Streptomyces genus AMD43 strain
스트렙토마이세스 속 AMD43 균주를 YEME 고체 배지에 접종하고 30℃에서 수일간 배양하였다.AMD43 strain of Streptomyces genus was inoculated in YEME solid medium and cultured at 30° C. for several days.
배양된 AMD43 균주의 포자를 50 mL의 YEME 액체 배지(물 1L 당 맥아 추출물 10 g, 효모 4 g, 및 포도당 4 g)에 접종하고, 30℃의 온도에서 200 rpm으로 진탕하면서 약 4일간 배양하였다.The cultured AMD43 strain spores were inoculated into 50 mL of YEME liquid medium (10 g of malt extract per 1 L of water, 4 g of yeast, and 4 g of glucose), and cultured for about 4 days while shaking at 200 rpm at a temperature of 30°C. .
10 mL의 AMD43 균주의 배양액을 200 mL의 YEME 액체 배지에 접종하고, 30℃의 온도에서 160 rpm으로 진탕하면서 약 4일간 배양하였다.10 mL of the AMD43 strain culture was inoculated into 200 mL of YEME liquid medium, and cultured for about 4 days while shaking at a temperature of 30° C. at 160 rpm.
그 후, 25 mL의 AMD43 균주의 배양액을 1 L의 YEME 액체 배지에 접종하고, 30℃의 온도에서 160 rpm으로 진탕하면서 약 4일간 배양하였다.Thereafter, 25 mL of the culture solution of the AMD43 strain was inoculated into 1 L of YEME liquid medium, and cultured for about 4 days while shaking at a temperature of 30° C. at 160 rpm.
1-3. 태안아미드 A 및 B의 분리 빛 정제1-3. Separation light purification of Taeanamide A and B
실시예 1-2에 기재된 바와 같이 배양한 스트렙토마이세스 속 AMD43 균주의 배양물을 수득하였다.A culture of the Streptomyces genus AMD43 strain cultured as described in Example 1-2 was obtained.
스탠드에 거치된 분별깔때기에 배양이 끝난 AMD43 균주 1 L와 약 2.5 L 부피의 에틸 아세테이트(EtOAc, 대정화금주식회사)를 넣어 준 뒤 마개를 막고 상하좌우로 3분간 흔들어 1차 추출을 진행하였다. 이후 다시 스탠드에 거치하여 물 층과 EtOAc 층이 완전히 나누어진 후 분별깔때기의 밸브를 열어 물 층을 제거하였다. 물층에 새로운 EtOAc를 첨가하고, 같은 방식으로 반복 추출을 진행하였다. EtOAc 층은 깨끗한 플라스크에 따로 받아 보관하였고, 100 g의 무수 소듐 설페이트(Anhydrous Sodium Sulfate)(대정화금주식회사)를 첨가하여 배양물에 남아있는 물을 제거하고, 여러 겹의 깨끗한 거즈를 통과시켜 이물질을 제거하였다. 물기가 제거된 EtOAc 층을 다시 3 L 부피의 둥근 플라스크로 옮겨 담은 후 감압건조기를 사용하여 감압 건조하였다. 총 18 L의 균주 배양으로부터 약 2.5 g의 조(crude) 추출물을 얻을 수 있었다.1 L of the cultured AMD43 strain and about 2.5 L of ethyl acetate (EtOAc, Daejeong Hwa-Geum Co., Ltd.) were put into a separatory funnel mounted on a stand, and the stopper was closed and shaken up, down, left, and right for 3 minutes to perform primary extraction. After that, it was mounted on a stand again, and after the water layer and the EtOAc layer were completely divided, the valve of the separatory funnel was opened to remove the water layer. Fresh EtOAc was added to the aqueous layer, and repeated extraction was performed in the same manner. The EtOAc layer was stored separately in a clean flask, and 100 g of Anhydrous Sodium Sulfate (Daejeong Hwa Gold Co., Ltd.) was added to remove the water remaining in the culture, and passed through several layers of clean gauze to remove foreign substances. was removed. The EtOAc layer from which the water was removed was transferred back to a 3 L round flask, and then dried under reduced pressure using a vacuum dryer. About 2.5 g of crude extract was obtained from a total of 18 L of strain culture.
수득된 추출물을 3등분하고 3등분한 추출물을 Sephadex LH-20 컬럼으로 분획하였다(이동상: 메탄올). 분획물의 조성 확인은 아질런트(Agilent technologies) 사의 1200 시리즈 LC와 6130 시리즈 질량분석기를 연결한 LC/MS를 사용하였다. LC/MS를 사용하여 7번째 분획(분획물 7) 및 8번째 분획(분획물 8)에서 신규 물질인 태안아미드(taeanamide) A와 태안아미드 B를 함유하는 것을 확인하였다.The obtained extract was divided into thirds, and the three-divided extract was fractionated with a Sephadex LH-20 column (mobile phase: methanol). To confirm the composition of the fraction, LC/MS was used in which Agilent technologies' 1200 series LC and 6130 series mass spectrometer were connected. Using LC/MS, it was confirmed that the 7th fraction (fraction 7) and 8th fraction (fraction 8) contained new substances taeanamide A and taeanamide B.
분획물 7과 분획물 8을 함께 메탄올에 용해시키고 증발시켜 농축하였다. 분획물은 크로마토그래피로 정제하였다. 분획물 7과 분획물 8을 Kromasil 컬럼(100-5-C18, 10 x 250 mm)을 사용하고 HPLC(high-performance liquid chromatography)에 주입하여, 45% 수용액 CH3CN (검출: UV 210 nm, 유속: 2 mL/분)의 등용매(isocratic) 조건 하에서 크로마토그래피를 수행하였다. 태안아미드 A(20 mg)와 태안아미드 B(40 mg)는 각각 약 19분 및 약 28분 분획에서 용출되었다.Fractions 7 and 8 were dissolved together in methanol and concentrated by evaporation. Fractions were purified by chromatography. Fraction 7 and Fraction 8 were injected into high-performance liquid chromatography (HPLC) using a Kromasil column (100-5-C18, 10 x 250 mm), 45% aqueous CH 3 CN (detection: UV 210 nm, flow rate: Chromatography was performed under isocratic conditions of 2 mL/min). Taeanamide A (20 mg) and Taeanamide B (40 mg) were eluted at about 19 minutes and about 28 minutes, respectively.
1-4. 태안아미드 A 및 태안아미드 B의 화학구조의 확인1-4. Identification of the chemical structures of Taeanamide A and Taeanamide B
태안아미드 A와 태안아미드 B의 구조는 1D 및 2D 핵자기 공명 스펙트럼(nuclear magnetic resonance: NMR) 스펙트럼을 기반으로 확인하였다. 핵자기 공명 스펙트럼(1H NMR, 13C NMR)은 브루커(Bruker) 사의 800 MHz NMR을, 용매는 DMSO-d6를 사용하였다.The structures of Taeanamide A and Taeanamide B were confirmed based on 1D and 2D nuclear magnetic resonance (NMR) spectra. A nuclear magnetic resonance spectrum ( 1 H NMR, 13 C NMR) was 800 MHz NMR manufactured by Bruker, and DMSO-d 6 was used as the solvent.
핵자기공명 스펙트럼에 의한 태안아미드 A와 태안아미드 B의 구조 위치 지정을 표 1에 나타내었다.Table 1 shows the structural positioning of Taeanamide A and Taeanamide B by nuclear magnetic resonance spectra.
[태안아미드 A(Taeanamide A)][Taeanamide A]
(1) 분자식: C51H87N11O17 (1) Molecular formula: C 51 H 87 N 11 O 17
(2) 분자량: 1126(2) molecular weight: 1126
(3) 색: 흰색(3) Color: white
(4) 1H-NMR (DMSO-d6, 800 MHz): 표 1 참조(4) 1 H-NMR (DMSO-d 6 , 800 MHz): see Table 1
(5) 13C-NMR (DMSO-d6, 200 MHz): 표 1 참조(5) 13 C-NMR (DMSO-d 6 , 200 MHz): see Table 1
[태안아미드 B(Taeanamide B)][Taeanamide B]
(1) 분자식: C52H89N11O17 (1) Molecular formula: C 52 H 89 N 11 O 17
(2) 분자량: 1140(2) molecular weight: 1140
(3) 색: 흰색(3) Color: white
(4) 1H-NMR (pyridine-d5, 800 MHz): 표 2 참조(4) 1 H-NMR (pyridine-d5, 800 MHz): see Table 2
(5) 13C-NMR (pyridine-d5, 200 MHz): 표 2 참조(5) 13 C-NMR (pyridine-d5, 200 MHz): see Table 2
핵자기공명 스펙트럼 자료로부터 분석된 태안아미드 A의 화학구조식을 하기에 나타내었다.The chemical structural formula of Taeanamide A analyzed from nuclear magnetic resonance spectrum data is shown below.
[태안아미드 A][Taeanamide A]
핵자기공명 스펙트럼 자료로부터 분석된 태안아미드 B의 화학구조식을 하기에 나타내었다.The chemical structural formula of Taeanamide B analyzed from nuclear magnetic resonance spectral data is shown below.
[태안아미드 B][Taeanamide B]
실시예 2. 태안아미드 A 및 B의 항암 활성의 확인Example 2. Confirmation of anticancer activity of Taeanamide A and B
태안아미드 A 및 B의 생물학적 활성을 확인하기 위해, 다양한 인간 암 세포에 대한 세포독성을 확인하였다.In order to confirm the biological activity of Taeanamide A and B, the cytotoxicity to various human cancer cells was confirmed.
인간 폐암 세포주 A-549, 인간 대장암 세포주 HCT116, 인간 위암 세포주 SNU638, 인간 간암 세포주 SK-HEP-1, 유방암 세포주 MDA-MB-231, 및 백혈병 세포주 K562를 한국 세포주 은행(Korean Cell Line Bank, Korea)로부터 구입하였다.Human lung cancer cell line A-549, human colorectal cancer cell line HCT116, human gastric cancer cell line SNU638, human liver cancer cell line SK-HEP-1, breast cancer cell line MDA-MB-231, and leukemia cell line K562 were prepared from the Korean Cell Line Bank, Korea. ) was purchased from
세포의 배양액은 10%(v/v) 열-불활성화 우태아 혈청(fetal bovine serum: FBS) 및 항균-항마이코박테라이 용액(100 units/mL 페니실린 G 소듐, 100 ㎍/mL 스트렙토마이신, 및 250 ng/mL 암포테리신(amphotericin) B)을 함유한 배지(A549, HCT116, SNU638, 및 K562 세포에 대해 RPMI-1640 배지; MDA-MB-231 및 SK-HEP-1에 대해 Dulbecco's modified Eagle's medium; 및 MRC-5에 대해 minimal essential medium)를 사용하였다.Cell cultures were prepared using 10% (v/v) heat-inactivated fetal bovine serum (FBS) and an antibacterial-antimycobacterial solution (100 units/mL penicillin G sodium, 100 μg/mL streptomycin, and 250 ng/mL amphotericin B) (RPMI-1640 medium for A549, HCT116, SNU638, and K562 cells; Dulbecco's modified Eagle's medium for MDA-MB-231 and SK-HEP-1) ; and minimal essential medium for MRC-5) was used.
세포 증식은 술포로다민(sulforhodamine B: SRB) 분석법으로 측정하였다. 간단히, 배양 중인 세포를 96-웰 플레이트에 접종하고, 30분 동안 인큐베이션하거나(제0일, 음성 대조군) 또는 정해진 시간에 화합물을 처리하였다. 비교군으로 에토포시드(etoposide)를 사용하였다. 인큐베이션 후, 세포를 고정하고, 건조시킨 후, 1%(v/v) 아세트산 중 0.4(w/v) SRB로 염색하였다. 부착되지 않은 염료는 세척하여 제거하고, 염색된 세포를 10mM Tris (pH 10.0)에 현탁하였다. 515 nm에서 흡광도를 측정하고, 세포 증식을 측정하였다. TableCurve 2D v5.01 소프트웨어(Systant Software Inc., Richmond, CA, USA)를 이용한 비선형 회귀분석법으로 50%의 세포 성장을 억제하는 화합물의 농도, 즉 IC50(50% inhibition concentration)을 산출하였다. 모든 시약은 Sigma-Aldrich에서 구입하였다. 산출된 IC50를 하기 표 3에 나타내었다. 양성 대조군으로서 에토포시드(etoposide)(Sigma Aldrich)를 사용하였다.Cell proliferation was measured by sulforhodamine B (SRB) assay. Briefly, cells in culture were seeded in 96-well plates and incubated for 30 min (day 0, negative control) or treated with compounds at set times. As a comparison group, etoposide was used. After incubation, cells were fixed, dried and stained with 0.4 (w/v) SRB in 1% (v/v) acetic acid. Non-adherent dye was removed by washing, and the stained cells were suspended in 10 mM Tris (pH 10.0). Absorbance was measured at 515 nm and cell proliferation was measured. By nonlinear regression analysis using TableCurve 2D v5.01 software (Systant Software Inc., Richmond, CA, USA), the concentration of the compound that inhibits 50% of cell growth, ie, IC 50 (50% inhibition concentration), was calculated. All reagents were purchased from Sigma-Aldrich. The calculated IC 50 is shown in Table 3 below. Etoposide (Sigma Aldrich) was used as a positive control.
표 3에 나타난 바와 같이, 태안아미드 A는 세포 성장 억제 효과가 나타나지 않았으나, 태안아미드 B는 모든 6종의 암세포에 대해 비교적 높은 세포 성장 억제 활성을 나타내었다.As shown in Table 3, Taeanamide A did not show a cell growth inhibitory effect, but Taeanamide B showed a relatively high cell growth inhibitory activity against all six types of cancer cells.
Claims (13)
[식 1]
R1-(C=O)-Ser-Thr-Ala-Thr-Pro-Gly-X-Ala-Leu-Ser-R2,
식 1에서, X는 C1 내지 C10 알킬아세트아미드로 치환된 글리신(Glyine; Gly 또는 G)이고,
R1은 포화 또는 불포화된 탄화수소 사슬이고,
R2는 없거나, 또는 치환 또는 비치환된 C1 내지 C20 알킬기, 치환 또는 비치환된 C1 내지 C20 알케닐기, 또는 치환 또는 비치환된 C1 내지 C20 알키닐기이다.A compound represented by Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof:
[Equation 1]
R 1 -(C=O)-Ser-Thr-Ala-Thr-Pro-Gly-X-Ala-Leu-Ser-R 2 ,
In Formula 1, X is glycine (Glyine; Gly or G) substituted with C 1 to C 10 alkylacetamide,
R 1 is a saturated or unsaturated hydrocarbon chain,
R 2 is absent, or is a substituted or unsubstituted C 1 to C 20 alkyl group, a substituted or unsubstituted C 1 to C 20 alkenyl group, or a substituted or unsubstituted C 1 to C 20 alkynyl group.
[식 2]
; 및
[식 3]
.The method according to claim 1, wherein the compound represented by Formula 1 is a compound represented by Formula 2 or Formula 3, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof:
[Equation 2]
; and
[Equation 3]
.
[식 4]
; 및
[식 5]
.The method according to claim 1, wherein the compound represented by Formula 1 is a compound represented by Formula 4 or Formula 5, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof:
[Equation 4]
; and
[Equation 5]
.
상기 균주를 배양한 배양액으로부터 청구항 1의 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 분리하는 단계를 포함하는,
청구항 1의 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 생산하는 방법.culturing the Streptomyces sp. AMD43 strain (Accession No.: KCTC14317BP); and
Comprising the step of isolating the compound of claim 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof from the culture solution of the strain,
A method for producing the compound of claim 1, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020200151116A KR102599650B1 (en) | 2020-11-12 | 2020-11-12 | Novel lipopeptide compound, a preparing method, and a use thereof |
PCT/KR2021/016155 WO2022103103A1 (en) | 2020-11-12 | 2021-11-08 | Novel lipid peptide compound, production method therefor, and use thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020200151116A KR102599650B1 (en) | 2020-11-12 | 2020-11-12 | Novel lipopeptide compound, a preparing method, and a use thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
KR20220064719A true KR20220064719A (en) | 2022-05-19 |
KR102599650B1 KR102599650B1 (en) | 2023-11-08 |
Family
ID=81601485
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020200151116A KR102599650B1 (en) | 2020-11-12 | 2020-11-12 | Novel lipopeptide compound, a preparing method, and a use thereof |
Country Status (2)
Country | Link |
---|---|
KR (1) | KR102599650B1 (en) |
WO (1) | WO2022103103A1 (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008013953A2 (en) * | 2006-07-27 | 2008-01-31 | Cell Signaling Technology, Inc. | Tyrosine phosphorylation sites |
US20080070268A1 (en) * | 2006-04-21 | 2008-03-20 | Wyeth | Differential expression profiling analysis of cell culture phenotypes and the uses thereof |
WO2009077864A2 (en) * | 2007-12-14 | 2009-06-25 | Transmedi Sa | Compositions and methods of detecting tiabs |
WO2010104747A2 (en) * | 2009-03-10 | 2010-09-16 | Baylor Research Institute | Antigen presenting cell targeted vaccines |
KR101723649B1 (en) | 2014-10-23 | 2017-04-06 | 서울대학교산학협력단 | Novel peptide compound, a preparing method thereof, and a use thereof |
-
2020
- 2020-11-12 KR KR1020200151116A patent/KR102599650B1/en active IP Right Grant
-
2021
- 2021-11-08 WO PCT/KR2021/016155 patent/WO2022103103A1/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080070268A1 (en) * | 2006-04-21 | 2008-03-20 | Wyeth | Differential expression profiling analysis of cell culture phenotypes and the uses thereof |
WO2008013953A2 (en) * | 2006-07-27 | 2008-01-31 | Cell Signaling Technology, Inc. | Tyrosine phosphorylation sites |
WO2009077864A2 (en) * | 2007-12-14 | 2009-06-25 | Transmedi Sa | Compositions and methods of detecting tiabs |
WO2010104747A2 (en) * | 2009-03-10 | 2010-09-16 | Baylor Research Institute | Antigen presenting cell targeted vaccines |
KR101723649B1 (en) | 2014-10-23 | 2017-04-06 | 서울대학교산학협력단 | Novel peptide compound, a preparing method thereof, and a use thereof |
Also Published As
Publication number | Publication date |
---|---|
WO2022103103A1 (en) | 2022-05-19 |
KR102599650B1 (en) | 2023-11-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR101522625B1 (en) | Novel cyclic peptide compound, a use thereof, and a preparing method thereof | |
KR20150055471A (en) | Novel compound, a preparing method thereof, and a use thereof as inhibitors of histone demethylase | |
US20200190140A1 (en) | Novel peptide compound, production method therefor, and use thereof | |
KR102120907B1 (en) | Method of producing saphenic acid and its derivatives and use thereof | |
Tan | Marine cyanobacteria: A treasure trove of bioactive secondary metabolites for drug discovery | |
KR102599650B1 (en) | Novel lipopeptide compound, a preparing method, and a use thereof | |
KR102389725B1 (en) | Cyclic peptide compound containing piperazic acid, a preparing method thereof, and a use thereof | |
Ahmad et al. | Cyanobacterial peptides with respect to anticancer activity: Structural and functional perspective | |
KR101721665B1 (en) | Amide-based derivative compound, preparing method and use thereof | |
KR20100080741A (en) | Microorganism of fusarium genus producing cyclic pentadepsipeptides | |
KR102301151B1 (en) | Peptide compound, a preparing method thereof, and a use thereof | |
KR102681872B1 (en) | New spiro-macrolide compounds, preparing method and use thereof | |
KR102112570B1 (en) | Novel rhamnolipid compounds and use thereof | |
KR20220005412A (en) | Tricyclic dilactone compound, preparing method and use thereof | |
JPH11180997A (en) | Novel antitumor compound | |
KR102442047B1 (en) | Fatty acid glyceride compound containing sulfate and amine group, preparing method and use thereof | |
CN115650913B (en) | Quinone quinoline compound and preparation method and application thereof | |
KR102308831B1 (en) | Pharmaceutical composition containing macrolide compound, preparing method thereof, and method using the same | |
WO2004078764A1 (en) | Gm-95-containing antitumor effect potentiator, combined antitumor preparation and antitumor agent | |
KR102567944B1 (en) | Novel adamantyl derivative or its pharmaceutically acceptable salts and use thereof | |
KR20230142242A (en) | Novel peptide-polyketide compound, or optical isomer thereof, or pharmaceutically acceptable salts thereof, uses thereof, and preparation method thereof | |
KR100915390B1 (en) | Composition comprising novel acetylenic alcohol compound or the extract of reniochalina sp. for preventing and treating cancer | |
WO2012020364A1 (en) | Di peptide derivative for the treatment of cancer | |
KR20230124853A (en) | Composition for preventing or treating diabetes comprising a novel adamantyl derivative or a pharmaceutically acceptable salt thereof | |
KR20090035323A (en) | Anti-cancer composition comprising dipeptide isolated from microorganism |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
E902 | Notification of reason for refusal | ||
E701 | Decision to grant or registration of patent right | ||
GRNT | Written decision to grant |