JP2010100537A - Nfat signal inhibitor and novel compound having nfat signal inhibitory activity - Google Patents
Nfat signal inhibitor and novel compound having nfat signal inhibitory activity Download PDFInfo
- Publication number
- JP2010100537A JP2010100537A JP2008271078A JP2008271078A JP2010100537A JP 2010100537 A JP2010100537 A JP 2010100537A JP 2008271078 A JP2008271078 A JP 2008271078A JP 2008271078 A JP2008271078 A JP 2008271078A JP 2010100537 A JP2010100537 A JP 2010100537A
- Authority
- JP
- Japan
- Prior art keywords
- group
- nfat
- nfat signal
- general formula
- component
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims description 28
- 239000003112 inhibitor Substances 0.000 title claims description 27
- 230000002401 inhibitory effect Effects 0.000 title abstract description 17
- 239000004480 active ingredient Substances 0.000 claims abstract description 25
- -1 isovaleroyl group Chemical group 0.000 claims description 17
- 125000005601 angeloyl group Chemical group 0.000 claims description 16
- CFNMUZCFSDMZPQ-GHXNOFRVSA-N 7-[(z)-3-methyl-4-(4-methyl-5-oxo-2h-furan-2-yl)but-2-enoxy]chromen-2-one Chemical compound C=1C=C2C=CC(=O)OC2=CC=1OC/C=C(/C)CC1OC(=O)C(C)=C1 CFNMUZCFSDMZPQ-GHXNOFRVSA-N 0.000 claims description 12
- HQKAYCHMYMSSEQ-YADHBBJMSA-N 3'-angeloyloxy-4'-isovaleryloxy-2',3'-dihydrooroselol Natural products CC=C(C)C(=O)O[C@H]1[C@H](Oc2ccc3ccc(=O)oc3c12)C(C)(C)OC(=O)CC(C)C HQKAYCHMYMSSEQ-YADHBBJMSA-N 0.000 claims description 6
- 125000000524 functional group Chemical group 0.000 claims description 6
- 150000004775 coumarins Chemical class 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 240000006493 Angelica atropurpurea Species 0.000 abstract description 14
- 235000011512 Angelica atropurpurea Nutrition 0.000 abstract description 10
- 239000000284 extract Substances 0.000 abstract description 10
- 230000001747 exhibiting effect Effects 0.000 abstract 2
- 239000003814 drug Substances 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 12
- 238000013518 transcription Methods 0.000 description 11
- 230000035897 transcription Effects 0.000 description 11
- 229940124597 therapeutic agent Drugs 0.000 description 10
- 201000004681 Psoriasis Diseases 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 206010012438 Dermatitis atopic Diseases 0.000 description 7
- 201000008937 atopic dermatitis Diseases 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000002537 cosmetic Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000003018 immunosuppressive agent Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 239000000419 plant extract Substances 0.000 description 6
- 230000001737 promoting effect Effects 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 241000196324 Embryophyta Species 0.000 description 5
- 108090000331 Firefly luciferases Proteins 0.000 description 5
- 108060001084 Luciferase Proteins 0.000 description 5
- 206010028311 Muscle hypertrophy Diseases 0.000 description 5
- 239000003435 antirheumatic agent Substances 0.000 description 5
- 229960003444 immunosuppressant agent Drugs 0.000 description 5
- 230000012042 muscle hypertrophy Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000004094 surface-active agent Substances 0.000 description 5
- 238000001890 transfection Methods 0.000 description 5
- XAQHSTCVGOTLHK-YADHBBJMSA-N 3'-angeloyloxy-4'-senecioyloxy-2',3'-dihydrooroselol Natural products CC=C(C)C(=O)O[C@H]1[C@H](Oc2ccc3ccc(=O)oc3c12)C(C)(C)OC(=O)C=C(C)C XAQHSTCVGOTLHK-YADHBBJMSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 239000005089 Luciferase Substances 0.000 description 4
- 108700008625 Reporter Genes Proteins 0.000 description 4
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 4
- XAQHSTCVGOTLHK-MKKZQTCBSA-N [(8s,9r)-8-[2-(3-methylbut-2-enoyloxy)propan-2-yl]-2-oxo-8,9-dihydrofuro[2,3-h]chromen-9-yl] (z)-2-methylbut-2-enoate Chemical compound C1=CC(=O)OC2=C3[C@@H](OC(=O)C(\C)=C/C)[C@@H](C(C)(C)OC(=O)C=C(C)C)OC3=CC=C21 XAQHSTCVGOTLHK-MKKZQTCBSA-N 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 230000001154 acute effect Effects 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- PGHMRUGBZOYCAA-ADZNBVRBSA-N ionomycin Chemical compound O1[C@H](C[C@H](O)[C@H](C)[C@H](O)[C@H](C)/C=C/C[C@@H](C)C[C@@H](C)C(/O)=C/C(=O)[C@@H](C)C[C@@H](C)C[C@@H](CCC(O)=O)C)CC[C@@]1(C)[C@@H]1O[C@](C)([C@@H](C)O)CC1 PGHMRUGBZOYCAA-ADZNBVRBSA-N 0.000 description 4
- PGHMRUGBZOYCAA-UHFFFAOYSA-N ionomycin Natural products O1C(CC(O)C(C)C(O)C(C)C=CCC(C)CC(C)C(O)=CC(=O)C(C)CC(C)CC(CCC(O)=O)C)CCC1(C)C1OC(C)(C(C)O)CC1 PGHMRUGBZOYCAA-UHFFFAOYSA-N 0.000 description 4
- 201000006417 multiple sclerosis Diseases 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 239000013612 plasmid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 230000002103 transcriptional effect Effects 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 102000004631 Calcineurin Human genes 0.000 description 3
- 108010042955 Calcineurin Proteins 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 102000000588 Interleukin-2 Human genes 0.000 description 3
- 108010002350 Interleukin-2 Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 102100034404 Nuclear factor of activated T-cells, cytoplasmic 1 Human genes 0.000 description 3
- 101710151542 Nuclear factor of activated T-cells, cytoplasmic 1 Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 108010052090 Renilla Luciferases Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 210000000988 bone and bone Anatomy 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 230000001861 immunosuppressant effect Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000003468 luciferase reporter gene assay Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 208000030159 metabolic disease Diseases 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- ZCCUUQDIBDJBTK-UHFFFAOYSA-N psoralen Chemical class C1=C2OC(=O)C=CC2=CC2=C1OC=C2 ZCCUUQDIBDJBTK-UHFFFAOYSA-N 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000002562 thickening agent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- DOUMFZQKYFQNTF-WUTVXBCWSA-N (R)-rosmarinic acid Chemical compound C([C@H](C(=O)O)OC(=O)\C=C\C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 DOUMFZQKYFQNTF-WUTVXBCWSA-N 0.000 description 2
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 2
- 241000125175 Angelica Species 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- 201000001178 Bacterial Pneumonia Diseases 0.000 description 2
- 208000009137 Behcet syndrome Diseases 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000000668 Chronic Pancreatitis Diseases 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 2
- 108010036949 Cyclosporine Proteins 0.000 description 2
- 206010014612 Encephalitis viral Diseases 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 206010027202 Meningitis bacterial Diseases 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 206010033645 Pancreatitis Diseases 0.000 description 2
- 206010033647 Pancreatitis acute Diseases 0.000 description 2
- 206010033649 Pancreatitis chronic Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 102000014128 RANK Ligand Human genes 0.000 description 2
- 108010025832 RANK Ligand Proteins 0.000 description 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- 206010040070 Septic Shock Diseases 0.000 description 2
- 230000006044 T cell activation Effects 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 239000006096 absorbing agent Substances 0.000 description 2
- 206010000891 acute myocardial infarction Diseases 0.000 description 2
- 201000003229 acute pancreatitis Diseases 0.000 description 2
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 201000009904 bacterial meningitis Diseases 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229960001265 ciclosporin Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
- 208000016097 disease of metabolism Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- QMDNUCYGVSWWRO-UHFFFAOYSA-N edulisin ii Chemical compound C1=CC(=O)OC2=C3C(OC(=O)C=C(C)C)C(C(C)(C)OC(=O)C=C(C)C)OC3=CC=C21 QMDNUCYGVSWWRO-UHFFFAOYSA-N 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- BJRNKVDFDLYUGJ-RMPHRYRLSA-N hydroquinone O-beta-D-glucopyranoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-RMPHRYRLSA-N 0.000 description 2
- 208000009326 ileitis Diseases 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 229940125721 immunosuppressive agent Drugs 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 208000000509 infertility Diseases 0.000 description 2
- 230000036512 infertility Effects 0.000 description 2
- 231100000535 infertility Toxicity 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 201000008383 nephritis Diseases 0.000 description 2
- 210000002997 osteoclast Anatomy 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 235000019271 petrolatum Nutrition 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000036303 septic shock Effects 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 201000008827 tuberculosis Diseases 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 201000002498 viral encephalitis Diseases 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- DSEKYWAQQVUQTP-XEWMWGOFSA-N (2r,4r,4as,6as,6as,6br,8ar,12ar,14as,14bs)-2-hydroxy-4,4a,6a,6b,8a,11,11,14a-octamethyl-2,4,5,6,6a,7,8,9,10,12,12a,13,14,14b-tetradecahydro-1h-picen-3-one Chemical compound C([C@H]1[C@]2(C)CC[C@@]34C)C(C)(C)CC[C@]1(C)CC[C@]2(C)[C@H]4CC[C@@]1(C)[C@H]3C[C@@H](O)C(=O)[C@@H]1C DSEKYWAQQVUQTP-XEWMWGOFSA-N 0.000 description 1
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 description 1
- QHBZHVUGQROELI-SOFGYWHQSA-N (E)-10-hydroxydec-2-enoic acid Chemical compound OCCCCCCC\C=C\C(O)=O QHBZHVUGQROELI-SOFGYWHQSA-N 0.000 description 1
- YRAQEMCYCSSHJG-NSHDSACASA-N (S)-columbianetin Chemical compound C1=CC(=O)OC2=C1C=CC1=C2C[C@@H](C(C)(O)C)O1 YRAQEMCYCSSHJG-NSHDSACASA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical class OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 240000007087 Apium graveolens Species 0.000 description 1
- 235000015849 Apium graveolens Dulce Group Nutrition 0.000 description 1
- 235000010591 Appio Nutrition 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 1
- 240000004160 Capsicum annuum Species 0.000 description 1
- 235000008534 Capsicum annuum var annuum Nutrition 0.000 description 1
- 235000007862 Capsicum baccatum Nutrition 0.000 description 1
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 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-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
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 229930191971 Edulisin Natural products 0.000 description 1
- 101150066002 GFP gene Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000009429 Ginkgo biloba extract Substances 0.000 description 1
- 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 1
- 108010060309 Glucuronidase Proteins 0.000 description 1
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 1
- 235000001287 Guettarda speciosa Nutrition 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 description 1
- 239000012097 Lipofectamine 2000 Substances 0.000 description 1
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 description 1
- 239000004909 Moisturizer Substances 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000021642 Muscular disease Diseases 0.000 description 1
- 201000009623 Myopathy Diseases 0.000 description 1
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- ZZAFFYPNLYCDEP-HNNXBMFYSA-N Rosmarinsaeure Natural products OC(=O)[C@H](Cc1cccc(O)c1O)OC(=O)C=Cc2ccc(O)c(O)c2 ZZAFFYPNLYCDEP-HNNXBMFYSA-N 0.000 description 1
- QHBZHVUGQROELI-UHFFFAOYSA-N Royal Jelly acid Natural products OCCCCCCCC=CC(O)=O QHBZHVUGQROELI-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002385 Sodium hyaluronate Polymers 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- MSCCTZZBYHQMQJ-AZAGJHQNSA-N Tocopheryl nicotinate Chemical compound C([C@@](OC1=C(C)C=2C)(C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)CC1=C(C)C=2OC(=O)C1=CC=CN=C1 MSCCTZZBYHQMQJ-AZAGJHQNSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- IJCWFDPJFXGQBN-RYNSOKOISA-N [(2R)-2-[(2R,3R,4S)-4-hydroxy-3-octadecanoyloxyoxolan-2-yl]-2-octadecanoyloxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCCCCCCCCCCCC IJCWFDPJFXGQBN-RYNSOKOISA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- XBJFCYDKBDVADW-UHFFFAOYSA-N acetonitrile;formic acid Chemical compound CC#N.OC=O XBJFCYDKBDVADW-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 229960000711 alprostadil Drugs 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- KZNIFHPLKGYRTM-UHFFFAOYSA-N apigenin Chemical compound C1=CC(O)=CC=C1C1=CC(=O)C2=C(O)C=C(O)C=C2O1 KZNIFHPLKGYRTM-UHFFFAOYSA-N 0.000 description 1
- 229940117893 apigenin Drugs 0.000 description 1
- XADJWCRESPGUTB-UHFFFAOYSA-N apigenin Natural products C1=CC(O)=CC=C1C1=CC(=O)C2=CC(O)=C(O)C=C2O1 XADJWCRESPGUTB-UHFFFAOYSA-N 0.000 description 1
- 235000008714 apigenin Nutrition 0.000 description 1
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical class CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 1
- 229960000271 arbutin Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000013528 artificial neural network Methods 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000004097 bone metabolism Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229940046731 calcineurin inhibitors Drugs 0.000 description 1
- 239000001728 capsicum frutescens Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- RZMKWKZIJJNSLQ-UHFFFAOYSA-M carpronium chloride Chemical compound [Cl-].COC(=O)CCC[N+](C)(C)C RZMKWKZIJJNSLQ-UHFFFAOYSA-M 0.000 description 1
- 229950003631 carpronium chloride Drugs 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 229940106189 ceramide Drugs 0.000 description 1
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000008406 cosmetic ingredient Substances 0.000 description 1
- 125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 235000018927 edible plant Nutrition 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 229940045109 genistein Drugs 0.000 description 1
- 235000006539 genistein Nutrition 0.000 description 1
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Natural products C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 description 1
- ZCOLJUOHXJRHDI-CMWLGVBASA-N genistein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 description 1
- 229940068052 ginkgo biloba extract Drugs 0.000 description 1
- 235000020686 ginkgo biloba extract Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 239000001685 glycyrrhizic acid Substances 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 101150054900 gus gene Proteins 0.000 description 1
- 230000003779 hair growth Effects 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- BEJNERDRQOWKJM-UHFFFAOYSA-N kojic acid Chemical compound OCC1=CC(=O)C(O)=CO1 BEJNERDRQOWKJM-UHFFFAOYSA-N 0.000 description 1
- WZNJWVWKTVETCG-UHFFFAOYSA-N kojic acid Natural products OC(=O)C(N)CN1C=CC(=O)C(O)=C1 WZNJWVWKTVETCG-UHFFFAOYSA-N 0.000 description 1
- 229960004705 kojic acid Drugs 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 238000000622 liquid--liquid extraction Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 229960003632 minoxidil Drugs 0.000 description 1
- 230000001333 moisturizer Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000004072 osteoblast differentiation Effects 0.000 description 1
- BJRNKVDFDLYUGJ-UHFFFAOYSA-N p-hydroxyphenyl beta-D-alloside Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- DOUMFZQKYFQNTF-MRXNPFEDSA-N rosemarinic acid Natural products C([C@H](C(=O)O)OC(=O)C=CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 DOUMFZQKYFQNTF-MRXNPFEDSA-N 0.000 description 1
- TVHVQJFBWRLYOD-UHFFFAOYSA-N rosmarinic acid Natural products OC(=O)C(Cc1ccc(O)c(O)c1)OC(=Cc2ccc(O)c(O)c2)C=O TVHVQJFBWRLYOD-UHFFFAOYSA-N 0.000 description 1
- 229940109850 royal jelly Drugs 0.000 description 1
- 239000005060 rubber Substances 0.000 description 1
- 210000002374 sebum Anatomy 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 239000001589 sorbitan tristearate Substances 0.000 description 1
- 235000011078 sorbitan tristearate Nutrition 0.000 description 1
- 229960004129 sorbitan tristearate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- 230000009772 tissue formation Effects 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 229950009883 tocopheryl nicotinate Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 229940045136 urea Drugs 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 150000003712 vitamin E derivatives Chemical class 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Images
Abstract
Description
本発明は、植物又は植物抽出物に含まれる活性成分を有効成分とする、NFAT(nuclear factor of activated T cells)シグナル阻害剤に関する。 The present invention relates to a NFAT (nuclear factor of activated T cells) signal inhibitor comprising an active ingredient contained in a plant or plant extract as an active ingredient.
Nuclear factor of activated T cells (以下、NFATと略称する)は、T細胞活性化に重要なInterleukin-2(IL-2)の転写を活性化する因子として発見され、免疫抑制剤であるサイクロスポリンA(以下、CsAと略称する)やタクロリムス(以下、FK506と略称する)の標的であるセリン/スレオニン脱リン酸化酵素カルシニューリンによりその転写活性調節が行われていることが報告されている(図3参照)。すなわちCsAやFK506はNFATシグナルを阻害することによりT細胞活性化を抑制する。CsAやFK506は移植免疫抑制剤としてのみならず、免疫系の関与することが知られている関節リウマチ、乾癬、アトピー性皮膚炎の治療薬としても認可されている。このようなNFATがNFAT結合配列(図3においては“NFAT site”)に結合することによって、当該NFAT結合配列より下流の遺伝子の転写が促進される系を『NFATシグナル』と称する。 Nuclear factor of activated T cells (hereinafter abbreviated as NFAT) was discovered as a factor that activates the transcription of Interleukin-2 (IL-2), which is important for T cell activation, and is an immunosuppressant cyclosporine. It has been reported that the transcriptional activity is regulated by serine / threonine phosphatase calcineurin which is a target of A (hereinafter abbreviated as CsA) and tacrolimus (hereinafter abbreviated as FK506) (FIG. 3). reference). That is, CsA and FK506 suppress T cell activation by inhibiting the NFAT signal. CsA and FK506 are approved not only as transplant immunosuppressants but also as therapeutic agents for rheumatoid arthritis, psoriasis, and atopic dermatitis, which are known to be involved in the immune system. A system in which such NFAT binds to an NFAT binding sequence (“NFAT site” in FIG. 3) to promote transcription of a gene downstream from the NFAT binding sequence is referred to as “NFAT signal”.
また、NFATは、免疫系への作用に留まらず、心筋・骨格筋の分化調節による筋組織形成、脳における神経ネットワークの形成、骨芽細胞分化調節による骨代謝など、多くの臓器で発現し、重要な役割を果たす"多機能転写因子"として捉えられるようになってきた。 Moreover, NFAT is not limited to the action on the immune system, it is expressed in many organs such as muscle tissue formation by regulating the differentiation of myocardium and skeletal muscle, formation of neural network in the brain, bone metabolism by regulating osteoblast differentiation, It has come to be understood as a "multifunctional transcription factor" that plays an important role.
NFATシグナルが生体において及ぼす役割としては上述したとおりであるが、NFATシグナルを阻害することで、免疫抑制作用(非特許文献2)、乾癬治療(非特許文献3)、アトピー性皮膚炎治療(非特許文献4)、(心)筋肥大抑制(非特許文献5)、抗リウマチ薬としての可能性(非特許文献6)及び破骨細胞分化抑制作用(非特許文献7)などが期待できると報告されている。また、前述のようにNFATは免疫性サイトカインIL-2を産生する経路を介していることから、NFATシグナル阻害剤は自己免疫疾患を含む免疫性サイトカインが関与していると考えられる疾患の治療または予防に有用である。かかる対象疾患としては、例えば各種のガン、各種白血病、各種肝炎、各種感染症、全身性エリテマトーデス、炎症性腸疾患(潰瘍性大腸炎、クローン病)、多発性硬化症、インスリン依存性糖尿病、消化性潰瘍、敗血症ショック、結核、不妊症、動脈硬化、ベーチェット病、喘息、腎炎、急性バクテリア髄膜炎、急性心筋梗塞、急性膵炎、急性ウイルス脳炎、成人呼吸促迫症候群、バクテリア肺炎、慢性膵炎、末梢血管疾患、敗血症、間質性肝疾患、時局性回腸炎、多発性硬化症などが挙げられる。したがって、新規にNFATシグナル阻害剤が同定されれば、免疫抑制剤、乾癬治療剤、アトピー性皮膚炎治療剤、(心)筋肥大抑制剤、抗リウマチ薬、骨代謝疾患治療剤及び、上記に列記したような新規な医薬用途が期待される。 The role of the NFAT signal in the living body is as described above. By inhibiting the NFAT signal, immunosuppressive action (Non-Patent Document 2), psoriasis treatment (Non-Patent Document 3), atopic dermatitis treatment (Non-Patent Document 2) Patent document 4), (heart) muscle hypertrophy suppression (non-patent document 5), possibility as an anti-rheumatic drug (non-patent document 6), osteoclast differentiation inhibitory action (non-patent document 7), etc. Has been. In addition, as described above, since NFAT is mediated by a pathway that produces the immune cytokine IL-2, NFAT signal inhibitors are used to treat diseases that are thought to involve immune cytokines including autoimmune diseases. Useful for prevention. Examples of such target diseases include various cancers, various leukemias, various hepatitis, various infectious diseases, systemic lupus erythematosus, inflammatory bowel diseases (ulcerative colitis, Crohn's disease), multiple sclerosis, insulin-dependent diabetes, digestion Ulcer, septic shock, tuberculosis, infertility, arteriosclerosis, Behcet's disease, asthma, nephritis, acute bacterial meningitis, acute myocardial infarction, acute pancreatitis, acute viral encephalitis, adult respiratory distress syndrome, bacterial pneumonia, chronic pancreatitis, peripheral Examples include vascular disease, sepsis, interstitial liver disease, localized ileitis, and multiple sclerosis. Therefore, if a new NFAT signal inhibitor is identified, an immunosuppressive agent, a psoriasis therapeutic agent, an atopic dermatitis therapeutic agent, a (heart) muscle hypertrophy inhibitor, an anti-rheumatic agent, a bone metabolic disease therapeutic agent, and the above New medical uses such as those listed are expected.
また、アンジェリカ属に属する植物又はその抽出物もしくはその含有成分について、NFATシグナルとの関連について示唆するものはない。アンジェリカ植物に含まれる成分については、非特許文献8を参照することができる。なお、現在のところ、NFATシグナル阻害活性を有する化合物としては、種々の食用植物に含まれるアピゲニン(非特許文献9)及びロスマリン酸(非特許文献10)が知られており、またNFATシグナル亢進活性を有する化合物としてゲニステイン(非特許文献11)が知られている。
In addition, there is no suggestion of a relationship with an NFAT signal for a plant belonging to the genus Angelica or an extract thereof or a component thereof. Non-patent
本願発明者らは、上述した実情に鑑み、天然物などから得られる安全で副作用がなく、有効なNFATシグナル阻害剤を提供することを目的とする。 In view of the above-described circumstances, the present inventors have aimed to provide an effective NFAT signal inhibitor that is safe and free from side effects obtained from natural products and the like.
本発明者らは、上記課題を解決するため鋭意研究を行った結果、アメリカンアンジェリカ(Angelica atropurpurea)の抽出物に含まれ、NFATシグナル阻害活性に寄与する活性成分の同定に成功し、本発明を完成するに至った。本発明は以下を包含する。 As a result of intensive studies to solve the above-mentioned problems, the present inventors have succeeded in identifying an active ingredient contained in an extract of American Angelica (Angelica atropurpurea) and contributing to NFAT signal inhibitory activity. It came to be completed. The present invention includes the following.
本発明に係るNFATシグナル阻害剤は、次の一般式(I):
ここで、上記一般式(I)中R1がアンゲロイル基、イソバレロイル基及びセネシオイル基からなる群から選ばれる少なくとも1種の官能基であり、R2はアンゲロイル基、イソバレロイル基、2メチルブチル基及びセネシオイル基からなる群から選ばれる少なくとも1種の官能基であることが好ましい。 Here, in the general formula (I), R1 is at least one functional group selected from the group consisting of an angeloyl group, an isovaleroyl group, and a senecioyl group, and R2 is an angeloyl group, an isovaleroyl group, a 2-methylbutyl group, and a senecioyl group. It is preferably at least one functional group selected from the group consisting of
さらに上記一般式(I)で表されるクマリン誘導体が、アルカンジェリシン、3’-angeloyloxy-4’-isovaleryloxy-2’,3’-dihydrooroselol、3’-angeloyloxy-4’-senecioyloxy-2’,3’-dihydrooroselol及び3’-hydroxy-4’-angeloyloxy-2’,3’-dihydrooroselolからなる群より選択される少なくとも1種の化合物であることが好ましい。 Furthermore, coumarin derivatives represented by the above general formula (I) are arcangelicin, 3'-angeloyloxy-4'-isovaleryloxy-2 ', 3'-dihydrooroselol, 3'-angeloyloxy-4'-senecioyloxy-2', It is preferably at least one compound selected from the group consisting of 3'-dihydrooroselol and 3'-hydroxy-4'-angeloyloxy-2 ', 3'-dihydrooroselol.
一方、本発明者らは、上記NFATシグナル阻害剤に含まれる化合物のなかで新規化合物を同定するに至った。すなわち、本発明に係る新規化合物は、次の一般式(III)で示される化合物である On the other hand, the present inventors came to identify a novel compound among the compounds contained in the NFAT signal inhibitor. That is, the novel compound according to the present invention is a compound represented by the following general formula (III)
本発明によれば、NFATシグナルを阻害するといった新規機能を有する活性成分を含むNFATシグナル阻害剤を提供することができる。また、本発明によれば、NFATシグナル阻害活性を有する新規化合物を提供することができる。 ADVANTAGE OF THE INVENTION According to this invention, the NFAT signal inhibitor containing the active ingredient which has a novel function of inhibiting an NFAT signal can be provided. Further, according to the present invention, a novel compound having NFAT signal inhibitory activity can be provided.
以下、本発明を詳細に説明する。
本発明に係るNFATシグナル阻害剤は、アメリカンアンジェリカ植物又は当該植物の抽出物などから得ることが出来る。ここで、アメリカンアンジェリカとは、学名をAngelica atropurpureaと称し、セリ科に分類される植物である。
Hereinafter, the present invention will be described in detail.
The NFAT signal inhibitor according to the present invention can be obtained from an American Angelica plant or an extract of the plant. Here, American Angelica is a plant that has the scientific name Angelica atropurpurea and is classified into the celery family.
ここで活性成分とは、次の一般式(I)で示されるクマリン誘導体若しくは薬理学的に許容されるその塩である。一般式(I)に示すように、活性成分は、クマリン誘導体の中でもアンギュラー型クマリン誘導体である。 Here, the active ingredient is a coumarin derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof. As shown in the general formula (I), the active ingredient is an angular type coumarin derivative among coumarin derivatives.
上記一般式(I)中、R1及びR2は水素原子又は一般式(II):
すなわち、活性成分として使用できるクマリン誘導体は、上述のように規定したR1、R2及びR3の範囲で種々の化合物を含むことになる。特に、上記R1としては、アンゲロイル基、イソバレロイル基及びセネシオイル基からなる群から選ばれる官能基であることが好ましい。また、上記R2はアンゲロイル基、イソバレロイル基、2メチルブチル基及びセネシオイル基からなる群から官能基であることが好ましい。さらに、上記R2がアンゲロイル基、イソバレロイル基、2メチルブチル基又はセネシオイル基であるクマリン誘導体を、脱アシル化することによってクマリン骨格の3'位をヒドロキシル基(上記R2が水素原子の場合に相当)とすることができる。 That is, the coumarin derivative that can be used as the active ingredient includes various compounds within the range of R1, R2, and R3 defined as described above. In particular, R1 is preferably a functional group selected from the group consisting of an angeloyl group, an isovaleroyl group, and a senecioyl group. R2 is preferably a functional group from the group consisting of an angeloyl group, an isovaleroyl group, a 2-methylbutyl group, and a senecioyl group. Further, by deacylating a coumarin derivative in which R2 is an angeloyl group, isovaleroyl group, 2methylbutyl group or senecioyl group, the 3 ′ position of the coumarin skeleton is converted into a hydroxyl group (corresponding to the case where R2 is a hydrogen atom). can do.
なかでも、活性成分としては、R1がアンゲロイル基であり、R2がアンゲロイル基であるクマリン誘導体、R1がイソバレロイル基であり、R2がアンゲロイル基であるクマリン誘導体、及びR1がセネシオイル基であり、R2がアンゲロイル基であるクマリン誘導体であることが好ましい。また、活性成分としては、これらクマリン誘導体を脱アシル化して得られるアンギュラー型フロクマリン誘導体も好ましい。 Among them, as active ingredients, R1 is an angeloyl group, R2 is an angeloyl group, a coumarin derivative, R1 is an isovaleroyl group, R2 is an angeloyl group, and R1 is a senecioyl group, R2 is A coumarin derivative that is an angeloyl group is preferred. Moreover, as an active ingredient, the angular type furocoumarin derivative obtained by deacylating these coumarin derivatives is also preferable.
特に、R1がアンゲロイル基であり、R2がアンゲロイル基であるクマリン誘導体はアルカンジェリシンとして抗腫瘍、抗炎症作用が知られた化合物である。また、R1がイソバレロイル基であり、R2がアンゲロイル基であるクマリン誘導体、例えば3’-angeloyloxy-4’-isovaleryloxy-2’,3’-dihydrooroselolは、本発明においてNFATシグナル阻害活性を有することが明らかになった公知化合物である。さらに、R1がセネシオイル基であり、R2がアンゲロイル基であるクマリン誘導体、例えば3’-angeloyloxy-4’-senecioyloxy-2’,3’-dihydrooroselolは、NFATシグナル阻害活性を有する新規化合物である。
In particular, a coumarin derivative in which
なお、上述したクマリン誘導体におけるNFATシグナル阻害活性は以下のように測定することができる。ここでNFATシグナル阻害とは、NFATに対して直接的又は間接的に作用してNFATによる転写促進活性を低減させることを意味する。NFATシグナル阻害作用を測定する方法としては、特に限定されないが、例えば公知のNFAT結合配列と当該NFAT結合配列の下流にレポーター遺伝子と有するプラスミドを導入した宿主を用いるレポーターアッセイを挙げることができる。なお、NFATの活性はカルシウムイオンに依存するため、レポーターアッセイはカルシウムイオンを宿主に流入させる条件下で行う。レポーター遺伝子としては、特に限定されず、従来、生化学実験の分野で使用されている如何なるレポーター遺伝子も使用することができる。例えばレポーター遺伝子としては、ルシフェラーゼ遺伝子、βグルクロニダーゼ遺伝子(GUS遺伝子)及びグリーンフルオレセントプロテイン遺伝子(GFP遺伝子)等を挙げることができる。 In addition, the NFAT signal inhibitory activity in the coumarin derivative mentioned above can be measured as follows. Here, NFAT signal inhibition means reducing the transcription promoting activity by NFAT by acting directly or indirectly on NFAT. The method for measuring the NFAT signal inhibitory action is not particularly limited. For example, a reporter assay using a host in which a known NFAT binding sequence and a plasmid having a reporter gene downstream of the NFAT binding sequence are introduced. Since the activity of NFAT depends on calcium ions, the reporter assay is performed under conditions where calcium ions are allowed to flow into the host. The reporter gene is not particularly limited, and any reporter gene conventionally used in the field of biochemical experiments can be used. For example, examples of the reporter gene include luciferase gene, β-glucuronidase gene (GUS gene), and green fluorescent protein gene (GFP gene).
NFAT結合配列とは、NFATが結合する配列からなるオリゴヌクレオチド、例えば、配列番号1に示すGGAGGAAAAACTGTTTCATACAGAAGGCGT(pNFAT-Luc、Stratagene)といった塩基配列を例示することができる。なお、上述したプラスミドにおいては、このようなNFAT結合配列を1セットとして複数セットを連結して導入してもよい。複数のNFAT結合配列を連結して使用することによって、NFATによる転写促進活性をより高感度に測定することができる。なお、NFATシグナル阻害活性は、上述したレポーターアッセイから算出したNFATシグナル阻害率として評価することができる。 Examples of the NFAT binding sequence include an oligonucleotide consisting of a sequence to which NFAT binds, for example, a base sequence such as GGAGGAAAAACTGTTTCATACAGAAGGCGT (pNFAT-Luc, Stratagene) shown in SEQ ID NO: 1. In the above-described plasmid, a plurality of sets of such NFAT binding sequences may be linked and introduced. By linking and using a plurality of NFAT binding sequences, the transcription promoting activity by NFAT can be measured with higher sensitivity. The NFAT signal inhibitory activity can be evaluated as the NFAT signal inhibition rate calculated from the reporter assay described above.
一方、活性成分であるクマリン誘導体のうち、上述したアルカンジェリシン、3’-angeloyloxy-4’-isovaleryloxy-2’,3’-dihydrooroselol及び3’-angeloyloxy-4’-senecioyloxy-2’,3’-dihydrooroselolについては、例えば、アメリカンアンジェリカ植物の植物抽出物から単離することができる。アメリカンアンジェリカ植物の植物抽出物は、アメリカンアンジェリカ植物の全草、葉、茎、花、果実、種子、根茎又は根等から常温又は加温下にて抽出するか又はソックスレー抽出器等の抽出器具を用いて抽出することにより得られる。植物抽出物を得るために用いられる抽出溶剤としては、極性溶剤又は非極性溶剤のいずれをも使用することができる。抽出溶剤としては、例えば水;メタノール、エタノール、プロパノール、ブタノール等のアルコール類;プロピレングリコール、ブチレングリコール等の多価アルコール類;アセトン、メチルエチルケトン等のケトン類;酢酸メチル、酢酸エチル等のエステル類;テトラヒドロフラン、ジエチルエーテル等の鎖状及び環状エーテル類;ポリエチレングリコール等のポリエーテル類;スクワラン、ヘキサン、シクロヘキサン、石油エーテル等の炭化水素類;トルエン等の芳香族炭化水素類;ジクロロメタン、クロロホルム、ジクロロエタン等のハロゲン化炭化水素類;及び二酸化炭素等が挙げられる。あるいは、上記溶剤の2種以上を組み合わせた混合物を、抽出溶剤として用いることができる。 On the other hand, among the coumarin derivatives that are active ingredients, the above-mentioned arcangelicin, 3'-angeloyloxy-4'-isovaleryloxy-2 ', 3'-dihydrooroselol and 3'-angeloyloxy-4'-senecioyloxy-2', 3 ' -Dihydrooroselol can be isolated from a plant extract of an American Angelica plant, for example. The plant extracts of American Angelica plants are extracted from whole plants, leaves, stems, flowers, fruits, seeds, rhizomes, roots, etc. of American Angelica plants at room temperature or under heating, or using an extractor such as a Soxhlet extractor. It is obtained by using and extracting. As an extraction solvent used for obtaining a plant extract, either a polar solvent or a nonpolar solvent can be used. Examples of the extraction solvent include water; alcohols such as methanol, ethanol, propanol and butanol; polyhydric alcohols such as propylene glycol and butylene glycol; ketones such as acetone and methyl ethyl ketone; esters such as methyl acetate and ethyl acetate; Chain and cyclic ethers such as tetrahydrofuran and diethyl ether; Polyethers such as polyethylene glycol; Hydrocarbons such as squalane, hexane, cyclohexane and petroleum ether; Aromatic hydrocarbons such as toluene; Dichloromethane, chloroform, dichloroethane, etc. And halogenated hydrocarbons; and carbon dioxide. Alternatively, a mixture obtained by combining two or more of the above solvents can be used as the extraction solvent.
特に、上述したアルカンジェリシン、3’-angeloyloxy-4’-isovaleryloxy-2’,3’-dihydrooroselol及び3’-angeloyloxy-4’-senecioyloxy-2’,3’-dihydrooroselolは、95%エタノールを使用した植物抽出物から単離することができる。具体的には、上記植物等抽出物をクロマトグラフィー液々分配等の分離技術に供し、当該抽出物から不活性な夾雑物を除去することで単離することができる。また、アルカンジェリシンを脱アシル化することによって3’-hydroxy-4’-angeloyloxy-2’,3’-dihydrooroselolが得られる。 In particular, the above-mentioned arcangelicin, 3'-angeloyloxy-4'-isovaleryloxy-2 ', 3'-dihydrooroselol and 3'-angeloyloxy-4'-senecioyloxy-2', 3'-dihydrooroselol use 95% ethanol Can be isolated from plant extracts. Specifically, it can be isolated by subjecting the plant extract to a separation technique such as chromatographic liquid-liquid distribution and removing inactive impurities from the extract. Moreover, 3'-hydroxy-4'-angeloyloxy-2 ', 3'-dihydrooroselol is obtained by deacylating arcangelicin.
ただし、本発明においては、上記化学式(I)で示される化合物であれば、従来公知の化合物を活性成分として使用することができる。上記化学式(I)で示される公知化合物としては、例えば、アサマンチン(Athamantin)、シニフォリンB(Cniforin B)、エデュリシンII(Edulisin II)及びエデュリシンV(Edulisin V)を挙げることができ、活性成分として使用することができる。 However, in the present invention, a conventionally known compound can be used as an active ingredient as long as it is a compound represented by the above chemical formula (I). Examples of known compounds represented by the above chemical formula (I) include asamantin, ciforin B, edulisin II, and edulisin V, which are used as active ingredients. can do.
上述した活性成分は、NFATによる転写促進活性を低減させることから、細胞や組織におけるNFATシグナルを阻害することができる。具体的には、上述した活性成分を、対象とする細胞や組織に接触させることによって、当該細胞や組織におけるNFATシグナルを阻害することができる。これにより、当該細胞や組織においては、NFATシグナルによって生ずる種々の遺伝子発現を転写レベルで抑制することができる。 Since the active ingredient described above reduces the transcription promoting activity by NFAT, it can inhibit the NFAT signal in cells and tissues. Specifically, the NFAT signal in the cell or tissue can be inhibited by bringing the active ingredient described above into contact with the target cell or tissue. Thereby, in the cells and tissues, various gene expressions caused by NFAT signals can be suppressed at the transcription level.
本発明に係るNFATシグナル阻害剤は、NFATによる転写促進活性を低減させることから、NFATによる転写促進活性の亢進に起因する症状や疾患に対する治療剤、又は予防剤として使用することができる。NFATによる転写促進活性の亢進に起因する症状や疾患としては、免疫系疾患、乾癬、アトピー性皮膚炎、心筋を含む筋肥大症、リウマチ、骨代謝疾患、各種のガン、各種白血病、各種肝炎、各種感染症、全身性エリテマトーデス、炎症性腸疾患(潰瘍性大腸炎、クローン病)、多発性硬化症、インスリン依存性糖尿病、消化性潰瘍、敗血症ショック、結核、不妊症、動脈硬化、ベーチェット病、喘息、腎炎、急性バクテリア髄膜炎、急性心筋梗塞、急性膵炎、急性ウイルス脳炎、成人呼吸促迫症候群、バクテリア肺炎、慢性膵炎、末梢血管疾患、敗血症、間質性肝疾患、時局性回腸炎、多発性硬化症等を挙げることができる。したがって、本発明に係るNFATシグナル阻害剤は、免疫抑制剤、乾癬治療剤、(心)筋肥大抑制剤、抗リウマチ薬及び骨代謝疾患治療剤等として使用することができる。 Since the NFAT signal inhibitor according to the present invention reduces the transcription promoting activity by NFAT, it can be used as a therapeutic agent or a preventive agent for symptoms and diseases caused by the enhanced transcription promoting activity by NFAT. Symptoms and diseases resulting from the enhanced transcription promoting activity by NFAT include immune system diseases, psoriasis, atopic dermatitis, myopathy including myocardium, rheumatism, bone metabolic diseases, various cancers, various leukemias, various hepatitis, Various infections, systemic lupus erythematosus, inflammatory bowel disease (ulcerative colitis, Crohn's disease), multiple sclerosis, insulin-dependent diabetes, peptic ulcer, septic shock, tuberculosis, infertility, arteriosclerosis, Behcet's disease, Asthma, nephritis, acute bacterial meningitis, acute myocardial infarction, acute pancreatitis, acute viral encephalitis, adult respiratory distress syndrome, bacterial pneumonia, chronic pancreatitis, peripheral vascular disease, sepsis, interstitial liver disease, localized ileitis, Examples include multiple sclerosis. Therefore, the NFAT signal inhibitor according to the present invention can be used as an immunosuppressant, a psoriasis therapeutic agent, a (cardiac) muscle hypertrophy inhibitor, an anti-rheumatic drug, a bone metabolic disease therapeutic agent, and the like.
本発明に係るNFATシグナル阻害剤を医薬用途として使用する場合、剤形として、特に限定されないが、例えば散剤、顆粒剤、カプセル剤、丸剤、錠剤等の固形製剤、水剤、懸濁剤、乳剤等の液剤、軟膏剤等が挙げられる。本発明に係るNFATシグナル阻害剤を経口投与の医薬用組成物として使用する場合、上記NFATシグナル阻害剤の他、経口投与剤の形態に応じて一般に用いられる、賦形剤、崩壊剤、結合剤、滑沢剤、界面活性剤、アルコール類、水、水溶性高分子、甘味料、矯味剤、酸味料等を添加し、常法に従って製造することができる。経口投与用医薬組成物としては、免疫抑制剤、乾癬治療剤、(心)筋肥大抑制剤及び抗リウマチ薬等が挙げられる。本発明に係るNFATシグナル阻害剤を経皮投与の医薬用組成物として使用する場合、上記NFATシグナル阻害剤の他、経皮投与剤の形態に応じて一般に用いられる、植物油、動物油、合成油、脂肪酸、及び天然、合成のグリセライド等の油性基剤、滑沢剤、界面活性剤、アルコール類、増粘剤等を添加し、常法に従って製造することができる。経皮投与用医薬組成物としては、免疫抑制剤、乾癬治療剤、アトピー性皮膚炎治療剤等が挙げられる。 When the NFAT signal inhibitor according to the present invention is used for pharmaceutical purposes, the dosage form is not particularly limited, but for example, solid preparations such as powders, granules, capsules, pills, tablets, liquids, suspensions, Examples thereof include liquids such as emulsions and ointments. When the NFAT signal inhibitor according to the present invention is used as a pharmaceutical composition for oral administration, in addition to the NFAT signal inhibitor, an excipient, a disintegrant, and a binder that are generally used according to the form of the oral administration agent , Lubricants, surfactants, alcohols, water, water-soluble polymers, sweeteners, corrigents, acidulants and the like, and can be produced according to conventional methods. Examples of the pharmaceutical composition for oral administration include an immunosuppressant, a psoriasis therapeutic agent, a (heart) muscle hypertrophy inhibitor and an anti-rheumatic drug. When using the NFAT signal inhibitor according to the present invention as a pharmaceutical composition for transdermal administration, in addition to the NFAT signal inhibitor, generally used according to the form of the transdermal administration agent, vegetable oil, animal oil, synthetic oil, Fatty acids and oily bases such as natural and synthetic glycerides, lubricants, surfactants, alcohols, thickeners, and the like can be added and produced according to conventional methods. Examples of the pharmaceutical composition for transdermal administration include immunosuppressive agents, psoriasis therapeutic agents, and atopic dermatitis therapeutic agents.
一方、上述した活性成分は化粧料として使用することもできる。この場合には、剤形としては、特に限定されるものではないが、例えば、油中水型又は水中油型の乳化化粧料、クリーム、ローション、ジェル、フォーム、エッセンス、ファンデーション、パック、スティック及びパウダー等が挙げられる。当該化粧料には、上述した活性成分の他に、化粧料成分として一般に使用されている油分、界面活性剤、紫外線吸収剤、アルコール類、キレート剤、pH調整剤、防腐剤、増粘剤、色素類、香料及び各種皮膚栄養剤等を任意に組合せて配合することができる。具体的には、皮膚化粧料に配合される薬効成分、例えば微粒子酸化亜鉛、酸化チタン、パーソールMCX、パーソール1789等の紫外線吸収剤、アスコルビン酸等のビタミン類、ヒアルロン酸ナトリウム、ワセリン、グリセリン、尿素等の保湿剤、ホルモン剤、及びコウジ酸、アルブチン、プラセンタエキス、ルシノール等の他の美白成分、ステロイド剤、アラキドン酸代謝物やヒスタミン等に代表される化学伝達物質産生・放出抑制剤(インドメタシン、イブプロフェン)、レセプター拮抗剤等の抗炎症剤、抗男性ホルモン剤、ビタミンA酸、ローヤルゼリーエキス、ローヤルゼリー酸等の皮脂分泌抑制剤、ニコチン酸トコフェロール、アルプロスタジル、塩酸イソクスプリン、塩酸トラゾリン等の抹消血管拡張剤及び末梢血管拡張作用のある炭酸ガス等、ミノキシジル、塩化カルプロニウム、トウガラシチンキ、ビタミンE誘導体、イチョウエキス、センブリエキス等の血行促進剤、ペンタデカン酸グリセリド、ニコチン酸アミド等の細胞賦活化剤、ヒノキチオール、L-メントール、イソプロピルメチルフェノール等の殺菌剤、グリチルリチン酸およびその誘導体またはその塩等の薬剤、セラミド及びセラミド類似化合物等を添加配合することができる。 On the other hand, the active ingredient mentioned above can also be used as a cosmetic. In this case, the dosage form is not particularly limited, and examples thereof include water-in-oil or oil-in-water emulsified cosmetics, creams, lotions, gels, foams, essences, foundations, packs, sticks, and the like. Powder etc. are mentioned. In addition to the above-mentioned active ingredients, the cosmetics include oils, surfactants, ultraviolet absorbers, alcohols, chelating agents, pH adjusters, preservatives, thickeners, which are commonly used as cosmetic ingredients. Pigments, fragrances, various skin nutrients, and the like can be combined in any combination. Specifically, medicinal ingredients blended in skin cosmetics, for example, ultraviolet absorbers such as fine particle zinc oxide, titanium oxide, persole MCX, persole 1789, vitamins such as ascorbic acid, sodium hyaluronate, petrolatum, glycerin, urea Moisturizers such as humectants, hormonal agents, and other whitening ingredients such as kojic acid, arbutin, placenta extract, lucinol, steroids, arachidonic acid metabolites and histamine, and other chemical transmitter production / release inhibitors (indomethacin, Ibuprofen), anti-inflammatory agents such as receptor antagonists, anti-androgen agents, vitamin A acid, royal jelly extract, sebum secretion inhibitors such as royal jelly acid, peripheral blood vessels such as tocopherol nicotinate, alprostadil, isoxpurine hydrochloride, and trazoline hydrochloride Dilator and peripheral vasodilatory effect Certain carbon dioxide, minoxidil, carpronium chloride, red pepper tincture, vitamin E derivatives, ginkgo biloba extract, assembly extract, etc. Bactericides such as phenol, glycyrrhizic acid and its derivatives or salts thereof, ceramide and ceramide-like compounds, etc. can be added and blended.
上述した活性成分を医薬、医薬部外品又は化粧料として使用する場合、配合量は、通常、医薬、医薬部外品又は化粧料の全組成の0.00001〜5重量%、特に0.0001〜0.1重量%とすることが好ましい。また、本発明に係るNFATシグナル阻害剤を医薬として用いる場合、上述した活性成分の投与量は、通常の成人で0.01mg〜1g/1日とすることが望ましい。 When the above-mentioned active ingredient is used as a medicine, quasi-drug or cosmetic, the compounding amount is usually 0.00001 to 5% by weight, particularly 0.0001 to 0.1% by weight, based on the total composition of the drug, quasi-drug or cosmetic. It is preferable that Moreover, when using the NFAT signal inhibitor based on this invention as a pharmaceutical, it is desirable that the dosage of the active ingredient mentioned above shall be 0.01 mg-1 g / day in a normal adult.
また、上述した活性成分を化粧品、医薬又は医薬部外品として使用する場合、例えばチョーク、タルク、フラー土、カオリン、デンプン、ゴム、コロイドシリカナトリウムポリアクリレート等の粉体;例えば鉱油、植物油、シリコーン油等の油又は油状物質;例えばソルビタントリオレエート、ソルビタントリステアレート、グリセロールモノオレエート、高分子シリコーン界面活性剤等の乳化剤;パラ−ヒドロキシベンゾエートエステル等の防腐剤;ブチルヒドロキシトルエン等の酸化防止剤;グリセロール、ソルビトール、2−ピロリドン−5−カルボキシレート、ジブチルフタレート、ゼラチン、ポリエチレングリコール等の湿潤剤;トリエタノールアミン又は水酸化ナトリウムのような塩基を伴う乳酸等の緩衝剤;グリセリン脂肪酸エステル、ソルビタン脂肪酸エステル、ショ糖脂肪酸エステル、アルキルグルコシド等の界面活性剤;密ろう、オゾケライトワックス、パラフィンワックス等のワックス類;増粘剤;活性増強剤;着色料;香料等、を必要に応じ適宜組合せて用いることができる。 When the above-mentioned active ingredient is used as cosmetics, medicines or quasi drugs, for example, powders such as chalk, talc, fuller's earth, kaolin, starch, rubber, colloidal silica sodium polyacrylate; for example mineral oil, vegetable oil, silicone Oils or oily substances such as oils; for example, emulsifiers such as sorbitan trioleate, sorbitan tristearate, glycerol monooleate, polymeric silicone surfactants; preservatives such as para-hydroxybenzoate esters; antioxidants such as butylhydroxytoluene Agents; wetting agents such as glycerol, sorbitol, 2-pyrrolidone-5-carboxylate, dibutyl phthalate, gelatin, polyethylene glycol; buffers such as lactic acid with a base such as triethanolamine or sodium hydroxide; glycerin fatty acid Requires surfactants such as stealth, sorbitan fatty acid esters, sucrose fatty acid esters, alkyl glucosides; waxes such as beeswax, ozokerite wax, paraffin wax; thickeners; activity enhancers; coloring agents; Can be used in appropriate combinations.
以下、実施例により本発明をさらに具体的に説明する。但し、本発明はこれら実施例にその技術的範囲が限定されるものではない。
〔実施例1〕アメリカンアンジェリカからの活性成分類の単離
(1)図1に示す工程に従って、アメリカンアンジェリカ(Angelica atropurpurea(セリ科)の根茎から本発明の化合物「成分A」、「成分B」及び「成分C」を単離した。
Hereinafter, the present invention will be described more specifically with reference to examples. However, the technical scope of the present invention is not limited to these examples.
Example 1 Isolation of Active Ingredients from American Angelica (1) According to the process shown in FIG. 1, the compounds “Component A” and “Component B” of the present invention were obtained from the root of American Angelica (Angelica atropurpurea). And “Component C” was isolated.
(2)アンジェリカ(Angelica atropurpurea)の根茎(160g)を95%エタノール-水(1.6L)に5日間浸漬して抽出し、95%エタノール-水抽出液を得た。この抽出液をろ過後、ロータリーエバポレーターで濃縮し、固形分14.3gを得た。この濃縮乾固物1gを中圧ODSカラムクロマトグラフィ(内径2.6×30cm)に付し、アセトニトリル-0.1% TFA系で溶出し以下の画分(fr. A〜K)を得た。
fr. A: 0.23 g
fr. B: 0.01 g
fr. C: 0.03 g
fr. D: 0.07 g
fr. E: 0.05 g
fr. F: 0.02 g
fr. G: 0.02 g
fr. H: 0.15 g
fr. I: 0.24 g
fr. J: 0.10 g
fr. K: 0.03 g
(2) Angelica atropurpurea rhizome (160 g) was extracted by immersing it in 95% ethanol-water (1.6 L) for 5 days to obtain a 95% ethanol-water extract. The extract was filtered and then concentrated on a rotary evaporator to obtain 14.3 g of a solid content. 1 g of this concentrated dried product was subjected to medium pressure ODS column chromatography (inner diameter 2.6 × 30 cm) and eluted with acetonitrile-0.1% TFA system to obtain the following fractions (fr. A to K).
fr. A: 0.23 g
fr. B: 0.01 g
fr. C: 0.03 g
fr. D: 0.07 g
fr. E: 0.05 g
fr. F: 0.02 g
fr. G: 0.02 g
fr. H: 0.15 g
fr. I: 0.24 g
fr. J: 0.10 g
fr. K: 0.03 g
(3)上記(2)で得られたfr. I(0.24g)を分取高速液体クロマトグラフィ(内径10×250mm)に付し、アセトニトリル-0.1% TFA系(58%)系で溶出し、以下の画分(fr. I-1〜I-8)を得た。
fr. I - 1: 46.5 mg
fr. I - 2: 27.6 mg
fr. I - 3: 3.4 mg
fr. I - 4: 6.3 mg
fr. I - 5: 18.8 mg
fr. I - 6: 84.6 mg
fr. I - 7: 5.4 mg
fr. I - 8: 46.9 mg
本発明の化合物は、分析の結果、fr. I-6(成分A)、fr. I-8(成分B)、fr. I-5(成分C)にほぼ単一化合物として得られた。
(3) The fr.I (0.24g) obtained in (2) above was subjected to preparative high performance liquid chromatography (inner diameter 10 × 250mm) and eluted with acetonitrile-0.1% TFA system (58%) system. Fractions (fr. I-1 to I-8) were obtained.
fr.I-1: 46.5 mg
fr. I-2: 27.6 mg
fr.I-3: 3.4 mg
fr. I-4: 6.3 mg
fr. I-5: 18.8 mg
fr. I-6: 84.6 mg
fr. I-7: 5.4 mg
fr. I-8: 46.9 mg
As a result of analysis, the compound of the present invention was obtained as an almost single compound in fr. I-6 (component A), fr. I-8 (component B), and fr. I-5 (component C).
〔実施例2〕成分A、成分B及び成分Cの同定
(1)実施例1で得られた化合物について、1H NMR解析及び13C NMR解析を行った。
1H NMR(500 MHz, CDCl3)及び13C NMR(125 MHz, CDCl3)解析の結果として得られたデータを表1に示す。
[Example 2] Identification of component A, component B and component C (1) The compound obtained in Example 1 was subjected to 1 H NMR analysis and 13 C NMR analysis.
Table 1 shows data obtained as a result of 1 H NMR (500 MHz, CDCl 3 ) and 13 C NMR (125 MHz, CDCl 3 ) analysis.
(2)表1に示した解析結果より、成分A、成分B及び成分Cの化合物は下記構造を有するアンギュラー型フロクマリン誘導体であることが示された。 (2) From the analysis results shown in Table 1, it was shown that the compounds of Component A, Component B and Component C are angular furocoumarin derivatives having the following structure.
すなわち、成分A、成分B及び成分Cは、それぞれアルカンジェリシン、3’-angeloyloxy-4’-isovaleryloxy-2’,3’-dihydrooroselol及び3’-angeloyloxy-4’-senecioyloxy-2’,3’-dihydrooroselolであることが判った。ここで、成分Cの3’-angeloyloxy-4’-senecioyloxy-2’,3’-dihydrooroselolは過去に報告例がなく、新規化合物であった。 That is, component A, component B and component C are each an alkangelicin, 3'-angeloyloxy-4'-isovaleryloxy-2 ', 3'-dihydrooroselol and 3'-angeloyloxy-4'-senecioyloxy-2', 3 ' -It was found to be dihydrooroselol. Here, 3'-angeloyloxy-4'-senecioyloxy-2 ', 3'-dihydrooroselol of component C was a novel compound with no report in the past.
〔実施例3〕成分A(アルカンジェリシン)の脱アシル体の調製
本例では、実施例1及び2で成分Aとして単離したアルカンジェリシンの脱アシル化を行った。まず、成分A(70mg)を7mLのアセトンに溶解後、濃アンモニア水7mLを添加し、室温で一昼夜攪拌した。反応液を濃縮後(75mg)、分取高速液体クロマトグラフィ(内径10×250mm)に付し、0.1%ギ酸-アセトニトリル系で溶出し、主生成物を分取した(17mg)。
[Example 3] Preparation of deacylated form of component A (alkangelicin) In this example, the desacylation of the arcangelicin isolated as component A in Examples 1 and 2 was performed. First, component A (70 mg) was dissolved in 7 mL of acetone, 7 mL of concentrated aqueous ammonia was added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated (75 mg), subjected to preparative high performance liquid chromatography (inner diameter 10 × 250 mm), and eluted with 0.1% formic acid-acetonitrile system to fractionate the main product (17 mg).
〔実施例4〕成分A(アルカンジェリシン)の脱アシル体の同定
(1)実施例3で得られた化合物について、1H NMR解析及び13C NMR解析を行った。1H NMR(500 MHz, CDCl3)及び13C NMR(125 MHz, CDCl3)解析の結果として得られたデータを表2に示す。
[Example 4] Identification of deacylated form of component A (alcangelicin) (1) The compound obtained in Example 3 was subjected to 1 H NMR analysis and 13 C NMR analysis. The data obtained as a result of 1 H NMR (500 MHz, CDCl 3 ) and 13 C NMR (125 MHz, CDCl 3 ) analyzes are shown in Table 2.
(2)表2に示した解析分析より、実施例3における生成物はアルカンジェリシンの3’位のアンゲロイル基が脱離した、下記構造を有するアンギュラー型フロクマリン誘導体であることが示された。 (2) From the analytical analysis shown in Table 2, it was shown that the product in Example 3 was an angular furocoumarin derivative having the following structure, from which the angeloyl group at the 3'-position of the arcangelicin had been eliminated.
〔実施例5〕NFATシグナル阻害効果
本例では、実施例1で得られた成分A、成分B及び成分C並びに実施例3で調製した成分Aの脱アシル体についてのNFATシグナル阻害効果を検証した。
[Example 5] NFAT signal inhibitory effect In this example, the NFAT signal inhibitory effect of the component A, component B and component C obtained in Example 1 and the deacylated form of component A prepared in Example 3 was verified. .
(1)評価システムのための材料及び方法
細胞培養
上記評価システムには、ヒト腎(HEK293)細胞をATCC(American Type Culture Collection)より購入し、使用した。HEK293細胞は、DMEM(High glucose、10% heat-inactivated FBS)中37℃、5% CO2条件下で培養した。
(1) Materials and methods for evaluation systems
Cell culture In the above evaluation system, human kidney (HEK293) cells were purchased from ATCC (American Type Culture Collection) and used. HEK293 cells were cultured in DMEM (High glucose, 10% heat-inactivated FBS) at 37 ° C. and 5% CO 2 .
プラスミド、トランスフェクション
上記評価システムには、NFAT結合配列の下流にホタルルシフェラーゼが導入されたプラスミドpNFAT-Luc(Stratagene)をHEK293細胞にトランスフェクションしたものを使用した。詳細には、NFAT転写活性の評価用に4連のNFAT結合配列の下流にホタルルシフェラーゼ遺伝子が導入されたpNFAT-luc(STRATAGENE)をHEK293細胞にトランスフェクションした。また、トランスフェクション効率によるばらつきをなくすことを目的として、ホタルルシフェラーゼに由来するシグナルを補正するためにCMV promoterの下流にウミシイタケルシフェラーゼが導入されたpRL-CMV(Promega)を同時にトランスフェクションした。
Plasmid and Transfection The HEK293 cells were transfected with plasmid pNFAT-Luc (Stratagene) in which firefly luciferase was introduced downstream of the NFAT binding sequence. Specifically, pNFAT-luc (STRATAGENE) in which a firefly luciferase gene was introduced downstream of a quadruple NFAT binding sequence was transfected into HEK293 cells for evaluation of NFAT transcriptional activity. In addition, in order to eliminate variation due to transfection efficiency, pRL-CMV (Promega) in which a Renilla luciferase was introduced downstream of the CMV promoter was simultaneously transfected in order to correct a signal derived from firefly luciferase.
トランスフェクションは、LipofectAMINE 2000 reagent(Invitrogen)を用いて使用説明書に従って行った。トランスフェクションの8時間後に培地を交換し、一晩インキュベートした。その後、実施例1で得られた成分A、成分B及び成分C並びに実施例3で調製した成分Aの脱アシル体を添加し、その1時間後に1μM Ionomycinを添加した。8時間後、ルシフェラーゼレポーターアッセイを行った。 Transfection was performed using LipofectAMINE 2000 reagent (Invitrogen) according to the instruction manual. The medium was changed 8 hours after transfection and incubated overnight. Thereafter, component A, component B and component C obtained in Example 1 and the deacylated form of component A prepared in Example 3 were added, and 1 μM Ionomycin was added 1 hour later. After 8 hours, a luciferase reporter assay was performed.
ルシフェラーゼレポーターアッセイ
ルシフェラーゼレポーターアッセイは、Dual-Glo Luciferase Assay System(Promega)を用い、使用説明書に従って行った。すなわち、培地を除去後、PBSにより2倍希釈したDual-Glo luciferase reagentを加え、攪拌した後、20分後にホタルルシフェラーゼ活性を測定した。その後、等量のDual-Glo Stop&Glo reagentを加え、攪拌した後にウミシイタケルシフェラーゼ活性を測定した。ルシフェラーゼ活性測定はMiniLumat LB 9506(EG&G BERTHOLD)を用いて行い、ルシフェラーゼによる発光量を定量的に検出した。双方ともルシフェラーゼ活性の測定時間は2秒とした。
Luciferase reporter assay The luciferase reporter assay was performed using Dual-Glo Luciferase Assay System (Promega) according to the instruction manual. That is, after removing the medium, Dual-Glo luciferase reagent diluted 2-fold with PBS was added, stirred, and firefly luciferase activity was measured 20 minutes later. Thereafter, an equal amount of Dual-Glo Stop & Glo reagent was added and stirred, and then Renilla luciferase activity was measured. The luciferase activity was measured using MiniLumat LB 9506 (EG & G BERTHOLD), and the amount of luminescence by luciferase was quantitatively detected. In both cases, the measurement time for luciferase activity was 2 seconds.
NFATシグナル阻害率の算出
全てのNFAT転写活性(ホタルルシフェラーゼ活性)はトランスフェクション効率補正のために導入されたウミシイタケルシフェラーゼ活性にて除することで補正した。その後、NFATシグナル阻害率を以下の式にて算出した。
NFATシグナル阻害率(%)=100−(試験サンプル及びIonomycin添加群−無刺激群)/(Ionomycinのみ添加群−無刺激群)×100
上記計算により、Ionomycin刺激によるNFATシグナル活性化をテストサンプルが何%阻害したかについて算出することができる。
Calculation of NFAT signal inhibition rate All NFAT transcriptional activity (firefly luciferase activity) was corrected by dividing by the Renilla luciferase activity introduced for transfection efficiency correction. Thereafter, the NFAT signal inhibition rate was calculated by the following formula.
NFAT signal inhibition rate (%) = 100− (test sample and Ionomycin added group−unstimulated group) / (Ionomycin only added group−unstimulated group) × 100
Based on the above calculation, it is possible to calculate how much the test sample inhibited NFAT signal activation by Ionomycin stimulation.
結果
NFATシグナル阻害率を算出した結果を図2に示す。図2から判るように、実施例1で得られた成分A、成分B及び成分C並びに実施例3で調製した成分Aの脱アシル体は、いずれもNFATシグナルを阻害した。すなわち、成分A、成分B及び成分Aの脱アシル体は、NFATにより正に制御される転写を抑制することができる。したがって、成分A、成分B及び成分Aの脱アシル体は、優れたNFATシグナル阻害剤であり、例えば免疫抑制剤、乾癬治療剤、アトピー性皮膚炎治療剤、(心)筋肥大抑制剤及び抗リウマチ薬等の候補物質として同定されたこととなる。
result
The results of calculating the NFAT signal inhibition rate are shown in FIG. As can be seen from FIG. 2, component A, component B and component C obtained in Example 1 and the deacylated form of component A prepared in Example 3 all inhibited the NFAT signal. That is, the deacylated form of component A, component B, and component A can suppress transcription that is positively controlled by NFAT. Therefore, the deacylated form of component A, component B and component A are excellent NFAT signal inhibitors, such as immunosuppressants, psoriasis treatment agents, atopic dermatitis treatment agents, (heart) muscle hypertrophy inhibitor and anti-antibody agents. It was identified as a candidate substance such as a rheumatic drug.
Claims (4)
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2008271078A JP5339848B2 (en) | 2008-10-21 | 2008-10-21 | NFAT signal inhibitor and novel compound having NFAT signal inhibitory activity |
US13/124,521 US8420836B2 (en) | 2008-10-21 | 2009-10-21 | NFAT signal inhibitor and hair-growing agent |
PCT/JP2009/005523 WO2010047103A1 (en) | 2008-10-21 | 2009-10-21 | Nfat signal inhibitor and hair-growing agent |
CN200980140484.7A CN102177162B (en) | 2008-10-21 | 2009-10-21 | NFAT signal inhibitor and hair-growing agent |
EP09821803.5A EP2348025B1 (en) | 2008-10-21 | 2009-10-21 | Nfat signal inhibitor and hair-growing agent |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2008271078A JP5339848B2 (en) | 2008-10-21 | 2008-10-21 | NFAT signal inhibitor and novel compound having NFAT signal inhibitory activity |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2010100537A true JP2010100537A (en) | 2010-05-06 |
JP5339848B2 JP5339848B2 (en) | 2013-11-13 |
Family
ID=42291523
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008271078A Expired - Fee Related JP5339848B2 (en) | 2008-10-21 | 2008-10-21 | NFAT signal inhibitor and novel compound having NFAT signal inhibitory activity |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP5339848B2 (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002066041A1 (en) * | 2001-02-23 | 2002-08-29 | Herbal Detox Therapy Aps | Natural composition |
-
2008
- 2008-10-21 JP JP2008271078A patent/JP5339848B2/en not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002066041A1 (en) * | 2001-02-23 | 2002-08-29 | Herbal Detox Therapy Aps | Natural composition |
Non-Patent Citations (5)
Title |
---|
JPN6013016289; Planta Medica Vol.64, No.2, 1998, p.174-176 * |
JPN6013016290; Planta Medica Vol.57, No.3, 1991, p.242-246 * |
JPN6013016293; Planta Medica Vol.60, No.4, 1994, p.333-336 * |
JPN6013016295; Cancer Letters Vol.201, No.2, 2003, p.133-137 * |
JPN6013016298; Pharmaceutical and Pharmacological Letters Vol.7, No.4, 1997, p.157-160 * |
Also Published As
Publication number | Publication date |
---|---|
JP5339848B2 (en) | 2013-11-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2009051740A (en) | Nfat signal inhibitor and nfat signal inhibition method | |
JP5527951B2 (en) | External preparation, hair restorer, NFAT signal inhibitor and calcineurin inhibitor | |
US8808758B2 (en) | NFAT signal inhibitor and calcineurin inhibitor | |
US8420836B2 (en) | NFAT signal inhibitor and hair-growing agent | |
JP2009051741A (en) | Nfat signal inhibitor and nfat signal inhibition method | |
JP5339848B2 (en) | NFAT signal inhibitor and novel compound having NFAT signal inhibitory activity | |
JP5351488B2 (en) | NFAT signal inhibitor and hair restorer, and novel compound having NFAT signal inhibitory and hair growth activity | |
JP2019199437A (en) | Skin external preparation | |
JP5547381B2 (en) | Hair restorer and NFAT signal inhibitor | |
JP2013060460A (en) | Nfat signal inhibitor and nfat signal-inhibiting method | |
JP5946510B2 (en) | Melanin production inhibitor, cosmetic, and method for producing melanin production inhibitor | |
JP2010001227A (en) | Hair-growing agent, nfat signal inhibitor and calcineurin inhibitor | |
KR102501845B1 (en) | Composition for skin regeneration and wound healing comprising the extract of Cynanchum wilfordii as an active ingredient | |
JP7325779B1 (en) | CD39 expression promoter | |
JP2010100536A (en) | Hair growing agent | |
JP2010013403A (en) | Nfat signal inhibitor and nfat signal-inhibiting method | |
JP2013166731A (en) | Endothelin activity inhibitor and whitening agent | |
JP5405782B2 (en) | Ceramide production promoter and moisturizer | |
JP2010208973A (en) | Il-8 and gm-csf expression inhibitor | |
WO2020230331A1 (en) | Apj expression promoter | |
KR101920260B1 (en) | External composition comprising a melanogenesis inhibitor | |
KR20230018694A (en) | Composition for Skin Whitening Comprising Phaitanthrin A | |
JP5620657B2 (en) | Sunburn cell formation inhibitor | |
KR20210143901A (en) | Novel compounds and their uses | |
JP5604077B2 (en) | Skin preparation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20110421 |
|
RD03 | Notification of appointment of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7423 Effective date: 20120416 |
|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20120417 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130409 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130610 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20130709 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20130806 |
|
R151 | Written notification of patent or utility model registration |
Ref document number: 5339848 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R151 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |