JP5548363B2 - 新規な蛍光染料およびその使用 - Google Patents
新規な蛍光染料およびその使用 Download PDFInfo
- Publication number
- JP5548363B2 JP5548363B2 JP2008537196A JP2008537196A JP5548363B2 JP 5548363 B2 JP5548363 B2 JP 5548363B2 JP 2008537196 A JP2008537196 A JP 2008537196A JP 2008537196 A JP2008537196 A JP 2008537196A JP 5548363 B2 JP5548363 B2 JP 5548363B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- enzyme
- substrate
- dye
- fluorescence lifetime
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000007850 fluorescent dye Substances 0.000 title claims description 23
- 238000000034 method Methods 0.000 claims description 69
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 52
- 239000000758 substrate Substances 0.000 claims description 42
- 150000001875 compounds Chemical class 0.000 claims description 41
- -1 succinimidyl ester Chemical class 0.000 claims description 41
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 38
- 239000000975 dye Substances 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 29
- 102000004190 Enzymes Human genes 0.000 claims description 26
- 108090000790 Enzymes Proteins 0.000 claims description 26
- 229940088598 enzyme Drugs 0.000 claims description 26
- 125000004429 atom Chemical group 0.000 claims description 21
- 238000003776 cleavage reaction Methods 0.000 claims description 19
- 102000004169 proteins and genes Human genes 0.000 claims description 18
- 108090000623 proteins and genes Proteins 0.000 claims description 18
- 230000007017 scission Effects 0.000 claims description 18
- 125000003277 amino group Chemical group 0.000 claims description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 230000027455 binding Effects 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 13
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 12
- 230000002829 reductive effect Effects 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 239000012491 analyte Substances 0.000 claims description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 10
- 125000000524 functional group Chemical group 0.000 claims description 10
- 210000004027 cell Anatomy 0.000 claims description 9
- 230000008859 change Effects 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 125000000542 sulfonic acid group Chemical group 0.000 claims description 9
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 229910019142 PO4 Inorganic materials 0.000 claims description 7
- NIXOWILDQLNWCW-UHFFFAOYSA-M acrylate group Chemical group C(C=C)(=O)[O-] NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000003368 amide group Chemical group 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 238000003384 imaging method Methods 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000005504 styryl group Chemical group 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 238000002372 labelling Methods 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
- 239000010452 phosphate Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 239000000523 sample Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical group CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 3
- 150000001720 carbohydrates Chemical class 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 239000005556 hormone Substances 0.000 claims description 3
- 229940088597 hormone Drugs 0.000 claims description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 3
- 238000012360 testing method Methods 0.000 claims description 3
- IHDBZCJYSHDCKF-UHFFFAOYSA-N 4,6-dichlorotriazine Chemical compound ClC1=CC(Cl)=NN=N1 IHDBZCJYSHDCKF-UHFFFAOYSA-N 0.000 claims description 2
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 claims description 2
- 150000001299 aldehydes Chemical class 0.000 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- 150000001718 carbodiimides Chemical class 0.000 claims description 2
- 230000004709 cell invasion Effects 0.000 claims description 2
- 210000000170 cell membrane Anatomy 0.000 claims description 2
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 150000002540 isothiocyanates Chemical class 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 150000002632 lipids Chemical class 0.000 claims description 2
- 230000000813 microbial effect Effects 0.000 claims description 2
- 239000002773 nucleotide Substances 0.000 claims description 2
- 125000003729 nucleotide group Chemical group 0.000 claims description 2
- MCYTYTUNNNZWOK-LCLOTLQISA-N penetratin Chemical group C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CC=CC=C1 MCYTYTUNNNZWOK-LCLOTLQISA-N 0.000 claims description 2
- 108010043655 penetratin Proteins 0.000 claims description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 2
- 150000008300 phosphoramidites Chemical class 0.000 claims description 2
- 125000004437 phosphorous atom Chemical group 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 239000013077 target material Substances 0.000 claims description 2
- 239000003053 toxin Substances 0.000 claims description 2
- 231100000765 toxin Toxicity 0.000 claims description 2
- 108700012359 toxins Proteins 0.000 claims description 2
- 230000009870 specific binding Effects 0.000 claims 4
- 108090000631 Trypsin Proteins 0.000 claims 3
- 102000004142 Trypsin Human genes 0.000 claims 3
- 239000012588 trypsin Substances 0.000 claims 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims 2
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical group C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 claims 2
- 102000035195 Peptidases Human genes 0.000 claims 2
- 108091005804 Peptidases Proteins 0.000 claims 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 claims 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 claims 2
- 239000004365 Protease Substances 0.000 claims 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims 2
- 241000251468 Actinopterygii Species 0.000 claims 1
- 108700023418 Amidases Proteins 0.000 claims 1
- 241000271566 Aves Species 0.000 claims 1
- 102000011727 Caspases Human genes 0.000 claims 1
- 108010076667 Caspases Proteins 0.000 claims 1
- 102000003908 Cathepsin D Human genes 0.000 claims 1
- 108090000258 Cathepsin D Proteins 0.000 claims 1
- 108090000317 Chymotrypsin Proteins 0.000 claims 1
- 241000196324 Embryophyta Species 0.000 claims 1
- 108010067770 Endopeptidase K Proteins 0.000 claims 1
- 108010013369 Enteropeptidase Proteins 0.000 claims 1
- 102100029727 Enteropeptidase Human genes 0.000 claims 1
- 108090000371 Esterases Proteins 0.000 claims 1
- 108010088842 Fibrinolysin Proteins 0.000 claims 1
- 102000003886 Glycoproteins Human genes 0.000 claims 1
- 108090000288 Glycoproteins Proteins 0.000 claims 1
- 108010031186 Glycoside Hydrolases Proteins 0.000 claims 1
- 102000005744 Glycoside Hydrolases Human genes 0.000 claims 1
- 108060003393 Granulin Proteins 0.000 claims 1
- 241000238631 Hexapoda Species 0.000 claims 1
- 102000004856 Lectins Human genes 0.000 claims 1
- 108090001090 Lectins Proteins 0.000 claims 1
- 102000003729 Neprilysin Human genes 0.000 claims 1
- 108090000028 Neprilysin Proteins 0.000 claims 1
- 101710163270 Nuclease Proteins 0.000 claims 1
- 108010067372 Pancreatic elastase Proteins 0.000 claims 1
- 102000016387 Pancreatic elastase Human genes 0.000 claims 1
- 108090000526 Papain Proteins 0.000 claims 1
- 108090000284 Pepsin A Proteins 0.000 claims 1
- 102000057297 Pepsin A Human genes 0.000 claims 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims 1
- 108010090804 Streptavidin Proteins 0.000 claims 1
- 108090000787 Subtilisin Proteins 0.000 claims 1
- 108090001109 Thermolysin Proteins 0.000 claims 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 claims 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 claims 1
- 102000005922 amidase Human genes 0.000 claims 1
- 125000000539 amino acid group Chemical group 0.000 claims 1
- 239000000427 antigen Substances 0.000 claims 1
- 102000036639 antigens Human genes 0.000 claims 1
- 108091007433 antigens Proteins 0.000 claims 1
- 230000001580 bacterial effect Effects 0.000 claims 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 102000023732 binding proteins Human genes 0.000 claims 1
- 108091008324 binding proteins Proteins 0.000 claims 1
- 229960002685 biotin Drugs 0.000 claims 1
- 235000020958 biotin Nutrition 0.000 claims 1
- 239000011616 biotin Substances 0.000 claims 1
- 230000001413 cellular effect Effects 0.000 claims 1
- 229960002376 chymotrypsin Drugs 0.000 claims 1
- 230000002538 fungal effect Effects 0.000 claims 1
- 238000000338 in vitro Methods 0.000 claims 1
- 238000001727 in vivo Methods 0.000 claims 1
- 239000002523 lectin Substances 0.000 claims 1
- 230000004807 localization Effects 0.000 claims 1
- 229940055729 papain Drugs 0.000 claims 1
- 235000019834 papain Nutrition 0.000 claims 1
- 229940111202 pepsin Drugs 0.000 claims 1
- 229940012957 plasmin Drugs 0.000 claims 1
- 235000019833 protease Nutrition 0.000 claims 1
- 235000019419 proteases Nutrition 0.000 claims 1
- 230000009257 reactivity Effects 0.000 claims 1
- 238000012216 screening Methods 0.000 claims 1
- 229960001322 trypsin Drugs 0.000 claims 1
- 229960005356 urokinase Drugs 0.000 claims 1
- 239000007787 solid Substances 0.000 description 64
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 62
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 43
- 239000000203 mixture Substances 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 36
- XJGFWWJLMVZSIG-UHFFFAOYSA-N 9-aminoacridine Chemical compound C1=CC=C2C(N)=C(C=CC=C3)C3=NC2=C1 XJGFWWJLMVZSIG-UHFFFAOYSA-N 0.000 description 34
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 33
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 32
- 229960001441 aminoacridine Drugs 0.000 description 31
- 239000011541 reaction mixture Substances 0.000 description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- 239000000047 product Substances 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 28
- 229910001873 dinitrogen Inorganic materials 0.000 description 28
- 238000005481 NMR spectroscopy Methods 0.000 description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 238000004458 analytical method Methods 0.000 description 26
- 238000003786 synthesis reaction Methods 0.000 description 22
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 20
- FCMRXGNTHSDIKX-UHFFFAOYSA-N 3-(9-aminoacridin-2-yl)propanoic acid Chemical compound C1=C(CCC(O)=O)C=C2C(N)=C(C=CC=C3)C3=NC2=C1 FCMRXGNTHSDIKX-UHFFFAOYSA-N 0.000 description 19
- 238000010992 reflux Methods 0.000 description 19
- XUVKSPPGPPFPQN-UHFFFAOYSA-N 10-Methyl-9(10H)-acridone Chemical compound C1=CC=C2N(C)C3=CC=CC=C3C(=O)C2=C1 XUVKSPPGPPFPQN-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- 238000003556 assay Methods 0.000 description 16
- 235000019439 ethyl acetate Nutrition 0.000 description 16
- 239000000725 suspension Substances 0.000 description 16
- 108090000397 Caspase 3 Proteins 0.000 description 15
- 102000003952 Caspase 3 Human genes 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 238000002189 fluorescence spectrum Methods 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 239000011347 resin Substances 0.000 description 13
- 229920005989 resin Polymers 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000010828 elution Methods 0.000 description 11
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 9
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- PSXXCXSMBDHBDN-UHFFFAOYSA-N n-(9-aminoacridin-2-yl)acetamide Chemical compound C1=CC=CC2=C(N)C3=CC(NC(=O)C)=CC=C3N=C21 PSXXCXSMBDHBDN-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- AMOPBNMABDFREG-UHFFFAOYSA-N acridine-3,9-diamine Chemical compound C1=CC=CC2=NC3=CC(N)=CC=C3C(N)=C21 AMOPBNMABDFREG-UHFFFAOYSA-N 0.000 description 8
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 125000005647 linker group Chemical group 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 238000005576 amination reaction Methods 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000006887 Ullmann reaction Methods 0.000 description 6
- 239000001099 ammonium carbonate Substances 0.000 description 6
- 235000012501 ammonium carbonate Nutrition 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 238000000423 cell based assay Methods 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 238000007363 ring formation reaction Methods 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- OWWOJXUVGYXFIJ-UHFFFAOYSA-N 2-(4-bromoanilino)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=C(Br)C=C1 OWWOJXUVGYXFIJ-UHFFFAOYSA-N 0.000 description 5
- 150000005027 9-aminoacridines Chemical class 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- 238000010256 biochemical assay Methods 0.000 description 5
- 230000005587 bubbling Effects 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- IUIQLBLQXIKAMS-UHFFFAOYSA-N n-(9-aminoacridin-3-yl)acetamide Chemical compound C1=CC=CC2=NC3=CC(NC(=O)C)=CC=C3C(N)=C21 IUIQLBLQXIKAMS-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- IOQZSOCPFYNJIG-UHFFFAOYSA-N 1-nitroacridin-9-amine Chemical compound C1=CC([N+]([O-])=O)=C2C(N)=C(C=CC=C3)C3=NC2=C1 IOQZSOCPFYNJIG-UHFFFAOYSA-N 0.000 description 4
- XFCZAISPFKZFDF-UHFFFAOYSA-N 3-bromoacridin-9-amine Chemical compound BrC1=CC=C2C(N)=C(C=CC=C3)C3=NC2=C1 XFCZAISPFKZFDF-UHFFFAOYSA-N 0.000 description 4
- RFGXJQLQGRJKMD-UHFFFAOYSA-N 3-nitroacridin-9-amine Chemical compound [O-][N+](=O)C1=CC=C2C(N)=C(C=CC=C3)C3=NC2=C1 RFGXJQLQGRJKMD-UHFFFAOYSA-N 0.000 description 4
- FTGPOQQGJVJDCT-UHFFFAOYSA-N 9-aminoacridine hydrochloride Chemical compound Cl.C1=CC=C2C(N)=C(C=CC=C3)C3=NC2=C1 FTGPOQQGJVJDCT-UHFFFAOYSA-N 0.000 description 4
- 0 C*1C=Cc2nc3ccccc3c(N)c2C=C1 Chemical compound C*1C=Cc2nc3ccccc3c(N)c2C=C1 0.000 description 4
- FCXMXTMQASDIDU-UHFFFAOYSA-N acridine-2,9-diamine Chemical compound C1=CC=CC2=C(N)C3=CC(N)=CC=C3N=C21 FCXMXTMQASDIDU-UHFFFAOYSA-N 0.000 description 4
- FLCWLOFMVFESNI-UHFFFAOYSA-N acridine-9(10H)-thione Chemical compound C1=CC=C2C(=S)C3=CC=CC=C3NC2=C1 FLCWLOFMVFESNI-UHFFFAOYSA-N 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 150000003840 hydrochlorides Chemical class 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- KWFFJSWVWUCMGV-UHFFFAOYSA-N n-(6,9-diaminoacridin-3-yl)acetamide Chemical compound C1=CC(N)=CC2=NC3=CC(NC(=O)C)=CC=C3C(N)=C21 KWFFJSWVWUCMGV-UHFFFAOYSA-N 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 150000007523 nucleic acids Chemical class 0.000 description 4
- 235000021317 phosphate Nutrition 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- CKLXEMOWJOCGGZ-UHFFFAOYSA-N 10-methylacridine-9-thione Chemical compound C1=CC=C2N(C)C3=CC=CC=C3C(=S)C2=C1 CKLXEMOWJOCGGZ-UHFFFAOYSA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 3
- QFSMBYCXODQZJA-UHFFFAOYSA-N 2-nitroacridin-9-amine Chemical compound C1=C([N+]([O-])=O)C=C2C(N)=C(C=CC=C3)C3=NC2=C1 QFSMBYCXODQZJA-UHFFFAOYSA-N 0.000 description 3
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 3
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 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 3
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical class OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 description 3
- 239000000999 acridine dye Substances 0.000 description 3
- NDNCMVVGTGZIMI-UHFFFAOYSA-N acridine-1,9-diamine Chemical compound C1=CC=C2C(N)=C3C(N)=CC=CC3=NC2=C1 NDNCMVVGTGZIMI-UHFFFAOYSA-N 0.000 description 3
- FZEYVTFCMJSGMP-UHFFFAOYSA-N acridone Chemical class C1=CC=C2C(=O)C3=CC=CC=C3NC2=C1 FZEYVTFCMJSGMP-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- FIRHQRGFVOSDDY-UHFFFAOYSA-N ethyl 1-hydroxytriazole-4-carboxylate Chemical compound CCOC(=O)C1=CN(O)N=N1 FIRHQRGFVOSDDY-UHFFFAOYSA-N 0.000 description 3
- 238000001506 fluorescence spectroscopy Methods 0.000 description 3
- JCEBYORAYVOGJI-UHFFFAOYSA-N n-(9-amino-6-nitroacridin-3-yl)acetamide Chemical compound C1=CC([N+]([O-])=O)=CC2=NC3=CC(NC(=O)C)=CC=C3C(N)=C21 JCEBYORAYVOGJI-UHFFFAOYSA-N 0.000 description 3
- WGTGSKVBGAMODT-UHFFFAOYSA-N n-(9-aminoacridin-1-yl)acetamide Chemical class C1=CC=C2C(N)=C3C(NC(=O)C)=CC=CC3=NC2=C1 WGTGSKVBGAMODT-UHFFFAOYSA-N 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 3
- WWQYLWXXBSGIFC-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-(9-aminoacridin-2-yl)propanoate Chemical compound C1=C2C(N)=C3C=CC=CC3=NC2=CC=C1CCC(=O)ON1C(=O)CCC1=O WWQYLWXXBSGIFC-UHFFFAOYSA-N 0.000 description 2
- QUEKGYQTRJVEQC-UHFFFAOYSA-N 2516-96-3 Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl QUEKGYQTRJVEQC-UHFFFAOYSA-N 0.000 description 2
- VALMAHPRLZLCAT-UHFFFAOYSA-N 3-bromo-9-chloroacridine Chemical compound BrC1=CC=C2C(Cl)=C(C=CC=C3)C3=NC2=C1 VALMAHPRLZLCAT-UHFFFAOYSA-N 0.000 description 2
- JOUFIQVFVDNYRT-UHFFFAOYSA-N 9-chloro-1-nitroacridine Chemical compound C1=CC=C2C(Cl)=C3C([N+](=O)[O-])=CC=CC3=NC2=C1 JOUFIQVFVDNYRT-UHFFFAOYSA-N 0.000 description 2
- WQOKOTQIPRXZEN-UHFFFAOYSA-N 9-chloro-2-nitroacridine Chemical compound C1=CC=CC2=C(Cl)C3=CC([N+](=O)[O-])=CC=C3N=C21 WQOKOTQIPRXZEN-UHFFFAOYSA-N 0.000 description 2
- WYSFRKRTNWKBCD-UHFFFAOYSA-N 9-chloro-3-nitroacridine Chemical compound C1=CC=CC2=NC3=CC([N+](=O)[O-])=CC=C3C(Cl)=C21 WYSFRKRTNWKBCD-UHFFFAOYSA-N 0.000 description 2
- PSUVZUZXZWBYBX-UHFFFAOYSA-N CN1C=2C=CC=CC2C(C2=CC=CC=C12)=O.CN1C=2C=CC=CC2C(C2=CC=CC=C12)=O Chemical compound CN1C=2C=CC=CC2C(C2=CC=CC=C12)=O.CN1C=2C=CC=CC2C(C2=CC=CC=C12)=O PSUVZUZXZWBYBX-UHFFFAOYSA-N 0.000 description 2
- 238000007341 Heck reaction Methods 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 150000001251 acridines Chemical class 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229940027998 antiseptic and disinfectant acridine derivative Drugs 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000000295 emission spectrum Methods 0.000 description 2
- RJQIVOKOZOWWNY-UHFFFAOYSA-N ethyl 2-(acridin-9-ylamino)acetate Chemical compound C1=CC=C2C(NCC(=O)OCC)=C(C=CC=C3)C3=NC2=C1 RJQIVOKOZOWWNY-UHFFFAOYSA-N 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000001215 fluorescent labelling Methods 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- OHRHENLWULLQHE-UHFFFAOYSA-N n-(9-chloro-6-nitroacridin-3-yl)acetamide Chemical compound C1=CC([N+]([O-])=O)=CC2=NC3=CC(NC(=O)C)=CC=C3C(Cl)=C21 OHRHENLWULLQHE-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical group [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000000527 sonication Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000001161 time-correlated single photon counting Methods 0.000 description 2
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 2
- XJRIDJAGAYGJCK-UHFFFAOYSA-N (1-acetyl-5-bromoindol-3-yl) acetate Chemical compound C1=C(Br)C=C2C(OC(=O)C)=CN(C(C)=O)C2=C1 XJRIDJAGAYGJCK-UHFFFAOYSA-N 0.000 description 1
- VIZLMXQJBOYAIH-UHFFFAOYSA-N 1-chloroacridine Chemical group C1=CC=C2C=C3C(Cl)=CC=CC3=NC2=C1 VIZLMXQJBOYAIH-UHFFFAOYSA-N 0.000 description 1
- CVLMVMQNJODBLJ-UHFFFAOYSA-N 1-methyl-10h-acridin-9-one Chemical class N1C2=CC=CC=C2C(=O)C2=C1C=CC=C2C CVLMVMQNJODBLJ-UHFFFAOYSA-N 0.000 description 1
- FJNZOTVFXOADDQ-UHFFFAOYSA-N 1-nitro-10h-acridin-9-one Chemical compound N1C2=CC=CC=C2C(=O)C2=C1C=CC=C2[N+](=O)[O-] FJNZOTVFXOADDQ-UHFFFAOYSA-N 0.000 description 1
- DEEULBIVHZVMHX-UHFFFAOYSA-N 1-nitroacridine Chemical compound C1=CC=C2C=C3C([N+](=O)[O-])=CC=CC3=NC2=C1 DEEULBIVHZVMHX-UHFFFAOYSA-N 0.000 description 1
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical class NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 1
- RGHQKFQZGLKBCF-UHFFFAOYSA-N 2-bromoethyl acetate Chemical compound CC(=O)OCCBr RGHQKFQZGLKBCF-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- JRQDVRIQJJPHEQ-UHFFFAOYSA-N 3970-35-2 Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1Cl JRQDVRIQJJPHEQ-UHFFFAOYSA-N 0.000 description 1
- YCBWLMWEQURJHX-UHFFFAOYSA-N 4-(trifluoromethyl)cyclohexan-1-amine Chemical compound NC1CCC(C(F)(F)F)CC1 YCBWLMWEQURJHX-UHFFFAOYSA-N 0.000 description 1
- WCKQPPQRFNHPRJ-UHFFFAOYSA-N 4-[[4-(dimethylamino)phenyl]diazenyl]benzoic acid Chemical compound C1=CC(N(C)C)=CC=C1N=NC1=CC=C(C(O)=O)C=C1 WCKQPPQRFNHPRJ-UHFFFAOYSA-N 0.000 description 1
- BPXINCHFOLVVSG-UHFFFAOYSA-N 9-chloroacridine Chemical compound C1=CC=C2C(Cl)=C(C=CC=C3)C3=NC2=C1 BPXINCHFOLVVSG-UHFFFAOYSA-N 0.000 description 1
- QAYNSPOKTRVZRC-UHFFFAOYSA-N 99-60-5 Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1Cl QAYNSPOKTRVZRC-UHFFFAOYSA-N 0.000 description 1
- GDALETGZDYOOGB-UHFFFAOYSA-N Acridone Natural products C1=C(O)C=C2N(C)C3=CC=CC=C3C(=O)C2=C1O GDALETGZDYOOGB-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical group OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- SMVTUIPNOVMGGV-CSKARUKUSA-N CC(C)COC(/C=C/c(ccc1nc2c3cccc2)cc1c3N)=O Chemical compound CC(C)COC(/C=C/c(ccc1nc2c3cccc2)cc1c3N)=O SMVTUIPNOVMGGV-CSKARUKUSA-N 0.000 description 1
- LMFPCPNKPMHNBU-UHFFFAOYSA-N CC(C)COC(CCc(cc1)cc2c1nc(cccc1)c1c2N)=O Chemical compound CC(C)COC(CCc(cc1)cc2c1nc(cccc1)c1c2N)=O LMFPCPNKPMHNBU-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical group O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 102000016943 Muramidase Human genes 0.000 description 1
- 108010014251 Muramidase Proteins 0.000 description 1
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000005577 anthracene group Chemical group 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 210000003850 cellular structure Anatomy 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000010549 co-Evaporation Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 238000000695 excitation spectrum Methods 0.000 description 1
- 230000005281 excited state Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 1
- 238000012921 fluorescence analysis Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002668 lysine derivatives Chemical class 0.000 description 1
- 239000004325 lysozyme Substances 0.000 description 1
- 229960000274 lysozyme Drugs 0.000 description 1
- 235000010335 lysozyme Nutrition 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 230000009149 molecular binding Effects 0.000 description 1
- 150000002772 monosaccharides Chemical group 0.000 description 1
- CHMBIJAOCISYEW-UHFFFAOYSA-N n-(4-aminophenyl)acetamide Chemical compound CC(=O)NC1=CC=C(N)C=C1 CHMBIJAOCISYEW-UHFFFAOYSA-N 0.000 description 1
- MTCIKUZSQNOGRU-UHFFFAOYSA-N n-(6-acetamido-9-aminoacridin-3-yl)acetamide Chemical compound C1=CC(NC(C)=O)=CC2=NC3=CC(NC(=O)C)=CC=C3C(N)=C21 MTCIKUZSQNOGRU-UHFFFAOYSA-N 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- ZQFUPHSLJYKTAB-UHFFFAOYSA-N oxane-2,6-dione Chemical compound O=C1CCCC(=O)O1.O=C1CCCC(=O)O1 ZQFUPHSLJYKTAB-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- QTBVTOLYOCEVEQ-UHFFFAOYSA-N tert-butyl 3-(9-aminoacridin-2-yl)propanoate Chemical compound C1=CC=CC2=C(N)C3=CC(CCC(=O)OC(C)(C)C)=CC=C3N=C21 QTBVTOLYOCEVEQ-UHFFFAOYSA-N 0.000 description 1
- 238000004454 trace mineral analysis Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B15/00—Acridine dyes
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/531—Production of immunochemical test materials
- G01N33/532—Production of labelled immunochemicals
- G01N33/533—Production of labelled immunochemicals with fluorescent label
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/582—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with fluorescent label
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
- Y10T436/145555—Hetero-N
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Analytical Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Cell Biology (AREA)
- Pathology (AREA)
- Food Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Physics & Mathematics (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- General Physics & Mathematics (AREA)
- Organic Chemistry (AREA)
- Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0522029.8 | 2005-10-28 | ||
| GB0522029A GB0522029D0 (en) | 2005-10-28 | 2005-10-28 | Novel fluorescent dyes and uses |
| GB0613334A GB0613334D0 (en) | 2006-07-05 | 2006-07-05 | Novel fluorescent dyes and uses thereof (II) |
| GB0613334.2 | 2006-07-05 | ||
| PCT/GB2006/004015 WO2007049057A2 (en) | 2005-10-28 | 2006-10-27 | Novel fluorescent dyes and uses thereof |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2009513766A JP2009513766A (ja) | 2009-04-02 |
| JP2009513766A5 JP2009513766A5 (enExample) | 2013-12-26 |
| JP5548363B2 true JP5548363B2 (ja) | 2014-07-16 |
Family
ID=37968186
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2008537196A Expired - Fee Related JP5548363B2 (ja) | 2005-10-28 | 2006-10-27 | 新規な蛍光染料およびその使用 |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US9127164B2 (enExample) |
| EP (1) | EP1940965B1 (enExample) |
| JP (1) | JP5548363B2 (enExample) |
| CA (1) | CA2627628A1 (enExample) |
| WO (1) | WO2007049057A2 (enExample) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0712109D0 (en) * | 2007-06-22 | 2007-08-01 | Edinburgh Instr | Fluorescence lifetime and fluorescence assays |
| US20110236983A1 (en) * | 2009-12-29 | 2011-09-29 | Joseph Beechem | Single molecule detection and sequencing using fluorescence lifetime imaging |
| WO2012110833A2 (en) | 2011-02-18 | 2012-08-23 | Almac Sciences (Scotland) Limited | Fluorescence modulators |
| US20140080162A1 (en) | 2011-03-25 | 2014-03-20 | Almac Sciences (Scotland) Limited | Fluorescence lifetime epigenetics assays |
| GB201122099D0 (en) | 2011-12-22 | 2012-02-01 | Almac Sciences Scotland Ltd | Dyes |
| CN103373967A (zh) * | 2013-07-08 | 2013-10-30 | 大连九信生物化工科技有限公司 | 一种申嗪霉素的合成方法 |
| WO2016116111A1 (en) * | 2015-01-21 | 2016-07-28 | Københavns Universitet | Substituted acridine-like and xanthenium-like fluorescent dyes |
| RU2622753C1 (ru) * | 2016-11-17 | 2017-06-19 | Федеральное государственное бюджетное учреждение "Национальный научно-практический центр сердечно-сосудистой хирургии имени А.Н. Бакулева" Министерства здравоохранения Российской Федерации (ФГБУ "ННПЦССХ им. А.Н. Бакулева" Минздрава России) | Способ определения активности ангиотензин-превращающего фермента в тканях сердца |
| CN108640873A (zh) * | 2018-06-25 | 2018-10-12 | 福建医科大学 | 一种亚胺类吖啶衍生物荧光探针及其制备方法和检测MORAb-3-1抗体应用 |
| CN108947901A (zh) * | 2018-06-25 | 2018-12-07 | 福建医科大学 | 一种亚胺类吖啶衍生物荧光探针制备及检测甲状腺球蛋白抗体的方法 |
| CN109354586A (zh) * | 2018-09-29 | 2019-02-19 | 福建医科大学 | 一种亚胺类吖啶荧光探针制备及标记口腔鳞癌细胞中bcl-2蛋白方法 |
| CA3127235A1 (en) | 2019-01-21 | 2020-07-30 | Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E. V. | Sulfonated 2(7)-aminoacridone and 1-aminopyrene dyes and their use as fluorescent tags, in particular for carbohydrate analysis |
| EP4069784A1 (en) | 2019-12-06 | 2022-10-12 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Aminoacridine and aminopyrene dyes and their use as fluorescent tags, in particular for carbohydrate analysis |
| CN115109066B (zh) * | 2022-06-30 | 2023-04-07 | 武汉工程大学 | 一种大斯托克斯位移检测弹性蛋白酶的荧光探针及其制备方法与应用 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE393411C (de) * | 1921-10-11 | 1924-04-04 | Hoechst Ag | Verfahren zur Darstellung von Akridinderivaten |
| US5296599A (en) | 1991-09-19 | 1994-03-22 | Millipore Corporation | Activated carbamates compounds |
| IL149402A0 (en) | 1999-11-29 | 2002-11-10 | Aventis Pharma Sa | Arylamine derivatives and their use as anti-telomerase agent |
| DE10117430A1 (de) | 2001-04-06 | 2002-10-10 | Nicole Marme | Hochempfindlicher und hochspezifischer Enzymnachweis mit einer Nachweisgrenze bis in den femtomolaren Bereich |
| GB0113435D0 (en) | 2001-06-04 | 2001-07-25 | Amersham Pharm Biotech Uk Ltd | Acridone derivatives as labels for fluorescence detection of target materials |
| GB0208987D0 (en) | 2002-04-19 | 2002-05-29 | Amersham Biosciences Uk Ltd | Methods for measuring protein kinase and phosphatase activity |
| GB0208989D0 (en) * | 2002-04-19 | 2002-05-29 | Amersham Biosciences Uk Ltd | Methods for measuring enzyme activity |
-
2006
- 2006-10-27 CA CA 2627628 patent/CA2627628A1/en not_active Abandoned
- 2006-10-27 EP EP20060808365 patent/EP1940965B1/en not_active Not-in-force
- 2006-10-27 JP JP2008537196A patent/JP5548363B2/ja not_active Expired - Fee Related
- 2006-10-27 WO PCT/GB2006/004015 patent/WO2007049057A2/en not_active Ceased
- 2006-10-27 US US12/091,792 patent/US9127164B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| EP1940965B1 (en) | 2014-03-26 |
| EP1940965A2 (en) | 2008-07-09 |
| US9127164B2 (en) | 2015-09-08 |
| CA2627628A1 (en) | 2007-05-03 |
| US20090226940A1 (en) | 2009-09-10 |
| WO2007049057A2 (en) | 2007-05-03 |
| WO2007049057A3 (en) | 2007-10-04 |
| JP2009513766A (ja) | 2009-04-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5548363B2 (ja) | 新規な蛍光染料およびその使用 | |
| JP4790598B2 (ja) | メソ置換シアニン色素標識化試薬 | |
| EP1129092B1 (en) | Porphyrin compounds, their conjugates and assay methods based on the use of said conjugates | |
| US20120015373A1 (en) | Acridone derivatives as labels for fluorescence detection of target materials | |
| JP3984475B2 (ja) | 蛍光検出法および試薬 | |
| US6277984B1 (en) | Monomethine cyanines rigidized by a two-carbon chain | |
| JP2002529466A5 (enExample) | ||
| JP2002508428A (ja) | 硬化トリメチンシアニン色素 | |
| JP4098839B2 (ja) | インドシアニン化合物 | |
| CA2336904A1 (en) | Novel fluorescent lanthanide chelates | |
| EP3137898B1 (en) | Fluorescent molecular sensor for targeting changes in protein surfaces, and methods of use thereof | |
| Dong et al. | A strategy to enhance the water solubility of luminescent β-diketonate-Europium (III) complexes for time-gated luminescence bioassays | |
| JP2001002951A (ja) | 新規な蛍光色素およびその蛍光マーカーとしての使用 | |
| JP2015506462A (ja) | アクリジンおよびアクリジニウム誘導体ベースの蛍光色素 | |
| EP3469370B1 (en) | Background blockers for binding assays | |
| JP2000111480A (ja) | 新規標識試薬 | |
| US20040029290A1 (en) | Fluorescent dye complexes | |
| JP7479660B2 (ja) | 蛍光色素 | |
| JP2002518413A (ja) | 新規な化合物 | |
| KR20190043075A (ko) | 메로시아닌계 화합물, 이를 포함하는 생체분자 표지용 염료, 키트 및 조영제 조성물 | |
| AU2002257963A1 (en) | Acridone derivatives as labels for fluorescence detection of target materials |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20090424 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20090424 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20091027 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20120604 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20120904 |
|
| A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20120911 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20121105 |
|
| A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20121112 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20121204 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130729 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20131029 |
|
| A524 | Written submission of copy of amendment under article 19 pct |
Free format text: JAPANESE INTERMEDIATE CODE: A524 Effective date: 20131029 |
|
| 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: 20140428 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20140519 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 5548363 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| LAPS | Cancellation because of no payment of annual fees |