JP7455816B2 - クマリン系架橋試薬 - Google Patents
クマリン系架橋試薬 Download PDFInfo
- Publication number
- JP7455816B2 JP7455816B2 JP2021514981A JP2021514981A JP7455816B2 JP 7455816 B2 JP7455816 B2 JP 7455816B2 JP 2021514981 A JP2021514981 A JP 2021514981A JP 2021514981 A JP2021514981 A JP 2021514981A JP 7455816 B2 JP7455816 B2 JP 7455816B2
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- Prior art keywords
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- coumarin
- oxo
- substituted
- independently
- Prior art date
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- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 title description 337
- 229960000956 coumarin Drugs 0.000 title description 181
- 235000001671 coumarin Nutrition 0.000 title description 172
- 239000003431 cross linking reagent Substances 0.000 title description 2
- -1 dinitrophenyl Chemical group 0.000 claims description 130
- 238000006243 chemical reaction Methods 0.000 claims description 108
- 239000003153 chemical reaction reagent Substances 0.000 claims description 105
- 102000004190 Enzymes Human genes 0.000 claims description 65
- 108090000790 Enzymes Proteins 0.000 claims description 65
- 150000001875 compounds Chemical class 0.000 claims description 63
- 238000000034 method Methods 0.000 claims description 63
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 62
- 125000000217 alkyl group Chemical group 0.000 claims description 51
- 125000000524 functional group Chemical group 0.000 claims description 40
- 239000012472 biological sample Substances 0.000 claims description 35
- 150000002148 esters Chemical class 0.000 claims description 28
- 239000004202 carbamide Substances 0.000 claims description 27
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 20
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 16
- 150000001412 amines Chemical class 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- AWBOSXFRPFZLOP-UHFFFAOYSA-N 2,1,3-benzoxadiazole Chemical compound C1=CC=CC2=NON=C21 AWBOSXFRPFZLOP-UHFFFAOYSA-N 0.000 claims description 12
- 150000001408 amides Chemical class 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 235000000346 sugar Nutrition 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 11
- 238000002372 labelling Methods 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- LGRLWUINFJPLSH-UHFFFAOYSA-N methanide Chemical compound [CH3-] LGRLWUINFJPLSH-UHFFFAOYSA-N 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 150000003573 thiols Chemical class 0.000 claims description 10
- 239000002243 precursor Substances 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- 125000004999 nitroaryl group Chemical group 0.000 claims description 8
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 8
- 150000003648 triterpenes Chemical class 0.000 claims description 8
- 125000001894 2,4,6-trinitrophenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1[N+]([O-])=O)[N+]([O-])=O)[N+]([O-])=O 0.000 claims description 7
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 7
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 7
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 7
- 229940049706 benzodiazepine Drugs 0.000 claims description 7
- 150000005363 heterobiaryls Chemical group 0.000 claims description 7
- 150000003949 imides Chemical class 0.000 claims description 7
- JUVIOZPCNVVQFO-HBGVWJBISA-N rotenone Chemical compound O([C@H](CC1=C2O3)C(C)=C)C1=CC=C2C(=O)[C@@H]1[C@H]3COC2=C1C=C(OC)C(OC)=C2 JUVIOZPCNVVQFO-HBGVWJBISA-N 0.000 claims description 7
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims description 6
- 229910019142 PO4 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
- 150000001540 azides Chemical class 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 150000004820 halides Chemical class 0.000 claims description 5
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 4
- QRZUPJILJVGUFF-UHFFFAOYSA-N 2,8-dibenzylcyclooctan-1-one Chemical group C1CCCCC(CC=2C=CC=CC=2)C(=O)C1CC1=CC=CC=C1 QRZUPJILJVGUFF-UHFFFAOYSA-N 0.000 claims description 4
- 241001061127 Thione Species 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- CMUOJBJRZUHRMU-UHFFFAOYSA-N nitrourea Chemical compound NC(=O)N[N+]([O-])=O CMUOJBJRZUHRMU-UHFFFAOYSA-N 0.000 claims description 3
- 150000003952 β-lactams Chemical class 0.000 claims description 3
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical group C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 claims description 2
- 125000002009 alkene group Chemical group 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 96
- 239000000523 sample Substances 0.000 description 71
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 66
- 229940088598 enzyme Drugs 0.000 description 66
- 238000001514 detection method Methods 0.000 description 62
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 57
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- 125000005647 linker group Chemical group 0.000 description 33
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- 238000004128 high performance liquid chromatography Methods 0.000 description 25
- 150000004775 coumarins Chemical group 0.000 description 24
- 238000003556 assay Methods 0.000 description 23
- 239000002773 nucleotide Substances 0.000 description 23
- 125000003729 nucleotide group Chemical group 0.000 description 23
- 238000002953 preparative HPLC Methods 0.000 description 23
- ACMLKANOGIVEPB-UHFFFAOYSA-N 2-oxo-2H-chromene-3-carboxylic acid Chemical compound C1=CC=C2OC(=O)C(C(=O)O)=CC2=C1 ACMLKANOGIVEPB-UHFFFAOYSA-N 0.000 description 20
- 230000003993 interaction Effects 0.000 description 20
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- 230000009870 specific binding Effects 0.000 description 18
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 17
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 238000012575 bio-layer interferometry Methods 0.000 description 15
- 230000000295 complement effect Effects 0.000 description 15
- 239000002202 Polyethylene glycol Substances 0.000 description 14
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- 150000001720 carbohydrates Chemical class 0.000 description 10
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- 241000283973 Oryctolagus cuniculus Species 0.000 description 9
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- WKXVETMYCFRGET-UHFFFAOYSA-N 1,3-thiazole-2-sulfonamide Chemical compound NS(=O)(=O)C1=NC=CS1 WKXVETMYCFRGET-UHFFFAOYSA-N 0.000 description 7
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- DKUZHSDZSMQOGQ-UHFFFAOYSA-N 3-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]propanoic acid Chemical compound NCCOCCOCCOCCOCCC(O)=O DKUZHSDZSMQOGQ-UHFFFAOYSA-N 0.000 description 7
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- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 125000006684 polyhaloalkyl group Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 238000011176 pooling Methods 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000006916 protein interaction Effects 0.000 description 1
- 210000004915 pus Anatomy 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 150000003220 pyrenes Chemical class 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- FDBYIYFVSAHJLY-UHFFFAOYSA-N resmetirom Chemical compound N1C(=O)C(C(C)C)=CC(OC=2C(=CC(=CC=2Cl)N2C(NC(=O)C(C#N)=N2)=O)Cl)=N1 FDBYIYFVSAHJLY-UHFFFAOYSA-N 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- XLXOKMFKGASILN-UHFFFAOYSA-N rhodamine red-X Chemical compound C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S(=O)(=O)NCCCCCC(O)=O)C=C1S([O-])(=O)=O XLXOKMFKGASILN-UHFFFAOYSA-N 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 150000007659 semicarbazones Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000006557 surface reaction Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 210000001138 tear Anatomy 0.000 description 1
- ZJXHVYSDMUKUCA-UHFFFAOYSA-N tert-butyl 3-aminopropanoate Chemical compound CC(C)(C)OC(=O)CCN ZJXHVYSDMUKUCA-UHFFFAOYSA-N 0.000 description 1
- VENKBTRFJOWPPW-UHFFFAOYSA-N tert-butyl n-[3-[2-(3-aminopropoxy)ethoxy]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCOCCOCCCN VENKBTRFJOWPPW-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- ABZLKHKQJHEPAX-UHFFFAOYSA-N tetramethylrhodamine Chemical compound C=12C=CC(N(C)C)=CC2=[O+]C2=CC(N(C)C)=CC=C2C=1C1=CC=CC=C1C([O-])=O ABZLKHKQJHEPAX-UHFFFAOYSA-N 0.000 description 1
- MUUHXGOJWVMBDY-UHFFFAOYSA-L tetrazolium blue Chemical compound [Cl-].[Cl-].COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC=CC=2)=CC=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 MUUHXGOJWVMBDY-UHFFFAOYSA-L 0.000 description 1
- RONADMZTCCPLEF-UHFFFAOYSA-M tetrazolium violet Chemical compound [Cl-].C1=CC=CC=C1C(N=[N+]1C=2C3=CC=CC=C3C=CC=2)=NN1C1=CC=CC=C1 RONADMZTCCPLEF-UHFFFAOYSA-M 0.000 description 1
- QOFZZTBWWJNFCA-UHFFFAOYSA-N texas red-X Chemical compound [O-]S(=O)(=O)C1=CC(S(=O)(=O)NCCCCCC(=O)O)=CC=C1C(C1=CC=2CCCN3CCCC(C=23)=C1O1)=C2C1=C(CCC1)C3=[N+]1CCCC3=C2 QOFZZTBWWJNFCA-UHFFFAOYSA-N 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical class [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- 229950003937 tolonium Drugs 0.000 description 1
- HNONEKILPDHFOL-UHFFFAOYSA-M tolonium chloride Chemical compound [Cl-].C1=C(C)C(N)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 HNONEKILPDHFOL-UHFFFAOYSA-M 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- ORHBXUUXSCNDEV-UHFFFAOYSA-N umbelliferone Chemical compound C1=CC(=O)OC2=CC(O)=CC=C21 ORHBXUUXSCNDEV-UHFFFAOYSA-N 0.000 description 1
- HFTAFOQKODTIJY-UHFFFAOYSA-N umbelliferone Natural products Cc1cc2C=CC(=O)Oc2cc1OCC=CC(C)(C)O HFTAFOQKODTIJY-UHFFFAOYSA-N 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 238000007794 visualization technique Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000001834 xanthenyl group Chemical class C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Images
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
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Description
のいずれかの構造によって定義される化合物である。
の構造を有する。
によって提供される構造を有する。
のいずれかの構造を有する。
のいずれかの構造を有する。
のいずれかの構造を有する。
を有する。
のいずれかの構造によって定義される化合物である。
のいずれかの構造を有する。
を有する。
を含む、方法である。
Zは結合、-CH-基、-CH-CH2-基、または-CH2-CH-基であり、
を含む、方法である。
のいずれかの構造を有する。
[00100] 本明細書で提供される見出しは、便宜上のものであり、開示される実施形態の範囲または意味を解釈するものではない。
の構造を有する。
の構造を有する。
の構造を有する。
の構造を有する。
の構造を有する。
の構造を有する。
のいずれかの構造を有する。
のいずれかの構造を有する。
のいずれかの構造を有する。
を有する。
を有する。
を有する。
(式中、各R11基は、Hまたは1~4個の炭素原子を有する低級アルキル基から独立して選択され、かつ式中、Rxは、HまたはC1~C4アルキル基である)
によって提供される構造を有する。
(式中、
R2は、ホスフェート、アミド、ニトロ、尿素、スルフェート、メチル、エステル、ベータ-ラクタム、または糖から選択される基であり、
R13はハロゲン化物であり、
R15、R16、R17、およびR18は、水素または1~4個の炭素原子を有する脂肪族基から独立して選択され、
R14は、-(CH2)wNH-、-O(CH2)wNH-、-N(H)C(O)(CH2)wNH-、-C(O)N(H)(CH2)wNH-、-(CH2)wO-、-O(CH2)wO-、-O(CH2CH2O)w-、-N(H)C(O)(CH2)wO-、-C(O)N(H)(CH2)wO-、-C(o)N(H)(CH2CH2O)w-、-(CH2)wS-、-O(CH2)wS-、-N(H)C(O)(CH2)wS-、-C(O)N(H)(CH2)wS-、-(CH2)wNH-、-C(O)N(H)(CH2CH2O)wCH2CH2NH、-C(O)(CH2CH2O)wCH2CH2NH-、-C(O)N(H)(CH2)NHC(O)CH(CH3)(CH2)wNH-、または-N(H)(CH2)wNH-であり、wは1~12の範囲の整数である)
によって提供される構造を有する。
(式中、wは1~12の範囲である)によって提供される構造を有する。いくつかの実施形態において、wは1~8の範囲である。他の実施形態において、wは2~8の範囲である。さらに他の実施形態では、wは2~6の範囲である。さらなる実施形態では、wは6である。
(式中、Tは、特異的結合実体、アミノ酸、ペプチド、タンパク質、糖類、ヌクレオシド、ヌクレオチド、オリゴヌクレオチド、薬物、脂質、またはナノ粒子から選択される置換基であり、
Rzは、上記で定義されるような検出可能な標識であり、
oは1~10の範囲の整数であり、
L1およびL2はリンカーであり、
Wは、置換もしくは非置換のクマリン部分、あるいはクマリンの置換もしくは非置換の誘導体または類縁体である部分を含み、
Zは結合、-CH-基、-CH-CH2-基、または-CH2-CH-基であり、
mおよびnは、独立して1~4の範囲の整数である)
のいずれかの構造を有する。
Abは、抗体であり、
Rzは、上記で定義されるような検出可能な標識であり、
oは1~10の範囲の整数であり、
L1およびL2はリンカーであり、
Wは、置換もしくは非置換のクマリン部分、あるいはクマリンの置換もしくは非置換の誘導体または類縁体である部分を含み、
Zは結合、-CH-基、-CH-CH2-基、または-CH2-CH-基であり、
mおよびnは、独立して1~4の範囲の整数である)
のいずれかの構造を有する。
(式中、NAは核酸であり、
Rzは、上記で定義されるような検出可能な標識であり、
oは1~10の範囲の整数であり、
L1およびL2はリンカーであり、
Wは、置換もしくは非置換のクマリン部分、あるいはクマリンの置換もしくは非置換の誘導体または類縁体である部分を含み、
Zは結合、-CH-基、-CH-CH2-基、または-CH2-CH-基であり、
mおよびnは、独立して1~4の範囲の整数である)
のいずれかの構造を有する。
Claims (13)
- 式(IA)または(IB):
(式中、
AおよびBは、独立して、反応性官能基であるか、ハプテン、色素原、またはフルオロフォアからなる群から選択される検出可能な標識であるか、またはチラミド部分、チラミド部分の誘導体である部分、およびキノンメチド前駆体部分からなる群から選択される酵素反応性部分であり、
L1およびL2はリンカーであり、
Wは、式(VA)、(VB)または(VC):
のいずれかの構造を有し、
Zは、-CH-基、-CH-CH2-基、または-CH2-CH-基であり、
mおよびnは、独立して1~4の範囲の整数であり、
式(VA)の部分は、0、1、2、3、または4個のR t 基で置換されてもよく、式(VB)の部分は、0、1、2、3、4、または5個のR t 基で置換されてもよく、各R t は、置換または非置換の直鎖または分岐鎖のC 1 ~C 12 アルキル基;置換または非置換の直鎖または分岐鎖のC 1 ~C 12 アルコキシ基、置換または非置換の直鎖または分岐鎖のC 1 ~C 12 ヘテロアルキル基;トリフルオロメチル基;ヒドロキシル基;硫酸基;シアノ基;ハロゲン;リン酸基;糖類;カルボン酸基;ニトロ基;-C(O)NR x R y ;-S-R x ;-SO 2 ;-SO 2 Cl;-SO 3 H;-SO 4 H;-SO 2 NR x R y ;-N(H)-NR x R y ;-NR x R y から独立して選択され、
式(VC)中のR 2 、R 3 、R 4 、およびR 6 は、置換または非置換の直鎖または分岐鎖のC 1 ~C 6 アルキル基;置換または非置換の直鎖または分岐鎖のC 1 ~C 6 アルコキシ基;置換または非置換の直鎖または分岐鎖のC 1 ~C 6 ヘテロアルキル基;トリフルオロメチル基;ヒドロキシル基;硫酸基;シアノ基;ハロゲン;リン酸基;糖類;カルボン酸基;ニトロ基;-C(O)NR x R y ;-S-R x ;-SO 2 ;-SO 2 Cl;-SO 3 H;-SO 4 H;-SO 2 NR x R y ;-N(H)-NR x R y ;-NR x R y から独立して選択され、
R 1 は、C 1 ~C 10 の置換または非置換の分岐鎖または非分岐鎖のアルキル基、-O-、-O-CH 2 -、-N(R x )-、または-S-であり、
R 5 は、C 1 ~C 10 の置換または非置換の分岐鎖または非分岐鎖のアルキル基、-C(O)-O-、-C(O)-N(H)-であり、
各Xは、独立して、結合、または置換もしくは非置換の直鎖もしくは分岐鎖のC 1 ~C 16 アルキル基;-[(CH 2 ) j -O] k -CH 2 -(jは1~4の範囲の整数であり、kは1~16の範囲の整数である);-N-R x -;-C(O)-N-R x -;または-N-R x -C(O)-であり、
R x およびR y は、独立してHまたはC 1 ~C 4 アルキル基である)
のいずれかの構造によって定義される、化合物。 - Aが酵素反応性部分であり、Bが検出可能な標識である、請求項1に記載の化合物。
- Aが反応性官能基であり、Bが検出可能な標識である、請求項1に記載の化合物。
- 前記ハプテンが、オキサゾール、ピラゾール、チアゾール、ベンゾフラザン、トリテルペン、尿素、ローダミンチオ尿素以外のチオ尿素、ジニトロフェニルまたはトリニトロフェニル以外のニトロアリール、ロテノイド、シクロリグナン、ヘテロビアリール、アゾアリール、およびベンゾジアゼピンからなる群から選択される、請求項1に記載の化合物。
- 前記酵素反応性部分が式(VIIIA):
(式中、
R12は、ホスフェート、アミド、ニトロ、尿素、スルフェート、メチル、エステル、ベータ-ラクタム、または糖から選択される基であり、
R13はハロゲン化物であり、
R15、R16、R17、およびR18は、水素または1~4個の炭素原子を有する脂肪族基から独立して選択され、
R14は、-(CH2)wNH-、-O(CH2)wNH-、-N(H)C(O)(CH2)wNH-、-C(O)N(H)(CH2)wNH-、-(CH2)wO-、-O(CH2)wO-、-O(CH2CH2O)w-、-N(H)C(O)(CH2)wO-、-C(O)N(H)(CH2)wO-、-C(o)N(H)(CH2CH2O)w-、-(CH2)wS-、-O(CH2)wS-、-N(H)C(O)(CH2)wS-、-C(O)N(H)(CH2)wS-、-(CH2)wNH-、-C(O)N(H)(CH2CH2O)wCH2CH2NH、-C(O)(CH2CH2O)wCH2CH2NH-、-C(O)N(H)(CH2)NHC(O)CH(CH3)(CH2)wNH-、または-N(H)(CH2)wNH-であり、式中、wは1~12の範囲の整数である)
によって提供される構造を有する、請求項1に記載の化合物。 - Bがクリックケミストリー反応に関与することができる反応性基である、請求項1に記載の化合物。
- 前記クリックケミストリー反応に関与することができる基が、DBCO基、アジド、TCO基、アルケン基、またはテトラジン基である、請求項7に記載の化合物。
- R1が、C1~C6の分岐鎖または非分岐鎖のアルキル基である、請求項1に記載の化合物。
- R5が、C1~C6の分岐鎖または非分岐鎖のアルキル基である、請求項1に記載の化合物。
- 各L1および/またはL2基が独立して式(VIA):
(式中、
fは0または1~24の範囲の整数であり、
jは1~24の範囲の整数であり、
R8は結合またはO、S、-N(Rc)(Rd)、または-N+(Rc)(Rd)(Re)であり、
RaおよびRbは独立してH、C1~C4アルキル基、F、Cl、または-N(Rc)(Rd)であり、
Rc、Rd、およびReは、HまたはC1~C4アルキル基から独立して選択され、
R9およびR10は、独立して、結合、または最大6個の炭素原子を有し、カルボニル、アミド、イミド、エステル、エーテル、アミン、チオン、またはチオールを含む基である)
を有する、請求項1に記載の化合物。 - 生物学的サンプル内の1つ以上の標的を検出する方法であって、
(a)前記生物学的サンプル内の前記標的のうちの1つの第1の標的を、前記生物学的サンプルを酵素および前記第1の標的に特異的な一次抗体を含むコンジュゲートと接触させることにより、酵素で標識することと、
(b)請求項1~12のいずれか一項に記載の化合物と前記生物学的サンプルを接触させることと、
(c)前記生物学的サンプルを1つ以上の試薬と接触させて、検出可能な標識を検出することと、
を含む、方法。
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