JP4759506B2 - 蛍光プローブ - Google Patents
蛍光プローブ Download PDFInfo
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- JP4759506B2 JP4759506B2 JP2006510271A JP2006510271A JP4759506B2 JP 4759506 B2 JP4759506 B2 JP 4759506B2 JP 2006510271 A JP2006510271 A JP 2006510271A JP 2006510271 A JP2006510271 A JP 2006510271A JP 4759506 B2 JP4759506 B2 JP 4759506B2
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- 239000007850 fluorescent dye Substances 0.000 title description 22
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 114
- 150000001875 compounds Chemical class 0.000 claims description 97
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 49
- 125000001424 substituent group Chemical group 0.000 claims description 49
- -1 R 31 Chemical compound 0.000 claims description 46
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- 125000003277 amino group Chemical group 0.000 claims description 26
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 125000006702 (C1-C18) alkyl group Chemical group 0.000 claims description 15
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 150000002500 ions Chemical class 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000004434 sulfur atom Chemical group 0.000 claims description 7
- 230000005591 charge neutralization Effects 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 210000001519 tissue Anatomy 0.000 description 21
- 239000000243 solution Substances 0.000 description 19
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 18
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- 229910052725 zinc Inorganic materials 0.000 description 15
- 239000011701 zinc Substances 0.000 description 15
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 14
- 210000003734 kidney Anatomy 0.000 description 13
- 238000005259 measurement Methods 0.000 description 13
- 238000007792 addition Methods 0.000 description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 12
- 229940125782 compound 2 Drugs 0.000 description 12
- 239000001301 oxygen Substances 0.000 description 12
- 229910052760 oxygen Inorganic materials 0.000 description 12
- 125000006239 protecting group Chemical group 0.000 description 12
- 230000005284 excitation Effects 0.000 description 11
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 229910052786 argon Inorganic materials 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 229910021645 metal ion Inorganic materials 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 230000035945 sensitivity Effects 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 5
- 238000002189 fluorescence spectrum Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 230000007935 neutral effect Effects 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- DYUUGILMVYJEHY-UHFFFAOYSA-N 1-$l^{1}-oxidanyl-4,4,5,5-tetramethyl-3-oxido-2-phenylimidazol-3-ium Chemical compound CC1(C)C(C)(C)N([O])C(C=2C=CC=CC=2)=[N+]1[O-] DYUUGILMVYJEHY-UHFFFAOYSA-N 0.000 description 4
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 230000035699 permeability Effects 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 229910001415 sodium ion Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 150000003852 triazoles Chemical class 0.000 description 4
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 3
- IQXUIDYRTHQTET-UHFFFAOYSA-N 4-amino-3-nitrophenol Chemical compound NC1=CC=C(O)C=C1[N+]([O-])=O IQXUIDYRTHQTET-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 239000012736 aqueous medium Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 239000008055 phosphate buffer solution Substances 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- QSSNLQPWTLQYTB-UHFFFAOYSA-N 4-(1-hydroxy-4,4,5,5-tetramethyl-3-oxidoimidazol-3-ium-2-yl)benzoic acid Chemical compound CC1(C)C(C)(C)N(O)C(C=2C=CC(=CC=2)C(O)=O)=[N+]1[O-] QSSNLQPWTLQYTB-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical class O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 2
- 238000002073 fluorescence micrograph Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 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
- YJBKVPRVZAQTPY-UHFFFAOYSA-J tetrachlorostannane;dihydrate Chemical compound O.O.Cl[Sn](Cl)(Cl)Cl YJBKVPRVZAQTPY-UHFFFAOYSA-J 0.000 description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ZWHOTPNCEFWATE-CQSZACIVSA-N (3R)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylpyrrolidine-1-carboxamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)O[C@H]1CN(CC1)C(=O)NC1=CC=CC=C1 ZWHOTPNCEFWATE-CQSZACIVSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000005103 alkyl silyl group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- LFMTUFVYMCDPGY-UHFFFAOYSA-N n,n-diethylethanamine oxide Chemical compound CC[N+]([O-])(CC)CC LFMTUFVYMCDPGY-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000006862 quantum yield reaction Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
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Description
化合物1の合成
39 mg の4-アミノ-3-ニトロフェノール (0.25 mmol)と10 mg のナトリウムハイドライド (60% in mineral oil) (0.25 mmol)を7 mlのジメチルホルムアミド(DMF)に溶かし、アルゴン下室温で10分間撹拌した。この間に67 mgの化合物A (0.10 mmol)を2 mlのDMFに溶かしておき、これを先の溶液に加え、アルゴン下室温で4時間撹拌した。シリカゲルクロマトグラフィーにて精製して濃緑色の固体を得た。(収率70%)
1H NMR (CDCl3 300MHz); δ 1.05 (t, 6H, J = 7.3 Hz), 1.42 (s, 12H), 1.87 (m, 4H), 2.04 (m, 2H), 2.68 (t, 4H, J = 5.0 Hz), 3.99 (t, 4H, J = 7.2 Hz), 5.99 (d, 2H, J = 14.4 Hz), 6.90 (s, 2H), 7.05 - 7.40 (m, 9H), 7.66 - 7.72 (m, 2H), 7.92 (d, 2H, J = 14.4 Hz)
MS (FAB); 657 (M - I- )
44 mgの化合物1(0.055 mmol)を2 mlのメタノールに溶かし、これに0.3 mlの濃塩酸を加え、更に250 mgの塩化スズ・2水和物 (1.1 mmol)を加えて、アルゴン下40℃で13時間撹拌した。室温に戻した後、pH 4となるまで水酸化ナトリウム水溶液を加え、溶液を減圧溜去した。得られた混合物を5 ml程度のメタノールに溶解してろ過した後に、溶液を減圧溜去した。これをシリカゲルクロマトグラフィーにて精製して濃緑色の固体を得た。(収率20%)
1H NMR (CD3OD 300MHz); δ 0.92 (t, 6H, J = 7.4 Hz), 1.31 (s, 12H), 1.74 (m, 4H), 1.92 (m, 2H), 2.61 (t, 4H, J = 6.0 Hz), 3.96 (t, 4H, J = 7.4 Hz), 6.02 (d, 2H, J = 14.1 Hz), 6.20 (dd, 1H, J = 8.4, 2.8 Hz), 6.45 (d, H, J = 2.8 Hz), 6.58 (d, 1H, J = 8.54 Hz), 7.08 - 7.15 (m, 4H), 7.24 - 7.30 (m, 4H), 7.98 (d, 2H, J = 14.1 Hz)
MS (FAB); 627 (M - I- )
93 mgの4-アミノ-3-ニトロフェノール (0.60 mmol)と24 mgのナトリウムハイドライド (60% in mineral oil) (0.60 mmol)を16 ml のDMFに溶かし、アルゴン下室温で10分間撹拌した。この間に180 mgの化合物B (0.24 mmol)を5 mlのDMFに溶かしておき、これを先の溶液に加え、アルゴン下室温で4時間撹拌した。シリカゲルクロマトグラフィーにて精製して濃緑色の固体を得た。(収率80%)
1H NMR (CD3OD 300MHz); δ 1.33 (s, 12H), 1.80 - 1.96 (m, 10H), 2.67 (t, 4H, J = 5.9 Hz), 2.78 (t, 4H, J = 7.0 Hz), 4.04 (t, 4H, J = 6.3 Hz), 6.12 (d, 2H, J = 14.3 Hz), 6.97 (d, 1H, J = 9.3 Hz), 7.08 - 7.31 (m, 9H), 7.61 (d, 1H, J = 2.9 Hz), 7.89 (d, 2H, J = 14.3 Hz)
MS (FAB); 845 (M - Na+ + 2H+) , 867 (M + H+), 889 (M + Na+)
100 mgの化合物3 (0.12 mmol)を4 mlのメタノールに溶かし、これに0.6 mlの濃塩酸を加え、更に450 mgの塩化スズ・2水和物(2.0 mmol)を加えて、アルゴン下40℃で13時間撹拌した。室温に戻した後、pH 7となるまで水酸化ナトリウム水溶液を加えてろ過した後に、溶液を減圧溜去した。得られた混合物を約10 mlのメタノールに溶かし、同様にろ過した後、溶液を減圧溜去した。これをシリカゲルクロマトグラフィーにて精製して濃緑色の固体を得た。(収率20%)
1H NMR (CD3OD 300MHz); δ 1.30 (s, 12H), 1.82 - 1.92 (m, 10H), 2.62 (t, 4H, J = 5.8 Hz), 2.77 (t, 4H, J = 6.7 Hz), 4.01 (t, 4H, J = 5.5 Hz), 6.05 (d, 2H, J = 14.2 Hz), 6.19 (dd, 1H, J = 8.4, 2.9 Hz), 6.45 ( d, 1H, J = 2.9 Hz), 6.58 (d, 1H, J = 8.4 Hz), 7.06 - 7.28 (m, 8H), 7.97 (d, 2H, J = 14.2 Hz)
MS (FAB); 815 (M - Na+ + 2H+) , 837 (M + H+), 859 (M + Na+)
2.0 gの4-アミノ-3-ニトロフェノール (13 mmmol)を100 mlのメタノールに溶かし、これに0.69 gの10%パラジウム炭素触媒(0.65 mmol)を少しずつ加えた。水素下室温で3時間撹拌した後、触媒を濾去し、濾液を減圧溜去して黒色の固体を得た。(収率92%)
1H NMR (CD3OD 300MHz); δ 6.07 (dd, 1H, J = 8.2, 2.7 Hz), 6.23 (d, 1H, J = 2.7 Hz), 6.56 (d, 1H, J = 8.2 Hz)
MS (EI); 124 (M+)
500 mgの化合物5 (4.0 mmol)を150 mlの0.2規定塩酸水溶液に溶かし、0 ℃で撹拌しながら、280 mgの亜硝酸ナトリウム(4.0 mmol)を少しずつ加えた。室温で1.5時間撹拌した後、pH 3となるまで水酸化ナトリウム水溶液を加えた。適当量の酢酸エチルで抽出した後、有機相を無水硫酸ナトリウムで乾燥した。溶液を減圧溜去して茶色の固体を得た。(収率80%)
1H NMR (CD3OD 300MHz); δ 6.88 (m, 2H), 7.64 (d, 1H, J = 9.7 Hz)
MS (EI); 135 (M+)
34 mgの化合物6(0.25 mmol)と10 mgのナトリウムハイドライド(50% in mineral oil) (0.25mmol)を7 mlのDMFに溶かし、アルゴン下室温で10分間撹拌した。この間に74 mgの化合物B (0.10 mmol)を 2 mlのDMFに溶かしておき、これを先の溶液に加え、アルゴン下室温で6時間撹拌した。シリカゲルクロマトグラフィーで粗精製した後、高速液体クロマトグラフィーで精製して緑色の固体を得た。(収率40%)
1H NMR (DMSO-d6 300MHz); δ 1.17 (s, 12H), 1.70 - 1.97 (m, 8H), 2.48 (m, 4H), 2.76 (t, 4H, J = 6.0 Hz), 4.12 (t, 4H, J = 6.6 Hz), 6.25 (d, 2H, J = 14.2 Hz), 7.13 - 7.48 (m, 10H), 7.81 (d, 2H, J = 14.2 Hz), 8.06 (d, 1H, J = 9.0 Hz)
MS (FAB); 826 (M - Na+ + 2H+) , 848 (M + H+), 870 (M + Na+)
HPLCによる分析条件は全ての測定で同一であり、ODSカラムを用い、溶媒A を0.1% TFA / 水、 溶媒Bを0.1% TFA, 20% 水 / アセトニトリルとして溶媒の勾配をA / B = 50 / 50 -> 0 / 100とした。化合物4をpH 7.4の0.1 mMリン酸緩衝液に溶解してHPLCによる分析を行ったところ、保持時間は2.4分であった。この溶液に、一酸化窒素ガスを吹き込んだpH 7.4の0.1 mMリン酸緩衝液を少量ずつ加えて、その度にHPLCによる分析を行うと、保持時間2.4分のピークは減少し、新たに保持時間3.4分のピークが増加することが観察された。これとは別にトリアゾール体の合成標品である化合物7をpH 7.4の0.1 mMリン酸緩衝液に溶解してHPLCによる分析を行ったところ、保持時間は3.4分であり、先の測定で新たに現れたピークの保持時間と一致した。以上の結果により、化合物4が一酸化窒素と反応してトリアゾール体である化合物7が生成することが確認できた。
化合物2を適量のメタノールに溶解し、吸収極大波長(766 nm)での吸光度が0.2になるように溶液を調製した。これとは別に、一酸化窒素ガスを吹き込んだメタノールを用意しておき、これを先の溶液に二回に分けて少量添加した。添加前、一回添加時、二回添加時の吸収スペクトル及び蛍光スペクトルをそれぞれ測定した。図1に吸収スペクトルの変化の様子を示す。吸収スペクトルは一酸化窒素による影響をほとんど受けなかった。図2に蛍光スペクトルの変化の様子を示す。765 nmでの励起による極大蛍光波長はいずれも786 nmであったが、その蛍光強度は一酸化窒素添加前では330であったものが、一回添加で1000、二回添加で2100にまで増加した。つまり、化合物2が一酸化窒素と反応することで生成するトリアゾール化合物により、極大蛍光波長の蛍光強度は少なくとも6.4倍に増加することが分かった。
一酸化窒素の供給源として自発的一酸化窒素発生剤であるNOC類(Hrabie, J.A., J. Org. Chem., 58, pp.1472-1476, 1993)のうちNOC-13(22℃、pH 7.4, 0.1Mリン酸緩衝液中での半減期 13.7分)を用い、反応液中に生成する一酸化窒素を化合物4と反応させた。反応溶媒としてpH 7.4の10 mMリン酸緩衝液を用い、化合物4、NOC-13共に5 μMとなるように調製し、37℃で蛍光強度の経時変化を測定した。図3に結果を示す。励起波長は765 nm、蛍光波長は790 nmで測定した。図中、1分のところでNOC-13のストックソリューションを加えた。経時的な蛍光強度の増大は、化合物4から一酸化窒素生成量に依存してトリアゾール体が生成していることを示している。
化合物2の生体内組織深部観察への応用
化合物2が生体組織中においても一酸化窒素を捕捉でき、かつ、外部からの観察が可能であることを確認するため、ラットの摘出腎臓の内部を血管に蛍光プローブを灌流することにより染め、腎臓外部から実体蛍光顕微鏡を用いて腎臓内部の蛍光強度変化を観察した。
麻酔したラットの右腎大動脈から灌流液を流した後、速やかに右腎を摘出し、近赤外光領域に対応した実体蛍光顕微鏡のステージ上に設置した(励起フィルター:730 nm±23 nm, 蛍光フィルター:770 nm long-pass)。灌流液に替えて、化合物2の溶解液を右腎内に導入したところ、腎臓外部から弱い蛍光が測定でき、化合物2が腎臓内部に負荷されたことを確認した。腎外部から観察した腎内部の近赤外蛍光画像を図4に示す。腎臓内部に存在する糸球体周りの毛細血管に由来すると考えられる丸い構造が浮かび上がっている。その後、灌流液と一酸化窒素供給化合物(NOC13)の溶解液を交互に流しながら、20秒毎に蛍光画像を取得した。それぞれの画像の画面全体の蛍光強度の平均値を算出し、経時的な変化をみたところ、一酸化窒素供給化合物を投与している間のみ蛍光強度が増大していることを確認した(図5)。
以上の結果より、化合物2が生体組織環境中においても一酸化窒素を検出する能力を有し、また、近赤外域の蛍光を利用することで生体組織の内部観察を外部から行うことが証明された。
Claims (6)
- 下記の一般式(IA):
- R23、R24、R25、R26、R27、R28、R29、R30、R31、及びR32が水素原子であり、R33及びR34がスルホ基で置換されたC1-6アルキル基であり、Z21が酸素原子であり、Y21及びY22が-C(CH3)2-である請求項1に記載の化合物。
- 請求項1又は2に記載の一般式(IA)で表される化合物を含む一酸化窒素測定用試薬。
- 下記の一般式(IB):
- R43、R44、R45、R46、R47、R48、R49、R50、R51、及びR52が水素原子であり、R53及びR54がスルホ基で置換されたC1-6アルキル基であり、Z41が酸素原子であり、Y41及びY42が-C(CH3)2-である請求項4に記載の化合物。
- 一酸化窒素の測定方法であって、(a)請求項1に記載の一般式(IA)で示される化合物と一酸化窒素とを反応させる工程;及び、(b)上記工程(a)において生成する請求項4に記載の一般式(IB)の化合物[ただし、R41及びR42は互いに結合してベンゼン環上の隣接した位置に環を形成する-N=N-NR58- (式中、R58は水素原子又は置換基を有していてもよいC1-6アルキル基を示す)で表される基を示す]を検出する工程を含む方法。
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JP2006510271A JP4759506B2 (ja) | 2004-02-23 | 2005-02-22 | 蛍光プローブ |
PCT/JP2005/002753 WO2005080331A1 (ja) | 2004-02-23 | 2005-02-22 | 蛍光プローブ |
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JPWO2005080331A1 JPWO2005080331A1 (ja) | 2007-10-25 |
JP4759506B2 true JP4759506B2 (ja) | 2011-08-31 |
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JP2006510271A Expired - Fee Related JP4759506B2 (ja) | 2004-02-23 | 2005-02-22 | 蛍光プローブ |
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US (2) | US20070298507A1 (ja) |
JP (1) | JP4759506B2 (ja) |
WO (1) | WO2005080331A1 (ja) |
Families Citing this family (10)
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JP4759506B2 (ja) | 2004-02-23 | 2011-08-31 | 哲雄 長野 | 蛍光プローブ |
US20080281104A1 (en) * | 2005-03-04 | 2008-11-13 | The University Of Tokyo | Membrane-Anchoring Fluorescent Probe |
JP5261718B2 (ja) * | 2006-03-03 | 2013-08-14 | 国立大学法人 東京大学 | 蛍光プローブ |
WO2008099914A1 (ja) | 2007-02-16 | 2008-08-21 | The University Of Tokyo | 蛍光プローブ |
US8465985B2 (en) | 2007-03-01 | 2013-06-18 | The University Of Tokyo | Fluorescent probe |
JPWO2009107769A1 (ja) * | 2008-02-29 | 2011-07-07 | 国立大学法人 東京大学 | 活性酸素測定用試薬 |
US20120065384A1 (en) * | 2009-03-04 | 2012-03-15 | The University Of Tokyo | Fluorescent mri probe |
CN103664735B (zh) * | 2012-09-18 | 2015-05-13 | 中国科学院烟台海岸带研究所 | 基于硝基还原检测细胞内硫化氢的荧光探针及其应用 |
CN108624081B (zh) * | 2018-05-29 | 2020-03-10 | 苏州百源基因技术有限公司 | 一种荧光染料及其制备方法与应用 |
CN110698508A (zh) * | 2019-10-10 | 2020-01-17 | 济南大学 | 一种一氧化氮和硫化氢双检测的荧光探针及其制备方法和应用 |
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- 2005-02-22 US US10/598,250 patent/US20070298507A1/en not_active Abandoned
- 2005-02-22 WO PCT/JP2005/002753 patent/WO2005080331A1/ja active Application Filing
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2010
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Also Published As
Publication number | Publication date |
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WO2005080331A1 (ja) | 2005-09-01 |
US7939330B2 (en) | 2011-05-10 |
JPWO2005080331A1 (ja) | 2007-10-25 |
US20070298507A1 (en) | 2007-12-27 |
US20110038803A1 (en) | 2011-02-17 |
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