CN109180638A - The second window of near-infrared emits Cyanine fluorochrome and its preparation method and application - Google Patents
The second window of near-infrared emits Cyanine fluorochrome and its preparation method and application Download PDFInfo
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- CN109180638A CN109180638A CN201811176045.9A CN201811176045A CN109180638A CN 109180638 A CN109180638 A CN 109180638A CN 201811176045 A CN201811176045 A CN 201811176045A CN 109180638 A CN109180638 A CN 109180638A
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- cyanine
- window
- fluorochrome
- cyanine fluorochrome
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- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 title claims abstract description 44
- BFMYDTVEBKDAKJ-UHFFFAOYSA-L disodium;(2',7'-dibromo-3',6'-dioxido-3-oxospiro[2-benzofuran-1,9'-xanthene]-4'-yl)mercury;hydrate Chemical compound O.[Na+].[Na+].O1C(=O)C2=CC=CC=C2C21C1=CC(Br)=C([O-])C([Hg])=C1OC1=C2C=C(Br)C([O-])=C1 BFMYDTVEBKDAKJ-UHFFFAOYSA-L 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000007850 fluorescent dye Substances 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000003384 imaging method Methods 0.000 claims abstract description 7
- 210000002751 lymph Anatomy 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 69
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- 230000015572 biosynthetic process Effects 0.000 claims description 23
- 238000003786 synthesis reaction Methods 0.000 claims description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- 239000002202 Polyethylene glycol Substances 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 229920001223 polyethylene glycol Polymers 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 238000004440 column chromatography Methods 0.000 claims description 14
- 239000002872 contrast media Substances 0.000 claims description 10
- 238000010791 quenching Methods 0.000 claims description 10
- 230000000171 quenching effect Effects 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 239000012074 organic phase Substances 0.000 claims description 9
- 230000001376 precipitating effect Effects 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims description 9
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 8
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 claims description 7
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 7
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 7
- 239000001632 sodium acetate Substances 0.000 claims description 7
- 235000017281 sodium acetate Nutrition 0.000 claims description 7
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- -1 substituted-phenyl ethyl Chemical group 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- 239000007848 Bronsted acid Substances 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- 150000003973 alkyl amines Chemical class 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 229910001914 chlorine tetroxide Inorganic materials 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 150000001875 compounds Chemical group 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 125000001814 trioxo-lambda(7)-chloranyloxy group Chemical group *OCl(=O)(=O)=O 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 3
- 239000008367 deionised water Substances 0.000 claims description 3
- 229910021641 deionized water Inorganic materials 0.000 claims description 3
- 238000001514 detection method Methods 0.000 claims description 3
- 210000004211 gastric acid Anatomy 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 238000000108 ultra-filtration Methods 0.000 claims description 3
- 238000002604 ultrasonography Methods 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 229910004039 HBF4 Inorganic materials 0.000 claims description 2
- 229910004713 HPF6 Inorganic materials 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 239000010813 municipal solid waste Substances 0.000 claims description 2
- KAHVZNKZQFSBFW-UHFFFAOYSA-N n-methyl-n-trimethylsilylmethanamine Chemical compound CN(C)[Si](C)(C)C KAHVZNKZQFSBFW-UHFFFAOYSA-N 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims 2
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 230000008033 biological extinction Effects 0.000 abstract description 7
- 210000002784 stomach Anatomy 0.000 abstract description 5
- 230000035515 penetration Effects 0.000 abstract description 3
- 239000012620 biological material Substances 0.000 abstract description 2
- 239000003471 mutagenic agent Substances 0.000 abstract description 2
- 231100000707 mutagenic chemical Toxicity 0.000 abstract description 2
- 239000002798 polar solvent Substances 0.000 abstract description 2
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 13
- 239000000243 solution Substances 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 5
- 239000000975 dye Substances 0.000 description 5
- 230000005284 excitation Effects 0.000 description 4
- ZEMZPXWZVTUONV-UHFFFAOYSA-N 2-(2-dicyclohexylphosphanylphenyl)-n,n-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 ZEMZPXWZVTUONV-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 238000006862 quantum yield reaction Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 206010019133 Hangover Diseases 0.000 description 2
- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-WFGJKAKNSA-N deuterated acetone Substances [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000000799 fluorescence microscopy Methods 0.000 description 2
- 239000003292 glue Substances 0.000 description 2
- 230000001926 lymphatic effect Effects 0.000 description 2
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 2
- 229910001623 magnesium bromide Inorganic materials 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- BXPGOVASPWDJAJ-UHFFFAOYSA-N methylsulfinylmethane;2,2,2-trifluoroacetic acid Chemical compound CS(C)=O.OC(=O)C(F)(F)F BXPGOVASPWDJAJ-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 238000012285 ultrasound imaging Methods 0.000 description 2
- HNGQQUDFJDROPY-UHFFFAOYSA-N 3-bromobenzenethiol Chemical compound SC1=CC=CC(Br)=C1 HNGQQUDFJDROPY-UHFFFAOYSA-N 0.000 description 1
- FTBCOQFMQSTCQQ-UHFFFAOYSA-N 4-bromobenzenethiol Chemical compound SC1=CC=C(Br)C=C1 FTBCOQFMQSTCQQ-UHFFFAOYSA-N 0.000 description 1
- QRXMUCSWCMTJGU-UHFFFAOYSA-N 5-bromo-4-chloro-3-indolyl phosphate Chemical compound C1=C(Br)C(Cl)=C2C(OP(O)(=O)O)=CNC2=C1 QRXMUCSWCMTJGU-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229910000530 Gallium indium arsenide Inorganic materials 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 239000002041 carbon nanotube Substances 0.000 description 1
- 229910021393 carbon nanotube Inorganic materials 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000002475 indoles Chemical group 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000006 pectoral fin Anatomy 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 238000005424 photoluminescence Methods 0.000 description 1
- 239000002096 quantum dot Substances 0.000 description 1
- 229910052761 rare earth metal Inorganic materials 0.000 description 1
- 150000002910 rare earth metals Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0076—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion
- A61K49/0082—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion micelle, e.g. phospholipidic micelle and polymeric micelle
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- 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
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
- C09B23/08—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines
- C09B23/083—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines five >CH- groups
-
- 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
- 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
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1003—Carbocyclic compounds
- C09K2211/1007—Non-condensed systems
-
- 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
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1092—Heterocyclic compounds characterised by ligands containing sulfur as the only heteroatom
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biomedical Technology (AREA)
- Materials Engineering (AREA)
- Dispersion Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention belongs to technical field of biological materials, specially a kind of the second window of near-infrared transmitting Cyanine fluorochrome and its preparation method and application.Cyanine fluorochrome provided by the invention, its molar extinction coefficient is big, it absorbs, launch wavelength is long and adjustable extent is wide, the less soluble mutagens color in polar solvent, have in water it is superior compared to existing common near-infrared the second window Heptamethine cyanines fluorescent dye it is anti-performance and brighter fluorescence intensity is quenched, therefore may be implemented to detect to the high-resolution imaging of mouse lymph and to the acidity of the deeper stomach of penetration depth.
Description
Technical field
The invention belongs to technical field of biological materials, and in particular to the Cyanine class of a kind of the second window of near-infrared transmitting
Fluorescent dye and preparation method thereof and the fluorescent dye are preparing answering in lymph imaging and gastric acid detection contrast agent
With.
Background technique
Molecular image technology such as X-ray common at present, Tomography (CT), magnetic resonance imaging (MRI) and ultrasound
Imaging (US) is used for the medical diagnosis to disease etc., but these methods have poor spatial resolution and its cannot achieve dynamic
The disadvantages of state real-time monitoring.Imaging-PAM is excellent due to having real-time, Noninvasive, the few, high-resolution of required sample size etc.
Point has been widely used in the fields such as life science and medicine.In recent years, researchers are dedicated to utilizing near-infrared
The transmitting light (nm of 1000 nm ~ 1700) of second window carries out fluorescence imaging, compared to wave band used in traditional fluorescence imaging
(400 nm-900 nm), in the second window of near-infrared, the absorption and scattering of biological tissue itself are weak, thus can be greatly
Improve image quality and penetration depth.Currently, common near-infrared the second window contrast agent includes some inorganic material such as rare earth
Doped nanoparticle, carbon nanotube, quantum dot etc., but their metabolism in vivo are slow and mechanism is still unknown so far
Really, furthermore the heavy metal element that contains has potential bio-toxicity, and which greatly limits their biologic applications values.
In contrast, the organic fluorescent dye of molecule-type has many advantages, such as that relative molecular weight is small, it is easy to be metabolized, exists in recent years
It is concerned in the application of the second window of near-infrared.Most typical example is indoles of the FDA approval for clinically angiography
Cyanines are green (ICG), have in recent years seminar find its second window of near-infrared fluorescent emission hangover shown it is excellent at
As effect.In addition, the Dai Hongjie seminar of Stanford University report it is a series of based on Donor-Acceptor-Donor (D-A-D) structure
Molecule-type fluorescent dye, universals be 808 nm excitation under can launch photoluminescence peak in the glimmering of 1000-1200 nm
Light realizes the imaging to tumour, lymph, cerebral vessels etc..But the molar extinction coefficient of this fluorochrome is low and excitation wave
Length, fluorescent brightness are even not so good as ICG and emit in the hangover of the second window of near-infrared.It is thus glimmering to cyanines class representated by ICG
It is current molecule-type fluorescent dye that photoinitiator dye, which carries out structure of modification to obtain brighter the second window of the near-infrared transmitting of more long wavelength,
The focus of design, this is because the fluorochrome have biggish molar extinction coefficient, higher fluorescence quantum yield and
The advantages that wide Wavelength tunable range.Regrettably, the cyanines class that the wavelength being had been reported that at present reaches the second window of near-infrared is glimmering
Photoinitiator dye shows molar extinction coefficient in water and is greatly reduced, and wavelength broadens and blue shift, and fluorescence is significantly quenched, and stability is poor
The disadvantages of, this severely limits its performances in subsequent bio application.
Summary of the invention
The purpose of the present invention is to provide a kind of good biocompatibility, photostability is high, anti-be quenched of fluorescence has excellent performance
The small organic molecule fluorescent dye and its preparation method and application of the second window of near-infrared transmitting.
The small organic molecule fluorescent dye of the second window of near-infrared transmitting provided by the invention, is that a kind of Cyanine class is glimmering
Photoinitiator dye, shown in the following formula (I) of general structure:
Wherein, R1And R2For H or N [(CH2)nCH3]2, R3For H or OCH3, n be 0 ~ 6 integer；X is selected from ClO4、PF6、BF4、
Cl、Br、I、CF3COO、CF3SO3、CH3COO or CH3SO3。
The preparation method of Cyanine fluorochrome formula proposed by the invention, chemical synthesis route are as follows:
Wherein, R1And R2For H or N [(CH2)nCH3]2, R3For H or OCH3, n be 0 ~ 6 integer；R5And R6For H or Br；X is selected from
ClO4、PF6、BF4、Cl、Br、I、CF3COO、CF3SO3Or CH3SO3。
The specific steps of preparation are as follows:
(1) synthesis of intermediate 1
Benzenethiol (compound 1) and substituted-phenyl ethyl acetoacetate (compound 2) will be replaced to be dissolved in polyphosphoric acids, 90 ~
It is reacted 1 ~ 3 hour at 100 DEG C；Trash ice quenching reaction is added after cooling, is extracted with dichloromethane, organic phase is concentrated and uses column chromatography
Isolated intermediate 1；Wherein the molar ratio of compound 1, compound 2 and polyphosphoric acids is 1:1.1:10 ~ 1:1.3:15
(1:(1. ~ 1.3): (10 ~ 15))；
(2) synthesis of intermediate 2
Under nitrogen protection, by intermediate 1, substituted alkylamine HN [(CH2)nCH3]2, Buchwald catalyst and inorganic base mix
In dry solvent, reacted 3 ~ 12 hours at 80 ~ 110 DEG C；It is filtered after being cooled to room temperature, organic phase concentration is simultaneously divided with column chromatography
From obtaining intermediate 2；Wherein, Buchwald catalyst is a kind of composition, is derived from palladium acetate, tris(dibenzylideneacetone) dipalladium
(Pd2dba3) one of and 2- dicyclohexyl phosphorus -2', 4', 6'- tri isopropyl biphenyl (X-Phos), the bis- (diphenyl of 4,5-
Phosphine) -9,9- xanthphos (XantPhos), in 2- dicyclohexylphosphino -2'- (N, TMSDMA N dimethylamine)-biphenyl (DavePhos)
One kind, the molar percentage that feeds intake is the 1 ~ 10% of intermediate 1；Intermediate 1, substituted alkylamine HN [(CH2)nCH3]2And nothing
The molar ratio of machine alkali is 1:2:1.2 ~ 1:5:3(1:(2 ~ 5): (1.2 ~ 3)), inorganic base can be selected from sodium tert-butoxide, cesium carbonate,
One of potassium carbonate and potassium phosphate；Solvent can be selected from toluene, one of dioxane and tetrahydrofuran；
(3) synthesis of intermediate 3
Intermediate 2 is dissolved in dry tetrahydrofuran, under nitrogen protection, methyl-magnesium-bromide is added, and it is small to react 0.5 ~ 2 at room temperature
When, 10% Bronsted acid quenching reaction is added, generates precipitating, filters to obtain intermediate 3；Wherein, the throwing of intermediate 2 and methyl-magnesium-bromide
Material molar ratio is 1:3 ~ 1:5, and Bronsted acid can be selected from HClO4、HPF6、HBF4、HCl、HBr、HI、CF3COOH、CF3SO3H and
CH3SO3One of H；
(4) synthesis of Cyanine fluorescent dye
Intermediate 3, two anil hydrochloride of malonaldehyde, sodium acetate are mixed in acetic anhydride, under nitrogen protection, in 80-130
It is reacted 2 ~ 8 hours at DEG C；It is added ether precipitating after reaction, filtering, with methylene chloride dissolving filter cake, and with column chromatography point
From finally obtaining Cyanine fluorescent dye；Wherein, intermediate 3, two anil hydrochloride of malonaldehyde and feeding intake for sodium acetate are rubbed
You are than being 1:0.5:1 ~ 1.5:0.5:1.5((1 ~ 1.5): 0.5:(1 ~ 1.5)).
It is Cyanine fluorochrome (structure is as shown in general formula I) that fluorescent dye, which is prepared, in the present invention, is drenched in preparation
Bar imaging and gastric acid detection contrast agent in apply, the specific steps are as follows:
Cyanine fluorochrome and phosphatide polyethylene glycol (2000) are dissolved in chloroform, stirred 0.5 ~ 1 hour, rotation is except molten
80 DEG C of deionized water dissolving is added in agent, vacuum drying after being heated to 80 DEG C, ultrasound passes through 30KD's again after being cooled to room temperature
Super filter tube is concentrated by ultrafiltration, and obtains final contrast agent.Wherein, the matter of Cyanine fluorochrome and phosphatide polyethylene glycol (2000)
Amount percentage is 1:500 ~ 1:50(1:(500 ~ 50)), the concentration of final contrast agent is 0.01 ~ 0.5 mM.
The micella can be used as contrast agent, for the lymphatic drainage imaging and the inspection of mouse stomach acidity to mouse leg
It surveys.
Cyanine fluorochrome provided by the invention, molar extinction coefficient is big, and absorption, launch wavelength are long and adjustable
Range is wide, the less soluble mutagens color in polar solvent, has in water compared to existing common seven methine of the second window of near-infrared
Cyanine fluorochrome it is superior it is anti-performance and brighter fluorescence intensity is quenched, therefore the high-resolution to mouse lymph may be implemented
Rate is imaged and detects to the acidity of the deeper stomach of penetration depth.
Cyanine fluorochrome (general formula I) of the invention, in dichloromethane solution, maximum absorption band be located at 932 ~
1014 nm, maximum emission peak are located at 980 ~ 1070 nm.
Cyanine fluorochrome (general formula I) of the invention, the molar extinction coefficient in dichloromethane solution are
115000~26000 M-1cm-1。
Cyanine fluorochrome (general formula I) of the invention, the fluorescence quantum yield in dichloromethane solution are
0.09~0.68%。
The micella that Cyanine fluorochrome (general formula I) and phosphatide polyethylene glycol 2000 of the invention is formed, in phosphoric acid
In salt buffer solution, maximum absorption band is located at 920 ~ 1015 nm, and maximum emission peak is located at 970 ~ 1065 nm.
The micella that Cyanine fluorochrome (general formula I) and phosphatide polyethylene glycol 2000 of the invention is formed, in phosphoric acid
Molar extinction coefficient in salt buffer solution is 45000 ~ 137500 M-1cm-1。
The micella that Cyanine fluorochrome (general formula I) and phosphatide polyethylene glycol 2000 of the invention is formed, in phosphoric acid
Fluorescence quantum yield in salt buffer solution is 0.016 ~ 0.22%.
The glue that Cyanine fluorochrome (3a, as shown below) of the invention is formed with phosphatide polyethylene glycol 2000
Beam, in phosphate buffer solution, under 808 nm excitation, when solution ph is changed to 1 from 5, fluorescent emission is blue from 1065 nm
Move to 980 nm.
The glue that Cyanine fluorochrome (3a, as shown below) of the invention is formed with phosphatide polyethylene glycol 2000
Beam, in phosphate buffer solution, under 808 nm excitation, when solution ph is changed to 1 from 5, the fluorescence of 1000-1300 nm
The ratio of the Fluorescence integral intensity of integrated intensity and 900-1300 nm drops to 0.459 from 0.865.
Detailed description of the invention
Fig. 1 is the absorption spectrogram of Cyanine fluorochrome (general formula I) in methylene chloride.
Fig. 2 is the fluorescent emission spectrogram of Cyanine fluorochrome (general formula I) in methylene chloride.
Fig. 3 is the micella that Cyanine fluorochrome (general formula I) and phosphatide polyethylene glycol 2000 are formed, slow in phosphate
It rushes in solution, it is bright with the second window of the near-infrared transmitting of ICG and its Heptamethine cyanines derivative I R26 at InGaAs CCD
Spend comparison diagram.
Fig. 4 is Cyanine fluorochrome (general formula I) and the micella of phosphatide polyethylene glycol 2000 formation to mouse leg
Lymphatic drainage imaging.
Fig. 5 is the micella pair that Cyanine fluorochrome (3a, as shown below) is formed with phosphatide polyethylene glycol 2000
Mouse stomach acidity detect and compareed with the result of standard pH meter.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, present invention following specific embodiments
It is illustrated, but the present invention is limited to absolutely not these examples.The following is only the preferred embodiment of the present invention, is only used for explaining this
Invention, it cannot be construed as a limitation to the scope of the present invention.It should be pointed out that all spirit of the invention and
Any modification, substitution or the improvement made within principle should all be included in the protection scope of the present invention.
Embodiment 1:
The preparation of Cyanine fluorochrome 1a, structural formula of compound are as follows:
。
Specific synthetic route is as follows:
。
Specific synthesis step is as follows:
(1) synthesis of intermediate 1
Benzenethiol (1.1 g, 10 mmol) and p-methoxyphenyl ethyl acetoacetate (2.6 g, 12 mmol) are dissolved in 22 g
In polyphosphoric acids, reacted 1 hour at 95 DEG C.Trash ice quenching reaction is added after cooling, is extracted with dichloromethane, organic phase concentration
And with column chromatography (petroleum ether/methylene chloride=1/1, v/v) isolated intermediate 1, yield 80%.1H NMR (400 MHz,
CDCl3) δ 8.55 (d, J = 8.0 Hz, 1H), 7.66 (m, 8.3 Hz, 4H), 7.57 (t, J = 7.4 Hz,
1H), 7.34 (s, 1H), 7.02 (d, J = 8.7 Hz, 2H), 3.88 (s, 3H)；
(2) synthesis of intermediate 2
Intermediate 1(268 mg, 1 mmol) it is dissolved in the dry tetrahydrofuran of 5 mL, under nitrogen protection, methyl bromide is added
The tetrahydrofuran solution (3 mL, 1.0 M) of magnesium reacts 1 hour at room temperature, and 10% perchloric acid quenching reaction is added, and generates precipitating,
Filter to obtain intermediate 3, yield 99%.1H NMR (400 MHz, CD3CN) δ 8.79 – 8.63 (m, 2H), 8.48 (d,
J = 8.0 Hz, 1H), 8.25 – 8.06 (m, 4H), 7.24 (d, J = 8.7 Hz, 2H), 3.96 (s, 3H),
3.18 (s, 3H)；
(4) synthesis of Cyanine fluorochrome 1a
Intermediate 2(184 mg, 0.5 mmol), two anil hydrochloride of malonaldehyde (64.7 mg, 0.25 mmol), sodium acetate
(41 mg, 0.5 mmol) is mixed in 5 mL acetic anhydride, under nitrogen protection, is reacted 2 hours at 100 DEG C.Reaction terminates
It filters while hot afterwards, with methylene chloride dissolving filter cake, and it is isolated most with column chromatography (methylene chloride/methanol=100/1, v/v)
Whole fluorescent dye 1a, yield 60%.1H NMR (400 MHz, DMSO-TFA) δ 8.45 (d, J = 7.1 Hz, 4H),
8.24 (s, 2H), 7.86 (d, J = 8.1 Hz, 6H), 7.70 – 7.51 (m, 6H), 7.16 (m, 1H),
7.09 (d, J = 8.8 Hz, 4H), 3.85 (s, 6H)。
Embodiment 2:
The preparation of Cyanine fluorochrome 2a, structural formula of compound are as follows:
。
Specific synthetic route is as follows:
。
Specific synthesis step is as follows:
(1) synthesis of intermediate 1
3- bromo thiophenol (2g, 10 mmol) and p-methoxyphenyl ethyl acetoacetate (2.6 g, 12 mmol) are dissolved in 22 g
In polyphosphoric acids, reacted 1 hour at 95 DEG C.Trash ice quenching reaction is added after cooling, is extracted with dichloromethane, organic phase concentration
And with column chromatography (petroleum ether/methylene chloride=1/1, v/v) isolated intermediate 1, yield 70%.1H NMR (400 MHz,
CDCl3) δ 8.37 (d, J = 8.6 Hz, 1H), 7.80 (s, 1H), 7.64 (d, J = 8.5 Hz, 2H),
7.26 (s, 1H), 7.20 (s, 1H), 7.01 (d, J = 8.7 Hz, 2H), 3.88 (s, 3H)；
(2) synthesis of intermediate 2
Under nitrogen protection, by intermediate 1(347 mg, 1 mmol), Pd2dba3(22.3 mg, 0.025 mmol),
DavePhos(9.8 mg, 0.025 mmol), and cesium carbonate (815 mg, 2.5 mmol) and diethylamine (520 μ L, 5
Mmol it) is mixed in the dry dioxane of 5mL, is reacted 12 hours at 100 DEG C.It is filtered after being cooled to room temperature, organic phase is dense
It contracts with column chromatography (dichloromethane eluent) isolated intermediate 2, yield 85%.1H NMR (400 MHz, CDCl3) δ
8.33 (d, J = 9.2 Hz, 1H), 7.63 (dd, J = 6.9, 1.9 Hz, 2H), 7.05 (s, 1H), 7.01
– 6.97 (m, 2H), 6.84 (dd, J = 9.2, 2.4 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H),
3.87 (s, 3H), 3.45 (q, J = 7.1 Hz, 4H), 1.23 (t, J = 7.1 Hz, 6H)；
(3) synthesis of intermediate 3
Intermediate 2(200 mg, 0.59 mmol) it is dissolved in the dry tetrahydrofuran of 5 mL, under nitrogen protection, methyl is added
The tetrahydrofuran solution (1.8 mL, 1.0 M) of magnesium bromide reacts 1 hour at room temperature, and 10% perchloric acid quenching reaction is added, raw
At precipitating, intermediate 3, yield 98% are filtered to obtain.1H NMR (400 MHz, Acetone-D6) δ 8.54 (d, J = 9.6
Hz, 1H), 8.27 (s, 1H), 8.06 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 17.0 Hz, 2H),
7.24 (d, J = 8.2 Hz, 2H), 3.96 (s, 3H), 3.83 (d, J = 7.1 Hz, 4H), 3.06 (s,
3H), 1.35 (t, J = 6.8 Hz, 6H)；
(4) synthesis of Cyanine fluorochrome 2a
Intermediate 3(219 mg, 0.5 mmol), two anil hydrochloride of malonaldehyde (64.7 mg, 0.25 mmol), sodium acetate
(41 mg, 0.5 mmol) is mixed in 5 mL acetic anhydride, under nitrogen protection, is reacted 5 hours at 100 DEG C.Reaction terminates
Ether precipitating is added afterwards, filtering divides with methylene chloride dissolving filter cake, and with column chromatography (methylene chloride/methanol=100/1, v/v)
From obtaining final fluorescent dye 2a, yield 47%.1H NMR (600 MHz, CD3CN) δ 7.48 (t, J = 11.8 Hz,
4H), 7.27 (d, J = 8.4 Hz, 4H), 7.23 (s, 2H), 6.78 (d, J = 8.4 Hz, 4H), 6.61
(d, J = 13.2 Hz, 2H), 6.47 (t, J = 12.2 Hz, 1H), 6.42 (dd, J = 9.1, 2.3 Hz,
2H), 6.33 (d, J = 2.4 Hz, 2H), 3.78 (s, 6H), 3.27 (q, J = 7.1 Hz, 8H), 1.09
(t, J = 7.3 Hz, 12H)。
Embodiment 3:
The preparation of Cyanine fluorochrome 3a, structural formula of compound are as follows:
。
Specific synthetic route is as follows:
。
Specific synthesis step is as follows:
(1) synthesis of intermediate 1
4- bromo thiophenol (2g, 10 mmol) and p-methoxyphenyl ethyl acetoacetate (2.6 g, 12 mmol) are dissolved in 22 g
In polyphosphoric acids, reacted 1 hour at 95 DEG C.Trash ice quenching reaction is added after cooling, is extracted with dichloromethane, organic phase concentration
And with column chromatography (petroleum ether/methylene chloride=1/1, v/v) isolated intermediate 1, yield 50%.1H NMR (400 MHz,
CDCl3) δ 8.63 (s, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H),
7.49 (d, J = 8.5 Hz, 1H), 7.18 (s, 1H), 6.99 (d, J = 8.4 Hz, 2H), 3.86 (s,
3H)；
(2) synthesis of intermediate 2
Under nitrogen protection, by intermediate 1(347 mg, 1 mmol), Pd2dba3(22.3 mg, 0.025 mmol),
DavePhos(9.8 mg, 0.025 mmol), and cesium carbonate (815 mg, 2.5 mmol) and diethylamine (520 μ L, 5
Mmol it) is mixed in the dry dioxane of 5mL, is reacted 12 hours at 100 DEG C.It is filtered after being cooled to room temperature, organic phase is dense
It contracts with column chromatography (dichloromethane eluent) isolated intermediate 2, yield 83%.1H NMR (400 MHz, CDCl3) δ
7.72 (d, J = 2.7 Hz, 1H), 7.66 – 7.62 (m, 2H), 7.47 (d, J = 8.9 Hz, 1H), 7.16
(s, 1H), 7.04 (d, J = 7.5 Hz, 1H), 7.00 – 6.95 (m, 2H), 3.86 (s, 3H), 3.46
(q, J = 7.1 Hz, 4H), 1.21 (t, J = 7.1 Hz, 6H)；
(3) synthesis of intermediate 3
Intermediate 2(200 mg, 0.59 mmol) it is dissolved in the dry tetrahydrofuran of 5 mL, under nitrogen protection, methyl is added
The tetrahydrofuran solution (1.8 mL, 1.0 M) of magnesium bromide reacts 1 hour at room temperature, and 10% perchloric acid quenching reaction is added, raw
At precipitating, intermediate 3, yield 97% are filtered to obtain.1H NMR (400 MHz, Acetone-D6) δ 8.77 (s, 1H),
8.43 (d, J = 9.2 Hz, 1H), 8.18 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 9.0 Hz, 1H),
7.44 (s, 1H), 7.25 (d, J = 8.1 Hz, 2H), 3.98 (s, 3H), 3.74 (d, J = 6.6 Hz,
4H), 3.13 (s, 2H), 1.32 (t, J = 6.8 Hz, 6H)；
(4) synthesis of Cyanine fluorochrome 3a
Intermediate 3(219 mg, 0.5 mmol), two anil hydrochloride of malonaldehyde (64.7 mg, 0.25 mmol), sodium acetate
(41 mg, 0.5 mmol) is mixed in 5 mL acetic anhydride, under nitrogen protection, is reacted 5 hours at 100 DEG C.Reaction terminates
Ether precipitating is added afterwards, filtering divides with methylene chloride dissolving filter cake, and with column chromatography (methylene chloride/methanol=100/1, v/v)
From obtaining final fluorescent dye 3a, yield 27%.1H NMR (500 MHz, DMSO-TFA) δ 8.37 (t, J = 12.7
Hz, 2H), 8.21 (s, 2H), 7.90 (d, J = 8.5 Hz, 4H), 7.83 (d, J = 7.9 Hz, 2H),
7.24-7.56 (m, 7H), 7.17 (d, J = 8.8 Hz, 4H), 3.88 (s, 6H), 3.56 (q, J = 7.0
Hz, 8H), 1.18 (t, J = 7.0 Hz, 12H)。
Embodiment 4:
Cyanine fluorochrome and phosphatide polyethylene glycol form the preparation method of micella, with fluorescent dye 3a and DOPE-
For PEG2000.Specific step is as follows:
1 mg Cyanine fluorochrome 3a and 100 mg DOPE-PEG2000 is dissolved in 20 mL chloroforms, after stirring 1 hour, rotation
Except solvent, the deionized water dissolving of 80 DEG C of 20 mL is added in vacuum drying after being heated to 80 DEG C, ultrasound, after being cooled to room temperature again
It is concentrated by ultrafiltration by the super filter tube of 30KD, obtains final contrast agent, concentration is 0.5 mM.
Application examples:
Mouse leg lymph is imaged in the micella that Cyanine fluorochrome 3a and phosphatide polyethylene glycol are formed.Specific steps are such as
Under:
The micellar solution that 50 μ L dye strengths are 200 μM is injected at the mouse flippers of anesthesia, with the external laser of 1064 nm
Device irradiates the right leg of mouse, and laser power density is 60 mW/cm2(referring to fig. 4).
The micella that Cyanine fluorochrome 3a and phosphatide polyethylene glycol are formed detects mouse stomach acidity.Specific step
It is rapid as follows:
The micellar solution that 20 μ L dye strengths are 500 μM is perfused in the Mouse oral of anesthesia, with the external laser of 808 nm
Thorax abdomen on the left of mouse is irradiated, laser power density is 200 mW/cm2, use 900 nm and 1000 nm long reduction of fractions to a common denominator optical filters
Not Shou Ji 900-1700 nm and 1000-1700 nm fluorescence and both calculate intensity rate, obtaining ratio, to substitute into calibration bent
Line computation obtains final pH value (referring to Fig. 5).
Claims (3)
1. the Cyanine fluorochrome of the second window of near-infrared transmitting, which is characterized in that compound structure general formula is as follows:
Wherein, R1And R2For H or N [(CH2)nCH3]2, R3For H or OCH3, n be 0 ~ 6 integer；X is selected from ClO4、PF6、BF4、Cl、
Br、I、CF3COO、CF3SO3、CH3COO or CH3SO3。
2. a kind of preparation method of Cyanine fluorochrome described in claim 1, which is characterized in that synthetic route is such as
Under:
Wherein, R1And R2For H or N [(CH2)nCH3]2, R3For H or OCH3, n be 0 ~ 6 integer；R5And R6For H or Br；X is selected from
ClO4、PF6、BF4、Cl、Br、I、CF3COO、CF3SO3Or CH3SO3；
Specific step is as follows:
(1) synthesis of intermediate 1
Benzenethiol (compound 1) and substituted-phenyl ethyl acetoacetate (compound 2) will be replaced to be dissolved in polyphosphoric acids, 90 ~
It is reacted 1 ~ 3 hour at 100 DEG C；Trash ice quenching reaction is added after cooling, is extracted with dichloromethane, organic phase is concentrated and uses column chromatography
Isolated intermediate 1；Wherein the molar ratio of compound 1, compound 2 and polyphosphoric acids is 1:(1. ~ 1.3): (10 ~
15)；
(2) synthesis of intermediate 2
Under nitrogen protection, by intermediate 1, substituted alkylamine HN [(CH2)nCH3]2, Buchwald catalyst and inorganic base mixing
In dry solvent, reacted 3 ~ 12 hours at 80 ~ 110 DEG C；It is filtered after being cooled to room temperature, organic phase concentration is simultaneously divided with column chromatography
From obtaining intermediate 2；Wherein, Buchwald catalyst is a kind of composition, is derived from palladium acetate, tris(dibenzylideneacetone) dipalladium
One of and 2- dicyclohexyl phosphorus -2', 4', 6'- tri isopropyl biphenyl, bis- (diphenylphosphine) -9,9- dimethyl oxa-s of 4,5-
One of anthracene, 2- dicyclohexylphosphino -2'- (N, TMSDMA N dimethylamine)-biphenyl, the molar percentage that feeds intake be intermediate 11 ~
10%；Intermediate 1, substituted alkylamine HN [(CH2)nCH3]2Molar ratio with inorganic base is 1:(2 ~ 5): (1.2 ~ 3), it is inorganic
Alkali is selected from sodium tert-butoxide, cesium carbonate, one of potassium carbonate and potassium phosphate；Solvent is selected from toluene, dioxane and tetrahydrofuran
One of；
(3) synthesis of intermediate 3
Intermediate 2 is dissolved in dry tetrahydrofuran, under nitrogen protection, methyl-magnesium-bromide is added, and it is small to react 0.5 ~ 2 at room temperature
When, 10% Bronsted acid quenching reaction is added, generates precipitating, filters to obtain intermediate 3；Wherein, the throwing of intermediate 2 and methyl-magnesium-bromide
Material molar ratio is 1:(3 ~ 5), Bronsted acid is selected from HClO4、HPF6、HBF4、HCl、HBr、HI、CF3COOH、CF3SO3H and CH3SO3H
One of；
(4) synthesis of Cyanine fluorescent dye
Intermediate 3, two anil hydrochloride of malonaldehyde, sodium acetate are mixed in acetic anhydride, under nitrogen protection, in 80-130
It is reacted 2 ~ 8 hours at DEG C；It is added ether precipitating after reaction, filtering, with methylene chloride dissolving filter cake, and with column chromatography point
From finally obtaining Cyanine fluorescent dye；Wherein, intermediate 3, two anil hydrochloride of malonaldehyde and feeding intake for sodium acetate are rubbed
You are than being (1 ~ 1.5): 0.5:(1 ~ 1.5).
3. the Cyanine fluorochrome of the second window of near-infrared transmitting as described in claim 1 is preparing lymph imaging
It is applied in the contrast agent of gastric acid detection, the specific steps are as follows:
Cyanine fluorochrome and phosphatide polyethylene glycol (2000) are dissolved in chloroform, stirred 0.5 ~ 1 hour, rotation is except molten
80 DEG C of deionized water dissolving is added in agent, vacuum drying after being heated to 80 DEG C, ultrasound passes through 30KD's again after being cooled to room temperature
Super filter tube is concentrated by ultrafiltration, and obtains final contrast agent；Wherein, the matter of Cyanine fluorochrome and phosphatide polyethylene glycol (2000)
Measuring percentage is (1:(500 ~ 50)), the concentration of final contrast agent is 0.01 ~ 0.5 mM.
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| CN113980036A (en) * | 2021-09-30 | 2022-01-28 | 复旦大学 | Alkaline, active oxygen and active nitrogen dual-response near-infrared fluorescent probe and preparation method and application thereof |
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| CN110079117A (en) * | 2019-04-22 | 2019-08-02 | 复旦大学 | The fluorescent dye and preparation method and application of near-infrared the second window excitation/emission |
| CN112225721A (en) * | 2020-10-21 | 2021-01-15 | 复旦大学 | Acid-responsive near-infrared lysosome organic small-molecule fluorescent probe and preparation method and application thereof |
| CN112409590A (en) * | 2020-10-21 | 2021-02-26 | 复旦大学 | Organic nano assembly for biological imaging of second window in near infrared region and preparation method and application thereof |
| CN112225721B (en) * | 2020-10-21 | 2021-09-17 | 复旦大学 | Acid-responsive near-infrared lysosome organic small-molecule fluorescent probe and preparation method and application thereof |
| CN114621182A (en) * | 2020-12-10 | 2022-06-14 | 中国科学院深圳先进技术研究院 | Derivatization reagent, synthesis method thereof and method for analyzing monoamine neurotransmitter in situ based on MALDI-MS |
| CN114621182B (en) * | 2020-12-10 | 2023-10-03 | 中国科学院深圳先进技术研究院 | Derivatization reagent, synthesis method thereof and MALDI-MS-based method for in-situ analysis of monoamine neurotransmitters |
| CN113135963A (en) * | 2021-03-16 | 2021-07-20 | 复旦大学 | Near-infrared second window emission rare earth complex fluorescent dye and preparation method and application thereof |
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