CN111303111B - 一类黄菁近红外二区染料、制备方法及荧光成像应用 - Google Patents
一类黄菁近红外二区染料、制备方法及荧光成像应用 Download PDFInfo
- Publication number
- CN111303111B CN111303111B CN202010207162.8A CN202010207162A CN111303111B CN 111303111 B CN111303111 B CN 111303111B CN 202010207162 A CN202010207162 A CN 202010207162A CN 111303111 B CN111303111 B CN 111303111B
- Authority
- CN
- China
- Prior art keywords
- dye
- infrared
- nir
- formula
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title abstract description 9
- 238000000799 fluorescence microscopy Methods 0.000 title abstract description 6
- 239000000975 dye Substances 0.000 claims description 22
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 8
- 239000007850 fluorescent dye Substances 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 abstract description 9
- 235000018417 cysteine Nutrition 0.000 abstract description 9
- 238000003384 imaging method Methods 0.000 abstract description 8
- 238000012360 testing method Methods 0.000 abstract description 5
- 238000011065 in-situ storage Methods 0.000 abstract description 4
- 239000000090 biomarker Substances 0.000 abstract description 3
- 238000011895 specific detection Methods 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000000523 sample Substances 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 238000000862 absorption spectrum Methods 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- -1 diphenylamino group Chemical group 0.000 description 5
- 230000005284 excitation Effects 0.000 description 5
- 238000002189 fluorescence spectrum Methods 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- 238000004949 mass spectrometry Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000011550 stock solution Substances 0.000 description 5
- 125000000542 sulfonic acid group Chemical group 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 150000008371 chromenes Chemical class 0.000 description 4
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- HDFGOPSGAURCEO-UHFFFAOYSA-N N-ethylmaleimide Chemical compound CCN1C(=O)C=CC1=O HDFGOPSGAURCEO-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- QDHFHIQKOVNCNC-UHFFFAOYSA-N butane-1-sulfonic acid Chemical compound CCCCS(O)(=O)=O QDHFHIQKOVNCNC-UHFFFAOYSA-N 0.000 description 3
- 150000002212 flavone derivatives Chemical class 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000011580 nude mouse model Methods 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- WZUODJNEIXSNEU-UHFFFAOYSA-N 2-Hydroxy-4-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C(O)=C1 WZUODJNEIXSNEU-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000006000 Knoevenagel condensation reaction Methods 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 2
- GHAZCVNUKKZTLG-UHFFFAOYSA-N N-ethyl-succinimide Natural products CCN1C(=O)CCC1=O GHAZCVNUKKZTLG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- JBOQAJUQZHIPGU-UHFFFAOYSA-N 2-bromocyclohexene-1-carbaldehyde Chemical compound BrC1=C(C=O)CCCC1 JBOQAJUQZHIPGU-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000555745 Sciuridae Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 1
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 238000012984 biological imaging Methods 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical class C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000012632 fluorescent imaging Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 1
- 229960004657 indocyanine green Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000012634 optical imaging Methods 0.000 description 1
- 239000012074 organic phase Substances 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
- 235000013824 polyphenols Nutrition 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000011896 sensitive detection Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
- C07D311/82—Xanthenes
-
- 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
- A61K49/0019—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
- A61K49/0032—Methine dyes, e.g. cyanine dyes
-
- 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
- A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
- A61K49/0043—Fluorescein, used in vivo
-
- 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
- C09B23/10—The polymethine chain containing an even number of >CH- groups
- C09B23/105—The polymethine chain containing an even number of >CH- groups two >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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/645—Specially adapted constructive features of fluorimeters
- G01N21/6456—Spatial resolved fluorescence measurements; Imaging
-
- 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
- C09K2211/1088—Heterocyclic compounds characterised by ligands containing oxygen as the only heteroatom
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N2021/6417—Spectrofluorimetric devices
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
- G01N2021/6432—Quenching
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Physics & Mathematics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Optics & Photonics (AREA)
- Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
Abstract
Description
技术领域
本发明属于精细化工领域,具体涉及一类黄菁近红外二区染料(Flavnirine)、制备方法及其荧光成像应用。
背景技术
对疾病的早期诊断是目前全世界生物学家和医疗工作者关注的热点,特别是利用灵敏度高、特异性强的检测手段实时、原位监测生物标志物具有重大挑战。相比于传统的光学成像技术如超声、CT或MRI等,荧光成像技术由于其非侵入式、高时空分辨率、实时性的显著优势,已经受到医学诊断、治疗等领域的广泛关注。目前,近红外一区(NIR-I,650-900nm)荧光染料(例如FDA批准的吲哚菁绿ICG等)已经被广泛应用于基础和临床研究。但是,NIR-I荧光成像技术由于穿透性不足等问题,仍然是在实际应用于手术指导和深层组织成像中的瓶颈制约。相较而言,近红外二区(NIR-II,1000-1700nm)的荧光信号能在保持微米级成像精度的同时,兼具了更高的信噪比和更深的组织穿透。因此,发展具有新颖结构的NIR-II染料将在疾病早期、特异性诊断方面展现出极大的应用潜力和市场价值。
苯并二噻二唑类染料和菁染料衍生物是已知的典型的NIR-II染料,通常基于共轭体系的拓展实现长波长荧光发射。但上述两类染料往往需要较为复杂的合成,难以进一步引入识别单元实现功能化,对生物标志物的特异性响应。此外,由于较大的π共轭体系,使得该类染料的化学稳定性和光稳定性较差,应用收到限制。因此,发展结构新颖、合成简便、稳定性好、易功能化的高性能NIR-II染料,已经成为重大的挑战和亟待解决的难题。
发明内容
本发明涉及一类结构简单、合成简便、稳定性好、可生物识别的黄菁NIR-II染料(Flavnirine)的制备及其荧光成像应用。该类染料以黄酮衍生物作为吸电子辅助荧光单元,以色烯衍生物作为电子给体,显著增加了该类染料的Stokes位移,实现了对染料吸收波长和发射波长的有效调控,其发射波长拓展至NIR-II区域。基于该类NIR-II荧光染料,通过引入磷酸酯、丙烯酰基、三氟甲磺酸酯等作为特异性识别单元,构建了系列点亮型NIR-II荧光探针。该类探针在活体肿瘤中实现了高信噪比、特异性的检测示踪成像。
本发明通过下述方案实施:
一类黄菁近红外二区染料(Flavnirine),其结构为式Ⅰ所示:
式Ⅰ中,
X为O或N;
R1独立选自式Ⅱ所示基团(其中曲线标记处为取代位,下同)中的任意一种;
其中所述式Ⅱ中:Y为O,S;R4选自H,二甲基氨基或二乙基氨基中的一种;R5选自H,磺酸基,二甲基氨基或二苯基氨基的一种;R6选自C1~C4的烃基或烃基磺酸盐的一种;
R2独立选自H或Ⅲ所示基团的任意一种;
R3独立选自式Ⅳ所示的检测基团的任意一种;
本发明另一个目的在于,揭示上述式I所示化合物的一种用途,即式I所示化合物作为NIR-II荧光探针在生物成像中的应用;或者说,在制备基于黄酮衍生物的NIR-II荧光探针。
此外,本发明还有一个目的在于,提供一种制备式I所示化合物的方法,所示方法的主要步骤是:由式Ⅱ所示化合物与式Ⅴ所示化合物经Knoevenagel缩合反应,制得目标化合物。
通用制备方法:
黄菁NIR-II染料合成采用模块化制备方式,合成简便,原料易得:以环己酮为起始原料,依次通过甲酰化反应、取代反应等,得到色烯衍生物;色烯衍生物进一步与黄酮衍生物发生Knoevenagel缩合反应,最后经过甲基去保护制得黄菁NIR-II染料(Flavnirine-OH)。进一步通过酰化反应等,可基于黄菁染料制得NIR-II荧光探针。
通用检测方法:
该类探针首先与被检测物(如酶或活性小分子)作用,检测基团离去,释放出具有酚羟基负离子的NIR-II荧光染料母体,经过825nm近红外光的激发,发射出1000-1200nm的NIR-II荧光。
附图说明
图1.Flavnirine-OH(详见实施例1)在二氯甲烷、二甲基亚砜和正丁醇中的紫外吸收图谱(1×10-5M);其中,横坐标为波长(nm),纵坐标为吸光度。
图2.Flavnirine-OH(详见实施例1)在二氯甲烷、二甲基亚砜和正丁醇中的荧光图谱(1×10-5M);其中,横坐标为波长(nm),纵坐标为荧光强度。
图3.探针Flavnirine-1随半胱氨酸增加吸收光谱的变化(1×10-5M),测试体系为PBS和DMSO(PBS比例为40%);其中,横坐标为波长(nm),纵坐标为吸光度。
图4.探针Flavnirine-1随半胱氨酸增加NIR-II荧光光谱的变化(1×10-5M),测试体系为PBS和DMSO(PBS比例为40%),激发波长为825nm;其中,横坐标为波长(nm),纵坐标为荧光强度。
图5.探针Flavnirine-1在A549皮下瘤模型小鼠上的NIR-II荧光活体成像应用。
具体实施方式
在本发明一个优选的技术方案中:
X为O;
R1独立选自式Ⅱ所示基团中的任意一种;
其中所述式Ⅱ中:Y为O,S;R4为二甲基氨基;R5选自磺酸基,二甲基氨基或二苯基氨基中的一种;R6选自乙基、丁基、丙基磺酸盐、丁基磺酸盐中的一种;
R2独立选自H或式Ⅲ所示基团的任意一种;
R3独立选自式Ⅱ所示的检测基团的任意一种;
在进一步优选的技术方案中,Y为O,R4为二甲基氨基,R5选自磺酸基、二甲基氨基或二苯基氨基中的一种,R6选自乙基、丁基、丙基磺酸盐、丁基磺酸盐中的一种;
更进一步优选的R5选自磺酸基、二甲基氨基或二苯基氨基中的一种,R6为丁基磺酸盐;
更进一步优选的R5为磺酸基。
下面通过实施例对本发明作进一步的阐述,其目的仅在于更好地理解本发明的内容。因此,所举之例并不限制本发明的保护范围:
实施例1
具体合成路线如下:
1. 1-甲酰基-2-溴环己烯的合成
在250mL三口瓶中加入N,N-二甲基甲酰胺(4.87mL,63.16mmol)和50mL氯仿,向反应体系中滴加三溴化磷(4.96mL,52.63mmol),0.5h后加入环己酮(2.07g,21.05mmol),室温搅拌15h。反应结束后,将反应液倒入碎冰中淬灭三溴化磷,用碳酸钠调节pH至7,分液取有机相,干燥、过滤、旋蒸得橘黄色液体,直接进行下一步反应。
2.色烯衍生物的合成
在100mL两口瓶中加入1-甲酰基-2-溴环己烯(1.89g,10.00mmol)、2-羟基-4-甲氧基苯甲醛(1.52g,10.00mmol)、Cs2CO3(9.77g,30.00mmol),100mLN,N-二甲基甲酰胺溶解,氩气保护,室温搅拌反应16h。反应结束后,旋蒸除去N,N-二甲基甲酰胺,柱层析分离,展开剂为二氯甲烷和乙酸乙酯(乙酸乙酯体积比为5%),得到500mg橘黄色固体,产率21%。
1H NMR(400MHz,CDCl3,ppm):δ=1.69-1.75(m,2H,-CH2-),2.45(t,J=6.04Hz,2H,-CH2-),2.55-2.59(m,2H,-CH2-),3.85(s,3H,-OCH3),6.65-6.67(m,3H,Ph-H,alkene-H),7.07-7.10(d,J=9.12Hz,1H,Ph-H),10.31(s,1H,-CHO).
Mass spectrometry(ESI positive ion mode for[M+H]+):m/z:calcd forC15H15O3 +:243.1016;found:243.1017.
3.Flavnirine-OCH3的合成
在50mL单口瓶中加入二甲基氨基黄酮杂环(50mg,0.137mmol)与色烯衍生物(33mg,0.137mmol),溶于15mL乙醇,加入乙酸钠(33mg,0.411mmol),氩气保护反应7h,反应温度为90℃。反应结束后,旋蒸除去乙醇,柱层析分离,展开剂为二氯甲烷和甲醇(甲醇体积比为1%),得29mg黑色固体,产率36%。
1H-NMR(400MHz,DMSO-d6,ppm):δ=1.84(t,J=5.6Hz,2H,-CH2-),2.71(s,2H,-CH2-),2.77(s,2H,-CH2-)3.26(s,6H,-N(CH3)2),3.92(s,3H,-OCH3),6.95-6.98(dd,1H,Ph-H),7.08(s,1H,Ph-H),7.19-7.26(m,2H,Ph-H),7.34-7.38(d,J=14.52Hz,2H,alkene-H),7.48-7.50(d,J=8.26Hz,1H,Ph-H),7.68-7.70(m,3H,Ph-H),8.21(s,1H,Ph-H),8.40-8.43(m,3H,Ph-H),8.78-8.81(d,J=14.2Hz,1H,alkene-H).
Mass spectrometry(ESI positive ion mode for[M]+):m/z:calcd forC33H30NO3 +:488.2220;found:488.2219.
4.Flavnirine-OH的合成
在50mL两口瓶中加入Flavnirine-OCH3(50mg,0.085mmol),溶于20mL二氯甲烷,冰水浴条件下滴加三溴化硼(1mL,0.010mol),之后室温搅拌氩气保护反应24h。反应结束后,向反应液中滴加水淬灭反应,加入100mL二氯甲烷,水洗3次(100mL×3),无水硫酸钠干燥、过滤、旋蒸得黑色固体。柱层析分离,展开剂为二氯甲烷和甲醇(甲醇体积比为2%),得到10mg黑色固体,产率20%。
1H-NMR(400MHz,DMSO-d6,ppm):δ=1.82(m,2H,-CH2-),2.67(t,2H,-CH2-),2.74(t,2H,-CH2-),3.15(s,6H,-N(CH3)2),6.70-6.72(dd,J1=8.68Hz,J2=1.68Hz,1H,Ph-H),6.86(s,1H,Ph-H),6.94-7.00(m,3H,Ph-H),7.38-7.41(d,J=8.76Hz,1H,Ph-H),7.47(s,1H,Ph-H),7.62-7.64(m,3H,Ph-H),7.90(s,1H,Ph-H),8.15-8.17(d,J=9.4Hz,1H,Ph-H),8.27-8.28(m,2H,Ph-H),8.46-8.49(d,J=13.56Hz,1H,alkene-H).
Mass spectrometry(ESI positive ion mode for[M]+):m/z:calcd forC32H28NO3 +:474.2064;found:474.2064.
实施例2
1.Flavnirine-1的合成
在50mL单口瓶中加入Flavnirine-OH(20mg,0.042mmol),溶于20mL二氯甲烷,加入三乙胺(0.023mL,0.169mmol),冰水浴条件下滴加丙烯酰氯(0.015mL,0.169mmol),室温搅拌氩气保护反应16h。反应结束后,加入100mL二氯甲烷溶解,水洗3次(100mL×3),无水硫酸钠干燥、过滤、旋蒸得黑色固体。柱层析分离,展开剂为二氯甲烷和甲醇(甲醇体积比为2%),得17mg黑色固体,产率65%。
1H-NMR(400MHz,DMSO-d6,ppm):δ=1.81-1.83(m,2H,-CH2-),2.67-2.70(m,4H,-CH2-),3.23(s,6H,-N(CH3)2),6.26-6.28(m,1H,Ph-H),6.45-6.52(m,1H,Ph-H),6.61-6.65(d,J=17.2Hz,1H,alkene-H),6.98(s,1H,Ph-H),7.10-7.12(dd,J1=8.36Hz,J2=2.12Hz,1H,Ph-H),7.18-7.23(m,3H,Ph-H),7.42(s,1H,Ph-H),7.48-7.51(d,J=8.36Hz,1H,Ph-H),7.62-7.71(m,3H,Ph-H),8.14(s,1H,Ph-H),8.32-8.39(m,3H,Ph-H),8.58-8.62(d,J=14.68Hz,1H,alkene-H).
Mass spectrometry(ESI positive ion mode for[M]+):m/z:calcd forC35H30NO4 +:528.2169;found:528.2171.
2.Flavnirine-2的合成
在50mL单口瓶中加入Flavnirine-OH(30mg,0.063mmol),溶于20mL二氯甲烷,加入三乙胺(0.035mL,0.254mmol),冰水浴条件下滴加三氟甲磺酸酐(0.043mL,0.254mmol),室温搅拌氩气保护反应16h。反应结束后,加入100mL二氯甲烷溶解,水洗3次(100mL×3),无水硫酸钠干燥、过滤、旋蒸得黑色固体。柱层析分离,展开剂为二氯甲烷和甲醇(甲醇体积比为2%),得15mg黑色固体,产率34%。
1H-NMR(400MHz,DMSO-d6,ppm):δ=1.82-1.85(m,2H,-CH2-),2.67-2.69(m,2H,-CH2-),2.75-2.76(m,2H,-CH2-),3.30(s,6H,-N(CH3)2),7.20(s,1H,Ph-H),7.24-7.27(dd,J1=8.60Hz,J2=2.44Hz,1H,Ph-H),7.35-7.41(m,3H,Ph-H),7.59-7.61(d,J=8.56Hz,1H,Ph-H),7.67-7.76(m,4H,Ph-H),8.32(s,1H,Ph-H),8.43-8.45(d,J=7.80Hz,2H,Ph-H),8.50-8.52(d,J=9.48Hz,1H,Ph-H),8.58-8.62(d,J=14.68Hz,1H,alkene-H).
Mass spectrometry(ESI positive ion mode for[M]+):m/z:calcd forC33H27F3NO5S+:606.1557;found:606.1557.
实施例3
染料Flavnirine-OH的吸收、荧光光谱
取实施例1制备的染料Flavnirine-OH溶于分析纯二甲基亚砜(DMSO)中,制成1.0×10-3M的储备液。分别取30μL上述储备液加入到3mL二氯甲烷、二甲基亚砜和正丁醇中,混合均匀后转移至光学石英比色皿(10×10mm)中测试其吸收和荧光光谱。如图1所示,其最大吸收波长位于760nm左右。如图2所示,以760nm作为激发波长NIR-II发射峰大约位于900-1200nm之间。
实施例4
探针Flavnirine-1对半胱氨酸的光谱响应
取实施例1制备的探针Flavnirine-1溶于分析纯二甲基亚砜中,制成1.0×10-3M的储备液。半胱氨酸溶于去离子水中,制成1.0×10-3M的储备液。然后制备多组3mL的PBS缓冲液体积比为40%的DMSO/PBS混合溶剂。取30μL上述储备液加入到已制备的DMSO/PBS混合溶剂中,分别加入不同比例的半胱氨酸,混合均匀,在37℃条件下孵育30min后测试其荧光光谱。如图3所示,当探针Flavnirine-1与半胱氨酸反应后,其吸收光谱中825nm处吸收峰急剧升高。如图4所示,以825nm为激发光,随着半胱氨酸比例的增加,其900-1200nm处的NIR-II荧光强度逐渐增强。
实施例5
探针Flavnirine-1应用于活体检测
本发明中所有活体实验均遵守实验室动物饲养和使用的规章制度,并得到华东理工大学大学动物饲养和使用委员会批准。实验用荷瘤裸鼠购自上海斯莱克动物实验有限公司,饲养在无菌室中层流通风橱内的无菌鼠笼中,使用高压蒸汽处理过的食物和水进行喂食。
为评估探针Flavnirine-1活体应用性能,采用荷瘤裸鼠作为成像对象。一组A549(人肺癌细胞)皮下瘤小鼠原位注射半胱氨酸抑制剂N-乙基马来酰亚胺(NEM),一组注射生理盐水。30min后同时对两组小鼠注射1.0×10-5M的探针Flavnirine-1溶液。注射后,使用Optical and X-ray Small Animal Imaging System对小鼠进行整体的光学成像,激发波长和接收波长分别为808nm和900-1700nm。成像实验前,对裸鼠进行含2.5%的异氟烷气体麻醉。从图5中看出,原位注射化合物Flavnirine-1后,未提前注射NEM小鼠出现明显的荧光信号。而注射NEM小鼠荧光信号较弱。表明化合物Flavnirine-1具有很好的点亮NIR-II荧光活体成像特性,可进一步应用于生物活体测试中。
Claims (2)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010207162.8A CN111303111B (zh) | 2020-03-23 | 2020-03-23 | 一类黄菁近红外二区染料、制备方法及荧光成像应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010207162.8A CN111303111B (zh) | 2020-03-23 | 2020-03-23 | 一类黄菁近红外二区染料、制备方法及荧光成像应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111303111A CN111303111A (zh) | 2020-06-19 |
CN111303111B true CN111303111B (zh) | 2023-01-10 |
Family
ID=71158854
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010207162.8A Active CN111303111B (zh) | 2020-03-23 | 2020-03-23 | 一类黄菁近红外二区染料、制备方法及荧光成像应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111303111B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115073438A (zh) * | 2021-03-11 | 2022-09-20 | 上海科技大学 | 一种off-on型近红外二区荧光探针及其制备方法和用途 |
CN113683562A (zh) * | 2021-07-20 | 2021-11-23 | 华东理工大学 | 一种新型抗溶剂猝灭的近红外二区染料、及其制备方法和应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6358684B1 (en) * | 1999-08-27 | 2002-03-19 | Pe Corporation | UV excitable fluorescent energy transfer dyes |
WO2010126077A1 (ja) * | 2009-04-30 | 2010-11-04 | 国立大学法人 東京大学 | 近赤外蛍光化合物 |
CN109111915A (zh) * | 2018-09-26 | 2019-01-01 | 湖南大学 | 一种氨基苯并吡喃花菁类荧光染料和探针及其合成方法与应用 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101776551B1 (ko) * | 2016-11-30 | 2017-09-11 | 한국생명공학연구원 | Alp 검출용 근적외선 형광 프로브 및 이의 제조방법 |
-
2020
- 2020-03-23 CN CN202010207162.8A patent/CN111303111B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6358684B1 (en) * | 1999-08-27 | 2002-03-19 | Pe Corporation | UV excitable fluorescent energy transfer dyes |
WO2010126077A1 (ja) * | 2009-04-30 | 2010-11-04 | 国立大学法人 東京大学 | 近赤外蛍光化合物 |
CN109111915A (zh) * | 2018-09-26 | 2019-01-01 | 湖南大学 | 一种氨基苯并吡喃花菁类荧光染料和探针及其合成方法与应用 |
Non-Patent Citations (4)
Title |
---|
A novel fluorescent probe for rapidly detection cysteine in cystinuria urine, living cancer/normal cells and BALB/c nude mice;Yanpeng Dai,et al.;《Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy》;20190827;第225卷;第117490页 * |
Forster Resonance Energy Transfer Switchable Self-Assembled Micellar Nanoprobe: Ratiometric Fluorescent Trapping of Endogenous H2S Generation via Fluvastatin-Stimulated Upregulation;Chunchang Zhao,et al.;《J. Am. Chem. Soc.》;20150612;第137卷;第8490-8498页 * |
含羟基氧杂蒽荧光染料的合成及其荧光成像应用;曾红等;《化学试剂》;20181231;第40卷(第12期);第1193-1196页 * |
基于菁染料高选择性检测半胱氨酸的近红外荧光探针;马亚光 等;《影像科学与光化学》;20180531;第36卷(第3期);第236-244页 * |
Also Published As
Publication number | Publication date |
---|---|
CN111303111A (zh) | 2020-06-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Qiu et al. | An unusual AIE fluorescent sensor for sequentially detecting Co2+-Hg2+-Cu2+ based on diphenylacrylonitrile Schiff-base derivative | |
CN109320536B (zh) | 一种基于Aza-BODIPY的近红外二窗的荧光探针及其制备与应用 | |
CN111303111B (zh) | 一类黄菁近红外二区染料、制备方法及荧光成像应用 | |
CN109111915A (zh) | 一种氨基苯并吡喃花菁类荧光染料和探针及其合成方法与应用 | |
CN111004624B (zh) | 一种具有ptt效应及聚集诱导发光增强效应的近红外荧光探针的制备 | |
CN105884748B (zh) | 一种马来酰亚胺丙酰哌嗪七甲川菁盐荧光载体及其制备方法和应用 | |
CN108690032A (zh) | 一种吩嗪稠合结构的荧光染料及其合成方法 | |
CN114149448A (zh) | 一种用于检测硝基还原酶的近红外荧光探针及应用 | |
Xia et al. | A self-assembled micellar nanoprobe for specific recognition of hydrazine in vitro and in vivo | |
CN110423487B (zh) | 一种Rhodol衍生物染料及其应用 | |
WO2013131235A1 (zh) | 一类以萘为母体的双光子荧光探针、其制备方法及应用 | |
CN114591632B (zh) | 一类氮杂吲哚-半花菁染料、其合成方法及应用 | |
CN114105982B (zh) | 基于萘酰亚胺的近红外染料、其制备及应用 | |
CN111592482A (zh) | 一种pH可逆激活型光热/光动力/荧光一体化探针分子 | |
CN111793371B (zh) | 一种3,5位不对称修饰bodipy类近红外荧光染料及其制备方法 | |
CN107383067B (zh) | 一种具有大斯托克斯位移的近红外发射氧杂蒽荧光染料制备方法 | |
CN105061515A (zh) | 一种磷光铱配合物的合成及其用于血吸虫尾蚴荧光标记 | |
Huang et al. | A novel red AIE fluorescent probe for ratiometric detection of carbon monoxide in vitro and in vivo | |
CN109503550B (zh) | 2-氮杂芳基-6-取代氨基喹唑啉酮化合物及其制备方法和应用 | |
CN108191880B (zh) | 一种具有咔唑-罗丹明杂化结构的荧光染料制备方法和应用 | |
CN114656447B (zh) | 一类基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针及其制备方法和应用 | |
CN110669350B (zh) | 一种哌啶基bodipy类红光荧光染料及其制备方法和应用 | |
CN115947777A (zh) | 一种近红外二区荧光化合物及其制备方法与应用 | |
Romero et al. | N1-aryl-2-(trifluoromethyl) benzo [b][1, 8] naphthyridin-4 (1H)-one as convenient platform to design high photostable and long-lived dyad fluorophore with potential application in live-cell imaging | |
CN111334080B (zh) | 一种高亮度、高光稳定性的碳酸酐酶荧光探针 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |