WO2023011656A1 - 一种荧光染料及其制备方法和用途 - Google Patents
一种荧光染料及其制备方法和用途 Download PDFInfo
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- WO2023011656A1 WO2023011656A1 PCT/CN2022/110699 CN2022110699W WO2023011656A1 WO 2023011656 A1 WO2023011656 A1 WO 2023011656A1 CN 2022110699 W CN2022110699 W CN 2022110699W WO 2023011656 A1 WO2023011656 A1 WO 2023011656A1
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- fluorescent dye
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- 239000007850 fluorescent dye Substances 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 52
- 150000001875 compounds Chemical class 0.000 claims description 41
- 125000004432 carbon atom Chemical group C* 0.000 claims description 28
- 108090000623 proteins and genes Proteins 0.000 claims description 21
- 102000004169 proteins and genes Human genes 0.000 claims description 21
- 238000001514 detection method Methods 0.000 claims description 18
- -1 1-methylpentyl Chemical group 0.000 claims description 16
- 125000002947 alkylene group Chemical group 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 238000001215 fluorescent labelling Methods 0.000 claims description 13
- 125000001931 aliphatic group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 12
- 108020004707 nucleic acids Proteins 0.000 claims description 12
- 102000039446 nucleic acids Human genes 0.000 claims description 12
- 150000007523 nucleic acids Chemical class 0.000 claims description 12
- 238000012360 testing method Methods 0.000 claims description 12
- 239000000523 sample Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 238000011002 quantification Methods 0.000 claims description 9
- 238000001921 nucleic acid quantification Methods 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000732 arylene group Chemical group 0.000 claims description 4
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 230000021615 conjugation Effects 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims description 4
- 125000001302 tertiary amino group Chemical group 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 claims description 2
- 125000004338 2,2,3-trimethylbutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000003562 2,2-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000003660 2,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000003764 2,4-dimethylpentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 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 claims description 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 claims description 2
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000005916 2-methylpentyl group Chemical group 0.000 claims description 2
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004336 3,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004337 3-ethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000005917 3-methylpentyl group Chemical group 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000005157 alkyl carboxy group Chemical group 0.000 claims description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 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 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 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 claims description 2
- 125000003367 polycyclic group Chemical group 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 18
- 230000004044 response Effects 0.000 abstract description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 58
- 239000000975 dye Substances 0.000 description 56
- 238000001308 synthesis method Methods 0.000 description 34
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 238000010189 synthetic method Methods 0.000 description 30
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 25
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- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 5
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 5
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- 230000015572 biosynthetic process Effects 0.000 description 5
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
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- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 3
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Images
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
- 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
- C09B23/04—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups one >CH- group, e.g. cyanines, isocyanines, pseudocyanines
-
- 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
- C09B57/00—Other synthetic dyes of known constitution
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/531—Production of immunochemical test materials
- G01N33/532—Production of labelled immunochemicals
- G01N33/533—Production of labelled immunochemicals with fluorescent label
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/582—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with fluorescent label
Definitions
- the invention relates to the technical field of fluorescent dyes, in particular to a fluorescent dye with low background fluorescence, good water solubility, high viscosity sensitivity and adjustable molecular structure, and a preparation method and application thereof.
- Cell viscosity is one of the important parameters affecting the diffusion rate of substances. By affecting the mobility of substances, it has a great impact on the transportation, signal transduction, recognition and interaction of biomacromolecules. At the same time, the change of intracellular viscosity has a certain relationship with the occurrence of atherosclerosis, diabetes, Alzheimer's disease and tumor, and it is a potential indicator of these diseases. Therefore, it is of great significance to detect the viscosity in cells. Due to its unique advantages of sensitivity, real-time, in-situ, and visualization, the fluorescence method is an important means of measuring intracellular microscopic viscosity.
- the measurement of intracellular viscosity generally uses fluorescent probes based on molecular rotors.
- Molecular rotors are a special class of fluorescent molecules.
- the energy lost in the non-radiative transition of the excited state changes with the change of viscosity.
- the increase in viscosity or surrounding rigidity will hinder the twisting of the molecular rotor, and the energy lost in the non-radiative transition of the molecular rotor will decrease. , specifically manifested as an increase in the fluorescence intensity of the molecular rotor. Therefore, the fluorescence intensity of the molecular rotor can directly reflect the viscosity of the intracellular microenvironment.
- Viscosity-responsive molecular rotor Fluorescent molecules are often used in the design of fluorescence-activated light-up probes (fluorogenic probes) in addition to detecting the micro-viscosity in cells. This is mainly because when the fluorescent molecule of the molecular rotor binds to protein, nucleic acid or other biomolecules, its twist rotation is limited (equivalent to an increase in viscosity), the fluorescence is lit, and the unbound molecules are in a twisted state and do not emit light. Fluorescence achieves low background for biomolecules and highly specific fluorescence lighting. Fluorescence imaging of low-abundance biomolecules in living organisms requires a lower background while ensuring a high signal-to-noise ratio.
- the widely used thiazole orange dye has a good signal-to-noise ratio when labeling macromolecular proteins and tRNA, but it also shows relatively strong background fluorescence, which is severely limited when labeling some small biomolecules with low abundance. . Therefore, it is extremely important to develop fluorescent dye molecules with low background, sensitive viscosity response, and high signal-to-noise ratio, and will have wider applications in more fields.
- the permanent bright fluorescent probes have a strong fluorescent background due to the problem that their own fluorescence cannot be quenched, such as traditional fluorescent dyes such as coumarin, fluorescein, and rhodamine , they themselves emit bright fluorescence in water. When combined with target substances, they must be washed before imaging, but often cause strong background fluorescence due to inability to wash thoroughly.
- the second is the background fluorescence caused by incomplete quenching of quenched fluorescent probes.
- rhodamine uses typical quenching groups to quench fluorescence with PET and FRET, and imaging RNA results in strong background fluorescence due to incomplete quenching. .
- the third is the background fluorescence caused by lipophilicity of environment-responsive fluorescent probes due to their poor water solubility.
- the environment-responsive fluorescent molecules themselves do not fluoresce in water. When combined with the target, the fluorescence is illuminated. However, if the water solubility of the fluorescent probe is too poor, it will bind to the cell membrane structure due to the principle of similarity and compatibility, so that it can also be activated. Some fluorescence, causing background problems. Therefore, as a viscosity-responsive fluorescent probe, to solve the problem of background fluorescence, improving the water solubility of the probe is a key factor.
- fluorescent dyes as fluorescent probes over fluorescent proteins
- the structure of small-molecule fluorescent dyes can be adjusted, so that the wavelength can be adjusted to achieve different colors of biomolecules.
- the structures of small-molecule fluorescent probes are adjustable, many of them require many steps in organic synthesis, and the yields of many molecular synthesis are not high, so a relatively high price has been paid.
- long wavelength has obvious advantages, but in the structure of existing dyes, long-wavelength molecules generally have relatively large conjugation, and large conjugation generally means that the water solubility of the compound is relatively poor, then Can cause problems with background fluorescence.
- the wavelength can be significantly changed, and the wavelength can be shifted to a longer wavelength, then the fluorescent molecular structure can be kept small and the wavelength can be lengthened, which can ensure that the dye molecule is water soluble. It will be of great significance for biological imaging to realize the long wavelength of dye molecules at the same time.
- the object of the present invention is to provide a fluorescent dye with low background fluorescence, good water solubility, sensitive viscosity response and adjustable wavelength.
- the present invention provides a kind of fluorescent dye, comprises electron donor part D, conjugated system E and electron acceptor part A, and described fluorescent dye is as formula (I)
- the electron donor moiety-D is (X 1 )(X 2 )N-, X 1 and X 2 are independently selected from hydrogen, alkyl, or modified alkyl, X 1 and X 2 are optionally connected to each other, and N Atoms together form an aliphatic ring;
- the conjugated system E is formed by at least one conjugation connection selected from an aromatic subcycle and an aromatic heterocyclic ring, wherein each hydrogen atom contained in the conjugated system E is optionally independently substituted by an alkyl group;
- X 1 and X 2 in the electron donor part D- are optionally together with the N atom to form an aliphatic heterocyclic ring with the conjugated system E;
- the electron acceptor moiety optionally forms a ring structure of the following formula (I-1):
- R 1 is independently selected from -O-, -S-, and -(NR a )-, wherein R a is selected from hydrogen, or alkyl;
- X is independently selected from hydrogen, alkyl or modified alkyl
- alkyl is C 1 -C 30 straight chain or branched chain alkyl; preferably, C 1 -C 10 straight chain or branched chain alkyl; preferably, C 1 -C 7 Straight chain or branched chain alkyl; preferably, C 1 -C 5 straight chain or branched chain alkyl; preferably, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl Base, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3 -Dimethylbuty
- the carbon atom is replaced, which means that the carbon atom or the carbon atom and the hydrogen atom on it are replaced by the corresponding group;
- the "aliphatic heterocyclic ring” is a saturated or unsaturated 4-10 membered monocyclic or polycyclic aliphatic heterocyclic ring containing at least one heteroatom selected from N, O, or S on the ring, and the aliphatic heterocyclic ring When it contains an S atom, it is -S-, -SO- or -SO 2 -; the aliphatic ring is optionally substituted by an alkyl group;
- arylene ring is a 6-13-membered monocyclic or fused bicyclic or fused polycyclic arylene group
- heteromatic ring is a 5-12 membered monocyclic or fused bicyclic or fused polycyclic heteroaromatic group containing at least one heteroatom selected from N, O, S or Si on the ring ;
- halogen atoms are each independently selected from F, Cl, Br, I;
- the "primary amino group” is RNH 2 group
- the "secondary amino group" is an RNHR' group
- the "tertiary amino group” is an RNR'R" group
- Each R, R', R" is independently a single bond, an alkyl group, an alkylene group, a modified alkyl group or a modified alkylene group;
- alkylene is C 1 -C 10 straight chain or branched chain alkylene, optionally C 1 -C 6 branched or branched chain alkylene;
- each of the modified alkyl groups or modified alkylene groups is independently selected from -OH, -O-, -NH 2 , ethylene glycol units (-(CH 2 CH 2 O)n-) , C 1 ⁇ C 8 alkyl, C 1 ⁇ C 8 haloalkyl (preferably C 2 ⁇ C 6 haloalkyl), C 1 ⁇ C 8 alkylcarboxy (preferably C 2 ⁇ C 6 alkylcarboxy) -SO 2 - A group of at least one of NH-, halogen atom, cyano group and nitro group, wherein n is 1-30, more preferably 1-10; more preferably 1-2;
- the C 1 -C 8 alkyl group is methyl, ethyl, propyl, isopropyl
- the C 1 -C 8 alkoxy group is methoxy, ethoxy, propoxy, Isopropoxy
- the C 1 -C 8 acyloxy is acetoxy, ethyl, propyl, isopropyl
- the C 1 -C 8 haloalkyl is trifluoromethyl, chloromethyl, bromine methyl;
- the aliphatic heterocycle is selected from morpholine, thiomorpholine, tetrahydropyridine;
- each of X1 and X2 is independently substituted by one or more C1-10 straight-chain or branched-chain alkyl groups selected from hydroxyl, cyano, halogen, and carboxyl;
- conjugated system E is selected from structures in the following formulas (I-2-1)-(I-2-20):
- conjugated system E and (X 1 )(X 2 )N- form an aliphatic ring as shown in (I-3-1)-(I-3-4):
- the electron acceptor part A is one selected from the following formulas (I-4-1)-(I-4-43):
- the fluorescent dye formula (I) is selected from compounds of the following formulas:
- the second aspect of the present invention is to provide the method for preparing above-mentioned fluorescent dye, it is characterized in that, comprise the synthetic reaction step of formula (a) compound and formula (b) compound reaction generation fluorescent dye shown in formula (I):
- the third aspect of the present invention is to provide the use of the above-mentioned fluorescent dyes in viscosity testing, protein fluorescent labeling, nucleic acid fluorescent labeling, protein quantification or detection, or nucleic acid quantification or detection.
- the fourth aspect of the present invention is to provide the use of the above-mentioned fluorescent dyes in the preparation of reagents for viscosity testing, protein fluorescent labeling, nucleic acid fluorescent labeling, protein quantification or detection, or nucleic acid quantification or detection.
- the fifth aspect of the present invention provides a fluorescence-activated light-up probe, which is characterized by comprising the above-mentioned fluorescent dye.
- the sixth aspect of the present invention provides the use of the above-mentioned fluorescence-activated light-up probe in protein fluorescent labeling, nucleic acid fluorescent labeling, protein quantification or detection, or nucleic acid quantification or detection.
- the seventh aspect of the present invention provides the use of the above-mentioned fluorescence-activated light-up probes in the preparation of protein fluorescent labels, nucleic acid fluorescent labels, protein quantification or detection, or nucleic acid quantification or detection reagents.
- the fluorescent dye obtained in the present invention has long-wavelength emission (the longest emission wavelength reaches 800nm). Its fluorescence intensity increases with the increase of environmental viscosity, the logarithm of fluorescence intensity and the logarithm of solvent viscosity have a good linear relationship, the relationship between fluorescence intensity and viscosity conforms to the Hoffman equation, and has a high slope, It is sensitive to viscosity, has a high activation factor and is insensitive to polarity changes.
- the fluorescent dye obtained in the present invention can be used to measure the viscosity of a sample, for example, it is applicable to the test of microscopic viscosity.
- the obtained fluorescent dye can specifically bind to the corresponding antibody, aptamer or amyloid, or bind to a protein label or enzyme through a ligand or inhibitor to obtain a series of fluorescent activation points Bright-type probes for fluorescent labeling, quantification, or monitoring of proteins, enzymes, or nucleic acids.
- Figure 1 is a diagram of the fluorescence emission intensity of dye dye7 (1 ⁇ 10 -5 M) under different viscosity conditions
- Fig. 2 is a linear relationship diagram between viscosity conditions and fluorescence intensity of dye dye7 (1 ⁇ 10 -5 M);
- Fig. 3 is a graph of fluorescence emission intensity of dye dye9 (1 ⁇ 10 -5 M) under different viscosity conditions
- Fig. 4 is a linear relationship diagram between viscosity conditions and fluorescence intensity of dye dye9 (1 ⁇ 10 -5 M);
- Fig. 5 is a diagram of fluorescence emission intensity of dye dye12 (1 ⁇ 10 -5 M) under different viscosity conditions
- Figure 6 is a linear relationship diagram between the viscosity condition and the fluorescence intensity of dye dye12 (1 ⁇ 10 -5 M);
- Fig. 7 is a graph of fluorescence emission intensity of dye dye25 (1 ⁇ 10 -5 M) under different viscosity conditions
- Figure 8 is a linear relationship diagram between the viscosity condition and the fluorescence intensity of dye dye25 (1 ⁇ 10 -5 M);
- Fig. 9 is a graph of fluorescence emission intensity of dye dye40 (1 ⁇ 10 -5 M) under different viscosity conditions
- Figure 10 is a linear relationship diagram between the viscosity condition and the fluorescence intensity of dye dye40 (1 ⁇ 10 -5 M);
- Fig. 11 is a diagram of fluorescence emission intensity of dye dye7 (1 ⁇ 10 -5 M) under different polarity conditions;
- Fig. 12 is a diagram of fluorescence emission intensity of dye dye9 (1 ⁇ 10 -5 M) under different polarity conditions
- Fig. 13 is a diagram of fluorescence emission intensity of dye dye12 (1 ⁇ 10 -5 M) under different polarity conditions
- Fig. 14 is a diagram of fluorescence emission intensity of dye dye25 (1 ⁇ 10 -5 M) under different polarity conditions;
- Fig. 15 is a diagram of fluorescence emission intensity of dye dye40 (1 ⁇ 10 -5 M) under different polarity conditions;
- Figure 16 is a comparison diagram of emission spectra of dye dye5 and dye6;
- Figure 17 is a comparison diagram of emission spectra of dyes dye11, dye12, and dye14;
- Figure 18 is a comparison diagram of emission spectra of dye dye12 and dye13;
- Figure 19 is the emission spectrum of dye dye39
- Figure 20 is the emission spectrum of dye dye42
- Figure 21 is a comparison of background fluorescence of dye dye1 and dye48 in PBS solution
- Figure 22 is a comparison of background fluorescence of dyes dye22 and dye49 in PBS solution
- Fig. 23 is a comparison chart of background fluorescence of dye dye40 and dye50 in PBS solution
- Figure 24 is a comparison of background fluorescence of dye dye9, dye10 and dye47 in PBS solution
- Figure 25 is a diagram of dyes dye1, dye12, dye25, dye41 used to label aptamers in cells;
- Figure 26 is the flow cytogram of dye dye3 binding RNA aptamer
- Figure 27 is the flow cytogram of dye dye13 binding RNA aptamer
- Figure 28 is the flow cytogram of dye dye21 binding RNA aptamer
- Figure 29 is a flow cytogram of dye dye34 binding to RNA aptamers
- Figure 30 is the flow cytogram of dye dye50 binding RNA aptamer
- the synthesis steps of dye2 refer to the synthesis method of dye1, and the yield is 76%.
- the synthesis steps of dye3 refer to the synthesis method of dye1, and the yield is 82%.
- the synthesis method of dye4 refers to the synthesis steps of dye1, and the yield is 70%.
- the synthesis method of compound 4 refers to the synthesis method of compound 3, and the yield is 56%.
- 1 H NMR (400MHz,DMSO-d 6 ) ⁇ 10.11(s,1H)6.98–6.94(m,1H),6.94–6.88(m,1H),6.57(td,J 7.5,1.2Hz,1H) ,3.57–3.42(m,2H),3.13–3.00(m,2H),2.87(s,3H).
- Dye5 was synthesized according to the synthesis method of dye1, and the yield was 65.8%.
- Dye6 refers to the synthetic method of dye1, and the yield is 75.8%.
- 1 H NMR (400MHz,DMSO-d 6 ) ⁇ 13.15(s,1H),7.42(s,1H),7.38–7.15(m,2H),6.82(d,J 8.7Hz,1H),3.76– 3.57(m,2H),3.13–3.05(m,2H),3.03(s,3H).
- Dye refers to the synthetic method of dye1, and the yield is 84.2%.
- Dye8 refers to the synthetic method of dye1, and the yield is 80.3%.
- Dye9 refers to the synthetic method of dye1, and the yield is 88.6%.
- Dye10 refers to the synthetic method of dye1, and the yield is 82.4%.
- Dye11 refers to the synthetic method of dye1, and the yield is 78.4%.
- Dye12 was synthesized according to dye1, and the yield was 78.3%.
- Dye13 was synthesized according to dye1, and the yield was 87.1%.
- Dye14 was synthesized according to the synthesis method of dye1, and the yield was 87.1%.
- Dye15 was synthesized according to dye1, and the yield was 84.7%.
- Dye17 was synthesized according to dye1, and the yield was 82.7%.
- Dye refers to the synthetic method of dye1, and the yield is 52.3%.
- 1H-NMR (400MHz, CDCl3): ⁇ 8.02(s, 1H), 7.57(s, 1H), 7.92(s, 1H), 3.95(m, 4H), 3.45(m, 8H), 3.25(s, 3H), 3.10(s, 3H).
- dye19 was synthesized according to the synthesis method of dye1, and the yield was 88.9%.
- 1 H-NMR (400MHz, CDCl 3 ): ⁇ 8.23(s, 1H), 7.57(s, 1H), 7.92(s, 1H), 3.25(s, 3H), 3.10(s, 3H) 3.08(m ,2H), 1.58-1.43(m,18H).
- Dye20 refers to the synthetic method of dye1, and the yield is 81.2%.
- Dye21 was synthesized according to the synthesis method of dye1, and the yield was 82.5%.
- Dye22 was synthesized according to the synthesis method of dye1, and the yield was 90.1%.
- Dye23 refers to the synthetic method of dye1, and the yield is 79.5%.
- Dye24 was synthesized according to the synthesis method of dye1, and the yield was 68.5%.
- Dye25 refers to the synthesis method of dye1, and the yield is 70.0%.
- dye26 refers to the synthetic method of dye17, and the yield is 70.0%.
- Dye27 was synthesized according to the synthesis method of dye1, and the yield was 65.9%.
- Dye28 was synthesized according to the synthesis method of dye1, and the yield was 65.9%.
- Dye29 was synthesized according to the synthesis method of dye1, and the yield was 55.1%.
- dye30 refers to the synthetic method of compound dye1, and the yield is 45.2%.
- Dye31 refers to the synthetic method of compound dye1, and the yield is 80.2%.
- the synthesis method of dye33 refers to compound dye1, and the yield is 60.2%.
- dye36 refers to the synthetic method of compound dye1, and the yield is 49.7%.
- Dye37 refers to the synthetic method of compound dye1, and the yield is 59.6%.
- the synthetic method of dye39 refers to compound dye1, and the yield is 58.2%.
- the synthetic method of dye40 refers to compound dye1, and the yield is 69.2%.
- the synthesis method of dye41 refers to compound dye1, and the yield is 56.6%.
- the synthetic method of dye42 refers to compound dye1, and the yield is 38.2%.
- Dye43 refers to the synthetic method of compound dye1, and the yield is 78.2%.
- dye44 was synthesized according to the synthetic method of compound dye1.
- dye45 was synthesized according to the synthesis method of dye1.
- dye46 was synthesized according to the synthesis method of dye1.
- the emission wavelengths of the above-mentioned molecular rotors are 620nm, 576nm, 650nm, 670nm, and 720nm, respectively.
- the results showed that the fluorescence intensity of the fluorescent dyes with the same concentration increased with the increase of the environmental viscosity.
- the logarithm of the fluorescence intensity and the logarithm of the solvent viscosity conform to the Huffman equation, have a good linear relationship, and have a high slope, as shown in Figures 2, 4, 6, 8, and 10, which prove that the above-mentioned dyes have a significant effect on the viscosity Responsive, can be used for viscosity testing of unknown samples.
- the fluorescent dye of the present invention has good specificity to the viscous environment, and can reduce the non-specific fluorescence caused by the polar response.
- Dyes dye1 and dye48; dye22 and dye49; dye40 and dye50; dye9, dye10 and dye47 were added to PBS to prepare a solution with a final concentration of 1 ⁇ 10 -5 M, and the corresponding maximum excitation wavelength was used to excite the dyes to detect their concentration in PBS.
- the fluorescence intensity in each group of samples is normalized with the maximum fluorescence intensity as 100, as shown in Figures 21, 22, 23, and 24 respectively. The results show that compared with the fluorescent dyes reported in the literature, the fluorescent dyes of the present application With a special electron-withdrawing group structure part, the fluorescent dye of this application has lower background fluorescence.
- the dye Before the binding, the dye basically does not emit fluorescence, but after the binding, the fluorescence is significantly activated, and the compound can also bind to the protein in the cell.
- the cells expressing the aptamer emit Bright fluorescence, and no fluorescence in cells that do not express the aptamer, which indicates that the dye of the present invention has good cell membrane permeability and can be used for labeling the aptamer in living cells.
- the detection results can be seen as follows As shown in the flow diagrams 26-29, dye3, dye13, dye21, and dye34 have very low dye background before binding, and the fluorescence is significantly activated after binding, and the dye can also combine with RNA aptamers to emit bright fluorescence in cells, basically There is no non-specific fluorescence activation, which shows that the fluorescent dye of the present invention has very low background fluorescence and very low non-specific fluorescence in cells, and can be used for labeling low-abundance biological macromolecules such as nucleic acids, while dye50 has obvious background fluorescence , as shown in Figure 30, is difficult to label low-abundance biomacromolecules such as nucleic acids.
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Abstract
Description
Claims (10)
- 一种荧光染料,包括电子供体部分D、共轭体系E和电子受体部分A,所述荧光染料如式(I)电子供体部分-D为(X 1)(X 2)N-,X 1、X 2独立地选自氢、烷基、或改性烷基,X 1,X 2任选相互连接,与N原子一起形成脂杂环;共轭体系E为选自亚芳香环、亚芳香杂环中的至少一种共轭连接而形成,其中共轭体系E所含的各氢原子任选独立地被烷基取代;电子供体部分D-中的X 1、X 2任选独立地和N原子一起与共轭体系E形成脂杂环;电子受体部分任选形成下式(I-1)环状结构:其中,R 1独立地选自-O-、-S-、和-(NR a)-,其中R a选自氢、或烷基;R 2独立地选自=O、=S、和=NH;R 3独立地选自=O、=S、=NH;X独立地选自氢、烷基或改性烷基;其中,所述“烷基”为C 1-C 30的直链或支链的烷基;优选地,为C 1-C 10直链或支链烷基;优选地,为C 1-C 7直链或支链烷基;优选地,为C 1-C 5直链或支链烷基;优选地,选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基,1-甲基丁基、2-甲基丁基、3-甲基丁基、异戊基、1-乙基丙基、新戊基、正己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、异己基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、正庚基、2-甲基己基、3-甲基己基、2,2-二甲基戊基、3,3-二甲基戊基、2,3-二甲基戊基、2,4-二甲基戊基、3-乙基戊基或2,2,3-三甲基丁基;所述“改性烷基”为烷基的任意碳原子被选自卤原子、-O-、-OH、-CO-、-SO 2-、-(S=O)-、伯氨基、仲氨基、叔氨基、中的至少一种基团置换所得的基团,所述改性烷基具有1~30个碳原子(可选地,所述改性烷基具有1~12个碳原子;可选地,所述改性烷基具有1~10个碳原子;可选地,所述改性烷基具有1~8个碳原子;可选地,所述改性烷基具有1~5 个碳原子;可选地,所述改性烷基具有1~2个碳原子),所述的碳原子被置换,是指碳原子或碳原子与其上的氢原子一起被相应的基团置换;所述“脂杂环”为环上含有选自N、O、或S中的至少一种杂原子的饱和或不饱和的4~10元单环或多环脂杂环,所述脂杂环上含有S原子时,其为-S-、-SO-或-SO 2-;所述脂杂环任选被烷基取代;所述“亚芳香环”为6~13元单环或稠合双环或稠合多环的亚芳香基团;所述“亚芳香杂环”为环上含有选自N、O、S或Si中的至少一种杂原子的5~12元单环或稠合双环或稠合多环的亚杂芳香基团;所述“卤原子”各自独立地选自F、Cl、Br、I;所述“伯胺基”为RNH 2基团;所述“仲胺基”为RNHR'基团;所述“叔胺基”为RNR'R”基团;各个R、R'、R”各自独立地为单键、烷基、亚烷基、改性烷基或改性亚烷基;所述“亚烷基”为C 1-C 10直链或支链亚烷基,可选为C 1-C 6支链或支链亚烷基;所述“改性亚烷基”为C 1-C 10(可选为C 1-C 6)烷基或亚烷基的任意碳原子被选自-O-、-OH、-CO-、-CS-、-(S=O)-中一种基团置换所得的基团;所述的碳原子被置换,是指碳原子或碳原子与其上的氢原子一起被相应的基团置换;
- 根据权利要求1所述的荧光染料,其特征在于,所述改性烷基或改性亚烷基各自独立地为含有选自-OH、-O-、-NH 2、乙二醇单元(-(CH 2CH 2O)n-)、C 1~C 8烷基、C 1~C 8卤代烷基(优选C 2~C 6卤代烷基)、C 1~C 8烷基羧基(优选C 2~C 6烷基羧基)-SO 2-NH-、卤原子、氰基、硝基中至少一种基团的基团,其中,n为1~30,更优选为1~10;更优选为1~2;可选地,所述C 1~C 8烷基为甲基、乙基、丙基、异丙基,所述C 1~C 8烷氧基为甲氧基、乙氧基、丙氧基、异丙氧基,所述C 1~C 8酰基氧基为乙酰氧基、乙基、丙基、异丙基,所述C 1~C 8卤代烷基为三氟甲基、氯甲基、溴甲基;可选地,所述脂杂环选自吗啉、硫代吗啉,四氢吡啶;可选地,X 1和X 2各自独立地被1个或多个选自羟基、氰基、卤原子、羧基的基团取代的C 1-10直链或支链烷基;
- 权利要求1-4任一项所述荧光染料荧光染料在粘度测试、蛋白荧光标记、核酸荧光标记、蛋白定量或检测、或者核酸定量或检测中的用途。
- 权利要求1-4任一项所述荧光染料在制备粘度测试、蛋白荧光标记、核酸荧光标记、蛋白定量或检测、或者核酸定量或检测试剂中的用途。
- 荧光激活点亮型探针,其特征在于,包括权利要求1-4任一项所述荧光染料。
- 权利要求8所述的荧光激活点亮型探针在蛋白荧光标记、核酸荧光标记、蛋白定量或检测、或者核酸定量或检测中的用途。
- 权利要求8所述的荧光激活点亮型探针在制备蛋白荧光标记、核酸荧光标记、蛋白定量或检测、或者核酸定量或检测试剂中的用途。
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