CN117903102B - Fluorescent probe and preparation method and application thereof - Google Patents
Fluorescent probe and preparation method and application thereof Download PDFInfo
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- 239000007850 fluorescent dye Substances 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 claims abstract description 18
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- QXAMGWKESXGGNV-UHFFFAOYSA-N 7-(diethylamino)-1-benzopyran-2-one Chemical compound C1=CC(=O)OC2=CC(N(CC)CC)=CC=C21 QXAMGWKESXGGNV-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000523 sample Substances 0.000 claims description 81
- 238000003384 imaging method Methods 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 14
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
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- OEDBHOAJDADPMY-UHFFFAOYSA-N 7-(diethylamino)-2-oxochromene-4-carbaldehyde Chemical compound O=CC1=CC(=O)OC2=CC(N(CC)CC)=CC=C21 OEDBHOAJDADPMY-UHFFFAOYSA-N 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000002438 mitochondrial effect Effects 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 3
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- RUVJFMSQTCEAAB-UHFFFAOYSA-M 2-[3-[5,6-dichloro-1,3-bis[[4-(chloromethyl)phenyl]methyl]benzimidazol-2-ylidene]prop-1-enyl]-3-methyl-1,3-benzoxazol-3-ium;chloride Chemical compound [Cl-].O1C2=CC=CC=C2[N+](C)=C1C=CC=C(N(C1=CC(Cl)=C(Cl)C=C11)CC=2C=CC(CCl)=CC=2)N1CC1=CC=C(CCl)C=C1 RUVJFMSQTCEAAB-UHFFFAOYSA-M 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
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- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
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- 229910001914 chlorine tetroxide Inorganic materials 0.000 description 1
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- 239000003068 molecular probe Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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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
- C07D311/94—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 condensed with rings other than six-membered or with ring systems containing such rings
-
- 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
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
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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
- 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
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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
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Radiology & Medical Imaging (AREA)
- Physics & Mathematics (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Materials Engineering (AREA)
- Acoustics & Sound (AREA)
- Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
Abstract
The invention belongs to the technical field of fluorescence and sensing materials, and particularly relates to a fluorescent probe and a preparation method and application thereof. The structural general formula of the fluorescent probe isR is carboxyl, alkyl or hydrogen. The preparation method of the fluorescent probe comprises the steps of heating cyclopentanone and a 4-diethylamino-2-hydroxybenzophenone compound for reaction to obtain an intermediate; and (3) reacting the intermediate with 7- (diethylamino) coumarin-3-formaldehyde to obtain the fluorescent probe. The preparation method has the advantages of readily available raw materials, simplicity in operation, environmental friendliness and the like. The fluorescent probe has gastric acid stability and viscosity responsiveness, can be used for visual fluorescence-photoacoustic bimodal monitoring of the gastritis of a living mouse and distinguishing tumor cells from normal cells, and has important application value.
Description
Technical Field
The invention belongs to the technical field of fluorescence and sensing materials, and particularly relates to a fluorescent probe and a preparation method and application thereof.
Background
The disclosure of this background section is intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Viscosity has been shown to be an important indicator of inflammation in organisms as an important parameter of the physiological environment (anal. Chem.,91 (2019), 8415-8421). Inflammation can be conveniently monitored by monitoring changes in viscosity in cells or organisms. However, conventional viscometers are not suitable for monitoring viscosity changes in cells and biological organs. Fluorescent probes are important tools in the field of biological detection, and have good selectivity, high sensitivity, non-invasiveness and excellent time-space resolution. Viscosity sensitive fluorescent probes have proven to be effective tools for monitoring viscosity changes in cells or biological organs. The biosensing detection of inflammation related diseases such as fatty liver, cancer, atherosclerosis and the like of mice is realized by using the viscosity sensitive probe.
Near infrared fluorescence-Photoacoustic (PA) dual mode probes have significant advantages in view of deep tissue imaging and signal fidelity. However, the use of molecular probes to monitor gastritis conditions in vivo in gastric acid environments is still a great challenge.
Disclosure of Invention
In view of the shortcomings of the prior art, a first object of the present invention is to provide a fluorescent probe having a large conjugated D-pi-a structure, an electron donor and an electron acceptor being connected by a rotatable C-C single bond, thereby achieving a weak fluorescent-photoacoustic signal in a low viscosity environment and a strong fluorescent-photoacoustic signal in a high viscosity environment.
The second object of the present invention is to provide a preparation method of the fluorescent probe, which has the advantages of easily available raw materials, simple operation, environmental friendliness and the like.
The third purpose of the invention is to provide the application of the fluorescent probe, wherein the fluorescent probe has high mitochondrial targeting, gastric acid stability and viscosity responsiveness, and has important application value in monitoring the gastritis in living bodies and distinguishing tumor cells.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
A fluorescent probe has a structural general formula shown in a formula (I):
Wherein R is carboxyl, alkyl or hydrogen, and R is single substitution or multiple substitution on benzene ring.
The preparation method of the fluorescent probe comprises the following steps:
① . Adding cyclopentanone shown in a formula (II) and a 4-diethylamino-2-hydroxybenzophenone compound shown in a formula (III) into a catalyst 1, performing heating reaction, and adding ice water and a catalyst 2 to obtain an intermediate shown in a formula (IV); the reaction scheme of step ① is shown in formula (1):
② . Mixing the intermediate obtained in the step ①, an organic solvent and 7- (diethylamino) coumarin-3-formaldehyde shown in the formula (V) for reaction to obtain a probe shown in the formula (I); the reaction scheme of step ② is shown in formula (2):
Further, in step ①, the 4-diethylamino-2-hydroxybenzophenone compound is 2- (4- (diethylamino) -2-hydroxybenzoyl) benzoic acid.
Further, in step ①, the catalyst 1 is concentrated sulfuric acid; the catalyst 2 is perchloric acid.
Further, the concentration of the perchloric acid is 70%.
Further, in step ①, the molar volume ratio of cyclopentanone, 4-diethylamino-2-hydroxybenzophenone compound, catalyst 1, catalyst 2 and ice water is (10.0-30.0) mmoL:10.0mmoL:11.0mL:1.1mL:300.0mL.
Further, in step ①, the temperature of the heating reaction is (60-120) DEG C, and the time is (1-5) h.
Further, in step ①, the catalyst 2 and ice water are added, and then the mixture is subjected to suction filtration, washing and vacuum drying.
Further, in step ②, the organic solvent is ethanol, dimethyl sulfoxide (DMSO), N-dimethylformamide, methanol, or the like.
Further, in step ②, the molar volume ratio of the intermediate, 7- (diethylamino) coumarin-3-carbaldehyde, and the organic solvent is (1.0-1.5) mmoL:1.0mmoL: (10.0-25.0) mL.
Further, in step ②, the temperature of the reaction is (50-100) °c.
Further, in step ②, the reaction time is 1 to 5 hours.
Further, in step ②, after the reaction is completed, recrystallization is performed.
The fluorescent probe can be applied to the field of fluorescence or photoacoustic imaging detection.
Further, the fluorescent probe may be used for in situ fluorescence or photoacoustic imaging of inflammation.
Further, the fluorescent probe can be used for in-situ fluorescence or photoacoustic imaging of gastritis.
Further, the fluorescent probe may be used for in situ fluorescence or photoacoustic imaging of cancer.
Further, the fluorescent probes can be used to distinguish tumor cells from normal cells.
The fluorescent probe needle prepared by the invention has a large conjugated D-pi-A structure, and the rotation of a single bond (rotor) of C-C in a molecule can adjust the fluorescence of the probe and the intensity of a photoacoustic signal:
In a high viscosity environment, the intramolecular rotation of the probe is limited, and the probe molecule shows strong fluorescence and photoacoustic signals; in a low viscosity environment, the intramolecular acceleration of the probe, the probe molecule shows weak fluorescence and photoacoustic signals.
In the preparation method of the fluorescent probe provided by the invention, cyclopentanone is used as a raw material in the first step of synthesis, so that the fluorescent emission of the product reaches more than 800 nm; in the second step of synthesis, ethanol or methanol is selected as a solvent, so that the product can be separated out in a solid form, the molecular purification method is simplified, and the purity of the product is improved.
The beneficial effects are that: the invention provides a viscosity response type near infrared fluorescence-photoacoustic dual-mode probe with high gastric acid stability, which solves the problem that the current viscosity response type fluorescence probe cannot be used for imaging of living gastritis. The preparation method of the fluorescent probe has the advantages of easily available raw materials, simple operation, environmental friendliness and the like; the fluorescent probe has good mitochondrial targeting, high stability and viscosity responsiveness to gastric acid environment, can be used for visible fluorescence-photoacoustic bimodal monitoring of the gastritis of living mice and distinguishing tumor cells from normal cells, and has important application value.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention. Embodiments of the present invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a fluorescent probe prepared in example 1;
FIG. 2 is a nuclear magnetic resonance spectrum of the fluorescent probe prepared in example 1;
FIG. 3 is a high resolution mass spectrum of the fluorescent probe prepared in example 1;
FIG. 4 is an infrared absorption spectrum of the fluorescent probe prepared in example 1;
FIG. 5 is a normalized fluorescence emission and ultraviolet absorbance spectra of the fluorescent probe prepared in example 1;
FIG. 6 is a graph showing fluorescence spectra of the fluorescent probe prepared in example 1 in different solvents;
FIG. 7 is a graph showing comparison of photostability of the fluorescent probe prepared in example 1 in PBS solution and glycerol;
FIG. 8 is a graph showing the results of a test for the stability of the fluorescent probe prepared in example 1 in a simulated gastric acid solution;
FIG. 9 is a graph showing fluorescence spectra of the fluorescent probe prepared in example 1 in PBS and glycerol mixed solutions of different viscosities;
FIG. 10 is a graph showing the linear relationship between fluorescence spectra of the fluorescent probe prepared in example 1 in PBS and glycerol mixed solutions of different viscosities;
FIG. 11 is a photo-acoustic image of the probe prepared in example 1 in a mixed solution of glycerol and PBS of different viscosities;
FIG. 12 is a graph showing the linear relationship of the photoacoustic intensity of a probe in a mixed solution of glycerol and PBS of different viscosities;
FIG. 13 is a graph showing cytotoxicity test results of the fluorescent probe prepared in example 1;
FIG. 14 is a graph showing the results of a living body biocompatibility test of the fluorescent probe prepared in example 1;
FIG. 15 is a graph showing the results of a mitochondrial co-localization test for the fluorescent probe prepared in example 1;
FIG. 16 is a graph showing the results of fluorescence confocal imaging of cancer cells and normal cells stained with the fluorescent probe prepared in example 1, FIG. 16 (a) is a graph showing fluorescence confocal imaging, and FIG. 16 (b) is a statistical graph showing the results of fluorescence intensity;
FIG. 17 is a graph showing the results of a test of the fluorescent probe prepared in example 1 for in vivo fluorescence imaging of a gastritis mouse, wherein FIG. 17 (a) is a graph showing fluorescence imaging, and FIG. 17 (b) is a statistical graph showing the results of fluorescence intensity;
FIG. 18 is a graph showing the results of in situ fluorescence imaging of gastritis mouse organs using the fluorescent probe prepared in example 1;
Fig. 19 is a graph showing the test results of using the fluorescent probe prepared in example 1 for in vivo photoacoustic imaging of a gastritis mouse;
Fig. 20 is an image of probe B for in situ photoacoustic imaging of a gastritis mouse organ.
Detailed Description
In the following description, specific details of the invention are set forth in order to provide a thorough understanding of the invention. The terminology used in the description of the invention herein is for the purpose of describing the advantages and features of the invention only and is not intended to be limiting of the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The medicines or reagents used in the present invention are used according to the product instructions or by the conventional methods of use in the art unless specifically stated. The technical scheme of the invention is further described according to the attached drawings and the specific embodiments.
Example 1
(1) 11ML of concentrated sulfuric acid was added to the 50mL flask, and then cooled to 0 ℃.20 mmoL cyclopentanone was added dropwise to cooled concentrated sulfuric acid and stirred at 0 ℃.10 mmoL2- (4- (diethylamino) -2-hydroxybenzoyl) benzoic acid was then added to the above mixture. The resulting mixture was heated to 90℃and stirred for 1.5h, after disappearance of 2- (4- (diethylamino) -2-hydroxybenzoyl) benzoic acid, the mixture was cooled to room temperature, then 300mL of ice water was slowly added, 1.1mL of 70% strength perchloric acid was added to the above solution, and stirred. Filtering the solid, washing a filter cake with water, and vacuum drying to obtain an intermediate A;
(2) Adding 1.0mmoL mL of ethanol and 1mmoL7- (diethylamino) coumarin-3-formaldehyde obtained in the step (1) into a 50mL flask, refluxing the mixture at 85 ℃ for 5 hours until 7- (diethylamino) coumarin-3-formaldehyde disappears, cooling the reaction solution to room temperature, separating out the product, filtering the precipitate, and recrystallizing with ethanol crystals to obtain the probe B. The reaction route is shown in the following formula:
The nuclear magnetic resonance hydrogen spectrum of the probe B prepared in this example is shown in FIG. 1, and the characterization data is as follows :1HNMR(DMSO-d6,500MHz,Fig.S1)ppm:13.31(s,1H),8.21(s,1H),8.21(d,J＝8.45Hz,1H),7.89(t,J＝7.55Hz,1H),7.77(t,J＝7.75Hz,1H),7.72(s,1H),7.61(d,J＝9.05Hz,1H),7.48(d,J＝7.55Hz,1H),7.29(s,1H),7.22(t,J＝8.60Hz,1H),7.07(t,J＝9.30Hz,1H),6.78(dd,J1＝9.10Hz,J2＝2.15Hz,1H),6.56(d,J＝2.00Hz,1H),3.66(q,J＝6.95Hz,4H),3.47(q,J＝6.85Hz,4H),3.21(m,2H),2.80-2.68(m,2H),1.22(t,J＝6.90Hz,6H),1.14(t,J＝6.95Hz,6H).
The nuclear magnetic resonance carbon spectrum of the probe B prepared in this example is shown in FIG. 2, and the characterization data is as follows :13CNMR(DMSO-d6,126MHz,Fig.S2)ppm:167.16,161.48,158.60,156.60,154.93,152.59,142.94,134.55,133.66,133.21,132.04,131.30,130.96,130.24,129.82,129.43,126.30,126.16,125.95,125.78,117.46,116.88,114.77,110.74,109.65,97.21,96.89,45.81,44.97,27.70,25.90,12.99,12.93.
The high resolution mass spectrum of probe B prepared in this example is shown in FIG. 3, and the characterization data is as follows :HRMS(ESI-TOF)calcd.forC37H37N2O5[M-ClO4]+589.2697,590.2731,found:589.2722,590.2714.
The infrared absorption spectrum of probe B prepared in this example is shown in FIG. 4, and the characterization data is as follows :FT-IR(KBr)vmax/cm -13438,2975,2919,1713,1608,1564,1459,1395,1342,1253,1170,1072,818,692(Fig.S8).
Example 2
(1) 11ML of concentrated sulfuric acid was added to the 50mL flask, and then cooled to 0 ℃.10 mmoL cyclopentanone was added dropwise to cooled concentrated sulfuric acid and stirred at 0℃and then 10mmoL2- (4- (diethylamino) -2-hydroxybenzoyl) benzoic acid was added to the above mixture, and the resulting mixture was heated to 120℃and stirred for 1h. After 2- (4- (diethylamino) -2-hydroxybenzoyl) benzoic acid disappeared, the mixture was cooled to room temperature, then 300mL of ice water was slowly added, 1.1mL of 70% perchloric acid was added to the above solution, stirred, the solid was filtered off with suction, the filter cake was washed with water, and dried in vacuo to give intermediate (a);
(2) 1.1mmoL of intermediate A, 10 mM DS SO,1mM L7- (diethylamino) coumarin-3-carbaldehyde were added to a 50mL flask, and the mixture was reacted at 100℃for 1 hour. The reaction solution was cooled to room temperature, 100mL of saturated brine was added to the reaction solution, extraction was performed three times with 50mL of methylene chloride, the extracts were combined, the methylene chloride was removed by drying, and the solid was recrystallized with ethanol to obtain probe B.
The nuclear magnetic resonance hydrogen spectrum of the probe B prepared in this example is shown in FIG. 1, and the characterization data is as follows :1HNMR(DMSO-d6,500MHz,Fig.S1)ppm:13.31(s,1H),8.21(s,1H),8.21(d,J＝8.45Hz,1H),7.89(t,J＝7.55Hz,1H),7.77(t,J＝7.75Hz,1H),7.72(s,1H),7.61(d,J＝9.05Hz,1H),7.48(d,J＝7.55Hz,1H),7.29(s,1H),7.22(t,J＝8.60Hz,1H),7.07(t,J＝9.30Hz,1H),6.78(dd,J1＝9.10Hz,J2＝2.15Hz,1H),6.56(d,J＝2.00Hz,1H),3.66(q,J＝6.95Hz,4H),3.47(q,J＝6.85Hz,4H),3.21(m,2H),2.80-2.68(m,2H),1.22(t,J＝6.90Hz,6H),1.14(t,J＝6.95Hz,6H).
Example 3
(1) 11ML of concentrated sulfuric acid was added to the 50mL flask, and then cooled to 0 ℃. 30mmoL cyclopentanone was added dropwise to cooled concentrated sulfuric acid and stirred at 0 ℃. 10mmoL2- (4- (diethylamino) -2-hydroxybenzoyl) benzoic acid was then added to the above mixture. The resulting mixture was heated to 60 ℃ and stirred for 5h. After 2- (4- (diethylamino) -2-hydroxybenzoyl) benzoic acid had disappeared, the mixture was cooled to room temperature, and then 300mL of ice water was slowly added. To the above solution, 1.1mL of 70% strength perchloric acid was added and stirred. Filtering the solid, washing a filter cake with water, and vacuum drying to obtain an intermediate A;
(2) 1.5mmoL intermediate A and 10mL methanol, 1mmoL7- (diethylamino) coumarin-3-carbaldehyde are added into a 50mL flask, and the mixture is refluxed at 60 ℃ for 4.5h until 7- (diethylamino) coumarin-3-carbaldehyde disappears. The reaction solution was cooled to room temperature, and a solid was precipitated. Suction filtration and recrystallization of the product with methanol to obtain probe B.
The nuclear magnetic resonance hydrogen spectrum of the probe B prepared in this example is shown in FIG. 1, and the characterization data is as follows :1HNMR(DMSO-d6,500MHz,Fig.S1)ppm:13.31(s,1H),8.21(s,1H),8.21(d,J＝8.45Hz,1H),7.89(t,J＝7.55Hz,1H),7.77(t,J＝7.75Hz,1H),7.72(s,1H),7.61(d,J＝9.05Hz,1H),7.48(d,J＝7.55Hz,1H),7.29(s,1H),7.22(t,J＝8.60Hz,1H),7.07(t,J＝9.30Hz,1H),6.78(dd,J1＝9.10Hz,J2＝2.15Hz,1H),6.56(d,J＝2.00Hz,1H),3.66(q,J＝6.95Hz,4H),3.47(q,J＝6.85Hz,4H),3.21(m,2H),2.80-2.68(m,2H),1.22(t,J＝6.90Hz,6H),1.14(t,J＝6.95Hz,6H).
Performance testing
(1) Preparing the probe prepared in the example 1 into a solution with the concentration of 20 mu M by taking water as a solvent, and testing the ultraviolet absorption spectrum and the fluorescence emission spectrum of the probe; the normalized ultraviolet absorption spectrum and fluorescence emission spectrum are shown in fig. 5, and the result shows that probe B exhibits long-wave near infrared emission (maximum emission wavelength is 802 nm) in water, and the maximum ultraviolet absorption is 605nm. The probe B has near infrared fluorescence emission and ultraviolet absorption, which shows that the probe B has good potential in-vivo fluorescence/photoacoustic imaging.
(2) The fluorescence spectra of the probes prepared according to the invention were tested in different solvents (glycerol, water, toluene, acetonitrile, N-dimethylformamide and petroleum ether). The probe prepared in example 1 was prepared into a solution with a concentration of 20. Mu.M using different solvents, and the fluorescence spectrum of the probe was tested using an excitation wavelength of 605nm, and the results are shown in FIG. 6, wherein the other solvents in FIG. 6 are water, toluene, acetonitrile, N-dimethylformamide and petroleum ether. From this figure, the probe has very low fluorescence in low viscosity solvents, regardless of the polarity of the solvent, indicating that the probe is insensitive to ambient polarity. However, when glycerol was used as a solvent, the fluorescence enhancement of the probe was evident, indicating that the probe fluorescence emission intensity was related to the environmental viscosity.
(3) The probes prepared according to the present invention were tested for their photostability in glycerol and PBS. The probe prepared in example 1 was prepared into a solution having a concentration of 20. Mu.M using glycerol and PBS as solvents, and the above solution was placed under an ultraviolet lamp and a fluorescent lamp. The fluorescence spectrum of the probe was measured using an excitation wavelength of 605nm, and the fluorescence intensity of the probe at a wavelength of 802nm was recorded, and the result is shown in FIG. 7. FIG. 7 is a statistical plot of the light stability test results of the probe in PBS and glycerol, showing that the probe has stronger fluorescence emission in glycerol and weaker fluorescence emission in PBS solution. After one hour of continuous illumination, the fluorescence intensity of the probe does not change obviously, and the probe has good light stability.
(4) The probes prepared according to the invention were tested for stability in gastric acid solution. A simulated gastric acid solution was prepared by the literature method (ColoidInterface. Sci.,44 (2021), 100491), and the probe prepared in example 1 was prepared as a solution having a concentration of 20. Mu.M using the simulated gastric acid solution. The fluorescence spectrum of the probe is tested by adopting the excitation wavelength of 605nm, the fluorescence intensity of the probe at the wavelength of 802nm is recorded, the result is shown in figure 8, the probe has good stability in simulated gastric acid, and after 1h continuous test, the fluorescence intensity of the probe does not have obvious change, so that the probe has good gastric acid stability.
(5) The fluorescence spectra of the probes prepared by the invention in glycerol and PBS mixed solutions with different viscosities are tested. The mixed solution of glycerin and PBS was prepared, the viscosity of the mixed solution was changed by gradually changing the volume fraction of glycerin, the volume fraction of glycerin was set to 0%, 10%, 20%, 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and 100%, reference (chem. Eng. J.,2023,464 (2023), 142521.) gave 0.99cP,1.41cP,3.03cP,5.71cP,7.64cP,12.4cP,17.3cP,29.4cP,53.0cP,68.5cP,135cP,182cP,261cP,483cP,953cP. each having a viscosity corresponding to a different volume fraction, and the probe prepared in example 1 was prepared as a solution having a concentration of 20 μm using a solution having a different viscosity as a solvent, and the fluorescence spectrum of the probe was measured using an excitation wavelength of 605nm, and the result is shown in fig. 9. From the graph, the fluorescence intensity of the probe is gradually enhanced with the increase of the volume fraction of the glycerol, which indicates that the probe has viscosity-dependent fluorescence emission characteristics;
The corresponding fluorescence intensities are shown in FIG. 10, the fluorescence intensity of the probe is gradually increased with the increase of the environmental viscosity, and a good linear correlation is exhibited. FIG. 10 shows that the probe can quantitatively detect the change in the environmental viscosity by the change in the fluorescence intensity.
(6) The mixed solution of glycerin and PBS with different viscosities is prepared, the viscosity of the mixed solution is changed by changing the volume fraction of glycerin, and the volume fractions of glycerin are respectively 0%,25%,50%,75% and 100%, and the viscosities corresponding to the different volume fractions are obtained by reference (chem. Eng. J.,2023,464 (2023), 142521.). The probe prepared in example 1 was prepared as a solution having a concentration of 200. Mu.M using the above solutions having different viscosities as solvents, and the photoacoustic signal of the probe was tested using an excitation wavelength of 680 nm. Fig. 11 is a photo-acoustic imaging diagram of a probe in a mixed solution of glycerol and PBS of different viscosities, showing that the intensity of the probe photo-acoustic signal increases gradually with increasing ambient viscosity; fig. 12 is a graph of the linear relationship between the photoacoustic signal intensity of the probe and the environmental viscosity in the mixed solution of glycerol and PBS with different viscosities, and the result shows that the probe has a good linear relationship between the photoacoustic signal intensity and the environmental viscosity, which indicates that the probe can be used for quantitatively detecting the change of the environmental viscosity through the intensity of the photoacoustic signal.
(7) The fluorescence probe prepared by the invention is tested for cytotoxicity. HeLa cells were cultured in DMEM medium containing 10% fetal bovine serum. HeLa cells were incubated in DMEM medium containing 10% fetal bovine serum for 24h on 96-well plates. HeLa cells were treated with the probes prepared in example 1 at different concentrations (0, 2.5, 5, 7.5, 10, 15, 20, 25, 30 and 40. Mu.M) respectively, and after 12 hours, cell viability was determined by the CCK-8 method. The test results are shown in FIG. 13, and the results show that the viability of the cells after the cells were treated with the probe at a concentration of 40. Mu.M was still more than 80%, confirming that the fluorescent probe prepared according to the present invention has no significant cytotoxicity.
(8) And testing the biocompatibility of the fluorescent probe prepared by the invention. BALB/c mice were fed with 100. Mu.L of probe B prepared in example 1 at a concentration of 400. Mu.M and the same volume of physiological saline, and the control group was saline-fed mice. After euthanasia of the mice by cervical dislocation, organs such as heart, liver, spleen, lung, kidney and stomach of the mice are immediately obtained by planing. The results of staining analysis of the tissue sections by H & E staining are shown in fig. 14, which shows that no significant lesions appear in the organs of mice fed with probe B and physiological saline, indicating that probe B has good biocompatibility.
(9) And testing whether the fluorescent probe prepared by the invention locates and mitochondria. HeLa cells were incubated with 100. Mu.L of probe B at a concentration of 400. Mu.M and mitochondrial co-localization dye Mito-TRACKER GREEN. The results of taking fluorescent images of Hela cells under the green channel and the red channel are shown in fig. 15, and the results show that Hela cells under the green channel and the red channel can be well overlapped, and it is confirmed that the probe B is mainly located at mitochondria of the cells.
(10) Normal cells (RAW 264.7 and 293T) and cancer cells (4T 1 and Hela) were cultured under the same conditions and then stained with 10 μm concentration of probe B prepared in example 1 for 10min. The fluorescence confocal image of the above cells is shown in fig. 16 (a), and the result shows that probe B has stronger fluorescence in cancer cells than in normal cells. The relative fluorescence intensities of the above cells are shown in FIG. 16 (b), and the result shows that there is a significant difference in fluorescence intensity between cancer cells and normal cells. Thus, probe B can be used to distinguish between cancer cells and normal cells.
(11) The sensitivity of the fluorescent probe to in-vivo viscosity fluctuation imaging is tested. After 100. Mu.L of probe B prepared in example 1at a concentration of 400. Mu.M was orally administered to a normal BALB/c mouse and a gastritis BALB/c mouse, respectively, for 10 minutes, in vivo fluorescence imaging was performed using PERKINELMER IVIS spectral imaging system, wherein the normal BALB/c mouse orally administered probe B was a control group, and the results are shown in FIG. 17 (a), and the results show that the fluorescence intensities were significantly different between the gastritis mouse and the control group. The relative fluorescence intensity values between the gastritis mice and the control group are shown in FIG. 17 (b), and the results show that the fluorescence intensity of the gastritis mice is significantly enhanced, 10 times that of the control group. The experiment shows that the probe B has high sensitivity to imaging of in vivo viscosity fluctuation and can be used for fluorescence imaging monitoring of the living gastritis.
After euthanasia of the mice by cervical dislocation, the mice were dissected. In vivo fluorescence imaging was performed using the same method, and the results are shown in fig. 18, which show that the fluorescence signal in vivo imaging is from the stomach thereof.
(12) After 100. Mu.L of probe B prepared in example 1 at a concentration of 400. Mu.M was orally administered for 10min, respectively, to normal BALB/c mice and gastritis BALB/c mice, fluorescence imaging of organs (heart, liver, spleen, lung, kidney and stomach) in the body was performed using TomoWave LOIS-3D photoacoustic imaging system, wherein the normal BALB/c mice were orally administered with probe B as a control group. The results are shown in fig. 19, and the results show that the photoacoustic intensity of the gastritis mice is significantly stronger than that of the control group. Photoacoustic imaging experiments prove that the probe B can be used for photoacoustic imaging monitoring of the gastritis of the mice.
The above-mentioned gastritis mice are euthanized by cervical dislocation method, and then the mice are dissected to obtain organs such as stomach, lung, heart, spleen, kidney and liver, and the photoacoustic imaging test of the organs is completed under the same conditions, and the result is shown in fig. 20, and the result shows that the photoacoustic signal of the gastritis mice is derived from stomach.
The above examples illustrate only a few embodiments of the invention and are not therefore to be construed as limiting the scope of the invention. It should be noted that modifications, substitutions, improvements, etc. can be made by others skilled in the art without departing from the spirit and scope of the present invention. The scope of the invention should, therefore, be determined with reference to the appended claims.
Claims (9)
1. The fluorescent probe is characterized by having a structural formula shown in a formula (I):
（I）。
2. the method for preparing the fluorescent probe according to claim 1, wherein the preparation method comprises the following steps:
① . Cyclopentanone shown in formula (II) and 2- (4- (diethylamino) -2-hydroxybenzoyl) benzoic acid shown in formula (III) are added into a catalyst 1, heating reaction is carried out, and ice water and the catalyst 2 are added to obtain an intermediate shown in formula (IV); the reaction scheme of step ① is shown in formula (1):
（1）；
② . Mixing the intermediate obtained in the step ①, an organic solvent and 7- (diethylamino) coumarin-3-formaldehyde shown in the formula (V) for reaction to obtain a probe shown in the formula (I); the reaction scheme of step ② is shown in formula (2):
（2）；
In step ①, the catalyst 1 is concentrated sulfuric acid, and the catalyst 2 is perchloric acid.
3. The method according to claim 2, wherein in step ①, the concentration of the perchloric acid is 70%.
4. The method according to claim 2, wherein in step ①, the molar volume ratio of cyclopentanone, 2- (4- (diethylamino) -2-hydroxybenzoyl) benzoic acid, catalyst 1, catalyst 2 and ice water is (10.0-30.0) mmoL:10.0 mmoL:11.0 mL:1.1 mL:300.0 mL;
The temperature of the heating reaction is (60-120) DEG C, and the time is (1-5) h;
the catalyst 2 and ice water are added, and then the filtration, the washing and the vacuum drying are also needed.
5. The method according to claim 2, wherein in step ②, the organic solvent is ethanol, dimethyl sulfoxide, N-dimethylformamide or methanol.
6. The method according to claim 2, wherein in step ②, the molar volume ratio of the intermediate, 7- (diethylamino) coumarin-3-carbaldehyde and the organic solvent is (1.0-1.5) mmoL:1.0 mmoL: (10.0-25.0) mL;
the temperature of the reaction is (50-100) DEG C, and the time is (1-5) h;
After the reaction is completed, recrystallization is also required.
7. Use of a fluorescent probe according to claim 1, characterized in that the fluorescent probe is used in the field of fluorescence imaging detection or in the field of photoacoustic imaging detection.
8. The use according to claim 7, wherein the fluorescent probe is used in the field of in situ fluorescent imaging detection of inflammation or in situ photoacoustic imaging detection.
9. The use according to claim 7, wherein the fluorescent probe is used in the field of in situ fluorescent imaging detection of cancer or in situ photoacoustic imaging detection.
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