CN112174839A - Lipid drop specific labeled fluorescent probe and synthetic method and application thereof - Google Patents
Lipid drop specific labeled fluorescent probe and synthetic method and application thereof Download PDFInfo
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- 150000002632 lipids Chemical class 0.000 title claims abstract description 44
- 239000007850 fluorescent dye Substances 0.000 title claims abstract description 40
- 238000010189 synthetic method Methods 0.000 title abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 15
- UHKAJLSKXBADFT-UHFFFAOYSA-N 1,3-indandione Chemical compound C1=CC=C2C(=O)CC(=O)C2=C1 UHKAJLSKXBADFT-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- -1 aromatic aldehyde compound Chemical class 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 238000001816 cooling Methods 0.000 claims abstract description 4
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- 238000001914 filtration Methods 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 19
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- 238000006243 chemical reaction Methods 0.000 claims description 13
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- 230000002194 synthesizing effect Effects 0.000 claims description 8
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- 238000002372 labelling Methods 0.000 claims description 3
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
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- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 3
- 239000005642 Oleic acid Substances 0.000 description 3
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- 230000009471 action Effects 0.000 description 3
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- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 3
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- 125000001424 substituent group Chemical group 0.000 description 2
- ODHXBMXNKOYIBV-UHFFFAOYSA-N triphenylamine Chemical compound C1=CC=CC=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 ODHXBMXNKOYIBV-UHFFFAOYSA-N 0.000 description 2
- OFGINXFWJLDDPY-UHFFFAOYSA-N 4-[4-(n-phenylanilino)phenyl]benzaldehyde Chemical compound C1=CC(C=O)=CC=C1C1=CC=C(N(C=2C=CC=CC=2)C=2C=CC=CC=2)C=C1 OFGINXFWJLDDPY-UHFFFAOYSA-N 0.000 description 1
- DLTDKNZISWUVBJ-UHFFFAOYSA-N 5-[4-(n-phenylanilino)phenyl]thiophene-2-carbaldehyde Chemical compound S1C(C=O)=CC=C1C1=CC=C(N(C=2C=CC=CC=2)C=2C=CC=CC=2)C=C1 DLTDKNZISWUVBJ-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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Abstract
The invention discloses a lipid drop specific labeled fluorescent probe and a synthetic method and application thereof, wherein the synthetic method comprises the following steps: the preparation method comprises the following steps of reacting an aromatic aldehyde compound with 1, 3-indandione in an organic solvent at 50-140 ℃ for 0.1-300 h in the presence of a catalyst, cooling to room temperature, adding dichloromethane, filtering, removing the solvent under reduced pressure, separating and purifying a product, and drying. The fluorescent probe disclosed by the invention has no fluorescence in an aqueous solution and almost no fluorescence in a common organic solvent, has remarkably enhanced fluorescence in grease, can specifically target lipid droplets in cells, and can be used for cell imaging of the lipid droplets.
Description
Technical Field
The invention belongs to the technical field of biomedicine, and particularly relates to a lipid drop specifically-labeled fluorescent probe, and a synthesis method and application thereof.
Background
Fluorescence imaging provides an intuitive and real-time observation mode for studying complex biological structures and physiological processes. The organic fluorescent probe is used as an important carrier of fluorescence imaging and plays an important role in researching organelles and cell physiological processes. Although many fluorescent probes for targeted labeling of mitochondrial, lysosomal and endoplasmic reticulum organelles are currently commercialized, lipid droplet imaging fluorescent probes remain few. And the imaging effect of the commercial lipid drop fluorescent probe has been achieved and is still unsatisfactory. On the one hand, the conventional fluorescent probe is difficult to realize long-time imaging observation due to poor light stability. On the other hand, near-infrared emission fluorescent probes with higher signal-to-noise ratio have yet to be developed further.
Lipid droplets are complex and dynamically-changing multifunctional organelles and play a very important role in processes such as intracellular energy transport and signal transduction. And atherosclerosis, fatty liver, obesity, etc. are also closely related to the abnormal metabolism of lipid droplets. The lipid drop specific fluorescent probe can visually observe the content of lipid drops in cells and the form and the change process of the lipid drops, and is favorable for researching the development process of lipid drop related diseases. Although some lipid droplet fluorescent probes have been commercialized at present, lipid droplet specific imaging fluorescent probes with better specificity and better photostability still need to be developed further. The development of the lipid drop specific fluorescent probe which has no fluorescence in water and the fluorescence in lipid drops is obviously enhanced has important research value and industrial application prospect.
Disclosure of Invention
The invention aims to: aiming at the defects in the prior art, the fluorescent probe specifically marked by the lipid drop and the synthesis method and the application thereof are provided.
The technical scheme adopted by the invention is as follows:
a lipid drop specific labeled fluorescent probe has a structure shown in the following formula I:
wherein R is1Is hydrogen atom, methyl or methoxy; r2Is benzene ring or thiophene.
The synthesis method of the lipid drop specific labeled fluorescent probe comprises the following steps:
reacting an aromatic aldehyde compound shown in a formula II with 1, 3-indandione in an organic solvent at 50-140 ℃ for 0.1-300 h in the presence of a catalyst, cooling to room temperature, adding dichloromethane, filtering, removing the solvent under reduced pressure, separating and purifying a product, and drying.
The D-pi-A type fluorescent molecule with a push-pull electronic structure is constructed on the basis of triphenylamine with different substituents and 1, 3-indandione, the obtained fluorescent probe has no fluorescence in solid and solution states, has strong fluorescence in oil, and can realize specific fluorescence imaging of intracellular lipid drops.
Further, the catalyst is at least one of triethylamine, piperidine and pyridine.
Further, the organic solvent is at least one of methanol, ethanol, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, diethyl ether, dimethyl sulfoxide, benzene, o-dichlorobenzene, chlorobenzene, toluene, xylene, 1, 4-dioxane, 1, 2-dichloroethane, N-dimethylformamide, and N, N-dimethylacetamide.
Further, the molar ratio of the aromatic aldehyde compound of formula II, the 1, 3-indandione and the catalyst is 0.001-100: 0.0001-100.
Furthermore, the molar ratio of the aromatic aldehyde compound of the formula II, the 1, 3-indandione and the catalyst is 0.01-10: 0.001-10.
Further, the molar ratio of the aromatic aldehyde compound of formula ii, 1, 3-indandione and catalyst is 1:1: 0.001.
Further, the reaction is carried out for 10-50 h at 90-120 ℃.
Further, the reaction was carried out at 100 ℃ for 24 hours.
The application of the fluorescent probe specifically labeled by the lipid drop in the aspect of specifically labeling the lipid drop.
In summary, due to the adoption of the technical scheme, the invention has the beneficial effects that:
1. according to the invention, a D-pi-A type fluorescent molecule with a push-pull electronic structure is constructed by triphenylamine and 1, 3-indandione with different substituents, the obtained fluorescent probe almost has no fluorescence in a conventional solvent and solid state, has strong fluorescence in grease, and can be used for cell imaging of lipid droplets;
2. the product of the invention has good lipid droplet specific imaging capability, can specifically mark lipid droplets in HeLa cells, can realize the real-time observation of the distribution and the form of the lipid droplets in living cells, and lays a solid foundation for biological imaging;
3. the preparation method is simple, the operation is simple and convenient, the raw materials are easy to obtain, and the industrial production is easy to realize.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is a nuclear magnetic hydrogen spectrum of the product of example 1;
FIG. 2 is a nuclear magnetic hydrogen spectrum of the product of example 2;
FIG. 3 is a nuclear magnetic hydrogen spectrum of the product of example 3;
FIG. 4 is a nuclear magnetic hydrogen spectrum of the product of example 4;
FIG. 5 is a graph showing fluorescence emission spectra of the product of example 3 in water and oleic acid;
FIG. 6 is a confocal laser imaging of the product of example 3 on lipids in HeLa cells; the scale bar is 25 μm.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the detailed description and specific examples, while indicating the preferred embodiment of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention. The components of embodiments of the present invention generally described and illustrated in the figures herein may be arranged and designed in a wide variety of different configurations.
Thus, the following detailed description of the embodiments of the present invention, presented in the figures, is not intended to limit the scope of the invention, as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without making any creative effort, shall fall within the protection scope of the present invention.
It is noted that relational terms such as "first" and "second," and the like, may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising an … …" does not exclude the presence of other identical elements in a process, method, article, or apparatus that comprises the element.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
The preferred embodiment of the invention provides a method for synthesizing a lipid drop specifically-labeled fluorescent probe, which comprises the following specific steps:
4' - (diphenylamino) biphenyl-4-carbaldehyde (0.50g,1.43mmol) and 1, 3-indandione (0.23g,1.58mmol) are dissolved in a mixed solution of 5mL of methanol and 5mL of toluene, 2 drops of piperidine are added to react at 100 ℃, the reaction progress is monitored by thin layer chromatography, after the reaction is finished, the mixture is cooled to room temperature and concentrated, and the product is separated and purified by silica gel column chromatography to obtain 0.56g of a reddish brown solid compound with the yield of 81.96%.1H NMR(400MHz,CDCl3):＝7.05-7.11(t,2H),7.12-7.20(m,6H),7.27-7.33(m,4H),7.55-7.60(d,2H),7.71-7.76(d,2H),7.79-7.85(m,2H),7.92(s,1H),7.99-8.05(m,2H)ppm.
Example 2
The preferred embodiment of the invention provides a method for synthesizing a lipid drop specifically-labeled fluorescent probe, which comprises the following specific steps:
5- (4- (diphenylamino) phenyl) thiophene-2-carbaldehyde (0.50g,1.41mmol) and 1, 3-indandione (0.22g,1.51mmol) are dissolved in a mixed solution of 5mL of methanol and 5mL of toluene, 2 drops of piperidine are added to react at 120 ℃, the progress of the reaction is monitored by thin layer chromatography, the mixture is cooled to room temperature after the reaction is finished, and the product is concentrated and separated and purified by silica gel column chromatography to obtain 0.58g of a reddish brown solid compound with the yield of 85.29%.1H NMR(400MHz,CDCl3):＝6.97-7.02(m,2H),7.11-7.19(m,6H),7.35-7.42(t,4H),7.68-7.71(d,1H),7.74-7.79(m,2H),7.88-7.96(m,4H),8.05(s,1H),8.23-8.27(d,2H)ppm.
Example 3
The preferred embodiment of the invention provides a method for synthesizing a lipid drop specifically-labeled fluorescent probe, which comprises the following specific steps:
5- (4- (Dixylylamino) phenyl) thiophene-2-carbaldehyde (0.60g,1.56mmol) and 1, 3-indandione (0.25g,1.72mmol) were dissolved in waterAdding 2 drops of piperidine into 10mL of toluene, reacting at 120 ℃, monitoring the reaction process by using thin layer chromatography, cooling to room temperature after the reaction is finished, concentrating, and separating and purifying the product by using silica gel column chromatography to obtain 0.60g of a reddish brown solid compound with the yield of 75.01%.1H NMR(400MHz,DMSO-d6):＝2.30(s,6H),6.90-6.94(d,2H),7.01-7.06(d,4H),7.25-7.23(d,4H),7.64-7.68(d,1H),7.68-7.74(d,2H),7.87-7.97(m,4H),8.03(s,1H),8.22-8.26(d,2H)ppm.
Example 4
The preferred embodiment of the invention provides a method for synthesizing a lipid drop specifically-labeled fluorescent probe, which comprises the following specific steps:
5- (4- (dimethoxyphenylamino) phenyl) thiophene-2-carbaldehyde (0.60g,1.44mmol) and 1, 3-indandione (0.23g,1.59mmol) were dissolved in 10mL of toluene, 2 drops of piperidine were added, the reaction was carried out at 120 ℃ and the progress of the reaction was monitored by thin layer chromatography, after the completion of the reaction, the mixture was cooled to room temperature and concentrated, and the product was isolated and purified by silica gel column chromatography to give 0.63g of a reddish brown solid compound in 80.25% yield.1H NMR(400MHz,DMSO-d6):＝3.77(s,6H),6.76-6.81(d,2H),6.95-7.00(m,4H),7.11-7.17(m,4H),7.62-7.64(d,1H),7.66-7.70(d,2H),7.88-7.94(m,4H),8.02(s,1H),8.21-8.23(d,1H)ppm.
Experimental example 1
The product of example 3 was dissolved in DMSO to prepare a 10mM stock solution. Then, the test solution was diluted with water or oleic acid to 5. mu.M, and then subjected to fluorescence test.
As shown in FIG. 5, it can be seen from the results of FIG. 5 that the fluorescence of the fluorescent probe is substantially free from fluorescence in the aqueous solution, while the fluorescence of the fluorescent probe is significantly enhanced in oleic acid. FIG. 5 shows the results that the fluorescent probe provided by the present invention can be used for lipid drop specific fluorescent labeling.
Experimental example 2
The product of example 3 was dissolved in DMSO to prepare a 10mM stock solution. The fluorescent probe was diluted to 10. mu.M with the medium for HeLa cell staining. Cells were further stained with the commercially available lipid drop fluorescent probe Bodipy 493/503 for 30 minutes after 1 hour incubation in an incubator to investigate the lipid drop imaging ability of the prepared fluorescent probes. After the cells were washed three times with PBS, photographs were observed with a laser confocal microscope. The results of the confocal reaction are shown in FIG. 6.
From the results of FIG. 6, it can be seen that the red fluorescence of the fluorescent probe can be well overlapped with the green fluorescence of Bodipy 493/503, and the overlap factor is 0.9344, indicating that the fluorescent probe of the present invention can be used for bioimaging of lipid droplets.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (8)
1. A lipid drop specific labeled fluorescent probe is characterized by having a structure shown as the following formula I:
wherein R is1Is hydrogen atom, methyl or methoxy; r2Is benzene ring or thiophene.
2. The method for synthesizing a lipid droplet-specific labeled fluorescent probe according to claim 1, comprising the steps of:
reacting an aromatic aldehyde compound shown in a formula II with 1, 3-indandione in an organic solvent at 50-140 ℃ for 0.1-300 h in the presence of a catalyst, cooling to room temperature, adding dichloromethane, filtering, removing the solvent under reduced pressure, separating and purifying a product, and drying.
3. The method of claim 2, wherein the catalyst is at least one of triethylamine, piperidine, and pyridine.
4. The method of claim 2, wherein the organic solvent is at least one of methanol, ethanol, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, diethyl ether, dimethyl sulfoxide, benzene, o-dichlorobenzene, chlorobenzene, toluene, xylene, 1, 4-dioxane, 1, 2-dichloroethane, N-dimethylformamide, and N, N-dimethylacetamide.
5. The method for synthesizing a lipid droplet-specific labeled fluorescent probe according to claim 2, wherein the molar ratio of the aromatic aldehyde compound of formula II, 1, 3-indandione and the catalyst is 0.001-100: 0.0001-100.
6. The method for synthesizing a lipid droplet-specific fluorescent probe according to claim 5, wherein the molar ratio of the aromatic aldehyde compound of formula II, 1, 3-indandione, and the catalyst is 0.01-10: 0.001-10.
7. The method for synthesizing a lipid droplet-specific fluorescent probe according to claim 2, wherein the reaction is carried out at 90 to 120 ℃ for 10 to 50 hours.
8. Use of a lipid droplet-specifically labeled fluorescent probe according to claim 1 for specifically labeling a lipid droplet.
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