CN112321549B - Far-red light lysosome fluorescent probe and preparation method and application thereof - Google Patents
Far-red light lysosome fluorescent probe and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of fluorescent probes, and particularly relates to a far-red light lysosome fluorescent probe and a preparation method and application thereof. The invention takes dialkyl aniline with strong electron supply type as a donor and TCF with strong electron deficiency type as an acceptor to construct a D-pi-A type conjugated compound, and strong charge transfer effect in molecules enables the emission wavelength to be red-shifted to reach a far-red light region, and simultaneously has large Stokes displacement; an alkoxy chain for enhancing water solubility is introduced into the compound, and the molecular weight of the compound is controlled, so that the compound has better solubility in water, and can not generate aggregation quenching phenomenon in cells within a working concentration range during application; dimethylamino is introduced into the molecule, and the dimethylamino can be positioned to lysosome when being applied in cells. In a comprehensive way, probe molecules are constructed from the three aspects of fluorescent groups, recognition groups and water solubility, and when the probe molecules are used for target labeling imaging of lysosomes, the probe molecules have high sensitivity, less self-absorption and less background interference.
Description
Technical Field
The invention belongs to the technical field of fluorescent probes, and particularly relates to a far-red light lysosome fluorescent probe and a preparation method and application thereof.
Background
The fluorescence imaging based on the fluorescent probe has the advantages of simple and convenient operation, small damage to cells, visualization and the like, and is widely applied to the labeling imaging in the cell field. Since biological background can emit fluorescence under light excitation, in order to avoid background interference, the accuracy and sensitivity of detection are improved, and the selection of fluorescent materials with longer emission wavelength is of great value. Meanwhile, the molecule needs to have better water solubility, so that aggregation-induced fluorescence quenching can be avoided when the molecule is applied in a biological environment, and the luminous performance of the molecule can be exerted to the maximum extent. Lysosomes, which are important organelles, contain a large number of hydrolytic enzymes that control the degradation of macromolecules such as proteins, polysaccharides, and nucleic acids, and play an important role in maintaining the life activities of cells. Therefore, the targeted imaging of lysosomes and the monitoring of the change process of the lysosomes are significant and can provide valuable information for the diagnosis of related diseases.
At present, the mature lysosome labeled probe sold in the market is mainly a derivative of BODIPY, the synthesis is relatively complex, the price is high, such as LysoTracker red DND-99, the maximum emission wavelength of the lyso Tracker red DND-99 can reach the red region, 590nm, and the Stokes shift is very small, and is only 13 nm; while LysoTracker Deep Red has a maximum emission wavelength in the far Red region, the Stokes shift is small, only 21 nm. The Stokes shift of the probe is too small and self-absorbing background interference is easily generated during use. In view of these disadvantages, there is a need to develop a fluorescent material with relatively simple preparation method, good water solubility, capability of emitting far-red light, and large Stokes shift, so as to obtain a lysosome fluorescent probe with low cost and high sensitivity.
Disclosure of Invention
In order to solve the defects of the prior art, the invention provides the lysosome fluorescent probe which has good water solubility and emits far-red light and the preparation method thereof, and the lysosome fluorescent probe can be used for target imaging of lysosomes. The compound has 556nm of maximum absorption wavelength, 638nm of maximum emission wavelength, large Stokes shift reaching 82nm and water solubility up to 12 mu M in simulated cell environment, and relatively simple synthesis, and when the compound is used for target marking of lysosomes, the maximum emission wavelength is positioned in a far-red light region, and the compound has the advantages of small background interference and self-absorption influence, high sensitivity and convenient and simple use.
The technical scheme provided by the invention is as follows:
a far-red light lysosome fluorescent probe has a molecular structural formula as shown in the following formula I:
The invention takes dialkyl aniline with strong electron supply type as a donor and TCF with strong electron deficiency type as an acceptor to construct a D-pi-A type conjugated compound, and strong charge transfer effect in molecules enables the emission wavelength to be red-shifted to reach a far-red light region, and simultaneously has large Stokes displacement; an alkoxy chain for enhancing water solubility is introduced into the compound, and the molecular weight of the compound is controlled to be small, so that the compound has good solubility in water, and can not generate aggregation quenching phenomenon in cells within a working concentration range during application; dimethylamino is introduced into the molecule, and the dimethylamino can be positioned to lysosome when being applied in cells. In a comprehensive way, probe molecules are constructed from the three aspects of fluorescent groups, recognition groups and water solubility, and when the probe molecules are used for target labeling imaging of lysosomes, the probe molecules have high sensitivity, less self-absorption and less background interference.
The invention also provides a preparation method of the far-red light lysosome fluorescent probe, which comprises the following steps:
1) dissolving a compound shown in a formula II, a catalyst I used for condensation reaction and an additive I in an organic solvent I, adding a compound shown in a formula III in an ice water bath, and reacting at room temperature after the addition is finished to obtain a compound shown in a formula IV, wherein the specific reaction formula is as follows:
2) dissolving a compound shown in a formula IV and a compound shown in a formula V in an organic solvent II, adding a catalyst II for condensation reaction, and reacting at room temperature to obtain a compound shown in a formula I, wherein the specific reaction formula is as follows:
wherein n is 1 or 2.
Specifically, in step 1):
the organic solvent I is selected from any one or more of dichloromethane, trichloromethane, 1, 2-dichloroethane, tetrahydrofuran, toluene, acetonitrile or 1, 4-dioxane;
the catalyst I is Dicyclohexylcarbodiimide (DCC) or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI);
the additive I is any one or a mixture of more of 4-dimethylamino pyridine, triethylamine or diisopropylethylamine;
the reaction time is 4-24 hours.
Specifically, in the step 2):
the organic solvent II is one or a mixture of more of tetrahydrofuran, 1, 4-dioxane, acetonitrile, methanol, ethanol or propanol;
the catalyst II is any one or a mixture of more of sodium acetate, potassium acetate, ammonium acetate, triethylamine, piperidine or tetrahydropyrrole;
the reaction time is 6-16 hours.
Specifically, in the step 2): and separating and purifying a mixed product obtained after the reaction at room temperature by silica gel column chromatography to obtain the compound shown in the formula I.
The invention also provides application of the far-red light lysosome fluorescent probe for targeted fluorescence imaging of lysosomes.
In particular, for targeted fluorescence imaging of intracellular lysosomes.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of the compound of formula I in example 1.
FIG. 2 is a mass spectrum of the compound of formula I in example 1.
FIG. 3 is a graph of the UV-VIS absorption spectrum and the fluorescence spectrum of the compound of formula I in phosphate buffered saline in example 1.
FIG. 4 is a graph of staining of lysosome co-localization experiments with formula I.
Detailed Description
The principles and features of this invention are described below in conjunction with examples which are set forth to illustrate, but are not to be construed to limit the scope of the invention.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The following examples are given in detail by taking n-1 in formula I as an example.
Example 1: synthesis of Compounds of formula I
(1) Synthesis of intermediate M3: compound M1(1.93g,0.01mol), dicyclohexylcarbodiimide (2.47g,0.012mol) (catalyst I) and 4-dimethylaminopyridine (0.06g,0.5mmol) (additive I) were dissolved in 50mL of dichloromethane (solvent I) under argon and a solution of monomer M2(1.33g,0.01mol) in dichloromethane (20mL) was slowly added dropwise. After the addition, the reaction was carried out at room temperature for 12 hours. Then, water was added for extraction and liquid separation, the organic phase was collected and dried over anhydrous sodium sulfate, and after concentration, separation by silica gel column chromatography with a eluent of dichloromethane/methanol (30: 1) was carried out to obtain intermediate M3(2.81g) in 91% yield.
(2) Synthesis of formula I: monomers M3(2.00g,6.48mmol) and M4(1.55g,7.78mmol) were dissolved in dry tetrahydrofuran/ethanol (30mL, v/v, 1/1) (solvent II) and sodium acetate (53mg, 0.65mmol) (catalyst II) was added and reacted at room temperature for 12 h. Water and dichloromethane were then added for extraction and separation, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography on silica gel with dichloromethane/methanol (25: 1) as eluent to give the compound of formula I (2.73g) in 86% yield.1HNMR(400MHz,CDCl3)δ[ppm]:7.63-7.55(m,3H),6.79(d,J＝16Hz,1H),6.72(d,J＝12Hz,2H),4.33(t,J＝4Hz,2H),4.24(s,2H),3.68(t,J＝4Hz,2H),3.59(t,J＝4Hz,2H),3.20(s,3H),2.55(t,J＝4Hz,2H),2.32(s,6H),1.76(s,6H).HRMS m/z：[M+H]+Calcd.490.2454；Found 490.2431.
Examples 2-7 were carried out with reference to the procedure of example 1. The details are shown in table 1 below:
TABLE 1 Experimental parameters and yield tables for examples 2-7
Example 8 lysosomal co-localization experiments with Compounds of formula I
To investigate the ability of formula I to target lysosomes in cells, we performed a lysosome co-localization experiment on formula I. HeLa cells were stained with Lysotraker Green DND-26(75nM, commercial lysosomal stain) and formula I (75nM), respectively, as shown in FIG. 4. FIG. 4a is an image of lysoTracker Green DND-26 against lysosomes in cells, with Green punctate fluorescence observed; FIG. 4b is an image of a cell of formula I, with bright red punctate fluorescence observed; when the graphs of fig. 4a and 4b are superimposed to obtain fig. 4c, the overlap ratio of the light emitting areas of the two is found to be as high as 94%, thereby proving that the compound of the formula I can be targeted to lysosomes and emit strong red fluorescence.
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, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (6)
1. A far-red light lysosome fluorescent probe is characterized in that the molecular structural formula is as shown in the following formula I:
2. the method for preparing a far-red lysosomal fluorescent probe according to claim 1, comprising the steps of:
1) dissolving a compound shown in a formula II, a catalyst I used for condensation reaction and an additive I in an organic solvent I, adding a compound shown in a formula III in an ice water bath, reacting at room temperature after the addition is finished, and separating to obtain a compound shown in a formula IV, wherein the specific reaction formula is as follows:
2) dissolving a compound shown in a formula IV and a compound shown in a formula V in an organic solvent II, adding a catalyst II for condensation reaction, reacting at room temperature, and separating to obtain a compound shown in a formula I, wherein the specific reaction formula is as follows:
wherein n is 1.
3. The method for preparing a far-red lysosomal fluorescent probe according to claim 2, wherein in step 1):
the organic solvent I is selected from any one or a mixture of more of dichloromethane, trichloromethane, 1, 2-dichloroethane, tetrahydrofuran, toluene, acetonitrile or 1, 4-dioxane;
the catalyst I is dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride;
the additive I is any one or a mixture of more of 4-dimethylamino pyridine, triethylamine or diisopropylethylamine;
the reaction time is 4-24 hours.
4. The method for preparing a far-red lysosomal fluorescent probe according to claim 2, wherein in step 2):
the organic solvent II is one or a mixture of more of tetrahydrofuran, 1, 4-dioxane, acetonitrile, methanol, ethanol or propanol;
the catalyst II is any one or a mixture of more of sodium acetate, potassium acetate, ammonium acetate, triethylamine, piperidine or tetrahydropyrrole;
the reaction time is 6-16 hours.
5. The method for preparing a far-red lysosomal fluorescent probe according to any one of claims 2 to 4, wherein:
in the step 1), adding a reaction product at room temperature into water for extraction and liquid separation, collecting an organic phase, drying the organic phase by using anhydrous sodium sulfate, and then carrying out chromatographic separation by using a silica gel column to obtain a compound shown in the formula IV;
in the step 2), separating and purifying a mixed product obtained after the reaction at room temperature through silica gel column chromatography to obtain the compound shown in the formula I.
6. Use of a far-red lysosomal fluorescent probe according to claim 1, wherein: a targeted fluorescence imaging agent for preparing lysosomes.
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