CN111533775A - Ratio type leucine aminopeptidase fluorescent probe, preparation method thereof and application thereof in liver tumor cell targeted imaging - Google Patents
Ratio type leucine aminopeptidase fluorescent probe, preparation method thereof and application thereof in liver tumor cell targeted imaging Download PDFInfo
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Abstract
The invention discloses a ratio type leucine aminopeptidase fluorescent probe, a preparation method thereof and application thereof in liver tumor cell targeted imaging. The structural formula of the ratio type leucine aminopeptidase fluorescent probe is shown as a formula III:
the ratio type leucine aminopeptidase fluorescent probe has the advantages of high fluorescence quantum yield, obvious ratio metering type characteristics, capability of realizing targeted imaging of liver tumor cells and the like. The fluorescent probe is successfully applied to target imaging of the leucine aminopeptidase of the liver tumor cells, and the fluorescent probe obtainsBetter application effect.
Description
Technical Field
The invention relates to the technical field of biological application of fluorescent probes, in particular to a ratio type leucine aminopeptidase fluorescent probe with liver tumor cell targeting capability, a preparation method thereof and application thereof in liver tumor cell targeting imaging.
Background
Liver cancer is one of common malignant tumors, has the characteristics of atypical symptoms at the early stage of diseases, rapid disease development and the like, realizes early accurate diagnosis and can effectively improve the cure rate. Leucine Aminopeptidase (LAP) is an important liver tumor marker and widely distributed in human tissues, and the activity change of the leucine aminopeptidase is closely related to the growth, division and migration of liver tumor cells. At present, the activity change of leucine aminopeptidase in blood is one of the reference indexes for clinical early diagnosis of liver tumor. However, due to the restriction of ex situ detection, it is difficult to obtain accurate data of LAP activity changes of liver tumor cells by the blood route. Therefore, there is an urgent need to develop an in situ and efficient method for detecting the LAP activity of liver tumor cells, which provides an important reference for the early diagnosis of liver cancer.
The fluorescence imaging technology has the advantages of in-situ detection, high space-time resolution and the like, becomes a powerful tool for detecting the activity of tumor markers, and the fluorescence probe with excellent performance is the key for the successful application of the technology. Based on the principle that the N-terminal leucine amido bond of the LAP hydrolysis probe realizes fluorescent response, researchers at home and abroad design a large number of small-molecule LAP fluorescent probes, especially the preparation of near-infrared ratio type LAP fluorescent probes, and an important tool is provided for LAP activity detection. However, the problem of targeting of a fluorescent probe to liver tumor cells still needs to be solved for realizing accurate detection of the activity of the liver tumor cells LAP, and at present, LAP fluorescent probes with liver tumor cell targeting capability have not been reported yet.
Disclosure of Invention
In view of the above, the present invention provides a ratiometric leucine aminopeptidase fluorescent probe with liver tumor cell targeting ability;
the invention also provides a preparation method of the ratio type leucine aminopeptidase fluorescent probe with the liver tumor cell targeting capability;
the invention also provides application of the ratio type leucine aminopeptidase fluorescent probe with liver tumor cell targeting capability in liver tumor cell targeting imaging.
The technical scheme of the invention is as follows:
the invention provides a ratio type leucine aminopeptidase fluorescent probe shown in a formula III:
the invention also provides a preparation method of the ratio type leucine aminopeptidase fluorescent probe. As shown in fig. 1, the preparation method comprises the following steps: adding a compound I, Fmoc-Leu-OH, diisopropylethylamine, 1-ethyl- (3-dimethylaminopropyl) carbodiimide and 1-hydroxybenzotriazole into a mixed solution (volume ratio is 1: 1) of dichloromethane and DMF according to a certain molar ratio, stirring at 25 ℃ for reacting for 24 hours, and purifying a reaction solution to obtain a compound II; the compound I, Fmoc-Leu-OH, diisopropylethylamine, 1-ethyl- (3-dimethylaminopropyl) carbodiimide and 1-hydroxybenzotriazole in a molar ratio of 0.5-1: 2:2: 2:2, preferably 1:1.2:1.2:1.2: 2; adding a compound II and a dimethylamine tetrahydrofuran solution into a dichloromethane solution according to a certain ratio, reacting for 1h at a certain temperature, and purifying the reaction solution to obtain a compound III; the compound II is a dimethylamine tetrahydrofuran solution, and the molar ratio of the compound II to the dimethylamine tetrahydrofuran solution is 0.5-1.5: 10, preferably 1: 8; the reaction temperature is preferably from 25 ℃ to 35 ℃.
The invention also provides a ratio type leucine aminopeptidase fluorescent probe applied to target imaging of the leucine aminopeptidase of the liver tumor cells, which comprises the following steps: confocal Laser Scanning Microscopy (CLSM) was used to study fluorescence imaging of formula III fluorescent probes at HuH7 and a549 cells. After incubating the fluorescent probe of formula III (10. mu.M) with HuH7 and A549 cells respectively for 30 minutes, fluorescence spectrum imaging is obtained, and the excitation wavelength is selected to be 405 nm.
Compared with the prior art, the ratio type leucine aminopeptidase fluorescent probe provided by the invention has the following advantages:
the ratio type leucine aminopeptidase fluorescent probe has the advantages of obvious ratio metering characteristic, good water solubility, capability of realizing targeted imaging of the leucine aminopeptidase of liver tumor cells and the like. The fluorescent probe is successfully applied to target imaging of the leucine aminopeptidase of the liver tumor cells, and a better imaging effect is achieved.
Drawings
FIG. 1 is a reaction scheme of a ratiometric leucine aminopeptidase fluorescent probe of the present invention.
FIG. 2 shows fluorescence emission spectra of the ratiometric leucine aminopeptidase fluorescent probe (10. mu.M) of the present invention at pH 7.5 with the addition of 0U/L and 100U/L leucine aminopeptidase concentrations.
FIG. 3 is a graph showing the fluorescence effect of the ratio-type leucine aminopeptidase fluorescent probe of the present invention at pH 7.5, at an excitation wavelength of 375nm and an emission wavelength of 520nm, in different concentrations of leucine aminopeptidase.
FIG. 4 is a diagram of the effect of the ratio type leucine aminopeptidase fluorescent probe formula III of the present invention on targeted fluorescence imaging of liver tumor cells.
Detailed Description
For a better understanding of the present invention, reference is made to the following description taken in conjunction with the accompanying drawings and examples, but the scope of the invention as claimed should not be limited to the scope of the examples.
Example 1: preparation of Compound II
Adding 0.1mmol of a compound shown in a formula I, 0.15mmol of Fmoc-Leu-OH, 0.15mmol of diisopropylethylamine, 0.15mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide and 0.15mmol of 1-hydroxybenzotriazole into 100ml (volume ratio of 1: 1) of a mixed solution of dichloromethane and DMF, stirring, reacting at 25 ℃ for 24 hours under the protection of nitrogen, removing a reaction solvent under reduced pressure after the reaction is finished, and separating a crude product by column chromatography, wherein dichloromethane: methanol is taken as a mobile phase with a ratio of 10:1, and 380mg of the compound shown as the formula II is obtained.
1H NMR(400MHz,DMSO)8.93(dd,J＝8.6,1.3Hz,1H),8.78(dd,J＝4.0,1.5Hz,1H),8.54(s,1H),7.88(d,J＝7.5Hz,2H),7.79(d,J＝7.8Hz,1H),7.70(dd,J＝7.4,3.0Hz,2H),7.61(d,J＝8.0Hz,1H),7.54(dd,J＝8.6,4.1Hz,1H),7.41(t,J＝7.4Hz,2H),7.31(t,J＝7.1Hz,2H),7.27–7.23(m,1H),7.20–7.11(m,1H),6.94(d,J＝8.0Hz,1H),6.20(s,2H),5.76(s,2H),5.60(d,J＝9.2Hz,1H),5.42(d,J＝5.9Hz,1H),5.22(d,J＝5.6Hz,1H),4.99(d,J＝5.5Hz,1H),4.30–4.25(m,2H),4.14(d,J＝5.2Hz,1H),4.04–3.99(m,2H),3.81(d,J＝4.4Hz,1H),3.71–3.58(m,1H),2.30(s,1H),1.17(t,J＝7.1Hz,2H),0.77(dd,J＝16.7,6.5Hz,6H).13C NMR(101MHz,DMSO)173.32,170.79,156.51,147.35,146.55,146.13,144.26,144.16,141.16,137.80,137.60,134.37,129.35,128.84,128.66,128.08,127.49,126.45,125.77,125.69,122.25,121.55,120.55,114.10,108.60,88.47,75.59,73.73,69.53,69.12,66.05,55.35,52.68,47.10,24.55,21.75,21.21.
Example 2: preparation of Compound II
Adding 0.1mmol of a compound shown in a formula I, 0.12mmol of Fmoc-Leu-OH, 0.12mmol of diisopropylethylamine, 0.12mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide and 0.12mmol of 1-hydroxybenzotriazole into 100ml (volume ratio of 1: 1) of a mixed solution of dichloromethane and DMF, stirring, reacting at 25 ℃ for 24 hours under the protection of nitrogen, removing a reaction solvent under reduced pressure after the reaction is finished, and separating a crude product by column chromatography, wherein dichloromethane: methanol 10:1 as a mobile phase to obtain 396mg of the compound shown in the formula II.
Example 3: preparation of Compound III
Adding 0.1mmol of compound II and 0.5mmol of dimethylamine tetrahydrofuran solution into 30ml of dichloromethane solution, reacting for 1h at 50 ℃, removing the reaction solvent under reduced pressure after the reaction is finished, and separating the crude product by column chromatography, wherein dichloromethane: methanol 8:1 as a mobile phase to obtain 320mg of the compound shown in the formula III.
1H NMR(400MHz,DMSO)8.95(d,J＝8.6Hz,1H),8.80(d,J＝2.8Hz,1H),8.57(s,1H),8.37(s,2H),7.63(d,J＝8.0Hz,1H),7.57(dd,J＝8.6,4.0Hz,1H),6.96(d,J＝8.0Hz,1H),5.62(d,J＝9.2Hz,1H),4.50(dd,J＝11.5,8.7Hz,2H),4.20–1.16(m,4H),3.97(s,2H),3.86(d,J＝2.8Hz,1H),3.68(dd,J＝9.4,3.1Hz,1H),1.79(d,J＝18.1Hz,1H),1.60–1.41(m,2H),0.75(dd,J＝18.8,6.3Hz,6H).13C NMR(101MHz,DMSO)170.50,147.42,146.56,145.83,137.60,134.42,128.81,126.44,122.28,121.48,114.36,108.90,88.49,75.37,73.67,69.52,69.04,65.66,51.00,24.02,22.63,22.05.HRMS(ESI)calcd for[III+H]+C23H32N6O6487.2300,found 487.2315,[III+Na]+C23H31N6O6Na509.2125,found 509.2132.
Example 4: preparation of Compound III
Adding 0.1mmol of compound II and 0.8mmol of dimethylamine tetrahydrofuran solution into 30ml of dichloromethane solution, reacting for 1h at 30 ℃, removing the reaction solvent under reduced pressure after the reaction is finished, and separating the crude product by column chromatography, wherein dichloromethane: methanol 8:1 as a mobile phase to obtain 410mg of the compound shown in the formula III.
Example 5: fluorescence probe formula III, at pH 7.5 with the addition of 0U/L and 100U/L leucine aminopeptidase emission spectroscopy determination.
The fluorescent probe III prepared in example 4 was accurately weighed, prepared with dimethyl sulfoxide as a fluorescent probe stock solution at a concentration of 10mM, and 1. mu.L of the fluorescent probe stock solution was pipetted into a mixed solution of phosphate buffer and DMSO (volume 1mL, volume ratio 9:1) at a fluorescent probe concentration of 10. mu.M. One of the two solutions is added with 1 mu L of leucine aminopeptidase mother liquor, so that the concentration of leucine aminopeptidase in the reaction system is 100U/L. For the other set blank, the reaction was carried out at 37 ℃ for 5 minutes with an excitation wavelength of 375nm, and the fluorescence emission spectra of the two mixtures were measured, and the results are shown in FIG. 2. The fluorescent probe III has a strong fluorescence emission peak at 432nm before reacting with leucine aminopeptidase, and has a strong fluorescence emission peak at 520nm after reacting with leucine aminopeptidase, thereby showing the characteristics of an obvious ratio type probe.
Example 6: and (3) adding leucine aminopeptidase with different concentrations into the fluorescent probe formula III under the conditions that the pH value is 7.5 and the excitation wavelength is 375nm to obtain the fluorescent detection effect.
The fluorescent probe III prepared in example 4 was accurately weighed, a 10mM fluorescent probe stock solution was prepared from dimethyl sulfoxide, 1. mu.L of a mixed solution (volume: 1mL, volume ratio: 9:1) of phosphate buffer and DMSO was pipetted using a pipette, the concentration of the fluorescent probe in the solution was 10. mu.M, 1. mu.L of leucine aminopeptidase stock solutions with different concentrations (final concentrations of leucine aminopeptidase in the reaction system were 0U/L, 20U/L, 40U/L, 60U/L, and 100U/L), and the fluorescence intensity was measured after 5min at 37 ℃. The excitation wavelength is 375nm, the emission wavelength is 520nm, and the fluorescence intensity is shown in figure 3, and the result shows that the concentration of the leucine aminopeptidase detected by the fluorescent probe and the fluorescence intensity present a good linear relationship.
Example 7: fluorescent probe type III targeted imaging effect on liver tumor cells
The fluorescent probe III prepared in example 4 was accurately weighed, prepared with dimethyl sulfoxide as a fluorescent probe stock solution at a concentration of 10mM, and added to a mixed solution of phosphate buffer and DMSO (volume: 1mL, volume ratio: 9:1) by pipetting 1. mu.L. Respectively incubating the fluorescent probe III (10 mu M) with a liver tumor cell strain HuH7 and a non-small cell lung cancer cell strain A549 together, carrying out fluorescence imaging on the fluorescent probe III in the formula in HuH7 and A549 cells by using a confocal laser scanning microscope, selecting excitation wavelength at 405nm, and obtaining fluorescence imaging images at 2min and 30 min. As shown in FIG. 4, the fluorescent probe III shows a good targeted imaging effect on a liver tumor cell line HuH 7.
It should be noted that, in example 7, the use of the non-small cell lung cancer cell line a549 as a control group is only one embodiment of the present invention, and in other examples, when the fluorescent probe III (10 μ M) is incubated with the hepatoma cell line HuH7 and other tumor cell lines respectively, the finally obtained fluorescence imaging graph shows that the fluorescent probe III also has a better target imaging effect on the hepatoma cell line HuH 7.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (7)
1. A ratio type leucine aminopeptidase fluorescent probe is characterized in that the structural formula is shown as a formula III:
2. a preparation method of a ratio type leucine aminopeptidase fluorescent probe is characterized by comprising the following steps:
the method comprises the following steps: carrying out Fmoc-Leu-OH, diisopropylethylamine, 1-ethyl- (3-dimethylaminopropyl) carbodiimide and 1-hydroxybenzotriazole on the basis of the molar ratio of (0.5-1: 2:2: 2): 2, adding the mixture into a mixed solution (volume ratio is 1: 1) of dichloromethane and DMF, stirring and reacting for 24 hours at 25 ℃, and purifying reaction liquid to obtain a compound II;
step two: adding a compound II and a dimethylamine tetrahydrofuran solution into a dichloromethane solution according to a molar ratio of 0.5-1.5: 10, reacting at the temperature of 25-35 ℃ for 1h, and purifying the reaction solution to obtain a compound III.
3. The method for preparing a ratiometric leucine aminopeptidase fluorescent probe according to claim 2, wherein the molar ratio in the first step is 1:1.2:1.2:1.2: 2.
4. The method for preparing a ratiometric leucine aminopeptidase fluorescent probe according to claim 2, wherein the molar ratio in step two is 1: 8.
5. The method of claim 2, wherein the temperature in step two is 30 ℃.
6. Use of the ratiometric leucine aminopeptidase fluorescent probe of claim 1 for targeted imaging of liver tumor cells.
7. The use of the ratiometric leucine aminopeptidase fluorescent probe of claim 6 for targeted imaging of liver tumor cells, wherein the fluorescent probe formula III is configured as 10 μ M fluorescent reagent, and after incubation of the fluorescent reagent with HuH7 and A549 cells respectively for 30 minutes, fluorescence spectroscopic imaging is obtained using a Confocal Laser Scanning Microscope (CLSM) with excitation wavelength selected to be 405 nm.
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| CN114478473A (en) * | 2022-01-25 | 2022-05-13 | 南方医科大学 | Synthesis and application of leucine aminopeptidase chemiluminescence detection reagent |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114478473A (en) * | 2022-01-25 | 2022-05-13 | 南方医科大学 | Synthesis and application of leucine aminopeptidase chemiluminescence detection reagent |
| CN114478473B (en) * | 2022-01-25 | 2024-05-03 | 南方医科大学 | Synthesis and application of leucine aminopeptidase chemiluminescence detection reagent |
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