CN113416230B - Glutamine fluorescent probe and preparation method and application thereof - Google Patents

Glutamine fluorescent probe and preparation method and application thereof Download PDF

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CN113416230B
CN113416230B CN202110677752.1A CN202110677752A CN113416230B CN 113416230 B CN113416230 B CN 113416230B CN 202110677752 A CN202110677752 A CN 202110677752A CN 113416230 B CN113416230 B CN 113416230B
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崔佳燕
黄瑾
马磊
黄维维
邱子言
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Abstract

The invention discloses a glutamine fluorescent probe with a general formula (I) and a preparation method and application thereof. The structural module of the probe comprises: glutamine, a linker and a fluorescent reporter group. The glutamine fluorescent probe can be used as a tool molecule for monitoring the glutamine flux in cells in real time. Preferably, the fluorescent probe with the structure can display the glutamine uptake condition of the lesion site of the animal tumor model, reflect the distribution and the size of tumors in vivo and enrich the detection means of the tumors in small animal living body imaging and human cancer screening.

Description

Glutamine fluorescent probe and preparation method and application thereof
Technical Field
The invention relates to the technical field of compounds, in particular to the field of pharmaceutical chemistry, and specifically relates to a glutamine fluorescent probe and a preparation method and application thereof.
Background
Cancer cells are the source of cancer. Compared with normal cells, cancer cells have the characteristics of unlimited proliferation, transformation and easy metastasis. Cancer cells require a large intake of nutrients to meet their property of unlimited proliferation.
Cancer cell metabolism the well-known "Warburg effect" indicates that cancer cells are capable of high-rate consumption of glucose. FDG-PET (glucose radiotracer-positron emission tomography) which has been developed for human body can trace cancer cells according to their glucose metabolism, thereby precisely locating cancer cells and tissues. However, FDG-PET does not always provide a relatively accurate clinical diagnosis.
Glutamine is a non-essential amino acid and is the free amino acid with the highest content in the blood circulation of the body. The carbon of glutamine can be used for the synthesis of amino acids and fatty acids, and the nitrogen of glutamine can be used for the synthesis of purines and pyrimidines. High levels of glutamine in the blood provide a carbon source and a nitrogen source for cancer cells, support biosynthesis, energy metabolism and homeostatic balance in cancer cells, and promote tumor growth. On 7.4.2021, a research paper titled Cell-programmed nutrient characterization in the tissue micro environment was published in Nature journal by the research team of the university of Van der Pauw medical center, which overturns the development and perfection of cancer metabolic models and basic cancer cognition for 100 years.
At present, the detection means of glutamine in cancer cells mainly comprise the following methods: high performance liquid chromatography, enzyme linked immunosorbent assay, and glutamine/glutamic acid conversion assay. The high performance liquid chromatography needs a plurality of sample pretreatment steps, and the sample preparation is complex. The enzyme-linked immunoassay method relates to the use of antibodies, and has long time consumption and high requirement on temperature in the experimental process. The glutamine/glutamic acid conversion test method relates to the use of glutaminase, and has high requirements on the storage and transportation of a kit. Therefore, at present, no method which is simple in treatment, low in cost, easy to store and easy to detect is used for detecting the glutamine in the cancer cells.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a glutamine fluorescent probe which can be used for monitoring the glutamine flux in cells in real time and reflecting the size and distribution of tumors in an animal tumor model, and a preparation method and application thereof.
In order to achieve the above object, the present invention provides, in a first aspect, a glutamine fluorescent probe characterized by having a general formula (1) including glutamine (Gln), a linker and a fluorescent reporter group F:
Figure BDA0003121539360000021
wherein the content of the first and second substances,
the Gln group has the structure
Figure BDA0003121539360000029
The Linker has the structure of
Figure BDA00031215393600000210
Wherein n is an integer of 1-8, or the Linker does not exist;
f is a fluorescent reporter group with the structure of
Figure BDA00031215393600000211
Preferably, the glutamine fluorescent probe is one of the following compounds,
Figure BDA0003121539360000028
the invention also provides a preparation method of the glutamine fluorescent probe, which comprises the following steps:
Fmoc-Gln (Trt) and 2-chlorotrityl chloride resin are subjected to coupling reaction to generate Fmoc-Gln (Trt) -2-CTC resin, and the reaction solvent is DMF or DCM; after Fmoc group removal, the resin reacts with Fmoc-Linker to generate Fmoc-Linker-Gln (Trt) -2-CTC resin, and the reaction solvent is DMF or DCM; after Fmoc group is removed, the resin reacts with a fluorescence reporter group, and the reaction solvent is DMF or DCM; finally cracking the resin to obtain the corresponding glutamine fluorescent probe.
The glutamine fluorescent probe can be used as a tool molecule for monitoring the glutamine flux in cells in real time. Preferably, the fluorescent probe with the structure can display the ingestion condition of the glutamine at the lesion site of the animal tumor model, reflect the distribution and the size of the tumor in vivo and enrich the detection means of the tumor in the living body imaging of the small animal.
Drawings
FIG. 1 is a graph showing intracellular fluorescence after 4 hours without addition of the glutamine fluorescent probe and after addition of the glutamine fluorescent probe.
FIGS. 2a and 2b are contrast images of before and after the use of glutamine fluorescence probe, respectively.
Detailed Description
For a further understanding of the present invention, the following description of the preferred embodiments of the present invention is given in conjunction with the examples, but it is to be understood that these descriptions are only intended to further illustrate the features and advantages of the present invention, and not to limit the claims of the present invention.
All starting materials for the present invention, without particular limitation as to their source, may be purchased commercially or prepared according to conventional methods well known to those skilled in the art.
To further illustrate the present invention, the glutamine fluorescent probe provided by the present invention is described in detail with reference to the following examples, and the scope of the present invention is not limited by the following examples.
EXAMPLE 1 preparation of Glutamine fluorescent Probe 1
Preparation of Fmoc-Gln (Trt) -2-CTC resin
The 2-chlorotrityl chloride resin (1g,0.4 mmol/g-3 mmol/g) was swollen in 10mL DCM for 1h, filtered and washed 3 times with DCM. Fmoc-Gln (Trt) (2g,3.4mmol), DIPEA (0.85g,6.6mmol) were added and reacted in DCM at room temperature for 2 h. After the reaction was complete, the coupling solution was removed by filtration and washed 3 times with DCM.
Preparation of Fmoc-Acp-Gln (Trt) -2-CTC resin
10mL of 20% piperidine/DMF solution was added to the resin obtained in the previous step and reacted for 30 min. The reaction is finished when ninhydrin test is positive. After the reaction was completed, it was filtered and washed 5 times with DMF. Fmoc-6-aminocaproic acid (1.7g,4.9mmol), HOBt (0.79g,5.9mmol), DIC (0.74g,5.9mmol) were added and reacted in DMF at room temperature for 2 h. When ninhydrin test is negative, the reaction is complete. After the reaction was completed, the coupling solution was removed by filtration and washed with DMF 3 times.
Preparation of FITC-Acp-Gln (Trt) -2-CTC resin
10mL of 20% piperidine/DMF solution was added to the resin obtained in the previous step and reacted for 30 min. When ninhydrin test is positive, the reaction is complete. After the reaction was completed, the mixture was filtered and washed 5 times with DMF. FITC (0.66g,1.7mmol) was added and the reaction was left to react in DMF solution at room temperature for 2 h. When ninhydrin test is negative, the reaction is complete. After the reaction was completed, the coupling solution was removed by filtration and washed with DMF 3 times. Methanol washes were performed 2 times to shrink the resin.
Preparation of FITC-Acp-Gln
To the resin obtained in the previous step, 10mL of TFE/DCM ═ 1:3(V/V) solution was added, reaction was carried out at room temperature for 2H, filtration was carried out, DCM was used for washing 3 times, the obtained filtrate was concentrated, and 10mL of TFA/H was added 2 And (3) reacting the solution with a 95:5(V/V) solution at room temperature for 2 hours, and recrystallizing with diethyl ether to obtain the fluorescent probe 1.
Compound FITC-Acp-Gln, C 32 H 32 N 4 O 9 S, yellow solid. 1 H NMR(400MHz,CDCl 3 )δ8.24(1H,s),7.73(1H,d,J＝8Hz),7.30(1H,d,J＝8Hz),7.19(2H,m),6.57(4H,m),4.18(1H,m),3.39(2H,m),2.14(4H,m),1.93(1H,m),1.74(1H,m),1.56(4H,m),1.34(2H,m).MS(ESI):m/z 649.20[M+H] + 。
EXAMPLE 2 preparation of Glutamine fluorescent Probe 2
Preparation of Fmoc-Gln (Trt) -2-CTC resin
The 2-chlorotrityl chloride resin (1g,0.4 mmol/g-3 mmol/g) was swollen in 10mL DCM for 1h, filtered and washed 3 times with DCM. Fmoc-Gln (Trt) (2g,3.4mmol), DIPEA (0.85g,6.6mmol) were added and reacted in DCM at room temperature for 2 h. After the reaction was complete, the coupling solution was removed by filtration and washed 3 times with DCM.
Preparation of Rhodamine B-Gln (Trt) -2-CTC resin
10mL of 20% piperidine/DMF solution was added to the resin obtained in the previous step and reacted for 30 min. When ninhydrin test is positive, the reaction is complete. After the reaction was completed, the mixture was filtered and washed 5 times with DMF. Rhodamine B (2.4g,4.8mmol), PyAOP (2.5g,4.8mmol), HOAt (0.68g,4.8mmol), DIPEA (1.2g,4.8mmol) were dissolved in DMF, stirred at room temperature for 10min, added to the above resin and reacted at room temperature for 2 h. When ninhydrin test is negative, the reaction is complete. After the reaction was completed, the coupling solution was removed by filtration and washed with DMF 3 times. Methanol washes were performed 2 times to shrink the resin.
Preparation of Rhodamine B-Gln
To the resin obtained in the previous step, 10mL of a solution of TFE: DCM ═ 1:3(V/V) was added, the mixture was reacted at room temperature for 2h, filtered, and washed with DCM 3Next, the resulting filtrate was concentrated, and 10mL of TFA H was added 2 And (3) reacting the solution with a 95:5(V/V) solution at room temperature for 2 hours, and recrystallizing with diethyl ether to obtain the fluorescent probe 2.
Rhodamine compound B-Gln, C 33 H 39 N 4 O 5 + Dark red solid. 1 H NMR(400MHz,CDCl 3 )δ7.98(1H,m),7.49(1H,m),7.38(1H,m),7.29(1H,m),7.20(2H,m),6.87(2H,m),6.79(2H,m),4.33(1H,m),3.64(8H,m),2.34(2H,m),1.85(2H,m),1.27(6H,t),1.17(6H,t).MS(ESI):m/z 571.29[M] + 。
Example 3
The prepared glutamine fluorescent probe is used for detecting the flux of glutamine in cancer cells in real time.
Before the experiment, the non-small cell lung cancer cell A549 was inoculated at 100000 cells/well into a glass-bottom culture dish exclusive for a 35mm confocal microscope and cultured in a DMEM complete medium containing fetal bovine serum (volume ratio: 10%), penicillin (100. mu.g/mL) and streptomycin (100. mu.g/mL). Placing the culture dish in a container containing 5% CO by volume 2 And cultured in an incubator at 37 ℃ for 24 hours. A549 cells were washed three times with PBS (phosphate buffered saline, pH 7.4). Adding 1mL of Hoechst 33258 staining solution and cell membrane red fluorescent probe Dil, and placing in a container containing 5% CO by volume 2 And culturing in an incubator at 37 ℃ for 20-30 minutes. The staining solution was discarded and a549 cells were washed three times with PBS. Adding DMEM medium containing glutamine fluorescent probe (FITC-Acp-Gln, 4mM) and placing in a medium containing 5% CO by volume 2 Cultured in an incubator at 37 ℃. After 4 hours, the medium was discarded, and the A549 cells were washed three times with PBS and observed for intracellular glutamine fluorescence uptake under a rotary confocal microscope (Nikon CSU-W1 SoRa).
As shown in FIG. 1, when no glutamine fluorescent probe was added, no green fluorescence was evident in the cells; when 4 hours later, the glutamine fluorescent probe shows obvious green fluorescence in the cell, which indicates that the cell effectively takes up glutamine, and the probe can be used for detecting the glutamine flux in the cell.
Example 4
The prepared glutamine fluorescent probe is used for imaging the distribution and the size of the tumor in an animal tumor model.
A549-luc cells capable of stably expressing luciferase are used for constructing a nude mouse lung metastasis model. Selecting 6-week-old female nude mice, and mixing 100 μ L of the nude mice with 5 × 10 6 A549-luc cell suspension was injected into mice by tail vein injection. After 3 weeks of normal feeding, 0.5mg/kg glutamine fluorescence probe (Rhodamine B-Gln) was injected into the abdominal cavity of each mouse, and the circulation was in vivo for 6 hours. After 6 hours, 2mg of luciferase substrate D-luciferin is injected into the abdominal cavity of each mouse, and the transfer condition of the lung of the mouse can be detected by using bioluminescence in a small animal living body imaging system after 10min of reaction, and then the glutamine uptake condition of the lung transfer part is detected by using fluorescence.
The results are shown in FIGS. 2a and 2b, and the use of the luciferase substrate D-luciferin in FIG. 2a clearly shows the success of modeling the nude mouse lung metastasis model. The imaging display part of the glutamine fluorescent probe is highly overlapped with the imaging display part of the fluorescein in the graph in fig. 2b, which shows that the glutamine fluorescent probe can be used for detecting the distribution and the size of the tumor in the tumor model.
In this specification, the invention has been described with reference to specific embodiments thereof. It will, however, be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention. The description is thus to be regarded as illustrative instead of limiting.

Claims (6)

1. The application of glutamine fluorescent probe in preparing reagent for dynamic monitoring of intracellular glutamine flux, wherein the glutamine fluorescent probe has a structure of a general formula (1),
Figure FDA0003777113420000011
wherein the content of the first and second substances,
the Gln group has the structure
Figure FDA0003777113420000012
The Linker has the structure of
Figure FDA0003777113420000013
Wherein n is an integer of 1-8, or the Linker does not exist;
f is a fluorescent reporter group with the structure
Figure FDA0003777113420000014
2. The use of the glutamine fluorescence probe according to claim 1 in preparing a reagent for dynamic monitoring of intracellular glutamine flux, characterized in that the glutamine fluorescence probe is one of the following compounds,
Figure FDA0003777113420000015
3. the application of glutamine fluorescent probe in preparing reagent for imaging tumor distribution and size in animal tumor model includes the structure of glutamine fluorescent probe in general formula (1),
Figure FDA0003777113420000021
wherein the content of the first and second substances,
the structure of the Gln group is
Figure FDA0003777113420000022
The Linker has the structure of
Figure FDA0003777113420000023
Wherein n is an integer of 1-8, or the Linker does not exist;
f is a fluorescent reportGroup of the structure
Figure FDA0003777113420000024
4. The use of the glutamine fluorescence probe of claim 1 in preparing a reagent for imaging tumor distribution and size in an animal tumor model, wherein the glutamine fluorescence probe is one of the following compounds,
Figure FDA0003777113420000025
5. the application of glutamine fluorescent probe in preparing reagent for imaging distribution and size of tumor in human body is characterized by that said glutamine fluorescent probe has the structure of general formula (1),
Figure FDA0003777113420000026
wherein the content of the first and second substances,
the Gln group has the structure
Figure FDA0003777113420000031
The Linker has the structure of
Figure FDA0003777113420000032
Wherein n is an integer of 1-8, or the Linker does not exist;
f is a fluorescent reporter group with the structure of
Figure FDA0003777113420000033
6. The use of the glutamine fluorescence probe of claim 1 in preparing a reagent for imaging tumor distribution and size in a human body, wherein the glutamine fluorescence probe is one of the following compounds,
Figure FDA0003777113420000034
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