CN114479102A - Azo reductase and glutathione double-response type supramolecular fluorescent probe as well as preparation and application thereof - Google Patents
Azo reductase and glutathione double-response type supramolecular fluorescent probe as well as preparation and application thereof Download PDFInfo
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- 108010024636 Glutathione Proteins 0.000 title claims description 22
- 229960003180 glutathione Drugs 0.000 title claims description 21
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- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
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Abstract
The invention provides an azobenzene calix [4] arene compound as a host molecule, a hemicyanine near-infrared probe reagent as an object molecule, and the probe is assembled and constructed through non-covalent interaction between the host molecule and the object molecule.
Description
Technical Field
The invention relates to a supramolecular fluorescent probe, in particular to an azo reductase and glutathione double-response type supramolecular fluorescent probe and a preparation method thereof, and also relates to a supramolecular fluorescent probe which can lighten near-infrared fluorescent signals under the combined action of azo reductase and glutathione in an anoxic tumor to realize accurate imaging detection of the tumor, belonging to the technical field of compound synthesis and the technical field of fluorescence imaging.
Technical Field
Cancer is a serious disease seriously harming human life and health, human mortality caused by cancer accounts for the second of all disease mortality, and accurate diagnosis of cancer is the key to clinical treatment of cancer. The fluorescence imaging technology has the advantages of high imaging speed, high sensitivity, no ionizing radiation and the like, can carry out real-time and specific tracking and detection on the processes of occurrence, metastasis and the like of tumors in organisms, and has wide application in the field of accurate diagnosis of cancersAnd (4) foreground. In recent years, researchers at home and abroad have developed a plurality of tumor characteristic factors, such as activated fluorescent probes of low oxygen, high-concentration glutathione, micro-acid and the like, for tumor specific fluorescence imaging detection (Chevalier, A., et al,Chem. Asian J.2017, 12, 2008-2028; Umezawa, K. et al., Nat. Chem. 2017, 9, 279–286; Yin, C. X. et al., Angew. Chem. Int. Ed.2017, 56, 13188-13198). However, the fluorescent probes currently developed generally respond only to a single characteristic factor in a tumor, and are highly susceptible to interference from "false positive" signals (Wu, l. et al,Nat. Rev. Chem.2021, 5, 406-421). Therefore, the development of fluorescent probes responding to various characteristic factors in the tumor for accurate imaging detection of the tumor is urgently needed.
Hypoxia is a common important feature of solid tumors, and most tumors have a hypoxic microenvironment during growth. The tumor hypoxia is caused by imbalance between the reduction of oxygen supply capacity caused by blood vessel abnormality and the high oxygen consumption of tumor cells, and the rapidly proliferating tumor cells further accelerate the consumption of oxygen, so that the degree of hypoxia is increased. At present, hypoxia has become one of the important indicators for clinical evaluation of tumor progression. Hypoxia leads to increased levels of azoreductase in tumor cells. Glutathione is a sulfydryl micromolecule in cells, and the oxidation-reduction balance in the cells is maintained through the dynamic change of oxidized glutathione and reduced glutathione. Studies have shown that hypoxia can also lead to high expression of glutathione in tumor cells, with glutathione levels in hypoxic tumor cells being much higher than in normal cells. Therefore, the development of the fluorescent probe activated by two tumor characteristic factors, namely azoreductase and glutathione, can effectively distinguish tumor tissues from normal tissues, and has important significance for accurate imaging detection of tumors.
Disclosure of Invention
The invention aims to provide a double-response type supramolecular fluorescent probe of azoreductase and glutathione;
the invention also aims to provide a preparation method of the supramolecular fluorescent probe;
the invention also aims to provide the application of the supramolecular fluorescent probe as a fluorescent imaging reagent for accurately detecting tumor cells.
Mono-and supramolecular fluorescent probes
The invention relates to an azobenzene calix [4] arene compound as a host molecule and a hemicyanine near-infrared probe reagent as a guest molecule, which are assembled to form a supermolecule fluorescent probe through non-covalent interaction between the host molecule and the guest molecule.
The chemical structural formula of the main molecule azobenzene calix [4] aromatic compound is as follows:
wherein R is1、R2Independently selected from hydrogen, methyl, ethyl, propyl, amyl, methoxyl, nitryl, amino, hydroxyl, trifluoromethyl, difluoromethyl, N-dimethyl, N-diethyl, N-dipropyl, N-diisopropyl, N-dihydroxymethyl, N-dihydroxyethyl, carboxyl, sulfonic group, phenyl and benzyl.
The chemical structural formula of the guest molecule hemicyanine near-infrared probe is shown as the following formula:
wherein n is independently selected from an integer of 1-20; r3Independently selected from hydrogen, methyl, ethyl, propyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxyethyl, carboxyl, sulfonic group, phenyl, benzyl; y is independently selected from imino, mercapto and ether.
Preparation of the supramolecular fluorescent probe: respectively dissolving a host molecule azobenzene calix [4] arene compound and a guest molecule hemicyanine near-infrared probe reagent in an organic solvent, mixing the materials into a water solvent according to a molar ratio of 1: 0.1-1: 10, and carrying out reaction ultrasonic treatment at 0-100 ℃ for 0.01-20 h to obtain the azobenzene calix [4] arene near-infrared probe reagent.
The organic solvent is at least one of tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N-dimethylformamide, methanol, ethanol, dioxane, ethylamine, hydroxypropionic acid, ethylenediamine, glycerol, diglyme, pyridine, acetone and hexamethylphosphoramide.
FIG. 1 is a schematic diagram of the preparation of the supramolecular fluorescent probe of the invention. The invention takes an azobenzene calix [4] arene compound with azoreductase response performance as a host molecule and a hemicyanine near-infrared probe with glutathione response as a guest molecule, and assembles the two molecules in an aqueous solution in a non-covalent interaction mode between the host molecule and the guest molecule to prepare the supermolecule fluorescent probe. Azobenzene calix [4] arene main molecules in the supramolecular fluorescent probe can be reduced by azoreductase in an anoxic tumor to release a hemicyanine near-infrared probe; and the released hemicyanine near-infrared probe is further activated by high-concentration glutathione in a tumor microenvironment. Through this cascade activation, the supramolecular fluorescent probe illuminates the near-infrared fluorescent signal. Compared with the currently developed fluorescent probe which is only activated by single characteristic factors (glutathione, azo reduction, micro acid and the like) in the tumor, the supramolecular fluorescent probe provided by the invention can simultaneously respond to two characteristic factors, namely azo reductase and glutathione in the hypoxic tumor, has high selectivity and sensitivity on the tumor, and has important significance on the aspect of accurate detection of the tumor.
Imaging performance and application of supramolecular fluorescent probe
The imaging performance of the supramolecular fluorescent probe and the specific application of the supramolecular fluorescent probe in the invention to precise fluorescence imaging analysis of tumors are explained by taking the supramolecular fluorescent probe prepared in example 1 as an example.
First, Hep G2 cells were cultured in a cell culture chamber at 37 ℃ in an atmosphere of 21% oxygen and 5% carbon dioxide for 24 hours (the medium was a DMEM high-sugar medium containing 10% fetal bovine serum), and then the cells were digested with trypsin and transferred to a cell imaging dish. Subsequently, the cells were cultured at 37 ℃ under 0.2% oxygen atmosphere for 20 hours. After the fluorescent probe A solution prepared in example 1 was added, the cells were cultured in a cell culture chamber at 37 ℃ in a 5% carbon dioxide atmosphere for 2 hours, the medium in the imaging dish was washed with PBS buffer, and fluorescence imaging was performed using a laser scanning confocal microscope. FIG. 2 is an image of fluorescent probe A in hypoxic HepG2 cells. As can be seen from FIG. 2, the tumor cells exhibit strong fluorescence, indicating that the supramolecular fluorescent probe can enter the cells and be activated by azoreductase and glutathione in the cells, and illuminating the near-infrared fluorescent signals to realize the fluorescent detection of the tumor cells.
We further studied the imaging analysis of supramolecular fluorescent probe A on tumor sites in tumor-bearing mice. After the supramolecular fluorescent probe A is injected into a tumor-bearing mouse, a small animal living body fluorescence imager is used for fluorescence imaging, and the result is shown in the attached figure 3. In FIG. 3, No. 1 is a graph of fluorescence image of a mouse before injecting the supramolecular fluorescent probe A, and No. 2 is a graph of fluorescence image of a mouse 18 hours after injecting the supramolecular fluorescent probe. As can be seen from FIG. 3, no fluorescence signal was observed at the tumor site of the mice before administration, while a significant fluorescence signal was observed at the tumor site of the mice 18 hours after injection of the supramolecular fluorescent probe. The results show that the prepared supramolecular fluorescent probe can be used for the fluorescent imaging analysis of tumors in living bodies.
A large number of experiments show that the azobenzene calix [4] arene compound is used as a host molecule, the hemicyanine near-infrared probe reagent is used as a guest molecule, and the supermolecule fluorescent probe is formed by assembling through non-covalent interaction between the host molecule and the guest molecule, can be used for jointly acting with azoreductase and glutathione in an anoxic tumor with high sensitivity and high selectivity to lighten near-infrared fluorescent signals, so that the fluorescent imaging analysis of tumor cells is realized, and the method has important significance in the aspect of accurate detection of tumors.
Drawings
FIG. 1 is a schematic diagram of the preparation of the supramolecular fluorescent probe of the invention.
FIG. 2 is an image of fluorescent probe A in hypoxic HepG2 cells.
FIG. 3 is a graph of fluorescence imaging of fluorescent probe A in tumor-bearing mice.
FIG. 4 is a NMR spectrum of Compound 1 of example 1.
FIG. 5 is a NMR spectrum of Compound 1 of example 1.
FIG. 6 is a NMR spectrum of Compound 2 of example 1.
FIG. 7 is a NMR carbon spectrum of Compound 2 of example 1.
FIG. 8 is a mass spectrum of the fluorescent probe A prepared in example 1.
Detailed Description
The preparation, performance and application of the supramolecular fluorescent probe of the invention are further illustrated below with reference to specific examples.
Example 1 preparation and Properties of supramolecular fluorescent Probe A
(1) Synthesis of host molecule: hydrochloric acid (0.2 mL) was added to an aqueous solution of p-trifluoromethylaniline (161 mg), and sodium nitrite (80 mg) was slowly added thereto at 0 ℃ and stirred for 0.5 hour. Add the above solution to the cup [4]]Aromatic hydrocarbon-25, 26,27, 28-tetraphenol (50 mg) and sodium acetate (246 mg) in a mixed solution of methanol and N, N-dimethylformamide, reacting at room temperature for 12 hours, concentrating under reduced pressure, and separating by column chromatography to obtain the main molecular compound 1. Of host molecule Compound 11H NMR and13the C NMR data are shown in FIGS. 4 and 5.1H NMR (400 MHz, DMSO-d 6): δ 13.02 (s, 4 H), 7.90-7.91 (m, 8 H), 7.82-7.84 (m, 16 H), 4.10-4.43 (m, 4 H), 3.69-3.70 (m, 4 H). 13C NMR (100 MHz, DMSO-d 6) Delta 160.7, 155.1, 145.0, 131.1, 126.9, 124.7, 123.0, 32.2. The synthetic formula is as follows:
(2) synthesis of guest molecules: the compound CyNH was added to a dry round bottom flask2(102 mg) and p-dimethylaminopyridine (30 mg), 5mL of methylene chloride was added, and the mixture was stirred at 0 ℃ for 10 minutes, followed by the addition of triphosgene (20 mg) and stirring for 30 minutes. Adding a compound bis (2-hydroxyethyl) disulfide (50 muL), stirring the mixture at room temperature for 12 hours, concentrating under reduced pressure, and purifying by column chromatography to obtain a guest molecule compound 2. Of guest molecule Compound 21H NMR and13the C NMR data are shown in FIGS. 5 and 6.1H NMR (400 MHz, DMSO-d 6): δ 10.37 (s, 1H), 8.52 (d, J=15.2 Hz, 1H), 8.19 (d, J=7.2 Hz, 1H), 7.77-7.8 (m, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.40-7.52 (m, 3H), 7.32 (d, J=8.4 Hz, 1H), 6.94 (d, J=7.2 Hz, 1H), 6.53 (d, J=14.8 Hz, 1H),5.74 (s, 1H), 4.35 (t, J=6.4 Hz, 2H), 3.86 (s, 3H), 3.62-3.63 (m, 2H), 3.03 (t, J=6.4 Hz, 2H), 2.83 (t, J=6.4 Hz, 2H), 2.63-2.69 (m, 4H), 1.79-1.81 (m, 2H), 1.73 (s, 6H). 13C NMR (101 MHz, DMSO-d 6) δ 177.8, 160.0, 156.9, 153.1, 144.6, 142.6, 142.3, 141.9, 139.2, 132.4, 128.8, 128.2, 127.6, 127.1, 122.7, 116.6, 115.6, 113.8, 113.2, 106.9, 105.1, 103.9, 62.6, 59.4, 54.9, 41.1, 36.7, 32.7, 28.5, 27.2, 23.5, 19.9. The synthetic formula is as follows:
(3) preparation of supramolecular fluorescent probe A: mixing 100 mu L of dimethyl sulfoxide solution of a host molecule compound 1 (1 mM) and 50 mu L of dimethyl sulfoxide solution of a guest molecule compound 2 (1 mM) into 9.85 mL of water, and performing ultrasonic treatment at 25 ℃ for 10 min to obtain the supramolecular fluorescent probe A. The mass spectrum is shown in FIG. 6. As in FIG. 6, inm/z[ solution ] =1675.47 [ see ]m/z Compound 1] + [m/zCompound 2]The characteristic peak of (A) indicates that the compound 1 and the compound 2 form a stable supramolecular complex in a molar ratio of 1:1, and the successful preparation of the supramolecular fluorescent probe A is proved.
The imaging of fluorescent probe A in hypoxic HepG2 cells and in tumor-bearing mice is shown in FIGS. 2 and 3.
Example 2: preparation of supramolecular fluorescent probe B
(1) Synthesis of host molecule compound: hydrochloric acid (0.2 mL) was added to an aqueous solution of p-methylaniline (107 mg), and sodium nitrite (80 mg) was slowly added thereto at 0 ℃ and stirred for 0.5 hour. Adding the solution into a mixed solution of calix [4] arene-25, 26,27, 28-tetraphenol (50 mg) and sodium acetate (246 mg) in methanol and N, N-dimethylformamide, reacting at room temperature for 12 hours, concentrating under reduced pressure, and performing column chromatography to obtain a main molecular compound 3. The synthetic formula is as follows:
(2) synthesis of guest molecules: the same as in example 1.
(3) Preparation of supramolecular fluorescent probe B: 500 μ L of a N, N-dimethylformamide solution of a host compound 3 (0.1 mM) and 50 μ L of a N, N-dimethylformamide solution of a compound 2 (1 mM) were mixed into 9.45 mL of water, and an ultrasonic wave was performed at 5 ℃ for 60 min to prepare a supramolecular fluorescent probe B.
The imaging performance of the supramolecular fluorescent probe B in hypoxic HepG2 cells and in tumor-bearing mice was similar to that of example 1. The results show that the supramolecular fluorescent probes prepared from different host compounds can realize the fluorescent imaging detection of tumors.
Example 3: preparation of supramolecular fluorescent probe C
(1) Synthesis of host molecule compound 1: the same as example 1;
(2) guest molecule synthesis of compound 2: the same as example 1;
(3) preparation of supramolecular fluorescent probe C: 100 mu L of methanol solution of the host molecular compound 1 (1 mM) and 500 mu L of methanol solution of the guest molecular compound 2 (0.1 mM) are mixed into 9.4 mL of water, and the supramolecular fluorescent probe C is prepared after ultrasonic treatment for 15 hours at 80 ℃.
The imaging performance of the supramolecular fluorescent probe C in hypoxic HepG2 cells and in tumor-bearing mice was substantially similar to that of example 1. The result shows that the preparation of the supramolecular fluorescent probe can be realized under different solvents.
Claims (6)
1. A bi-response type supramolecular fluorescent probe of azobenzene calix [4] arene compounds is taken as a host molecule, a hemicyanine near-infrared probe reagent is taken as a guest molecule, and the supramolecular fluorescent probe is formed by assembling through non-covalent interaction between the host molecule and the guest molecule.
2. The double-responsive supramolecular fluorescent probe of azoreductase and glutathione as claimed in claim 1, which is characterized in that: the chemical structural formula of the main molecule azobenzene calix [4] aromatic compound is as follows:
wherein R is1、R2Independently selected from hydrogen, methyl, ethyl, propyl, amyl, methoxyl, nitryl, amino, hydroxyl, trifluoromethyl, difluoromethyl, N-dimethyl, N-diethyl, N-dipropyl, N-diisopropyl, N-dihydroxymethyl, N-dihydroxyethyl, carboxyl, sulfonic group, phenyl and benzyl.
3. The double-responsive supramolecular fluorescent probe of azoreductase and glutathione as claimed in claim 1, which is characterized in that: the chemical structural formula of the guest molecule hemicyanine near-infrared probe is shown as the following formula:
wherein n is independently selected from an integer of 1-20; r3Independently selected from hydrogen, methyl, ethyl, propyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxyethyl, carboxyl, sulfonic group, phenyl, benzyl; y is independently selected from imino, mercapto and ether.
4. The method for preparing the azo reductase and glutathione double-response type supramolecular fluorescent probe as claimed in claim 1, comprises the steps of dissolving a host molecule azobenzene calix [4] arene compound and a guest molecule hemicyanine near-infrared probe reagent respectively with an organic solvent, mixing the dissolved compounds with a water solvent according to a molar ratio of 1: 0.1-1: 10, and carrying out reaction and ultrasonic treatment at 0-100 ℃ for 0.01-20 hours to obtain the azo reductase and glutathione double-response type supramolecular fluorescent probe.
5. The method for preparing the azo reductase and glutathione double-response type supramolecular fluorescent probe as claimed in claim 4, wherein the method comprises the following steps: the organic solvent is at least one of tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N-dimethylformamide, methanol, ethanol, dioxane, ethylamine, hydroxypropionic acid, ethylenediamine, glycerol, diglyme, pyridine, acetone and hexamethylphosphoramide.
6. The use of the azo reductase and glutathione double-responsive supramolecular fluorescent probe as claimed in claim 1 as a fluorescence imaging reagent.
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