CN111303102B - Nitroreductase responsive hypoxic probe compound and preparation and application thereof - Google Patents
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Abstract
A hypoxia probe compound responding to nitroreductase and preparation and application thereof. The invention relates to a preparation method of a fluorescent probe compound (I) capable of responding to nitroreductase and application thereof in hypoxic analysis and imaging. The fluorescent probe can realize high-sensitivity and high-specificity response to the tumor microenvironment hypoxia-related nitroreductase; secondly, the compound is prepared through condensation reaction, the conjugation degree of molecules is obviously improved, and thus the absorption and fluorescence emission wavelengths are obviously red-shifted compared with dyes such as coumarin, rhodamine and the like, so that the interference is smaller when the hypoxic probe is used for analysis and imaging; the probe is constructed through an intramolecular charge transfer mechanism (ICT), is a signal enhancement type probe and has small background signals.
Description
(I) technical field
The invention relates to a preparation method of a fluorescent probe compound capable of responding nitroreductase and application thereof in hypoxic analysis and imaging.
(II) background of the invention
In recent years, the research on cancer is more and more intensive, and the tumor microenvironment is found to play an important role in the occurrence, development and metastasis of tumors. Compared with tumor cells with obvious individual difference, the tumor microenvironment is relatively stable, is not easily influenced by environmental factors, is not easily resistant to drugs, and has important research significance. The tumor microenvironment mainly has the characteristics of hypoxic, slightly acidic environment, reductive environment, specific biological enzyme expression up-regulation and the like. The tumor microacid environment is caused by the high metabolism of glucose by cancer cells and the formation of acidic lactic acid products. In addition, the growth rate of tumor cells is much faster than the production rate of their internal blood vessels, and the rapidly growing tumor cells need to absorb more oxygen and nutrients from the surrounding blood vessels to meet their growth needs, thus easily creating hypoxic regions in solid tumors. An important feature of hypoxic cells in the tumor area is the high expression of reductases, mainly including nitroreductase, quinone reductase, azo reductase, etc. If the micro-environmental factors such as micro acidity, reducibility, hypoxic oxygen and the like of the tumor are not considered, the cancer diagnosis and treatment method is constructed only based on the research of the in vitro cell level, and when the method is applied to animals and human bodies, a good reappearance effect cannot be obtained. Therefore, the method has important theoretical significance and application prospect in imaging research of tumor microenvironment.
The development of fluorescence imaging technology is not supported by fluorescent probes. The fluorescence imaging technology based on the fluorescence probe has the advantages of visualization, in-situ, no damage and the like, and is widely applied to biological imaging analysis of cells and living body level. Among the commonly used fluorescent probes, the small-molecule fluorescent probe has the advantages of easy synthesis and modification, easy adjustment of spectrum, high fluorescence quantum yield, good biocompatibility and the like, and can be constructed by various different principles such as Intramolecular Charge Transfer (ICT), photoinduced Electron Transfer (PET), fluorescence Resonance Energy Transfer (FRET) and the like, so that the research on the responsiveness of a specific target substance is realized. For example, rhodamine dyes have the advantages of high fluorescence quantum yield, large molar absorption coefficient, good light stability, wide pH application range, good biocompatibility and the like. In addition, the rhodamine's ' off-on ' response mechanism can be used for constructing various enhanced fluorescent probes, can well avoid the interference of background fluorescence, and thus can be widely applied to the analysis and detection of various biomolecules.
The Intramolecular Charge Transfer (ICT) refers to a process in which molecules with push-pull electronic structures undergo intramolecular electron transfer in an excited state to form intramolecular positive and negative charge separation, and the macroscopic representation thereof is a red shift or a blue shift of a spectrum. The basic principle is that two ends of a fluorophore in the fluorescent probe are respectively connected with an electron supply group and an electron withdrawing group in a conjugated bond mode to form a conjugated system with a push-pull effect. When the recognition unit in the electron group interacts with the target molecule, it affects the properties of the fluorophore and thus causes a spectral change. The fluorescent dye capable of being used for constructing a response type fluorescent probe is prepared by utilizing the coumarin derivative containing the hydroxyl and the 4-diethylaminoketone acid, and the fluorescent dye can construct an enhanced fluorescent probe capable of specifically responding to hypoxia-related nitroreductase through an intramolecular charge transfer mechanism (ICT), so that biological analysis and fluorescence imaging are performed.
Disclosure of the invention
The invention aims to provide a preparation method of a fluorescent probe compound capable of responding to nitroreductase and application of the fluorescent probe compound in hypoxic analysis and imaging.
The technical scheme adopted by the invention is as follows:
a fluorescent probe compound capable of responding to nitroreductase has a structure shown in formula (I):
the present invention also relates to a method for preparing the fluorescent probe compound, which comprises:
(1) Dissolving the coumarin derivative containing the hydroxyl group shown in the formula (II) and the 4-diethylamino keto acid shown in the formula (III) in sulfonic acid, stirring and reacting for 10-20 hours at 90-100 ℃, cooling to room temperature, adding water, and separating and purifying the solid obtained by suction filtration to obtain an intermediate shown in the formula (VI);
(2) Dissolving the intermediate shown in the formula (VI) in N, N-dimethylformamide, then adding potassium carbonate and nitrobenzyl bromide, stirring and reacting for 12-18 hours at 50-60 ℃, adding water after the reaction is completed, and separating and purifying the solid obtained by suction filtration to obtain the fluorescent probe compound shown in the formula (I).
Preferably, the ratio of the amount of the hydroxyl-containing coumarin derivative to the amount of the 4-diethylaminoketone acid substance in the step (1) is 1:1.
Preferably, the ratio of the amounts of the intermediate, potassium carbonate and nitrobenzyl bromide species in step (2) is 1.
Specifically, the separation and purification method in the step (1) comprises the following steps: and (3) carrying out suction filtration on the obtained solid, taking dichloromethane and methanol with the volume ratio of 100-3:1 as an eluent, separating and purifying by using column chromatography, carrying out rotary evaporation on the collected sample to remove the solvent, pulping by using ethyl acetate and dichloromethane, and drying the solid obtained by suction filtration in vacuum to obtain the intermediate shown in the formula (VI).
Specifically, the separation and purification method in the step (2) is as follows: and (2) separating and purifying the solid obtained by suction filtration by using petroleum ether and ethyl acetate with the volume ratio of 10-0:1 as an eluent through column chromatography, removing the solvent from the collected sample by rotary evaporation, pulping by using ethyl acetate and methanol respectively, and drying the solid obtained by suction filtration in vacuum to obtain the fluorescent probe compound shown in the formula (I).
The compound (I) has a positive charge and usually participates in the reaction in the form of a salt such as a hydrochloride. The nitrobenzyl group in the compound is an electron-withdrawing group, so that Intramolecular Charge Transfer (ICT) is weaker. Upon reaction with nitroreductase, the nitro group in the compound is reduced and then a fluorescent molecule is released through a rearrangement-elimination reaction, thereby allowing for enhanced Intramolecular Charge Transfer (ICT) of the compound. The compound has obvious change of absorption and fluorescence signals when responding to hypoxia-related nitroreductase. The compound has high response sensitivity and strong specificity to the hypoxia-related nitroreductase, and can be used for analysis, detection and imaging research.
The invention also relates to application of the fluorescent probe compound as a hypoxic probe in hypoxic analysis and imaging. Hypoxia is a common symptom of most solid tumors, mainly due to insufficient oxygen supply caused by increased oxygen consumption due to rapid tumor proliferation and altered tumor vasculature.
Specifically, the probe is used for analyzing and detecting hypoxia-related nitroreductase.
Alternatively, the probes are used for hypoxic cell fluorescence imaging.
The invention has the following beneficial effects: the fluorescent probe compound can realize high-sensitivity and high-specificity response to hypoxia-related nitroreductase in a tumor microenvironment; secondly, the compound is prepared by condensation reaction, the conjugation degree of molecules is obviously improved, so that the absorption and fluorescence emission wavelengths are obviously red-shifted compared with dyes such as coumarin, rhodamine and the like, and the interference is smaller when the hypoxic probe is used for analysis and imaging; the probe is constructed through an intramolecular charge transfer mechanism (ICT), is a signal enhancement type probe and has small background signals.
(IV) description of the drawings
FIG. 1 shows the synthetic route and response principle of the hypoxic probe of the invention;
FIG. 2 is a nuclear magnetic hydrogen spectrum representation diagram of the intermediate of the present invention;
FIG. 3 is a nuclear magnetic hydrogen spectrum representation diagram of the hypoxic probe of the invention;
FIG. 4 is a graph showing the absorption (A) and fluorescence (B) spectra of the intermediate and hypoxic probe of the present invention;
FIG. 5 is a graph showing the absorption (A) and fluorescence (B) spectra of the present invention to examine the response of a probe to hypoxia-related nitroreductase;
FIG. 6 is a graph showing the change of fluorescence spectrum of a hypoxic probe (A) when nitroreductase with different concentrations is added to the probe, and a graph showing the change of fluorescence spectrum of a probe when ions, redox molecules, amino acids, proteins, and other substances are added to the probe (B);
FIG. 7 shows the survival of normal liver cells 7701 and liver cancer cells 7721 after 24 hours incubation with hypoxic probes of different concentrations;
FIG. 8 is the fluorescence imaging of the hypoxic probe of the invention in hypoxic and non-hypoxic states of hepatoma cells.
(V) detailed description of the preferred embodiments
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:
example 1: synthesis method and application of hypoxic probe
1. Synthesis of intermediates (synthetic route see figure 1):
dissolving 10g of hydroxyl-containing coumarin derivative and 15.3g of 4-diethylamino keto acid with equimolar amount in 100mL of sulfonic acid, stirring and reacting for 16 hours at 95 ℃, cooling to room temperature, adding 200mL of water, performing suction filtration and pressure reduction to obtain a solid mixture, performing column chromatography separation and purification by using dichloromethane and methanol (100/1-3/1) as eluents, performing rotary evaporation on a collected sample to remove a solvent, performing pulping treatment by using 150mL of ethyl acetate and dichloromethane (1:1), and performing suction filtration to obtain a solid, and drying in vacuum, thereby obtaining the intermediate (VI). The structure is characterized by nuclear magnetic hydrogen spectrum, and the result is shown in figure 2. The absorption and fluorescence spectra are shown in FIG. 4.
2. Synthesis of hypoxic probe:
5g of the intermediate was dissolved in 35mL of N, N-Dimethylformamide (DMF), and 1.2-fold molar amount of 1.44g of potassium carbonate and 2.24g of nitrobenzyl bromide were added, and the reaction was stirred at 50 ℃ for 16 hours. And after the reaction is finished, adding 250mL of water into the solution, performing suction filtration on the obtained solid mixture, using petroleum ether and ethyl acetate (10/1-0/1) as eluent, performing column chromatography separation and purification, performing rotary evaporation on the collected sample to remove the solvent, then respectively pulping with 25mL of ethyl acetate and methanol, and performing vacuum drying on the obtained solid after suction filtration to obtain the hypoxic probe (namely the fluorescent probe compound (I)). The structure is characterized by nuclear magnetic hydrogen spectrum, and the result is shown in figure 3. The absorption and fluorescence spectrum are shown in figure 4, compared with the intermediate, the absorption of the hypoxic probe is obviously blue-shifted, and the fluorescence emission around 660nm disappears.
Capacity of hypoxic probe to respond to nitroreductase:
a5. Mu.g/mL fluorescent probe was reacted in 10mM PBS (pH = 7.4) with reduced Nicotinamide Adenine Dinucleotide (NADH) (50. Mu.M) and Nitroreductase (NTR) (0.025-5. Mu.g/mL) at 37 ℃ for half an hour, and then the changes in absorbance and fluorescence were measured.
FIG. 5 shows the absorbance and fluorescence changes of hypoxic probe with the addition of reduced Nicotinamide Adenine Dinucleotide (NADH) and Nitroreductase (NTR) separately and simultaneously. It can be found that when NADH and nitroreductase are added separately, the absorption of the solution at about 600nm and the fluorescence emission at 660nm are not obviously changed, and the absorption of the solution at the wave band is obviously enhanced after NADH is added because NADH has absorption at 350 nm. When NADH and nitroreductase are added simultaneously, the absorption and fluorescence of the solution are obviously enhanced, which shows that when NADH is used as an electron donor, the probe can respond to hypoxia-related nitroreductase, so that the absorption and fluorescence of the solution are changed. And the greater the concentration of nitroreductase added, the more obvious the signal change. FIG. 6A shows the change of fluorescence signal of the probe after adding nitroreductase in the concentration range of 0.025-5. Mu.g/mL, and it can be seen that the fluorescence signal of the solution increases with the increase of the concentration of nitroreductase.
Specific experiments:
fluorescent probes of 5 μ g/mL in 10mM PBS (pH = 7.4) solution were separately contacted with metal ions (Na) + 、K + 、Ca 2+ 、Mg 2+ 5 mM), redox molecules (AA, H) 2 O 2 GSH, DTT, 5 mM), amino acids (Arg, try, cys, his, leu, glu,5 mM) and proteins (BSA, HSA,5mg/mL; SOD, GOx, 5. Mu.g/mL) and 50. Mu.M NADH were reacted at 37 ℃ for half an hour, and then the change in fluorescence was detected. It can be seen from FIG. 6B that none of the fluorescence signals of the solutions was significantly changed when these substances were analyzed. As can be seen from the results, the probe has the specific response capability to the hypoxia-associated nitroreductase.
Cytotoxicity experiments:
the invention additionally investigates the cytotoxicity of the hypoxic probe. After the 96-well plate is inoculated with the normal hepatocyte 7701 and the hepatoma carcinoma cell 7721, the cytotoxicity of the cells after incubation of fluorescent probes with different concentrations for 24 hours is analyzed by a CCK-8 cell viability detection experiment, and the result is shown in FIG. 7. It can be seen that the probe has no significant toxicity to both cancer cells and normal cells over a range of concentrations. Therefore, the probe is not only suitable for analysis and detection research, but also suitable for fluorescence imaging research at the level of cells and the like.
Fluorescence imaging experiment:
the invention further considers the research of the hypoxic probe used for cell fluorescence imaging. After cancer cells were inoculated on a 35mm petri dish, the plate was incubated in 1% oxygen and normoxic environment for 24 hours, then reacted with a 5 μ g/mL probe for a period of time and stained with DAPI for cell nuclei, and finally subjected to imaging studies using a confocal fluorescence microscope with cells untreated with the probe as a control and an excitation wavelength of 633nm. As shown in FIG. 8, in the case of the cells in the normoxic or hypoxic state, red fluorescence was not observed after laser irradiation at 633nm, unless the reaction with the probe was carried out. When the cell in the normal oxygen state reacts with the hypoxic probe and is irradiated by laser, only weak red fluorescence can be observed. When the cell in the hypoxia state reacts with the hypoxic probe and then is irradiated by laser, obvious red fluorescence can be observed. This result demonstrates that the probe constructed by the present invention can be used for imaging of hypoxia.
And (4) conclusion:
the imaging research on the tumor microenvironment has important theoretical significance and application prospect. The invention mainly provides a hypoxic probe capable of responding nitroreductase and a preparation method thereof. The probe can realize high-sensitivity and high-specificity response to the tumor microenvironment hypoxia-related nitroreductase, and has the following advantages: 1) The probe is prepared through condensation reaction, the conjugation degree of molecules is obviously improved, so that the absorption and fluorescence wavelengths are obviously red-shifted compared with dyes such as coumarin, rhodamine and the like, and the interference is smaller when the probe is used for analysis and imaging; 2) The probe is constructed through an intramolecular charge transfer mechanism (ICT), is a signal enhancement type probe and has small background signals.
Claims (8)
1. A fluorescent probe compound capable of responding to nitroreductase has a structure shown in formula (I): :
2. a method of making the fluorescent probe compound of claim 1, the method comprising:
(1) Dissolving the coumarin derivative containing the hydroxyl group shown in the formula (II) and the 4-diethylamino keto acid shown in the formula (III) in sulfonic acid, stirring and reacting at 90-100 ℃ for 10-20 hours, cooling to room temperature, adding water, and performing suction filtration to obtain a solid, separating and purifying to obtain an intermediate shown in the formula (VI);
(2) Dissolving the intermediate shown in the formula (VI) in N, N-dimethylformamide, adding potassium carbonate and nitrobenzyl bromide, stirring at 50-60 ℃ for reaction for 12-18 hours, adding water after the reaction is completed, and separating and purifying the solid obtained by suction filtration to obtain the fluorescent probe compound shown in the formula (I).
3. The method according to claim 2, wherein the ratio of the amount of the hydroxy-containing coumarin derivative to the amount of the 4-diethylaminoketo acid substance in step (1) is 1:1.
4. The process of claim 2, wherein in step (2) the ratio of the amounts of intermediate, potassium carbonate and nitrobenzyl bromide species is 1.
5. The method according to claim 2, wherein the separation and purification method in step (1) is as follows: and (3) carrying out suction filtration on the obtained solid, taking dichloromethane and methanol as eluent, separating and purifying by using column chromatography, carrying out rotary evaporation on the collected sample to remove the solvent, pulping by using ethyl acetate and dichloromethane, and drying the solid obtained by suction filtration in vacuum to obtain the intermediate shown in the formula (VI).
6. The method according to claim 2, wherein the separation and purification method in step (2) is as follows: and (3) carrying out suction filtration on the obtained solid, taking petroleum ether and ethyl acetate as eluent, separating and purifying by using column chromatography, carrying out rotary evaporation on the collected sample to remove the solvent, pulping by using ethyl acetate and methanol respectively, and drying the solid obtained by suction filtration in vacuum to obtain the fluorescent probe compound shown in the formula (I).
7. Use of the fluorescent probe compound of claim 1 as a hypoxic probe in fluorescence imaging.
8. The use according to claim 7, wherein the hypoxic probe is used for hypoxic cell fluorescence imaging.
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| CN111303102B (en) * | 2019-11-29 | 2022-10-25 | 福建医科大学孟超肝胆医院(福州市传染病医院) | Nitroreductase responsive hypoxic probe compound and preparation and application thereof |
| CN111635385B (en) * | 2020-07-01 | 2023-03-24 | 中南林业科技大学 | Mitochondrion-targeted two-photon excitation near-infrared emission hydrogen sulfide fluorescent probe and preparation method and application thereof |
| CN112321525B (en) * | 2020-11-12 | 2022-05-03 | 南京工业大学 | Method for synthesizing 3, 4-bis (4 '-aminofurazan-3' -yl) furoxan by one-step method |
| CN112679486A (en) * | 2021-01-18 | 2021-04-20 | 南开大学 | Preparation and application of photosensitizer based on nitroreductase response |
| CN114539230A (en) * | 2022-01-14 | 2022-05-27 | 东南大学 | Electrochemical luminophor and preparation method and application thereof |
| CN114478352B (en) * | 2022-01-28 | 2024-03-26 | 浙江工业大学 | Self-immobilized small molecular fluorescent probe and preparation method and application thereof |
| CN115010786B (en) * | 2022-06-02 | 2024-03-12 | 国家纳米科学中心 | GSH-hypoxia microenvironment double-response self-assembled fluorescent probe and preparation method and application thereof |
| CN115873011B (en) * | 2022-12-02 | 2023-09-08 | 安徽大学 | Cancer cell targeted fluorescent probe responding to nitroreductase in mitochondria and preparation method and application thereof |
| CN116925025A (en) * | 2023-08-09 | 2023-10-24 | 陕西理工大学 | Near infrared fluorescent probe for rapidly detecting nitroreductase and preparation and application thereof |
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