CN108276991B - Two-photon fluorescent probe for detecting pneumonia marker activity and synthetic method - Google Patents
Two-photon fluorescent probe for detecting pneumonia marker activity and synthetic method Download PDFInfo
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Abstract
The invention discloses a two-photon method for detecting pneumonia marker activityFluorescent probes and synthetic methods. The structural formula of the fluorescent probe is as follows:
when LTA is used4After the active center of the H protein recognizes the corresponding substrate portion in the probe, the amide bond is cleaved, thereby enhancing the fluorescence of the probe. The probe has good two-photon absorption property, so the probe has the advantages of deep tissue penetration, small damage to cell living bodies and the like. By targeting LTA4H and other biologically relevant components, and the detection of the LTA by the probe pair4H has high response sensitivity and good selectivity thereto. The imaging result of mouse nucleus and lung shows that the probe can detect LTA quickly and accurately in real time4H, and detecting pneumonia. The probe of the invention has novel structure and excellent photophysical property.
Description
Technical Field
The invention relates to a two-photon fluorescent probe for detecting the activity of a pneumonia marker and a synthetic method thereof, in particular to a two-photon fluorescent probe for detecting the activity of a pneumonia marker LTA4A two-photon fluorescent probe with activity on H protease and a synthetic method.
Background
Pneumonia is a pathogenic disease of the alveolar and respiratory bronchi, which causes local and systemic inflammatory reactions in patients. Furthermore, pneumonia causes various complications, such as meningitis, septicemia, lung abscess, brain injury and hearing impairment, so the incidence and mortality of pneumonia are high. Clinically, the diagnosis of pneumonia requires a variety of technical methods and clinical indicators, including chest X-ray and CT imaging scans, bacterial culture of blood and expectoration samples, and certain clinical features. Among them, chest fluoroscopy and CT imaging scanning are important means for diagnosing pneumonia, but are not suitable for all people, and may cause certain body injuries, such as cell canceration, chromosome abnormality, germ cell aberration, etc. Therefore, there is an urgent need to develop a non-invasive, rapid and in-situ accurate pneumonia imaging detection technology and a method for screening pneumonia inhibitors or pneumonia drugs.
The two-photon fluorescence imaging technology combined with the high-sensitivity and high-specificity fluorescent probe is an important imaging method for researching cell and living biological events and disease occurrence and development on a molecular level without damage and non-invasiveness. Because the excitation wavelength used by the two-photon imaging is in a near infrared region (690-950 nm), the two-photon imaging has the advantages of deeper tissue penetration depth, higher space-time resolution, lower phototoxicity and the like. Therefore, the use of fluorescent probes specifically responding to pneumonia marker molecules, diagnosis of pneumonia and screening of pneumonia inhibitors by two-photon fluorescence imaging would be an effective means.
LTA4H(Leukotriene A4Hydrolase) is an enzyme with dual activities, and LTA has been reported in the literature4H is a protein involved in polypeptide degradation in the host defense process, the expression content of the protein is increased in inflammatory processes such as pneumonia, and the protein is closely related to the occurrence and development of inflammation. Now for detecting LTA4H and a probe for screening an inhibitor thereof are extremely lacked, and the application of the H and the probe for screening the inhibitor is applied to cell and in vivo detection of LTA4H is a few probes.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a two-photon fluorescent probe for detecting the activity of a pneumonia marker, which is used for detecting a pneumonia marker LTA4The detection of H shows high sensitivity and high selectivity.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a two-photon fluorescent probe for detecting the activity of a pneumonia marker has a structural formula as follows:
When LTA is used4After the active center of the H protein recognizes the corresponding substrate part in the two-photon fluorescent probe, the amido bond is cut off so as to lead the active center of the H protein to cut off the amido bondThe fluorescence of the probe is obviously enhanced. The compound has good detection effect when being applied to the research of live cells and mouse pneumonia models.
The other purpose of the invention is to provide a synthesis method of the two-photon fluorescent probe, which comprises a raw material a and a raw material c, wherein carboxyl in the raw material a is firstly subjected to acyl halide reaction to obtain an intermediate b, and then the acyl halide group of the intermediate b and the amino of the raw material c are subjected to nucleophilic substitution reaction and the tert-butyloxycarbonyl group is removed, so that the two-photon fluorescent probe can be obtained;
the chemical structure of the raw material a is
The chemical structure of the raw material c is
Wherein Boc is tert-butyloxycarbonyl and X is halogen.
The invention also aims to provide the two-photon fluorescent probe for detecting LTA4Use of the activity of H protein. The detecting LTA4The activity of the H protein is used for non-treatment and disease detection.
The invention has the beneficial effects that:
1. the probe molecule has the two-photon excitation (690nm) property, has larger Stokes shift (80nm), effectively reduces self-absorption and improves the imaging accuracy.
2. Based on the substrate specificity of enzyme and photoinduced electron transfer principle, the specific detection LTA is designed and synthesized4H-active fluorescent probe ASPC, the probe is in contact with LTA4The reaction of H can emit strong green fluorescence, which can indicate LTA4Aminopeptidase Activity of H, and ASPC vs LTA4H has extremely high selectivity and cannot be cut off by other aminopeptidases, and is expected to be used as a detection platform for screening anti-inflammatory drugs in the future.
3. The probe molecule of the invention has lower cytotoxicity and small damage to cells and living bodies.
4. The probe molecule can simultaneously realize the imaging and dyeing of cells by single-photon and double-photon confocal.
5. The probe molecule can realize in-situ detection of pneumonia for pneumonia mice, and the detection result is consistent with that of pneumonia factor kit, which shows that ASPC can realize LTA of living body4H detection has extremely important significance.
6. The probe molecule of the invention has relatively simple synthesis steps, high yield and easy purification.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the application and, together with the description, serve to explain the application and are not intended to limit the application.
FIG. 1 is a fluorescence spectrum of absorption, single photon emission and two-photon emission before and after the reaction of the fluorescent probe of the present invention, wherein the abscissa is wavelength (nm), the left ordinate is ultraviolet absorption intensity, the right ordinate is fluorescence emission intensity, ● is LTA added to ASPC4Single photon absorption Spectroscopy before H ○ addition of LTA to ASPC4Single photon emission Spectrum before H ▲ addition of LTA to ASPC4Absorption Spectrum after H △ addition of LTA for ASPC4Single photon emission spectra after H;
FIG. 2 is a bar graph and a fluorescence spectrum of the fluorescent probe of the present invention and the selectivity of related intracellular amino acids, aminopeptidases, small molecules, etc.;
FIG. 3 is a single-photon and double-photon confocal fluorescence imaging diagram of the fluorescent probe of the invention in human stellate liver cell LX-2;
FIG. 4 is a two-photon confocal fluorescence imaging diagram of the fluorescence probe of the invention at different depths of the lung of a pneumonia mouse.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
As described in the background, the prior art exists for detecting LTA4H and a probe for screening an inhibitor thereof are extremely short, and in order to solve the technical problems, the application provides a two-photon fluorescent probe for detecting the activity of a pneumonia marker and a synthetic method thereof.
In one exemplary embodiment of the present application, a two-photon fluorescence probe for detecting activity of a marker for pneumonia is provided, and has a structural formula:
When LTA is used4After the active center of the H protein recognizes a corresponding substrate part in the two-photon fluorescent probe, an amido bond is cut off, so that the fluorescence of the probe is obviously enhanced. The compound has good detection effect when being applied to the research of live cells and mouse pneumonia models.
Another embodiment of the present application provides a method for synthesizing the above two-photon fluorescent probe, which includes a raw material a and a raw material c, performing an acyl halide reaction on a carboxyl group in the raw material a to obtain an intermediate b, performing a nucleophilic substitution reaction on an acyl halide group of the intermediate b and an amino group of the raw material c, and removing a tert-butoxycarbonyl group to obtain the two-photon fluorescent probe;
the chemical structure of the raw material a is
The chemical structure of the raw material c is
The synthetic route is as follows:
wherein Boc is tert-butyloxycarbonyl and X is halogen.
Preferably, the method comprises the following steps:
(1) dissolving the raw material a in a solvent, adding an acyl halide reagent, and carrying out acyl halide reaction to obtain an intermediate b;
(2) and dissolving the intermediate b and the raw material c in acetic acid, heating and carrying out reflux reaction to obtain the two-photon fluorescent probe.
The acid halide reagent is a compound capable of reacting with carboxyl to generate acid halide group, such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, phosgene, diphosgene, triphosgene or corresponding bromo-iodo compound.
In order to increase the solubility of the raw material a with the acid halogenating agent, it is further preferable that the solvent is dichloromethane because the raw material a has higher solubility in dichloromethane.
To further simplify the reaction procedure, the acid halogenating agent is thionyl chloride. More preferably, the reaction condition of acyl halide is room temperature reaction for 2-3 h. The room temperature is 20-25 ℃.
In order to obtain the intermediate b having a higher purity and to increase the reaction efficiency of the fluorescent probe, it is more preferable that the intermediate b is subjected to an acid halogenation reaction, and then the solvent is removed and then recrystallization is performed. More preferably, the solvent for recrystallization is a mixed solution of petroleum ether and dichloromethane in a volume ratio of 5: 1.
More preferably, the molar ratio of the raw material c to the intermediate b is 1:1 to 1.2.
Further preferably, the conditions for heating reflux reaction in step (2) are as follows: the temperature is 90 plus or minus 5 ℃, and the reaction time is 5 plus or minus 0.5 h.
In order to increase the purity of the fluorescent probe, it is more preferable to carry out a reflux reaction under heating, then remove the solvent, and then carry out silica gel column separation. The silica gel column separation takes dichloromethane as a solvent and ethyl acetate as an eluent.
In a third embodiment of the present application, there is provided a two-photon fluorescence probe as described above for detecting LTA4Use of the activity of H protein. The detecting LTA4The activity of the H protein is used for non-treatment and disease detection.
In order to make the technical solutions of the present application more clearly understood by those skilled in the art, the technical solutions of the present application will be described in detail below with reference to specific embodiments.
Example (b): synthesis of fluorescent probes
Dissolving the raw material a in 5mL of dichloromethane, adding 2mL of thionyl chloride, and reacting at room temperature for 2 h. After the reaction was completed, the solvent was removed by rotary evaporation. The subsequent petroleum ether: the mixture was recrystallized to yield a beige solid, compound b (82%).
Taking the compound b and the compound c (the mass ratio of the compound b to the compound c is 1:1), dissolving in 10mL of acetic acid, and heating under reflux at 90 ℃ for 5 h. After the reaction was completed, the solvent was removed by rotary evaporation. Redissolved with dichloromethane and separated through a silica gel column (eluent ethyl acetate) to give an off-white solid, ASPC (42%).
Nuclear magnetic and mass spectrum characterization:
1HNMR(400MHz,DMSO)2.41(s,3H),2.59-2.63(m,2H),2.65-2.80(m,2H),3.76-3.79 (m,1H),5.11(s,2H),6.28(s,1H),7.30-7.35(m,5H),7.55(d,J＝12HZ,1H),7.71(d,J＝12HZ, 1H),7.82(s,1H).
13CNMR(100MHz,DMSO)18.47,53.27,66.00,106.10,112.73,115.77,126.37,136.56, 142.73,153.64,154.09,160.54,171.39,174.11.
HR-MS date,m/z calcd for C21H20N2O5[M-H+]:381.1406,found:381.1487.
effect experiment:
in general, the dye molecules can be dissolved in physiological saline, buffer solution or water-soluble organic solvent such as acetonitrile, dimethylsulfoxide, etc., and then added with appropriate buffer solution and other organic reagents for the test. The photophysical properties of the probe ASPC in aqueous pH 7.4 buffered solutions and various common organic reagents were studied and used in live cell and mouse in vivo imaging experiments, respectively. The living cell staining method is to incubate the cultured cell in buffer solution containing probe molecule, remove the incubation liquid after certain incubation time, and perform two-photon laser confocal imaging. The mouse staining method is to inject the probe into the mouse lung in situ, and after a period of time, the mouse lung is subjected to two-photon laser confocal imaging.
Probes and LTA4Ultraviolet absorption, fluorescence emission and selectivity experiments of H reaction:
control group: ASPC (0.1 μ M), Tris-HCl (100mM), NaCl (100mM), pH 7.4; experimental groups: ASPC (0.1. mu.M), Tris-HCl (100mM), NaCl (100mM), pH 7.4, LTA4H (4 ng/mL). The control group and the experimental group were incubated at 37 ℃ for 90min, and then the ultraviolet absorption and fluorescence emission spectra were measured with the maximum absorption as the single photon excitation wavelength and 690nm as the two-photon excitation wavelength, respectively, and the spectra are shown in fig. 1. The abscissa is wavelength (nm), the left ordinate is ultraviolet absorption intensity, and the right ordinate is fluorescence emission intensity. It can be seen that it has a large stokes shift (80nm) and good single and two photon properties. FIG. 2 is a graph showing the response of ASPC to various biologically relevant components including various aminopeptidases (aminopeptidase N, leucine aminopeptidase, methionine aminopeptidase), amino acids (glycine, alanine, cysteine, lysine, arginine), salts (Zn)2+,Mg2+,Ca2+) Glucose and vitamin C. As shown in fig. 2, only if LTA4In the presence of H, the fluorescence intensity is obviously enhanced. This demonstrates that ASPC is responsible for LTA in comparison to other components in the organism4H has excellent selectivity, can be used in complex cellular and living biological environments and can specifically detect LTA4H activity.
The probe is used for living cell single-photon and double-photon confocal fluorescence imaging experiments:
human astrocyte LX-2 is cultured by a high-glucose DMEM culture solution, 10 mu M of probe Tris-HCl aqueous solution is respectively added, the cells are incubated for 20 minutes at 37 ℃, then the cells with the probe incubation solution are washed away, laser confocal fluorescence imaging is carried out, and the imaging can be seen under the conditions of single photon and two photons, but the imaging effect of the two photons is obviously better than that of the single photon. The cell damage using two-photon fluorescence imaging is small, which is beneficial for imaging (fig. 3). Wherein, FIG. 3 is a diagram of imaging of single-photon and double-photon confocal cells of human stellate liver cell LX-2. A-C images of normal cells stained with ASPC, D-F images of cells stimulated with LPS, which is capable of stimulating cells to produce inflammation, stained with ASPC. G to H are LPS (LTA in cells after LPS stimulation)4H. Increase of expression level of inflammatory factor and other related components), and staining ASPC (ASPC) of cells treated with ubenimex, an aminopeptidase inhibitor. A. D, G is single photon imaging, B, E, H is two photon imaging, and G, F, I is bright field. J is a fluorescence data output diagram of a single-photon and double-photon imaging diagram. The single photon excitation light is 405nm, the collected fluorescence is 420-500 nm, the two-photon excitation light is 690nm, and the collected fluorescence is 380-500 nm.
The probe is used for two-photon confocal fluorescence imaging experiments at different depths of the lung of a pneumonia mouse:
mice were administered LPS to induce pneumonia by intranasal administration, and LTA was assayed for 12h and 24h, respectively4H activity, 10 mu M ASPC injection in situ and incubation for 30min, in figure 4, A is a fluorescence imaging graph of a normal mouse lung after ASPC incubation, B is a fluorescence imaging graph of a mouse lung after LPS stimulation for 12H and then ASPC incubation, C is a fluorescence imaging graph of a mouse lung after LPS stimulation for 24H and then ASPC incubation, D is a fluorescence data output graph of a mouse lung imaging graph, E is a data output graph of a mouse pneumonia degree determination by an inflammation factor IL-1 β kit, two-photon excitation light is 690nm, fluorescence is collected at 380-520 nm, as can be seen in figure 4, the fluorescence intensity in the control mouse lung is obviously weaker than that of a mouse injected with LPS, and the culture time is prolonged along with LPS injectionAnd the lung fluorescence enhancement times of the 24h mice are also obviously higher than 12 h. This result suggests that the inflammation of the lungs of LPS-stimulated mice is gradually increased with time, resulting in LTA4The content of the inflammatory factor IL-1 β is also a key index for evaluating pneumonia, so that in order to confirm that mice treated by LPS have pneumonia, a commercial ELISA kit is used for measuring the content of IL-1 β in mouse lung tissue homogenate4Activity of H.
The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims (11)
1. Two-photon fluorescent probe in detection of LTA4The application of the H protein activity is characterized in that the structural formula of the probe is as follows:
2. the two-photon fluorescent probe of claim 1 in detecting LTA4The application of the H protein activity is characterized in that the preparation method of the probe comprises the following steps: firstly, carrying out acyl halogenation reaction on carboxyl in the raw material a to obtain an intermediate b, carrying out nucleophilic substitution reaction on the acyl halide group of the intermediate b and the amino group of the raw material c, and removing tert-butyloxycarbonyl group to obtain the two-photon fluorescent probe;
the chemical structure of the raw material a is
The chemical structure of the raw material c is
3. The use of claim 2, wherein the probe is prepared by the steps of:
(1) dissolving the raw material a in a solvent, adding an acyl halide reagent, and carrying out acyl halide reaction to obtain an intermediate b;
(2) and dissolving the intermediate b and the raw material c in acetic acid, heating and carrying out reflux reaction to obtain the two-photon fluorescent probe.
4. Use according to claim 3, wherein the solvent is dichloromethane.
5. Use according to claim 3, characterized in that the acid halogenating agent is thionyl chloride.
6. The method as claimed in claim 5, wherein the reaction conditions of the acyl halide reaction are room temperature reaction for 2-3 h.
7. Use according to claim 3, characterized in that the acylation is followed by a recrystallization after removal of the solvent.
8. The method as claimed in claim 7, wherein the solvent for recrystallization is a mixed solution of petroleum ether and dichloromethane in a volume ratio of 5: 1.
9. The method as claimed in claim 3, wherein the molar ratio of the raw material c to the intermediate b is 1: 1-1.2.
10. The use according to claim 3, wherein the heating reflux reaction in step (2) is carried out under the following conditions: the temperature is 90 plus or minus 5 ℃, and the reaction time is 5 plus or minus 0.5 h.
11. The method as claimed in claim 3, wherein the solvent is taken out after the reflux reaction, and the product is subjected to silica gel column separation.
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