CN109810107A - A kind of fluorescence probe and preparation method thereof identifying mercaptoamino acid - Google Patents

A kind of fluorescence probe and preparation method thereof identifying mercaptoamino acid Download PDF

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CN109810107A
CN109810107A CN201910157973.9A CN201910157973A CN109810107A CN 109810107 A CN109810107 A CN 109810107A CN 201910157973 A CN201910157973 A CN 201910157973A CN 109810107 A CN109810107 A CN 109810107A
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probe
fluorescence
fluorescence probe
buffer solution
detection
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刘兴江
肜一帆
王琛
揣攀峰
魏柳荷
周爽
高凯凯
李庆昊
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Zhengzhou University
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Zhengzhou University
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Abstract

A kind of fluorescence probe and preparation method thereof the invention discloses detection based on naphthalimide indoles containing mercaptoamino acid, structure is as follows:The probe is selectively good for detecting cysteine, homocysteine and glutathione, strong antijamming capability, and fast response time;There is long wavelength emission and big stoke shift in detection process simultaneously, the sensitivity and lesser background interference of detection can be improved.The probe can be used for biological sample and the intracellular detection containing mercaptoamino acid.

Description

A kind of fluorescence probe and preparation method thereof identifying mercaptoamino acid
Technical field
The invention belongs to chemical analysis detection technique fields, and in particular to a kind of fluorescence spy of the detection containing mercaptoamino acid The application of needle and the probe in detection mercaptoamino acid.
Background technique
Cysteine (Cys), homocysteine (Hcy) and reduced glutathione (GSH) are main biological thiols, It is the amino acid containing sulfydryl, plays an important role in the physiology of mammal life system and pathologic process.Half Guang ammonia The concentration abnormality of acid and a variety of diseases have the concentration of cysteine in relationship, such as human body it is too low when can cause slow growth, The diseases such as hepatic injury, research shows that the exception of semicystinol concentration is also related with the diseases such as skin injury, drowsiness and oedema;Homotype The concentration of cysteine increases related with diseases such as cardiovascular disease, Alzheimer disease and osteoporosis;Reduced glutathione It is main antioxidant in human body, human body can be protected from the damage of free radical, the redox state of organism is dense with it Spending has direct relation, and the concentration abnormality of the diseases such as oligoleukocythemia, cancer, AIDS and reduced glutathione also has closely Relationship.Therefore, it is meaningful that exploitation, which has high selection, highly sensitive method of the detection containing mercaptoamino acid,.
In recent years, fluorescence probe has become common method of the detection containing mercaptoamino acid, and being primarily due to fluorescence probe can To realize the non-destructive testing of high-spatial and temporal resolution, and it is easy to operate at low cost.Currently, having some about glimmering containing mercaptoamino acid The document report of light probe, but such most of fluorescence probe launch wavelength is in blue light or yellow region, and Stokes position It moves and is less than 100nm.The background interference of long wavelength emission (feux rouges or near infrared light) in the detection process is small, and penetration into tissue is strong, Detection in vivo has very big advantage.The fluorescence probe of big Stokes shift in the detection process excitation wavelength and The difference comparsion of launch wavelength is big, can reduce self-absorption and the interference of autofluorescence, to improve the sensitivity of detection.Mesh Before, research and development can be realized quickly detection mercaptoamino acid, and the fluorescence probe with long wavelength emission, big Stokes shift It is still challenge.
Summary of the invention
In order to overcome the deficiencies of the prior art, one of the object of the invention is to provide a kind of while having red emission and this big support Ke Si displacement, and quickly detect the fluorescence probe containing mercaptoamino acid;The second purpose is to provide preparation method.
Fluorescence probe in the present invention, structure are as follows:
Fluorescence probe in the present invention is prepared by following reaction, and synthesis process is as follows:
Specific synthetic method is as follows: (a) compound 1 is dissolved in glycol monoethyl ether, is heated to 115 DEG C until reaction solution Become clarification, hydrazine hydrate (80%) is then added dropwise dropwise into above-mentioned mixed liquor, is added dropwise to complete rear mixed liquor and continues to be heated to reflux instead It answers 3 hours, to after the reaction was completed, be cooled to room temperature, a large amount of crocus precipitatings is precipitated, filtration washing obtains compound 2.(b) will Intermediate 2 is dissolved in 3- methyl -2- butanone, and the concentrated sulfuric acid is then slowly added dropwise, and reaction mixture flows back stir under nitrogen protection It mixes 4 hours, 3- methyl -2- butanone is evaporated off to after completion of the reaction, depressurize rotation, obtains crude product, is separated with silica gel column layer pure Change obtains light yellow solid product 3.(c) compound 3 and parahydroxyben-zaldehyde are dissolved in dry toluene, are stirred and evenly mixed then Glacial acetic acid and piperidines is successively added dropwise into above-mentioned mixed liquor, after being added dropwise, return stirring 6 is small under nitrogen protection for mixed liquor When, decompression rotation is evaporated toluene, obtains crude product, uses column chromatography purifying and obtain red solid product 4.(d) by compound 4 It is dissolved in 2,4- dinitrophenyl chloride in dry methylene chloride, adds triethylamine, stirred 4 hours under ice-water bath, it will be anti- Liquid decompression rotation solvent evaporated is answered, crude product is obtained, is purified to obtain crocus solid product, i.e. probe with chromatography.
The testing mechanism of fluorescence probe of the invention is as follows:
Fluorescence probe unstressed configuration itself, reacts with mercaptoamino acid, and 2,4- dinitrobenzene parts are left away from probe, launches red Color fluorescence.
The maximum absorption band of fluorescence probe of the invention exists in 453nm with maximum emission peak after mercaptoamino acid reacts is contained 590nm, stoke shift 137nm.
The excitation wavelength that fluorescence probe of the invention selects during the test is 488nm.
Fluorescence probe of the invention is selectively good.The PBS buffer solution packet that the test system of probe is the 10mM that pH is 7.4 CTAB containing 1.0mM is tested at 25 DEG C.Probe itself is in fluorescent quenching state, is being separately added into 3.5 times of equivalent cysteines (Cys), after homocysteine (Hcy) and reduced glutathione (GSH), the fluorescence intensity at maximum emission wavelength 590nm Increase 24 times.And be added its detectable substance (Arg, Ile, Ser, His, Ala, Phe, Glu, Trp, Thr, Val, Lys, Asp, Tyr, Leu, Gly, Pro, Met) after, fluorescence intensity is almost without increase.
Fluorescence probe strong antijamming capability of the invention, other detectable substances (Arg, Ile, Ser, His, Ala, Phe, Glu, Trp, Thr, Val, Lys, Asp, Tyr, Leu, Gly, Pro, Met) in the presence of do not influence cysteine (Cys), homotype The detection effect of cysteine (Hcy) and reduced glutathione (GSH).
Fluorescence probe detection speed of the invention is fast.It is being separately added into 3.5 times of equivalent cysteines (Cys), half Guang of homotype After propylhomoserin (Hcy) and reduced glutathione (GSH) effect, fluorescence enhances immediately, reaches maximum value in 5min.
Fluorescence probe of the invention can be to cysteine (Cys), homocysteine (Hcy) and reduced glutathione (GSH) quantitative detection is carried out respectively.Fluorescence probe of the invention is linearly preferable, and linearly dependent coefficient is respectively as follows: cysteine (Cys) R=0.9857, homocysteine (Hcy) R=0.9969, reduced glutathione (GSH) R=0.9805.
Fluorescence probe of the invention has lower cytotoxicity, is measured by MTT method, dark to cultivate within 20 μM For 24 hours, survival rate is 95% or more.
Fluorescence probe of the invention has good cell membrane penetration, can be used for endogenous cellular containing mercaptoamino acid Detection.
Probe pH application range of the present invention is wider, detectable from pH=5.0 to pH=10.0.
Fluorescence probe of the invention also can be used for the detection that living body includes mercaptoamino acid.
Detailed description of the invention
Fig. 1 is fluorescence probe (10.0 μM) of the invention at PBS buffer solution (10mM, pH=7.4,1.0mM CTAB) In, change with the fluorescence spectrum after various concentration cysteine (Cys) effect, abscissa is wavelength, and ordinate is fluorescence intensity.
Fig. 2 is fluorescence probe (10.0 μM) of the invention at PBS buffer solution (10mM, pH=7.4,1.0mM CTAB) In, with fluorescence intensity at 590nm in cysteine (Cys) mechanism with the linear relationship of concentration, abscissa is concentration, indulges and sits It is designated as fluorescence intensity.
Fig. 3 is fluorescence probe (10.0 μM) of the invention at PBS buffer solution (10mM, pH=7.4,1.0mM CTAB) In, change with the fluorescence spectrum after various concentration homocysteine (Hcy) effect, abscissa is wavelength, and ordinate is fluorescence Intensity.
Fig. 4 is fluorescence probe (10.0 μM) of the invention in PBS buffer solution (10mM, pH=7.4,1.0mM CTAB) With for fluorescence intensity with the linear relationship of concentration, abscissa is concentration at 590nm in half homocysteine (Hcy) mechanism, Ordinate is fluorescence intensity.
Fig. 5 is fluorescence probe (10.0 μM) of the invention at PBS buffer solution (10mM, pH=7.4,1.0mM CTAB) In, change with the fluorescence spectrum after various concentration reduced glutathione (GSH) effect, abscissa is wavelength, and ordinate is fluorescence Intensity.
Fig. 6 is fluorescence probe (10.0 μM) of the invention in PBS buffer solution (10mM, pH=7.4,1.0mM CTAB) With for fluorescence intensity with the linear relationship of concentration, abscissa is concentration at 590nm in reduced glutathione (GSH) mechanism, indulge Coordinate is fluorescence intensity.
Fig. 7 is the selectivity of fluorescence probe of the invention, and fluorescence probe is at (10.0 μM) in PBS buffer solution (10mM, pH =7.4,1.0mM CTAB) with Cys, Hcy, GSH, Arg, Ile, Ser, His, Ala, Phe, Glu, Trp, Thr, Val, Lys, Fluorescence spectrum after Asp, Tyr, Leu, Gly, Pro, Met effect, abscissa is wavelength, and ordinate is fluorescence intensity.
Fig. 8 is the anti-interference of fluorescence probe of the invention, cysteine (Cys) and analyte (Arg, Ile, Ser, His, Ala, Phe, Glu, Trp, Thr, Val, Lys, Asp, Tyr, Leu, Gly, Pro, Met) when coexisting, exist with fluorescence probe (10.0 μM) are strong with the fluorescence after cysteine (Cys) effect in PBS buffer solution (10mM, pH=7.4,1.0mM CTAB) Spend ratio (IProbe+others/IProbe+Cys) histogram.
Fig. 9 is the anti-interference of fluorescence probe of the invention, homocysteine (Hcy) and analyte (Arg, Ile, Ser, His, Ala, Phe, Glu, Trp, Thr, Val, Lys, Asp, Tyr, Leu, Gly, Pro, Met) when coexisting, with fluorescence probe At (10.0 μM) in PBS buffer solution (10mM, pH=7.4,1.0mM CTAB) and after homocysteine (Hcy) effect Fluorescence intensity ratio (IProbe+others/IProbe+Hcy) histogram.
Figure 10 is the anti-interference of fluorescence probe of the invention, reduced glutathione (GSH) and analyte (Arg, Ile, Ser, His, Ala, Phe, Glu, Trp, Thr, Val, Lys, Asp, Tyr, Leu, Gly, Pro, Met) when coexisting, with fluorescence probe At (10.0 μM) in PBS buffer solution (10mM, pH=7.4,1.0mM CTAB) and after reduced glutathione (GSH) effect Fluorescence intensity ratio (IProbe+others/IProbe+GSH) histogram.
Figure 11 is fluorescence probe (10.0 μM) of the invention at PBS buffer solution (10mM, pH=7.4,1.0mM CTAB) In, probe changes with time with fluorescence intensity at 590nm in cysteine (Cys) mechanism, and abscissa is the time, indulges and sits It is designated as fluorescence intensity.
Figure 12 is fluorescence probe (10.0 μM) of the invention at PBS buffer solution (10mM, pH=7.4,1.0mM CTAB) In, probe changes with time with fluorescence intensity at 590nm in homocysteine (Hcy) mechanism, and abscissa is the time, Ordinate is fluorescence intensity.
Figure 13 is fluorescence probe (10.0 μM) of the invention at PBS buffer solution (10mM, pH=7.4,1.0mM CTAB) In, probe changes with time with fluorescence intensity at 590nm in reduced glutathione (GSH) mechanism, and abscissa is the time, Ordinate is fluorescence intensity.
Figure 14 is fluorescence probe (10.0 μM) of the invention in different pH value buffer solutions, with cysteine, homotype half The fluorescence intensity of cystine and glutathione effect front and back, abscissa pH, ordinate is fluorescence intensity.
Figure 15 is the copolymerization coke cell imaging that fluorescence probe of the invention detects the intracellular mercaptoamino acid of MCF-7,37 DEG C when imaging effect.A1-A3First 15min is cultivated with cysteine Cys (0.5mM) for cell to cultivate with (10.0 μM) of probe again The imaging of 15min;B1-B3First 15min is cultivated with homocysteine Hcy (0.5mM) for cell to cultivate with (10.0 μM) of probe again The imaging of 15min;C1-C315min first, which is cultivated, with glutathione (0.5mM) for cell cultivates 15min's with (10.0 μM) of probe again Imaging;D1-D3For the imaging of probe (10.0 μM) and cell culture 15min;E1-E3For cell first with NEM cultivate 15min again with The imaging of probe cultivation 15min.
Figure 16 is the toxicity test of fluorescence probe of the invention to cell.In probe molecule concentration 1.0 × 10-5mol/L When, cell survival rate is 95% or more.
Example is embodied
Embodiment 1: the synthesis of compound 2
Compound 1 (3.32g, 10.0mmol) is dissolved in 50mL glycol monoethyl ether, is heated to 115 DEG C until reaction solution becomes clear Clearly, it is then added dropwise dropwise into above-mentioned mixed liquor 3.0mL hydrazine hydrate (80%), is added dropwise to complete rear mixed liquor and continues to be heated to reflux instead It answers 3 hours, to after the reaction was completed, be cooled to room temperature, a large amount of crocus precipitatings is precipitated, filtration washing obtains compound 2.Yield: 2.32g;Yield: 81.9%.
Embodiment 2: the synthesis of compound 3
Intermediate 2 (1.98g, 7mmol) is dissolved in 3- methyl -2- butanone (100mL), the 3mL concentrated sulfuric acid is then slowly added dropwise, Reaction mixture return stirring 4 hours under nitrogen protection, to after completion of the reaction, 3- methyl -2- butanone is evaporated off in decompression rotation, Crude product is obtained, (petroleum ether/methylene chloride=1/10, v/v) is isolated and purified with silica gel column layer and obtains light yellow solid product 3. Yield: 1.13g;Yield: 48.5%.
Embodiment 3: the synthesis of compound 4
Compound 3 (1.0g, 3mmol) and parahydroxyben-zaldehyde (0.37g, 3mmol) are dissolved in the dry toluene of 20mL, stirring It mixes and glacial acetic acid (0.02mL) and piperidines (0.05mL) is then successively added dropwise into above-mentioned mixed liquor, after being added dropwise, mixed liquor Return stirring 6 hours under nitrogen protection, decompression rotation is evaporated toluene, obtain crude product, use column chromatography purifying (ethyl alcohol/ Methylene chloride=1/50, v/v) obtain red solid product 4.Yield: 0.68g;Yield: 51.7%.
Embodiment 4: the synthesis of probe
Compound 4 (0.483g, 1mmol), 2,4- dinitrophenyl chlorides (0.563g, 2.11mmol) are dissolved in dry two of 15mL It in chloromethanes, adds triethylamine (0.476g, 4.7mmol), is stirred 4 hours under ice-water bath, reaction solution decompression rotation is evaporated Solvent obtains crude product, with chromatography purify (ethyl acetate/dichloromethane=0.3:10, v/v) obtain crocus solid produce Product 5 are probe molecule.Yield: 1.13g;Yield: 48.5%.
Embodiment 6: probe molecule detects cysteine (Cys), homocysteine (Hcy) and reduction paddy Guang in cell The application of sweet peptide (GSH)
MCF-7 cell is incubated for 15min with the PBS buffer solution (10.0mM, pH=7.4) containing NEM (1.0mM) first, is buffered with PBS Liquid rinses 3 times;It is incubated for 15min with the PBS buffer solution containing probe (10.0 μM) again, after being rinsed 3 times with PBS buffer solution, uses laser Confocal fluorescent microscopic carries out cell fluorescence imaging, can't see fluorescence signal.MCF-7 cell is used containing probe (10.0 μM) PBS buffer solution be incubated for 15min, with PBS buffer solution rinse 3 times after, with laser confocal fluorescence microscope carry out cell fluorescence at Picture, it is seen that red fluorescent.MCF-7 cell is incubated with the PBS buffer solution (10.0mM, pH=7.4) containing Cys (0.5mM) first 15min is educated, is rinsed 3 times with PBS buffer solution;It is incubated for 15min with the PBS buffer solution containing probe (10.0 μM) again, uses PBS buffer solution After rinsing 3 times, cell fluorescence imaging is carried out with laser confocal fluorescence microscope, it is seen that intense red fluorescence signal.MCF-7 is thin Born of the same parents are incubated for 15min with the PBS buffer solution (10.0mM, pH=7.4) containing Hcy (0.5mM) first, are rinsed 3 times with PBS buffer solution; It is incubated for 15min with the PBS buffer solution containing probe (10.0 μM) again, after being rinsed 3 times with PBS buffer solution, with laser co-focusing fluorescence Microscope carries out cell fluorescence imaging, it is seen that intense red fluorescence signal.MCF-7 cell is first with the PBS for containing GSH (0.5mM) Buffer (10.0mM, pH=7.4) is incubated for 15min, is rinsed 3 times with PBS buffer solution;It is slow with the PBS containing probe (10.0 μM) again Fliud flushing is incubated for 15min, after being rinsed 3 times with PBS buffer solution, carries out cell fluorescence imaging with laser confocal fluorescence microscope, sees To intense red fluorescence signal.These are the result shows that fluorescence probe of the invention can be used for the inspection that cell includes mercaptoamino acid It surveys.

Claims (1)

1. a kind of fluorescence probe for identifying biological thiol, structural formula are as follows:
CN201910157973.9A 2019-03-02 2019-03-02 A kind of fluorescence probe and preparation method thereof identifying mercaptoamino acid Pending CN109810107A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113354584A (en) * 2021-06-15 2021-09-07 郑州大学 Naphthalimide fluorescent probe for distinguishing Cys, Hcy and GSH, and preparation method and application thereof
CN116840197A (en) * 2022-03-23 2023-10-03 中国科学院苏州生物医学工程技术研究所 2' -O-methyltransferase activity detection method, kit and application

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CN108530446A (en) * 2018-06-13 2018-09-14 郑州大学 A kind of fluorescence probe of identification benzenethiol

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CN105802606A (en) * 2014-12-29 2016-07-27 苏州罗兰生物科技有限公司 Preparation method and use of mercapto-containing amino acid fluorescent probe
CN108530446A (en) * 2018-06-13 2018-09-14 郑州大学 A kind of fluorescence probe of identification benzenethiol

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113354584A (en) * 2021-06-15 2021-09-07 郑州大学 Naphthalimide fluorescent probe for distinguishing Cys, Hcy and GSH, and preparation method and application thereof
CN113354584B (en) * 2021-06-15 2023-05-16 郑州大学 Naphthalimide fluorescent probe for distinguishing Cys, hcy and GSH, and preparation method and application thereof
CN116840197A (en) * 2022-03-23 2023-10-03 中国科学院苏州生物医学工程技术研究所 2' -O-methyltransferase activity detection method, kit and application

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