CN105884713A - Fluorescence-enhanced hydrogen sulfide molecular fluorescent probe and preparation method and application thereof - Google Patents

Fluorescence-enhanced hydrogen sulfide molecular fluorescent probe and preparation method and application thereof Download PDF

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CN105884713A
CN105884713A CN201610264719.5A CN201610264719A CN105884713A CN 105884713 A CN105884713 A CN 105884713A CN 201610264719 A CN201610264719 A CN 201610264719A CN 105884713 A CN105884713 A CN 105884713A
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hydrogen sulfide
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dichloromethane
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林伟英
任明光
邓贝贝
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University of Jinan
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Abstract

The invention discloses a fluorescence-enhanced hydrogen sulfide molecular fluorescent probe and a preparation method and application thereof and belongs to the technical field of analytic chemistry. The molecular formula of the probe molecules is C21H14N4O2S. The formula of the probe is as shown in formula (I). The fluorescence-enhanced hydrogen sulfide molecular fluorescent probe has the advantages that the probe is simple to prepare, mature in synthetic route, capable of fast and accurately detecting hydrogen sulfide in cells and achieving fluorescence imaging, applicable to the content sensing detecting of the hydrogen sulfide in water environments and biological cell systems, and promising in application prospect in field of biological molecular detection.

Description

A kind of Fluorescence Increasing type hydrogen sulfide fluorescence probe and its preparation method and application
Technical field
The present invention relates to a kind of Fluorescence Increasing type hydrogen sulfide fluorescence probe and its preparation method and application, belong to technical field of analytical chemistry.
Background technology
Hydrogen sulfide (H2S), produced by enzyme catalysis in vivo, and play important role in terms of the physiological function of regulation people.Such as, hydrogen sulfide may participate in hemoglobin change；Participate in the reduction of internal nitroso compound；Regulate the function of internal multiple enzyme；Regulation neurocyte and neuroendocrine；Vasodilator smooth muscle；Protection gastric mucosa, reduces the effect of pressure；Hydrogen sulfide can effectively remove hydrogen peroxide, superoxide anion, hypochlorous acid, Peroxynitrite etc..Experiment shows that hydrogen sulfide can be effectively reduced the neurotoxicity of AP induction.Hydrogen sulfide and FPG show as negative proportionate relationship, raise type-II diabetes patient's concentration of hydrogen sulfide and perhaps contribute to blood sugar lowering.But, in organism, hydrogen sulfide imbalance then can produce harm, such as senile dementia, Down's syndrome, diabetes, liver cirrhosis etc. to body.It is achieved that the detection of hydrogen sulfide is extremely important in organism.
H2S is as signaling molecule important in human body, and concentration change is very fast in vivo, so probe to have certain response speed, detects with the real-time of hydrogen sulfide in realizing organism.Complicated biotic environment can disturb the interference of sulfurated hydrogen detection, especially mercaptan.Also having multiple anion simultaneously in living things system, all the effect of probe may be produced impact, probe must have the selectivity of height.Additionally, efficiently sensing and the organism inner cell imaging of hydrogen sulfide in aqueous solution to be realized, so the hydrogen sulfide probe of design to have low fluorescence background and high fluorescence response signal.
At present, most hydrogen sulfide fluorescent probe selectivitys is the highest, and inconspicuous to the change of sulfurated hydrogen detection color, the highest to the fluorescence signal intensification factor of hydrogen sulfide response, is difficulty with detecting aqueous solution and intracellular hydrogen sulfide.
Summary of the invention
For current hydrogen sulfide fluorescence probe detection problem encountered and present situation, the present invention passes through MOLECULE DESIGN, synthesizes one and has that fluorescence signal is strong and height selective hydrogen sulfide fluorescence probe.This patent has good reproducibility based on hydrogen sulfide and combines the hydrogen sulfide fluorescent probe of excited state intramolecular proton transfer (ESIPT) mechanismic design nitrine, probe has the response (fluorescence signal intensity can strengthen more than 400 times) of stronger fluorescence signal to hydrogen sulfide, has good selection specificity.Fluorescence imaging application can be carried out with intracellular hydrogen sulfide in aqueous solution.
The present invention is by the following technical solutions:
A kind of Fluorescence Increasing type hydrogen sulfide fluorescence probe, it is characterised in that the molecular formula of described probe molecule is: C21H14N4O2S, its structural formula is as shown in formula I:
。
The preparation method of a kind of above-mentioned hydrogen sulfide fluorescence probe, it is characterised in that it comprises the following steps:
1) o-toluic acid of 1eq is dissolved in 25mL ethanol, is subsequently adding 1.2mL concentrated sulphuric acid, be heated to reflux 24 hours, be then peeled off purification and obtain compound 1-1；Described compound 1-1 structural formula is as follows:
；
2) being dissolved in acetonitrile by the AIBN of the NBS and 0.05 eq of the compound 1-1,1eq of 1eq, overnight, separating-purifying obtains compound 1-2 to heating reflux reaction；Described compound 1-2 structural formula is as follows:
；
3) by the NaN of 1eq compound 1-2 Yu 1.2eq3Being dissolved in DMF, nitrogen is protected, and room temperature back flow reaction is after 24 hours, and separating-purifying obtains compound 1-3；The structural formula of described compound 1-3 is as follows:
；
4) being dissolved in oxolane by 1eq compound 1-3, add the LiOH of a small amount of methanol, water and 5eq, nitrogen is protected, room temperature reaction 17 hours, is acidified by reactant liquor 3M hydrochloric acid solution, is then peeled off purification and obtains compound 1-4；Described compound 1-4 structural formula is as follows:
；
5) by 1eq salicylide and 1eq near amino thiophenols, the Na of 1eq2S2O5Being dissolved in DMF, nitrogen is protected, heating reflux reaction 2-3 hour, and after reaction completely, separating-purifying obtains compound 2-1；The structural formula of described compound 2-1 is as follows:
；
6) being dissolved in dichloromethane by the DCC of the DMAP, 1eq of the compound 1-4,1eq of 1eq compound 2-1 Yu 1eq, nitrogen is protected, and room temperature reaction 8 hours, separating-purifying obtains target-probe compound FN3-H2S。
In described step 1), process for separation and purification is: adding suitable quantity of water in reactant liquor, extract with dichloromethane, wash 2-3 time, salt is washed 2-3 time, and anhydrous sodium sulfate is dried, then pillar layer separation, and eluant proportioning is dichloromethane: petroleum ether=1:1.
Described step 2) in process for separation and purification be: pillar layer separation, eluant proportioning is dichloromethane: petroleum ether=1:1.
In described step 3), process for separation and purification is: ethyl acetate extracts 2 times, washes 2-3 time, and saline washs 2-3 time, and anhydrous sodium sulfate is dried, pillar layer separation, and eluant proportioning is dichloromethane: petroleum ether=1:2.
In described step 4), process for separation and purification is: extracts 2 times with dichloromethane, washes 2-3 time, and salt is washed 1 time, and anhydrous sodium sulfate is dried, pillar layer separation, and eluant proportioning is dichloromethane: petroleum ether=1:2.
In described step 5), process for separation and purification is: reactant liquor pours generation solid, then filtration under diminished pressure in a large amount of water, vacuum drying into, obtains net product.
In described step 6), process for separation and purification is: pillar layer separation, and eluant proportioning is dichloromethane: petroleum ether=1:1.
The synthetic route of above-mentioned hydrogen sulfide fluorescent probe is as follows:
The application of hydrogen sulfide fluorescence probe of the present invention, this fluorescent probe can apply to the content sensing detection of hydrogen sulfide in water environment and biological cell system；Described sensing detection comprises fluoroscopic examination, visual qualitative detection, and cell imaging detects.
Advantages of the present invention: the synthetic route of (1) probe is relatively easy, and last handling process is easy；(2) present invention achieves the quick detection of hydrogen sulfide molecular probe, have the advantages that selectivity is good, capacity of resisting disturbance is strong.Additionally, the most just can significantly observe strong fluorescence change under the change of solution colour and uviol lamp, it it is a kind of fluorescent probe with the sensing function that adds lustre to.Its significant color and fluorescence intensity change, make this probe present the high selectivity with in biological cell in aqueous, high-sensitivity detection hydrogen sulfide molecule, can carry out real-time qualitative and the detection of quantitative optical colorimetry.So, the present invention is a kind of simple, quickly, sensitive hydrogen sulfide molecular specificity detectable, have broad application prospects in biomolecule detection field.Its performance will combine accompanying drawing in an embodiment and describe in detail.
Accompanying drawing explanation
Fig. 1 is embodiment 1 middle probe FN3-H2S's1H NMR spectra；
Fig. 2 is probe FN3-H2S is with the situation of change adding fluorogram of sodium sulfide；
Fig. 3 is probe FN3-H2The S selectivity fluorogram to different ions and molecule；
Fig. 4 is probe FN3-H2The S selectivity histogram data to different ions and molecule；
Fig. 5 is probe FN3-H2S solution is at Na2The change of solution colour before and after S addition；
Fig. 6 is probe FN3-H2S solution is at Na2The change of fluorescence intensity after solution ultra violet lamp before and after S addition；
Fig. 7 is probe FN3-H2S exogenous hydrogen sulfide carries out imaging biological cells.
Detailed description of the invention
Below in conjunction with embodiment and accompanying drawing, the present invention will be further described, but the present invention is not limited by following embodiment, and in embodiment, the number of compound is for the number of compound in such scheme.
Embodiment 1
Compound FN3-H2The synthesis of S hydrogen sulfide fluorescent probe
( 1 ) compound 1-1 Synthesis:
By o-toluic acid (5.0g, 36.7mmol, 1eq) it is dissolved in 25mL ethanol, is subsequently adding 1.2mL concentrated sulphuric acid, be heated to reflux 24 hours, with the detection reaction of TCL plate, after reaction completely, cooling, add 20mL water, extract with dichloromethane, wash 2-3 time, salt 2-3 anhydrous sodium sulfate of washing is dried, decompression obtains thick product after being spin-dried for solvent, and separates with silicagel column, and silica gel particle size is 200-300 mesh, eluant proportioning is dichloromethane/petroleum ether=1:1, and yield is 89%.
( 2 ) compound 1-2 Synthesis:
By compound 1-1(1.97g, 12mmol, 1eq), NBS (2.35g, 13.2mmol, 1eq), AIBN(98.4mg, 0.6mmol, 0.05 eq) it is dissolved in 20mL acetonitrile, heating reflux reaction overnight, reacts with the detection of TCL plate, after reaction completely, decompression obtains thick product after being spin-dried for solvent, and separates with silicagel column, and silica gel particle size is 200-300 mesh, eluant proportioning is dichloromethane/petroleum ether=1:1, and yield is 56%.
( 3 ) compound 1-3 Synthesis:
By compound 1-2(1.1g, 4.53mmol, 1eq) it is dissolved in 3mL In DMF, be subsequently adding Hydrazoic acid,sodium salt (353mg, 5.43mmol, 1.2eq), nitrogen is protected, room temperature reaction 24 hours; with the detection reaction of TCL plate, after reaction completely, ethyl acetate extracts 2 times; wash 2-3 time; saline washs 2-3 time, and anhydrous sodium sulfate is dried, and decompression obtains thick product after being spin-dried for solvent; and separate with silicagel column; silica gel particle size is 200-300 mesh, and eluant proportioning is dichloromethane/petroleum ether=1:2, and yield is 82%.
( 4 ) compound 1-4 Synthesis:
By compound 1-3(900mg, 4.4mmol, 1eq) it is dissolved in 10mL In THF, add 2 mL methanol, 4 mL water, then add LiOH(528mg, 22mmol, 5eq), nitrogen is protected, room temperature reaction 17 hours.With the detection reaction of TCL plate, after reaction completely, reactant liquor 3M hydrochloric acid solution is acidified, extracts 2 times with dichloromethane, wash 2-3 time, salt is washed 1 time, and anhydrous sodium sulfate is dried, and decompression obtains thick product after being spin-dried for solvent, and separate with silicagel column, silica gel particle size is 200-300 mesh, and eluant proportioning is dichloromethane/petroleum ether=1:2, and yield is 86%.
( 5 ) compound 2-1 Synthesis:
By salicylide (961mg, 7.87mmol, 1eq) and Na2S2O5(1.5mg, 7.87mmol, 1eq) is dissolved in 10mL DMF; then near amino thiophenols (1.0g, 7.87mmol, 1eq) is added; nitrogen is protected, heating reflux reaction 2-3 hour, with the detection reaction of TCL plate; after reaction completely, cooling, it is poured in 200mL water; solid is had to produce; filtration under diminished pressure, vacuum drying, obtain net product.Yield is 92%.
( 6 ) compound FN3-H2S Synthesis:
By compound 1-4(9.1mg, 0.528mmol, 1eq); compound 2-1(100mg; 0.528mmol, 1eq), DMAP(201mg; 0.528mmol; 1eq, DCC(136mg, 0.528mmol; 1eq) it is dissolved in 5mL dichloromethane; nitrogen is protected, room temperature reaction 8 hours, with the detection reaction of TCL plate; after reaction completely; decompression obtains thick product after being spin-dried for solvent, and separates with silicagel column, and silica gel particle size is 200-300 mesh; eluant proportioning is dichloromethane/petroleum ether=1:1, and yield is 81%.This probe1H-NMR (400MHz, DMSO-d 6) (see figure 1) δ 8.40 (d,J = 7.4 Hz, 1H), 8.31 (d,J = 7.5 Hz, 1H), 8.09 (d,J = 7.8 Hz, 1H), 7.83 (dd,J = 19.6, 7.6 Hz, 2H), 7.71 (dd,J = 15.9, 7.5 Hz, 3H), 7.58 (t,J = 7.5 Hz, 2H), 7.54 – 7.48 (m, 1H), 7.44 (t,J = 7.5 Hz, 1H), 4.84 (s, 2H)
Embodiment 2
Compound FN3-H2S hydrogen sulfide fluorescent probe is with Na2S adds the change increasing fluorogram of equivalent
The FN of Example 1 preparation3-H2S hydrogen sulfide fluorescent probe is dissolved in dimethyl sulfoxide (DMSO), makes 1mmol/L storing solution.From storing solution, take out 40 μ L join in the middle of the centrifuge tube of 5mL, be diluted to 4 mL with the solution that PBS buffer solution (0.1mol/L, pH=7.4) and DMSO volume ratio are 3:1, add the Na of different equivalent (0-100 eq)2S standard solution, measures its photoluminescent property with 410nm for exciting light.Fluorescence spectrum is as shown in Fig. 2.From Figure 2 it can be seen that along with Na2S adds the increase fluorescence intensity of equivalent gradually to be strengthened.
Embodiment 3
Compound FN3-H2S fluorescent probe is to different molecular or the selectivity of ion
Fluorescent probe storing solution takes out from embodiment 2 40 μ L and joins in the middle of the centrifuge tube of 5mL, with PBS buffer solution (0.1mol/L, pH=7.4) it is that the solution of 3:1 is diluted to 4 mL with DMSO volume ratio, prepare a series of probe solution, it is separately added into competition molecule and the sodium sulfide standard solution of equimolar amounts of equimolar amounts, one of them solution is not added with ion as blank, and with the fluorescence emission spectrum change that 410nm is exciting light detection solution after 1h, result is as shown in Figure 3 and Figure 4.By Fig. 3 and Fig. 4 it is found that other ion-pair compounds FN3-H2The fluorescence of S has little to no effect, and the addition of sodium sulfide solution makes compound FN3-H2The fluorescence of S is obviously enhanced.
Embodiment 4
Compound FN3-H2The S fluorescent probe Visual retrieval to hydrogen sulfide
Taking out 40 μ L from embodiment 2 in fluorescent probe storing solution and join in the middle of the centrifuge tube of 5mL, add the sodium sulfide standard solution of 100 molar equivalents, sodium sulfide can make compound FN3-H2There is the change of obvious color in the buffer solution solution that PBS:DMSO volume ratio is 3:1 of S fluorescent probe, solution colour becomes light yellow (Fig. 5) from colourless.Sending bright blue-fluorescence (Fig. 6) along with the hydrogen sulfide induced fluorescence probe of macroscopic under uviol lamp, explanation is a kind of fluorescent probe with the sensing function that adds lustre to.
Embodiment 5
Compound FN3-H2S fluorescent probe is to cell exogenous hydrogen sulfide fluorescence imaging
Probe application of the present invention hydrogen sulfide of exogenous in HeLa cell is carried out fluorescence imaging application by us.Concrete operation step is as follows: being joined by 5 μMs of probe DMSO solution and carry out blue channel imaging with Laser Scanning Confocal Microscope after cultivating 30 min in CO2 gas incubator in the culture fluid (2mL) giving birth to HeLa cell, result is shown in Fig. 7.First light field imaging is carried out, it can be seen that cell profile (Fig. 7 a) substantially.Then carrying out being excited into picture with the laser of 405nm, it is 425nm-475nm that detector accepts scope, carries out fluorescence imaging by blue channel it is observed that do not adding Na2Before S, being barely perceivable cell has fluorescent emission (Fig. 7 b).But in system, add Na2S After the aqueous solution of 20 μMs, wait 30 After min, then carry out exciting with the laser of 405nm it is observed that intracellular have obvious blue light to send (Fig. 7 e), illustrate that this fluorescent probe can carry out fluorescence imaging with the hydrogen sulfide of exogenous.

Claims (9)

1. a Fluorescence Increasing type hydrogen sulfide fluorescence probe, it is characterised in that the molecular formula of described probe molecule is: C21H14N4O2S, its structural formula is as shown in formula I:
。
2. the preparation method of the hydrogen sulfide fluorescence probe described in a claim 1, it is characterised in that it comprises the following steps:
1) o-toluic acid of 1eq is dissolved in 25mL ethanol, is subsequently adding 1.2mL concentrated sulphuric acid, be heated to reflux 24 hours, be then peeled off purification and obtain compound 1-1；Described compound 1-1 structural formula is as follows:
；
2) being dissolved in acetonitrile by the AIBN of the NBS and 0.05 eq of the compound 1-1,1eq of 1eq, overnight, separating-purifying obtains compound 1-2 to heating reflux reaction；Described compound 1-2 structural formula is as follows:
；
3) by the NaN of 1eq compound 1-2 Yu 1.2eq3Being dissolved in DMF, nitrogen is protected, and room temperature back flow reaction is after 24 hours, and separating-purifying obtains compound 1-3；The structural formula of described compound 1-3 is as follows:
；
4) being dissolved in oxolane by 1eq compound 1-3, add the LiOH of a small amount of methanol, water and 5eq, nitrogen is protected, room temperature reaction 17 hours, is acidified by reactant liquor 3M hydrochloric acid solution, is then peeled off purification and obtains compound 1-4；Described compound 1-4 structural formula is as follows:
；
5) by 1eq salicylide and 1eq near amino thiophenols, the Na of 1eq2S2O5Being dissolved in DMF, nitrogen is protected, heating reflux reaction 2-3 hour, and after reaction completely, separating-purifying obtains compound 2-1；The structural formula of described compound 2-1 is as follows:
；
6) being dissolved in dichloromethane by the DCC of the DMAP, 1eq of the compound 1-4,1eq of 1eq compound 2-1 Yu 1eq, nitrogen is protected, and room temperature reaction 8 hours, separating-purifying obtains target-probe compound FN3-H2S。
The preparation method of hydrogen sulfide fluorescence probe the most according to claim 2, it is characterized in that, in described step 1), process for separation and purification is: add suitable quantity of water in reactant liquor, extract with dichloromethane, washing 2-3 time, salt is washed 2-3 time, and anhydrous sodium sulfate is dried, then pillar layer separation, eluant proportioning is dichloromethane: petroleum ether=1:1.
The preparation method of hydrogen sulfide fluorescence probe the most according to claim 2, it is characterised in that described step 2) in process for separation and purification be: pillar layer separation, eluant proportioning is dichloromethane: petroleum ether=1:1.
The preparation method of hydrogen sulfide fluorescence probe the most according to claim 2, it is characterized in that, in described step 3), process for separation and purification is: ethyl acetate extracts 2 times, wash 2-3 time, saline washs 2-3 time, anhydrous sodium sulfate is dried, pillar layer separation, and eluant proportioning is dichloromethane: petroleum ether=1:2.
The preparation method of hydrogen sulfide fluorescence probe the most according to claim 2, it is characterized in that, in described step 4), process for separation and purification is: extract 2 times with dichloromethane, wash 2-3 time, salt is washed 1 time, anhydrous sodium sulfate is dried, pillar layer separation, and eluant proportioning is dichloromethane: petroleum ether=1:2.
The preparation method of hydrogen sulfide fluorescence probe the most according to claim 2, it is characterised in that in described step 5), process for separation and purification is: reactant liquor pours generation solid, then filtration under diminished pressure in a large amount of water, vacuum drying into, obtains net product.
The preparation method of hydrogen sulfide fluorescence probe the most according to claim 2, it is characterised in that in described step 6), process for separation and purification is: pillar layer separation, eluant proportioning is dichloromethane: petroleum ether=1:1.
9. the application of the hydrogen sulfide fluorescence probe described in a claim 1, it is characterised in that described fluorescent probe can apply to the content sensing detection of hydrogen sulfide in water environment and biological cell system；Described sensing detection comprises fluoroscopic examination, visual qualitative detection, and cell imaging detects.
CN201610264719.5A 2016-04-26 2016-04-26 Fluorescence-enhanced hydrogen sulfide molecular fluorescent probe and preparation method and application thereof Pending CN105884713A (en)

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Publication number Priority date Publication date Assignee Title
CN107840829A (en) * 2017-11-02 2018-03-27 中南大学 A kind of fluorescence probe of specific recognition hydrogen sulfide
CN110305039A (en) * 2018-03-27 2019-10-08 孙治刚 A kind of application of novel fluorescence enhancement type probe in detection hydrogen sulfide
CN111072694A (en) * 2018-10-19 2020-04-28 复旦大学 Hydrogen sulfide identification detection fluorescent probe and preparation method and application thereof
CN111072694B (en) * 2018-10-19 2022-11-08 复旦大学 Hydrogen sulfide identification detection fluorescent probe and preparation method and application thereof
CN111233917A (en) * 2020-03-27 2020-06-05 中国人民解放军陆军防化学院 Fluorine ion detection small molecular probe and preparation method thereof

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Application publication date: 20160824