CN108373447B - Fluorescent probe for distinguishing dead/living cells and synthetic method and application thereof - Google Patents
Fluorescent probe for distinguishing dead/living cells and synthetic method and application thereof Download PDFInfo
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- CN108373447B CN108373447B CN201810107191.XA CN201810107191A CN108373447B CN 108373447 B CN108373447 B CN 108373447B CN 201810107191 A CN201810107191 A CN 201810107191A CN 108373447 B CN108373447 B CN 108373447B
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
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Abstract
The invention provides a fluorescent probe with variable target and fluorescence color and application thereof in distinguishing and imaging dead and live cells, wherein the chemical name of the fluorescent probe is as follows: 2- (6-methoxy-6-naphthylvinyl) -N-methyl-quinolinethide. Synthesized by the following steps: synthesizing 1, 2-dimethyl quinoline iodonium salt by using 2-methylquinoline and iodomethane; 1, 2-dimethyl quinoline iodonium salt and 6-methoxy-2-naphthaldehyde are condensed at room temperature by taking pyrrolidine as a catalyst to generate a product. The invention also provides an application of the fluorescent probe in distinguishing dead and live cells. The probe provided by the invention is simple in synthesis method, can distinguish and mark dead and live cells by two fluorescence colors and two dyeing positions, and has a great application prospect.
Description
Technical Field
The invention relates to a fluorescent probe with double targets and changeable fluorescent colors for distinguishing dead and living cells, a synthetic method and application thereof, and belongs to the field of organic small molecule fluorescent probes.
Background
the distinguishing and detecting of the dead and live cells has important significance in biology, medical science and related fields. In biology, the differential detection of dead and live cells is an important tool for studying the apoptosis process; in the field of medicine, distinguishing and detecting dead and live cells and counting the survival rate of cells are the most direct methods for confirming the drug effect and cytotoxicity of drugs. Therefore, the reagent capable of distinguishing and detecting the dead and live cells is an important research tool in the field of life science, can promote the development of life science, and has wide commercialization prospect.
To date, the detection of dead and live cells has relied on reagents that are capable of distinguishing between dead and live cells. First, by directly observing the cell morphology, one determines the state of the cell, which is difficult to eliminate. In addition, statistical studies of cell viability also require agents that give a discriminatory signal for dead and live cells. The current reagents for differentiating dead and live cells are classified into two types, i.e., colorimetric type and fluorescent type. Typical examples of the colorimetric reagents include tetrazolium compounds such as MTT and CCK-8. These compounds themselves have a short-wave and weak absorption spectrum and can be directly or indirectly reduced to formazan having a long-wave and strong absorption by the mitochondrial membrane potential in living cells, and thus the survival rate of living cells can be quantified by measuring the absorbance thereof. Compared thereto, the fluorescent probe has a wider application. By using the fluorescent probe, the state of a single cell can be observed in real time and in situ under a microscope, and the fluorescent probe has a greater promotion effect on life science research. Most of the probes for distinguishing dead cells from live cells which are commercially available and reported in the literature currently only mark dead cells or live cells, so that the inevitable uneven staining in the experimental operation causes great interference. Therefore, to avoid interference and give more accurate results, fluorescent probes for distinguishing between labeled dead and live cells need to be given, but such probes are currently rarely reported.
Disclosure of Invention
Aiming at the problem that a fluorescent probe for distinguishing and detecting dead/live cells is lack at present, the invention provides the fluorescent probe for distinguishing and detecting the dead/live cells, and the fluorescence color is variable.
Another object of the present invention is to provide a method for synthesizing the fluorescent probe.
It is still another object of the present invention to provide a use of the above fluorescent probe for discriminating between dead/live cells.
In order to achieve the purpose, the invention adopts the following technical scheme.
A fluorescent probe for distinguishing dead/living cells has a chemical name of 2- (6-methoxy-6-naphthylvinyl) -N-methyl-quinoline iodonium salt, MNQI for short, and the chemical structural formula of the fluorescent probe is shown as the formula (I):
Formula (I).
A method for synthesizing the fluorescent probe comprises the following steps:
(1) heating 2-methylquinoline and iodomethane in ethanol for reaction, and separating to obtain 1, 2-dimethyl-quinoline iodonium salt (compound 1);
(2) Dissolving 1, 2-dimethyl-quinoline iodonium salt and 6-methoxy-2-naphthaldehyde in ethanol, stirring at room temperature in the presence of pyrrolidine, separating out solids, filtering to obtain a crude product, and purifying to obtain the product, namely the fluorescent probe for distinguishing dead/live cells.
in the step (1), the molar ratio of the 2-methylquinoline to the methyl iodide is 1: 1-2. In the step (2), the molar ratio of the 1, 2-dimethyl-quinoline iodonium salt to the 6-methoxy-2-naphthaldehyde is 5: 4-6; the molar ratio of the 1, 2-dimethyl-quinoline iodonium salt to the pyrrolidine is 1: 1-9.
In the step (1), the reaction temperature is 40-60 ℃, and the reaction time is 24-48 hours.
the purification method in the step (2) is recrystallization in ethanol.
The synthetic route of the fluorescent probe is as follows:
。
The application of the target and the fluorescent probe with variable fluorescence color in distinguishing dead/living cells is characterized in that single photon excitation wavelength is 488 nm, dual-channel detection is carried out, and the detection wave band is 500-738 nm of green light wave band and 663-738 nm of near infrared wave band.
The working principle of the fluorescent probe is as follows:
the fluorescent probe is a cationic salt type compound, the monomer state is yellow green fluorescence (580 nm), the J -aggregation state is red fluorescence (660 nm), mitochondria in living cells have higher membrane potential, the probe is enriched on the mitochondria and presents J -aggregation state to emit red fluorescence, after the cells die or die, the membrane potential of the mitochondria disappears, the probe migrates into cell nucleus to present the monomer state to emit green fluorescence, thereby realizing the difference between the color and the dyeing position in the dead and living cells.
The invention has the following advantages:
The probe synthesis method is simple and high in yield, and can realize double-signal distinguishing detection of dead and live cells.
Drawings
FIG. 1 is an 1 H NMR spectrum of Compound 1;
FIG. 2 is an 13 C NMR spectrum of Compound 1;
FIG. 3 is an 1 H NMR spectrum of a fluorescent probe MNQI;
FIG. 4 is an 13 C NMR spectrum of a fluorescent probe MNQI;
FIG. 5 is a photograph of fluorescence imaging of stained live cells and dead cells of the probe MNQI;
FIG. 6 shows the co-localization of the MNQI probe with the mitochondrial crimson probe in living cells; and co-localization experiments of probe MNQI and nuclear probe Hoechst33342 in dead cells;
FIG. 7 shows the results of the cytotoxicity test of the probe MNQI.
Detailed Description
The present invention will be further described with reference to the following examples and drawings, but the present invention is not limited to the following examples; the compound numbers in the examples correspond to the numbers in the above-mentioned compounds.
example 1 Synthesis of fluorescent probes.
(1) Synthesis of 1, 2-dimethyl-quinoline iodonium salt (compound 1):
1 d 6 J J J J J J 13 d 6 5-10 mL of ethanol is added into a round bottom flask, 1.1-1.4 mL of 2-methylquinoline is added, 0.5-1.2 mL of iodomethane solution is added, the mixture is heated to 40-60 ℃ for reaction for 24-48 hours, after the reaction is finished, the reaction system is cooled to room temperature, solid is precipitated, and the solid is filtered and washed by ethanol to obtain 1, 2-dimethyl-quinoline iodonium salt (compound 1) with the yield of 92%.
(2) Synthesis of 2- (6-methoxy-6-naphthylvinyl) -N-methyl-quinoline iodonium salt (MNQI):
taking compound 1 (0.6 g, 2 mmol), adding acetic anhydride of 5mL, heating at 80 ℃ for 8 hours, evaporating solvent, and recrystallizing in ethanol to obtain pure product of 0.4g, which is yellow solid with a yield of 57%. its nuclear magnetic hydrogen spectrum and carbon spectrum are shown in FIG. 2 and FIG. 3.1 H NMR (400 MHz, DMSO- d 6) delta (ppm), 9.09 (d, J = 8.9 Hz, 1H), 8.65 (d, J = 9.0 Hz, 1H), 8.59 (d, J = 9.0 Hz, 1H), 8.45-8.31 (m, 3H), 8.26-8.13 (m, 2H), 8.07-7.90 (m, 4H), 7.44 (d, J = 2.5 Hz, 1H), 7.27 (dd, J = 8.9, 2.5, 1H), 7.72 (m, 4H), 7.72, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52-8.72, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52, 159.52.
example 2 cellular imaging of fluorescent probe MNQI.
(1) Cell culture, treatment and staining:
HeLa cells with a density of 3X 10 5 /mL are inoculated into a sterilized 35 mM imaging culture dish, the cells are cultured in a CO 2 incubator (the temperature is 37 ℃ and 5% CO 2) for more than 12 hours to adhere to the wall, adherent cells are treated by 4% paraformaldehyde for 30 minutes to obtain a dead cell sample, a probe DMSO solution obtained in example 1 with a concentration of 2.5 mM is prepared as a mother solution, the mother solution is added into the dead cell culture dish to ensure that the final concentration is 5 mu M, the culture is continued for 1 hour under the same condition respectively, then the cell culture solution is sucked away, the cells are washed by a culture medium for 3 times, and then the cell imaging experiment is carried out.
(2) Confocal microscopy imaging:
the fluorescence image obtained by using 488 nm as the excitation wavelength, the green channel collection wavelength of 500-550 nm and the near-infrared channel collection wavelength of 663-738 nm is shown in FIG. 5, in which the first column is live cell bright field imaging, green channel imaging, near-infrared channel imaging and the superposition image of the green channel and the near-infrared channel. As can be seen from fig. 5, after MNQI staining, the green channel fluorescence is weak in living cells, and the near-infrared channel fluorescence is strong and concentrated in cytoplasm; the green channel fluorescence in dead cells is strong and concentrated in cell nucleus, and the near infrared channel fluorescence is weak. Therefore, the probe MNQI can distinguish and detect dead and live cells through the fluorescent staining position and the fluorescent color double-signal change.
example 3 Probe MNQI was co-located with the commercial probe.
To further confirm the location of staining of the probe MNQI in dead and live cells, co-localized staining imaging was performed with MNQI in live and dead cells using the commercial mitochondrial dye mitochondrial dark red (MTDR) and the commercial nuclear dye (Hoechst33342), respectively.
In the cell co-localization experiment, cells were stained with 200 nM MTDR for 30min, 5. mu.M MNQI for 60 min, and then cell culture fluid was aspirated, and cells were washed 3 times with medium for cell imaging. Collecting fluorescence at 570-620 nm by using 488 nm as an excitation wavelength to collect an MNQI fluorescence signal; fluorescence at 663-738 nm is collected by using 633 nm as excitation wavelength to collect the fluorescence signal of MTDR. The fluorescence pictures obtained are shown in the first column of fig. 6, in which live cell bright field imaging, MTDR fluorescence imaging, MNQI fluorescence imaging and overlay of MTDR and MNQI are performed in order from left to right. It can be seen that the living cells reacted with the MNQI probe and then were red fluorescent, and the living cells reacted with the MTDR and then were green fluorescent; the double staining rate of the two dyes was 89% as calculated by NIS-Elements image processing software, indicating that the probe stained mitochondria in living cells.
In the co-localization experiment of dead cells (viable cells were treated with 4% paraformaldehyde for 30 min), cells were stained with 2 μ M Hoechst33342 for 30min, 5 μ M MNQI for 60 min, and then the cell culture fluid was aspirated off, and the cells were washed 3 times with medium for cell imaging. Collecting fluorescence of 500-550 nm by using 488 nm as an excitation wavelength to collect an MNQI fluorescence signal; fluorescence signals of Hoechst33342 were collected by collecting 425-475 nm fluorescence using 405 nm as excitation wavelength. The fluorescence pictures obtained are shown in the second column of fig. 6, in which live cell bright field imaging, Hoechst33342 fluorescence imaging, MNQI fluorescence imaging, and the superposition of Hoechst33342 and MNQI are performed in order from left to right. Obviously, the cell nucleus of the dead cell is blue fluorescence after the dead cell reacts with the Hoechst33342 probe; the dead cells fluoresce green after reaction with the MNQI probe, and MNQI stains the nuclear fraction in the dead cells.
Example 4 toxicity of the probe MNQI to cells.
HeLa cells having a cell density of 8000/mL are seeded into a part of wells of a 96-well plate, the remaining wells are filled with PBS buffer, and the cells are incubated in a CO 2 incubator under the following conditions that an experimental group is a cell sample after 2 hours, 24 hours and 36 hours of incubation with a medium containing 5. mu.M MNQI, a control group is a cell sample containing no dye, a blank group is a PBS buffer sample, after completion of incubation, a cell culture solution is exchanged with a fresh medium, 10. mu.L of MTT is added to each culture well, and the cells are further incubated for 4 hours, after completion of incubation, the medium is removed, 200. mu.L of DMSO is added to each well and shaken for 10min with a shaker to dissolve formazan, absorbance at 570nm of each well is measured using a microplate reader, and the survival rate (Survivalrate) of the cells can be calculated by the following equation:
A7, plotting 7 by taking the incubation time of the probe as the abscissa and the cell survival rate as the ordinate, wherein A sample is the absorbance of an experimental group, A c is the absorbance of a control group, and A b is the absorbance of a blank group, and the cell survival rate is still up to 90% after 36 hours of staining, which indicates that the toxicity of the probe to living cells is low.
Claims (7)
1. A fluorescent probe for distinguishing dead/living cells, which has a chemical name of 2- (6-methoxy-6-naphthylvinyl) -N-methyl-quinoline iodonium salt and a chemical structural formula shown in formula (I):
formula (I).
2. A method for synthesizing the fluorescent probe of claim 1, comprising the steps of:
(1) heating 2-methylquinoline and iodomethane in ethanol for reaction, and separating to obtain 1, 2-dimethyl-quinoline iodonium salt (compound 1);
(2) Dissolving 1, 2-dimethyl-quinoline iodonium salt and 6-methoxy-2-naphthaldehyde in ethanol, stirring at room temperature in the presence of pyrrolidine, separating out solids, filtering to obtain a crude product, and purifying to obtain a product, namely a fluorescent probe for distinguishing dead/live cells;
。
3. the synthesis method according to claim 2, wherein in the step (1), the molar ratio of the 2-methylquinoline to the methyl iodide is 1: 1-2.
4. The synthesis method according to claim 2, wherein in the step (1), the reaction temperature is 40-60 ℃ and the reaction time is 24-48 hours.
5. The synthesis method according to claim 2, wherein in the step (2), the molar ratio of the 1, 2-dimethyl-quinoline iodonium salt to the 6-methoxy-2-naphthaldehyde is 5: 4-6; the molar ratio of the 1, 2-dimethyl-quinoline iodonium salt to the pyrrolidine is 1: 1-9.
6. The synthesis method of claim 2, wherein the purification method in step (2) is recrystallization from ethanol.
7. Use of a fluorescent probe according to claim 1 in the preparation of a reagent for distinguishing dead cells from living cells.
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| CN109574922A (en) * | 2018-12-21 | 2019-04-05 | 济南大学 | A kind of mitochondrial membrane potential fluorescence probe and its synthetic method and application |
| CN109851553A (en) * | 2018-12-25 | 2019-06-07 | 济南大学 | A kind of mitochondria-kernel migration-type film potential fluorescence probe and its synthesis and application |
| CN110790722A (en) * | 2019-11-28 | 2020-02-14 | 济南大学 | Fluorescent probe for distinguishing dead and live cells and preparation method and application thereof |
| CN111217798A (en) * | 2020-02-24 | 2020-06-02 | 山西大学 | Coumarin-quinoline derivative and synthesis method and application thereof |
| CN112225711B (en) * | 2020-11-10 | 2022-06-17 | 山东大学 | PH-sensitive fluorescent probe capable of imaging cell nucleus and mitochondria in two colors simultaneously |
| CN112390790B (en) * | 2020-11-30 | 2022-09-06 | 西北师范大学 | Methyl quinoline-benzopyrylium derivative and preparation method and application thereof |
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| WO2011057229A2 (en) * | 2009-11-09 | 2011-05-12 | University Of Miami | Fluorescent analogs of neurotransmitters, compositions containing the same and methods of using the same |
| CN104845610A (en) * | 2015-04-21 | 2015-08-19 | 中国科学技术大学 | Fluorescent probes and their preparation method and use |
| CN106590630A (en) * | 2016-12-07 | 2017-04-26 | 山东大学 | Space-dependent type mitochondrial membrane potential fluorescent probe and application thereof |
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| WO2011057229A2 (en) * | 2009-11-09 | 2011-05-12 | University Of Miami | Fluorescent analogs of neurotransmitters, compositions containing the same and methods of using the same |
| CN104845610A (en) * | 2015-04-21 | 2015-08-19 | 中国科学技术大学 | Fluorescent probes and their preparation method and use |
| CN106590630A (en) * | 2016-12-07 | 2017-04-26 | 山东大学 | Space-dependent type mitochondrial membrane potential fluorescent probe and application thereof |
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