CN110437283A - A kind of potassium ion fluorescence probe and its preparation method and application - Google Patents
A kind of potassium ion fluorescence probe and its preparation method and application Download PDFInfo
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Abstract
The present invention relates to a kind of potassium ion fluorescence probe and its preparation method and application, the potassium ion fluorescence probe has structure shown in formula (I).Potassium ion fluorescence probe NK1 synthesis step provided by the invention is shorter and structure is simple, wherein ACLE is as K+Recognition unit, for BODIPY derivative as fluorogen and TPP as Mitochondrially targeted group, three's cooperation makes the potassium ion fluorescence probe not only selectivity with higher and sensitivity during identifying potassium ion.NK1 is small to human cervical carcinoma cell (HeLa) toxic side effect, and biocompatibility is high, can be with targetted mitochondria.In addition, NK1 provided by the invention can stream or outflow in potassium ion in qualitative monitoring cell mitochondrial.
Description
Technical field
The present invention relates to technical field of biological materials more particularly to a kind of potassium ion fluorescence probe and preparation method thereof and answer
With in particular to a kind of Mitochondrially targeted potassium ion fluorescence probe and its preparation method and application.
Background technique
Mitochondria potassium (K+) channel is a kind of transport protein in the mitochondrial inner membrane.Mitochondria K+Channel mediates thin
K between cytoplasm and mitochondria+Adjustable mitochondrial membrane potential is flowed into, mitochondria volume stable state is maintained, adjusts active oxygen object
The concentration of matter, and prevent the Ca in matrix2+Overload.In addition, mitochondria K+Channel is in cerebral anoxia or During Myocardial Infarction Process to thin
Born of the same parents' protection mechanism plays an important role, and also can be used as the Effective target site for the treatment of of cancer.Unfortunately, due to lack effective skill
Art, such as Mitochondrially targeted fluorescence K+Sensor, the Molecular Identification of these transport proteins and positioning are still imperfectly understood.Therefore,
In order to monitor Mitochondrial transmembrane K+The relationship between other biological parameter in flux and biological approach, there is an urgent need to mitochondrias
Target fluorescence K+The development and application of sensor.
2003, He etc. reported one kind hardly by Na+Ion, to K+The potassium ion ligand TAC of ion high special,
It is using three azepine cave ether TAC as K+It is glimmering to have synthesized novel potassium ion using 4- amino naphthalimide as chromophore for ion ligand
Optical sensor (A fluorescent sensor with high selectivity and sensitivity for
potassium in water[J].Journal of the American Chemical Society,2003,125(6):
1468-1469), as the result is shown the sensor in 160mM Na+Still to 2-10mM K in the presence of ion+There is biggish fluorescence response,
It can be used for detecting clinically extracellular K+Ion concentration detection.Since the TAC ligand has excellent performance, successfully develop
Some excellent sensors based on the ligand.This is K+Important breakthrough on ion transducer research history, the potassium developed
Ion ligand TAC is used till today always, it is considered to be best potassium ion binding partner.But synthesis and its complicated, reaction condition
Harshness, overall productivity are extremely low.And it can not realize Mitochondrially targeted.
Therefore, it is simple urgently to develop a kind of synthesis for this field, but selectivity is got well and the Mitochondrially targeted K of high sensitivity+It passes
Sensor monitors intracellular mitochondrial K+Concentration variation.
Summary of the invention
In view of the deficiencies of the prior art, one of the objects of the present invention is to provide a kind of potassium ion fluorescence probe, especially exist
In providing a kind of Mitochondrially targeted potassium ion fluorescence probe.The potassium ion fluorescence probe can targetted mitochondria, for potassium from
The detection selectivity with higher and sensitivity of son, while can flow or outflow in the intracellular potassium ion of qualitative monitoring, and synthesize
Method is simple.
For this purpose, the present invention adopts the following technical scheme:
The present invention provides a kind of potassium ion fluorescence probe (NK1), and the potassium ion fluorescence probe has to be tied shown in formula (I)
Structure；
In formula (I), the X is halogen.
In potassium ion fluorescence probe NK1 provided by the invention,(ACLE) it is used as K+Recognition unit, fluorine
Two pyrroles of boron (BODIPY) derivative is used as Mitochondrially targeted group as fluorogen and triphenylphosphine salt (TPP), and three cooperates,
Make the potassium ion fluorescence probe not only selectivity with higher and sensitivity during identifying potassium ion, it can be with target
To mitochondria, and can be to flow or outflow in the intracellular potassium ion of qualitative monitoring.
In addition, NK1 provided by the invention for human cervical carcinoma cell (HeLa) and Human normal hepatocyte (L02) substantially without
Toxic side effect, biocompatibility is high, and the synthetic method of ACLE is more simple compared to TAC, to simplify the synthesis step of NK1
Suddenly.
Potassium ion fluorescence probe NK1 for potassium ion recognition mechanism as shown in Figure 1, NK1 be not associated with potassium ion before, by
Electron effect in NK1 on N atom, cannot return to its ground state after causing the electronics light of chromophore molecule to excite and discharge
Photo induced electron transfer (PET) phenomenon occurs for fluorescence out, so as to cause fluorescent quenching；When being combined with potassium ion, it is lonely right to hinder
The PET of electronics is acted on, so that fluorescence is restored.
Preferably, the X is bromine, iodine or chlorine, preferably bromine.
The second object of the present invention is to provide a kind of preparation method of potassium ion fluorescence probe described in the first purpose, institute
Stating preparation method includes step (c): making compound ACLE-CHO and compound BODIPY-TPP reaction that potassium ion be prepared glimmering
Light probe, reaction equation are as follows:
The X is halogen.
In the present invention, compound BODIPY-TPP is according to document (A highly selective mitochondria-
targeting fluorescent K+Sensor [J] .Angew Chem Int Ed, 2015,54,12053-12057.) remembered
The method of load is prepared.
Preferably, in step (c), the reaction carries out in the presence of a catalyst, and the catalyst is piperidines.
Preferably, in step (c), the reaction carries out under reflux.
Preferably, in step (c), the solvent of the reaction includes ethyl alcohol and/or the tert-butyl alcohol.
Preferably, in step (c), time of the reaction is 20-25h, for example, 21h, 21.5h, 22h, 23h, 23.5h,
For 24 hours, 24.5h etc..
Preferably, further include step (b) before step (c): compound ACLE is prepared with phosphorus oxychloride reaction
Compound ACLE-CHO, reaction equation are as follows:
Preferably, in step (b), the time of the reaction is 2-4h.
Preferably, in step (b), the solvent of the reaction includes n,N-Dimethylformamide and/or methylene chloride.
Preferably, step (a) is carried out before step (b): compound 8 being made to react to obtain compound ACLE with compound 7,
Its reaction equation is as follows:
Preferably, in step (a), the reaction product of compound 8 and compound 7 is obtained into compound after precipitating reagent precipitates
ACLE。
In a preferred approach, the present invention obtains compound ACLE using the precipitating reagent precipitation method, not only easy to operate, and yield
Up to 60% or more.
Preferably, in step (a), the precipitating reagent includes sodium perchlorate monohydrate and/or sodium perchlorate.
Preferably, in step (a), the solvent of the reaction includes tetrahydrofuran and/or acetonitrile.
Preferably, in step (a), the reaction carries out under reflux.
Preferably, in step (a), time of the reaction is 20-25h, for example, 21h, 21.5h, 22h, 23h, 23.5h,
For 24 hours, 24.5h etc..
Preferably, the preparation method of the compound 8 includes the following steps:
(1) make compound 1 withReaction obtains compound 2, and reaction equation is as follows:
(2) make compound 2 and NH2NH2·H2O reacts to obtain compound 3, and reaction equation is as follows:
(3) compound 3 is made to react to obtain compound 8 with ethylene bromohyrin, reaction equation is as follows:
Preferably, in step (1), the reaction carries out in the presence of a catalyst, the catalyst include potassium iodide and/or
Sodium iodide.
Preferably, in step (1), the reaction carries out in the presence of acid binding agent, the acid binding agent include potassium carbonate and/or
Triethylamine.
Preferably, in step (1), the solvent of the reaction includes acetonitrile and/or n,N-Dimethylformamide.
Preferably, in step (1), time of the reaction is 20-25h, for example, 21h, 21.5h, 22h, 23h, 23.5h,
For 24 hours, 24.5h etc..
Preferably, in step (2), the reaction carries out in the presence of a catalyst, and the catalyst includes Pd/C.
Preferably, in step (2), the solvent of the reaction includes ethyl alcohol and/or methanol.
Preferably, in step (2), time of the reaction is 2-3h, for example, 2.1h, 2.2h, 2.3h, 2.4h, 2.5h,
2.6h, 2.7h, 2.8h, 2.9h etc..
Preferably, in step (3), the solvent of the reaction includes water and/or Isosorbide-5-Nitrae-dioxane.
Preferably, in step (3), the solvent of the reaction includes water and Isosorbide-5-Nitrae-dioxane, and the water and Isosorbide-5-Nitrae-two
The volume ratio of six ring of oxygen is 1-1.5:1, such as 1.1:1,1.2:1,1.3:1,1.4:1 etc..
Preferably, in step (3), the reaction carries out in the presence of a catalyst, the catalyst include potassium iodide and/or
Sodium iodide.
Preferably, in step (3), the reaction carries out in the presence of acid binding agent, the acid binding agent include potassium carbonate and/or
Calcium carbonate.
Preferably, in step (3), the reaction is 5-7 days in the time, such as 5.2 days, 5.3 days, 5.5 days, 5.8 days, 6
It, 6.3 days, 6.8 days etc..
Preferably, the preparation method of the compound 7 includes the following steps:
(1 ') makes tetraethylene-glycol react to obtain compound 7 with paratoluensulfonyl chloride, and reaction equation is as follows:
Preferably, in step (1 '), the solvent of the reaction includes methylene chloride and/or acetone.
Preferably, in step (1 '), the reaction carries out in the presence of acid binding agent, and the acid binding agent includes sodium hydroxide
And/or potassium hydroxide.
Preferably, in step (1 '), time of the reaction is 3-5h, for example, 3.2h, 3.4h, 3.6h, 3.8h, 4h,
4.2h, 4.4h, 4.6h, 4.8h etc..
The third object of the present invention is to provide potassium ion fluorescence probe described in a kind of first purpose and detects in potassium ion
In application.
Compared with the existing technology, the invention has the following beneficial effects:
In potassium ion fluorescence probe NK1 provided by the invention, ACLE is as K+Recognition unit, BODIPY derivative is as glimmering
Light blob and TPP as Mitochondrially targeted group, the potassium ion fluorescence probe not only have during identifying potassium ion compared with
High selectivity and sensitivity, can be with targetted mitochondria, and with stream in the intracellular potassium ion of qualitative monitoring or can outflow.
In addition, NK1 provided by the invention for human cervical carcinoma cell (HeLa) and Human normal hepatocyte (L02) substantially without
Toxic side effect, biocompatibility is high, and synthetic method is simple.
Detailed description of the invention
Fig. 1 is recognition mechanism figure of the potassium ion fluorescence probe provided by the invention for potassium ion.
Fig. 2 is the ultraviolet-visible absorption spectroscopy of NK1 in test case 1 of the present invention with K+The variation diagram of concentration.
Fig. 3 a is the fluorescence emission spectrum of NK1 in test case 2 of the present invention with K+The variation diagram of concentration.
Fig. 3 b be in test case 2 of the present invention fluorescence intensity of the NK1 at 572nm with K+The variation diagram of concentration.
Fig. 4 a is the fluorescence intensity of NK1 in test case 3 of the present invention with the variation diagram of other physiology relevant ions.
Fig. 4 b be in test case 3 of the present invention fluorescence intensity of the NK1 at 572nm with the variation diagram of different ions concentration.
Fig. 5 be in test case 4 of the present invention NK1 handle 4h, 8h and 16h after to the movable influence diagram of HeLa cell Proliferation.
Fig. 6 a is the merging figure of NK1, Mito-tracker Green and light field in test case 4 of the present invention.
Fig. 6 b is the fluorescence intensity regional distribution chart in straight line (in oval frame) meaning region in Fig. 6 a of the present invention.
Fig. 7 a is the intracellular K of L02 that NK1 induces nigericin in test case 5 of the present invention+The monitoring of interior stream or outflow
Figure.
Fig. 7 b is the intracellular K of L02 that NK1 induces ionmycin in test case 5 of the present invention+The monitoring of interior stream or outflow
Figure.
Fig. 7 c is the intracellular K of HeLa that NK1 induces nigericin in test case 5 of the present invention+The monitoring of interior stream or outflow
Figure.
Fig. 7 d is the intracellular K of HeLa that NK1 induces ionmycin in test case 5 of the present invention+The monitoring of interior stream or outflow
Figure.
Specific embodiment
Of the invention for ease of understanding, it is as follows that the present invention enumerates embodiment.Those skilled in the art are it will be clearly understood that the implementation
Example is only to aid in the understanding present invention, should not be regarded as a specific limitation of the invention.
Embodiment 1
It is specific as follows the present embodiment provides the preparation method of compound ACLE:
(1) synthesis of compound 7
Tetraethylene-glycol (9.7g, 50mmol) and potassium hydroxide (5.6g, 100mmol) are dissolved in 100mL methylene chloride
In, after ice bath is cooled to 0 DEG C, paratoluensulfonyl chloride (38.0g, 200mM) is added dropwise under nitrogen protection.Drop finishes, and the reaction was continued
4h.After completion of the reaction, saturation NaCl is washed 3 times, and methylene chloride extraction merges organic phase, dries, filters through anhydrous magnesium sulfate,
Concentration, silica gel column chromatography separation (PE:EA=1:1) obtain colourless transparent liquid 17.5g, yield 70%.
1H NMR(400MHz,CDCl3) δ 7.76 (d, J=8.2Hz, 4H), 7.32 (d, J=8.1Hz, 4H), 4.15-4.10
(m, 4H), 3.67-3.62 (m, 4H), 3.53 (m, 8H), 2.41 (s, 6H).
13C NMR (101MHz, CDCl3) δ 144.87 (s), 132.89 (s), 129.86 (s), 127.92 (s), 77.52
(s), 77.20 (s), 76.88 (s), 70.57 (d, J=16.7Hz), 69.34 (s), 68.62 (s), 21.61 (s).
(2) synthesis of compound 8
By 2- nitrophenol (11.2g, 80.0mmol), the bromo- 2- Ethyl Methyl Ether (16.4g, 120mmol) of 1-, potassium iodide
(6.72g, 40.0mmol) and potassium carbonate (12.0g, 88.0mmol) are dissolved in 500ml round-bottomed flask, are dissolved, are heated to 200mL
90 DEG C of back flow reactions are stayed overnight.Whether TLC monitoring reaction is complete, and after completion of the reaction, vacuum distillation removes solvent.It dissolves the residue in
100mL CH2Cl2In, saturation NaCl (3 × 100mL) is washed 3 times, and water phase uses CH again2Cl2(2 × 100mL) is extracted twice.It is associated with
Machine phase, anhydrous MgSO4It is dry, it filters, concentration, silica gel column chromatography separates (PE:EA=2:1), obtains yellow color solid (compound
2) 15.73g, yield 94%.
1H NMR (400MHz, Chloroform-d) δ 7.84 (dd, J=8.1,1.5Hz, 1H), 7.56-7.49 (m, 1H),
7.13 (d, J=8.4Hz, 1H), 7.05 (t, J=7.8Hz, 1H), 4.29-4.24 (m, 2H), 3.84-3.78 (m, 2H), 3.47
(s, 3H).
Compound 2 (12.8g, 62.9mmol) and 10%Pd/C (1.3g) are dissolved in the anhydrous EtOH of 100mL, ice bath is cooled to
0 DEG C or less.Then N is slowly dropped into constant pressure funnel2H4·H2O(10mL).After being added dropwise, ice bath is removed, is slowly heated up
To reflux.Reaction was completed after 2h, and after being cooled to room temperature, filtering, filtrate removes solvent through being evaporated under reduced pressure, dissolves the residue in
100mL CH2Cl2In, saturation NaCl (3 × 100mL) is washed 3 times, and water phase uses CH again2Cl2(2 × 100mL) is extracted twice.It is associated with
Machine phase, anhydrous MgSO4It is dry, it filters, concentration is directly used in the next step without further purification.Obtain weak yellow liquid (compound 3)
10g, yield 94%.
1H NMR (400MHz, Chloroform-d) δ 6.86-6.81 (m, 2H), 6.77-6.70 (m, 2H), 4.19-4.14
(m, 2H), 3.80-3.76 (m, 2H), 3.53 (s, 2H), 3.47 (s, 3H).
By compound 3 (11.0g, 65.8mmol), ethylene bromohyrin and CaCO3(13.16g, 131.6mmol) is dissolved in 200mL
In water and Isosorbide-5-Nitrae-dioxane mixed solution (1:1), back flow reaction 6 days.After completion of the reaction, it is filtered to remove calcium carbonate, decompression is steamed
Most of solvent is removed in distillation, and saturation NaCl is washed 3 times, and methylene chloride extraction merges organic phase, mistake dry through anhydrous magnesium sulfate
Filter, concentration, silica gel column chromatography separation (PE:EA=1:2) obtain dark red solution 12.0g, yield 71.4%.
1H NMR (400MHz, CDCl3) δ 7.14 (dd, J=7.8,1.6Hz, 1H), 7.03 (td, J=7.8,1.6Hz,
1H), 6.93-6.82 (m, 2H), 4.09-4.02 (m, 2H), 3.72-3.67 (m, 2H), 3.46-3.42 (m, 4H), 3.37 (s,
3H), 3.15-3.09 (m, 4H).
(3) synthesis of compound ACLE
100mL anhydrous THF and NaH (60% paraffin oil suspension, 2.5g) are added to 500mL double-neck flask, vacuumized
And reload nitrogen, after reflux 1 hour, then by compound 8 and (8.9g, 35.0mmol) and compound 7 (17.6g,
THF solution (100mL) 35.0mmol) is slowly added in above-mentioned solution, is added dropwise after 3h.Continue reflux 24 hours.It is cooling
Afterwards, it filters, is washed with THF, filtrate is concentrated under reduced pressure.Then residue is dissolved in 5mL methanol.It is molten that 15mL is added into the solution
Solve the sodium perchlorate monohydrate (4.9g, 35.0mmol) in methanol.Mixture is heated to reflux 1 hour, solvent is evaporated, it is remaining
Object re-crystallizing in ethyl acetate.It repeats crystallization to be repeated 2 times, obtains ACLE- sodium perchlorate complex compound, be white solid.Then will
Solid is dissolved in methylene chloride and aqueous mixtures (1:1) and is stirred overnight.Again by mixture CH2Cl2(50mL × 3) dilution, and
It is washed with saturation NaCl (50mL × 3).Merge organic layer, through anhydrous MgSO4It dries, filters, after concentration, obtains brown oil
9.0g, yield 62.4% are directly used in the next step without being further purified.
1H NMR (400MHz, Chloroform-d) δ 7.07-6.99 (m, 1H), 6.89-6.77 (m, 3H), 4.11-4.04
(m, 2H), 3.72-3.53 (m, 22H), 3.42 (t, J=5.9Hz, 4H), 3.38 (s, 3H).
13C NMR (101MHz, Chloroform-d) δ 152.16,140.09,121.28,113.73,71.10,70.73,
70.60,70.58,70.31,69.98,67.54,58.96,52.70.
Embodiment 2
It is specific as follows the present embodiment provides the preparation method of potassium ion fluorescence probe NK1 a kind of:
(1) synthesis of compound ACLE-CHO
ACLE (4.49g, 12mmol) is dissolved in 30mL DMF, -20 DEG C is cooled to, POCl is then slowly added dropwise again3
(18.5g, 120mmol), drop finish, and stir 30min at room temperature.It is again heated at 70 DEG C and reacts 1h.Reaction solution is added drop-wise to again
In 250g mixture of ice and water, methylene chloride is extracted 3 times, merges organic phase, and through drying, concentration, silica gel column chromatography separation is obtained
Pale yellow viscous liquid 2.87g, yield 54.
1H NMR(CDCl3, 300MHz): d=9.69 (s, 1H), 7.30 (dd, 1H, J=8.3Hz, 1.8Hz), 7.26 (d,
1H, J=1.8Hz), 6.93 (d, 1H, J=8.3Hz), 4.11-4.08 (m, 2H), 3.71-3.55 (m, 26H), 3.36ppm (s,
3H)；13C NMR(CDCl3, 75MHz): d=190.14,149.69,146.08,128.22,126.73,116.46,111.01,
70.70,70.61,70.55,70.48,70.42,69.95,67.46,58.65,52.61.
(2) synthesis of potassium ion fluorescence probe NK1
ACLE-CHO (180mg, 0.396mmol), BODIPY-TPP (333mg, 0.436mmol) and 1 drop piperidines are dissolved in
In 10mL dehydrated alcohol, reflux is for 24 hours.It is spin-dried for ethyl alcohol, is extracted with dichloromethane, saturated common salt is washed three times, and organic phase, nothing are merged
Water magnesium sulfate is dry, filters, and filtrate is spin-dried for vacuum distillation, alkali alumina column chromatography for separation, mobility DCM:MeOH=
50:1, solvent DCM:MeOH=25:2 obtain blue solid 76.0mg, yield 18.6%.
1H NMR (400MHz, Chloroform-d) δ 7.93-7.71 (m, 15H), 7.50 (d, J=16.2Hz, 1H),
7.21-7.07 (m, 5H), 6.98 (t, J=8.2Hz, 3H), 6.59 (s, 1H), 5.99 (s, 1H), 4.23-4.17 (t, 2H),
3.99 (s, 2H), 3.73-3.59 (m, 26H), 3.46 (s, 3H), 3.43 (s, 2H), 2.59 (s, 3H), 1.75-1.68 (m, 7H),
1.57-1.52 (m, 2H), 1.48 (s, 3H), 1.44 (s, 3H).
13C NMR (101MHz, Chloroform-d) δ 163.14,159.59,142.70,134.93,134.90,
133.79,133.69,130.51,130.39,129.42,127.03,122.07,119.03,118.17,117.52,115.00,
88.03,77.26,71.18,71.06,70.69,70.55,70.26,70.14,69.53,67.90,67.77,59.01,
58.94,56.24,52.64,47.15,30.20,30.04,29.70,28.95,26.46,25.75,25.33,23.58,
22.69,22.17,14.92,14.59,14.12.
HR-MS(ESI+)C65H78O8N3BF2P+, calculated value: 1108.55822, theoretical value 1108.55762, Δ=
0.54030ppm。
Test case 1
The variation of the ultraviolet-visible absorption spectroscopy of NK1 is tested:
NK1 solid is dissolved in DMSO and is configured to stock solution (2.5mM), 6 μ L NK1 stock solutions is taken to be added to 150 μ L
In cetyl trimethylammonium bromide (CTAB) aqueous solution (10mM), add 2844 μ L HEPES buffer solutions (pH=7.4,
5mM), make final concentration of 5 μM of NK1, the final concentration of 0.5mM of CTAB.Mixed solution is added in cuvette (1cm), potassium is measured
Ion concentration is the ultraviolet-visible absorption spectroscopy (Fig. 2) in the section 0-1000mM.
As seen from Figure 2, not plus when potassium ion, a length of 580nm of the maximum absorption wave of NK1, in certain model of >=580nm
In enclosing, absorbance increases with potassium concentration and reduces (such as Fig. 2 right arrow pointed location), as potassium concentration increases
Add, maximum absorption wavelength blue shift to 570nm or so, and have isobestic point at 575nm, between 570nm and isobestic point, inhales
Luminosity increases (such as Fig. 2 left arrow pointed location) with the raising of potassium concentration.Illustrate the benzene azepine -18- crown ether of NK1
After in conjunction with potassium ion, electron donation weakens, and PET effect weakens, and ultravioletvisible absorption is caused to have blue shift.
Test case 2
Tested K+Influence of the concentration to the fluorescence of NK1:
It takes 6 μ L NK1 stock solutions to be added in 150 μ L CTAB aqueous solutions (10mM), adds 2844 μ L HEPES buffering
Liquid (pH=7.4,5mM) makes final concentration of 5 μM of NK1, the final concentration of 0.5mM of CTAB.Mixed solution is added to fluorescence cuvette
In (1cm), measurement potassium concentration is the fluorescence emission spectrum spectrum in the section 0-1000mM, excitation wavelength 540nm, Ex/Em
Slit width is 5/5nm.
Test obtains the fluorescence emission spectrum of NK1 shown in Fig. 3 a with K+NK1 shown in the variation diagram and Fig. 3 b of concentration
Fluorescence intensity at 572nm is with K+The variation diagram of concentration；There are two emission peaks by NK1 it can be seen from Fig. 3 a, exist respectively
620nm and 572nm is wherein emission maximum at 620nm, and as potassium concentration is continuously increased, the fluorescence intensity of NK1 gradually increases
By force, maximum emission wavelength is from blue shift to 572nm.By Fig. 3 b it is found that 572nm fluorescence intensity change is significant, maximum power
Learn range F/F0≈160。F0To be not associated with K+Fluorescence intensity at 572nm before, F are in conjunction with respective concentration K+Later in 572nm
The fluorescence intensity at place.
Test case 3
The potassium ion selective of NK1 is studied:
(1) plus suitable stock solution is in HEPES buffer solution (10mM, PH=7.4), makes final concentration of 5 μM of NK1, work
Making liquid product is 3mL.By working solution loaded in the silica dish of the four sides 1cm light transmission, different metal ions Na is measured+(15mM), Mg2+
(2mM), Ca2+(2mM), Zn2+(2mM), Mn2+(50 μM), Cu2+(50 μM), Fe2+(50 μM), Fe3+(50 μM) are strong to NK1 fluorescence
The influence of degree, to test the selectivity and specificity of sensor NK1.
Test obtains the fluorescence intensity of NK1 shown in Fig. 4 a with the variation diagram of other physiology relevant ions.As shown in Fig. 4 a,
Add Na+、Mg2+、Ca2+、Zn2+、Mn2+、Cu2+、Fe2+And Fe3+Fluorescence intensity of the NK1 at 572nm and before ion is not added afterwards
Fluorescence intensity is almost the same, adds 5mM K+The fluorescence amplification that can cause about 2 times afterwards, adds the K of 150mM+After can cause about 60 times
Fluorescence amplification.Illustrate NK1 to the Na under physiological concentration+、Mg2+、Ca2+、Zn2+、Mn2+、Cu2+、Fe2+And Fe3+It is substantially insensitive,
It is big to potassium ion specificity.
(2) in order to continue study potassium ion selectivity and specificity, we also emphatically have studied and the same main group of potassium ion
And the similar Li of ionic radius+, Na+, Rb+And Cs+To the change curve of NK1 fluorescence.NK1 shown in Fig. 4 b is obtained at 572nm
Fluorescence intensity with different ions concentration variation diagram.
As shown in Figure 4 b, Li in figure+And Cs+Curve and Na+Registration is higher to be led to not differentiate, and specifically, works as concentration
When being 150mM, add K+F/F0Value is to add Li+29 times, be plus Na+23 times, be plus Rb+11 times, be plus Cs+24
Times, illustrate that NK1 has height potassium ion specificity.
Test case 4
The cytotoxicity and cell distribution of NK1 is tested:
(1) using MTT colorimetric method for determining for determine NK1 to the potential cytotoxicity of living cells, it is specific as follows:
Human cervical carcinoma cell (HeLa cell) culture is being contained into 10% heat-inactivated fetal calf serum (FBS) and 1% mould
In element/streptomysin DMEM culture medium, in 37 DEG C and 5%CO2It is cultivated in incubator.Then by HeLa cell (1 × 104A cell/
Hole) it is seeded in 37 DEG C of 96 orifice plates.After incubating 24 hours, handled cell 4 hours, 8 hours with the NK1 of various dose respectively and
16 hours.Use the cell of fresh culture processing as negative control group.The culture medium for removing each hole, after washing 3 times with PBS,
The MTT solution of 10 μ L and the culture medium of 100 μ L is added.After being incubated for 4 hours again, obtained first a ceremonial jade-ladle, used in libation body is dissolved in DMSO solution
In (150 μ L), with absorbance intensity at microplate reader (BioTek Synergy H4, USA) record 490nm and 510nm.All realities
Triplicate progress is tested, versus cell survival rate (%) is expressed as the percentage relative to untreatment control cell.
It tests after obtaining NK1 processing 4h, 8h and 16h as shown in Figure 5 to the movable influence diagram of HeLa cell Proliferation.By scheming
5 it is found that the cell survival rate of HeLa cell is 90% or more with after working concentration (2 μM) processing 4h, 8h and 16h of NK1,
Therefore NK1 is to HeLa cell without obvious toxic-side effects.
(2) the mitochondria target of subcellular organelle common location experimental verification NK1 is carried out using single-photon laser Laser Scanning Confocal Microscope
Tropism, specific as follows:
HeLa cell (20,000/hole) is inoculated into single-photon laser Laser Scanning Confocal Microscope (TCS-SP8, Leica, moral
State) in dedicated Glass bottom culture dish, after culture for 24 hours, culture medium is removed, changes the fresh culture culture containing 2 μM of NK1 into.It is incubated for
After 10min, culture medium is removed, is changed into containing 100nM mitochondria green fluorescence probe (Mito-Tracker Green, Thermo
Fisher Scientific, USA) fresh culture culture.After being incubated for 10min, culture medium is removed, it is molten with phosphate-buffered salt
Liquid (PBS) washs 3 times, finally uses plus 1mL PBS is into culture dish, observe under laser confocal microscope, the excitation wavelength of NK1
For 554nm, launch wavelength section is the section 560-610nm；The excitation wavelength of Mito-Tracker Green is 488nm, transmitting
Range of wavelengths is the section 490-540nm.
Test result is as shown in figure 6 a and 6b, wherein Fig. 6 a is the merging of NK1, Mito-tracker Green and light field
Figure.Fig. 6 b is the fluorescence intensity regional distribution chart in the signified region of straight line (in oval frame) in Fig. 6 a.It is calculated by software I mage Pro
The Pearson fitting coefficient of red fluorescence and green fluorescence is that 0.9, Mander fitting coefficient is 0.99, NK1 and Mito-
The fluorescence fitting coefficient of tracker Green is high, and thus provable NK1 has Mitochondrially targeted property.
Test case 5
NK1 is for detecting potassium ion dynamic change in cell mitochondrial
With fluorescence microplate reader (BioTek Synergy H4, the U.S.) verifying NK1 can qualitative monitoring by nigericin
(nigericin) (20 μM) or the K of (10 μM) of ionomycin (ionomycin) inductions+Interior stream or outflow, specific as follows:
HeLa cell (6000/hole) or L02 cell (12,000/hole) are inoculated into 96 orifice plates, after culture for 24 hours,
Be added the fresh culture culture that 100 μ L contain 2 μM of NK1, after being incubated for 30min, PBS is washed 3 times, be then respectively adding containing
A) blank；b)200mM K+；c)nigericin；d)nigericin+200mM K+；e)ionmycin；f)ionmycin+200mM
K+Culture medium, be placed in preheated microplate reader in advance and detect, excitation wavelength 540nm, detection launch wavelength is
572nm, every 30s detection is primary, persistently detects 40min.
As a result as shown in Fig. 7 a-7d, Fig. 7 a is the intracellular K of L02 that NK1 induces nigericin+Interior stream or the prison of outflow
Mapping, Fig. 7 b are the intracellular K of L02 that NK1 induces ionmycin+Interior stream or the monitoring figure of outflow, Fig. 7 c are NK1 pairs
The intracellular K of HeLa of nigericin induction+Interior stream or the monitoring figure of outflow, Fig. 7 d are that the HeLa that NK1 induces ionmycin is thin
K intracellular+Interior stream or the monitoring figure of outflow, wherein I0To be not associated with K+Fluorescence intensity at 572nm before, I are in conjunction with respective concentration
K+Fluorescence intensity at 572nm later, all in triplicate, single experimental data is made of average value ± variance for every group of experiment.
Blank group fluorescence intensity is basically unchanged it can be seen from Fig. 7 a-7d, adds 200mM K+It can cause NK1 fluorescence enhancement.
Nigericin or ionmycin can cause the fluorescence of NK1 to decline, and indicate intracellular efflux of K+ ions, and nigericin and
Ionmycin can all cause intracellular efflux of K+ ions.200mM K is added when simultaneously+When with nigericin or ionmycin,
The fluorescence of NK1 first enhances to be weakened afterwards, is indicated in cell mitochondrial and is outflowed after the first interior stream of potassium ion.And it was also found that L02 is thin
Born of the same parents' ratio HeLa cell is more sensitive to potassium concentration.NK1 can qualitative monitoring induced by nigericin or ionmycin it is intracellular
K+Interior stream or outflow, this result can be further used for high flux screening and go out the relevant drug of potassium-channel, to new drug development
With huge impetus.
Interpretation of result:
NK1 is using ACLE as potassium ion ligands specific, and two pyrroles of fluorine boron (BODIPY) is chromophore, triphenylphosphine salt
(TPP) the Mitochondrially targeted potassium ion fluorescent optical sensor synthesized for Mitochondrially targeted group.By above-mentioned performance test, obtain
Such as draw a conclusion:
(1) NK1 has more sensitive response, the larger (F/F of dynamics range to potassium ion (30-400mM)0≈ 160), have compared with
High brightness (QY is 5.5% in the presence of 150mM potassium ion), and physiological pH (5.5-9.0) is to the K of NK1+Sensing is without influence；
(2) NK1 is not only to Na+(15mM), Mg2+(2mM), Ca2+(2mM), Zn2+(2mM), Mn2+(50 μM), Cu2+(50μ
M), Fe2+(50 μM), Fe3+(50 μM) etc. substantially without response, also to same main group and the lesser rubidium (Rb of ionic radius difference+) and caesium
(Cs+) also substantially insensitive；
(3) the experiment display of cell subcellular organelle common location is carried out with laser confocal microscope, NK1 energy specific enrichment arrives
In the mitochondria of HeLa cell, which has good targeting to mitochondria；
(4) MTT screening display, NK1 have no toxic side effect substantially to human cervical carcinoma cell (HeLa), and biocompatibility is high；
(5) NK1 can also qualitative monitoring induced by nigericin (nigericin) and ionomycin (ionomycin)
Cell potassium ion in stream and outflow.The fast slowdown monitoring of high throughput to potassium ion flowing is realized using microplate reader for the first time.
The Applicant declares that the present invention is explained by the above embodiments detailed process equipment and process flow of the invention,
But the present invention is not limited to the above detailed process equipment and process flow, that is, it is above-mentioned detailed not mean that the present invention must rely on
Process equipment and process flow could be implemented.It should be clear to those skilled in the art, any improvement in the present invention,
Addition, selection of concrete mode of equivalence replacement and auxiliary element to each raw material of product of the present invention etc., all fall within of the invention
Within protection scope and the open scope.
Claims (10)
1. a kind of potassium ion fluorescence probe, which is characterized in that the potassium ion fluorescence probe has structure shown in formula (I)；
In formula (I), the X is halogen.
2. potassium ion fluorescence probe according to claim 1, which is characterized in that the X is bromine, iodine or chlorine, preferably bromine.
3. a kind of preparation method of potassium ion fluorescence probe according to claim 1 or 2, which is characterized in that the preparation
Method includes step (c): it reacts compound ACLE-CHO and compound BODIPY-TPP and potassium ion fluorescence probe is prepared,
Its reaction equation is as follows:
The X is halogen；
Preferably, in step (c), the reaction carries out in the presence of a catalyst, and the catalyst is piperidines；
Preferably, in step (c), the reaction carries out under reflux；
Preferably, in step (c), the solvent of the reaction includes ethyl alcohol and/or the tert-butyl alcohol；
Preferably, in step (c), the time of the reaction is 20-25h.
4. preparation method according to claim 3, which is characterized in that before the step (c) further include step (b): making
It closes object ACLE and compound ACLE-CHO is prepared in phosphorus oxychloride reaction, reaction equation is as follows:
Preferably, in step (b), the time of the reaction is 2-4h；
Preferably, in step (b), the solvent of the reaction includes n,N-Dimethylformamide and/or methylene chloride.
5. the preparation method according to claim 4, which is characterized in that carry out step (a) before step (b): making chemical combination
Object 8 reacts to obtain compound ACLE with compound 7, and reaction equation is as follows:
Preferably, in step (a), the reaction product of compound 8 and compound 7 is obtained into compound after precipitating reagent precipitates
ACLE；
Preferably, in step (a), the precipitating reagent includes sodium perchlorate monohydrate and/or sodium perchlorate；
Preferably, in step (a), the solvent of the reaction includes tetrahydrofuran and/or acetonitrile；
Preferably, in step (a), the reaction carries out under reflux；
Preferably, in step (a), the time of the reaction is 20-25h.
6. preparation method according to claim 5, which is characterized in that the preparation method of the compound 8 includes following step
It is rapid:
(1) compound 1 is made to react to obtain compound 2 with 2- bromo-ethyl-methyl ether, reaction equation is as follows:
(2) make compound 2 and NH2NH2·H2O reacts to obtain compound 3, and reaction equation is as follows:
(3) compound 3 is made to react to obtain compound 8 with ethylene bromohyrin, reaction equation is as follows:
7. preparation method according to claim 6, which is characterized in that in step (1), the reaction is in the presence of a catalyst
It carries out, the catalyst includes potassium iodide and/or sodium iodide；
Preferably, in step (1), the reaction carries out in the presence of acid binding agent, and the acid binding agent includes potassium carbonate and/or three second
Amine；
Preferably, in step (1), the solvent of the reaction includes acetonitrile and/or n,N-Dimethylformamide；
Preferably, in step (1), the time of the reaction is 20-25h.
8. preparation method according to claim 6 or 7, which is characterized in that in step (2), the reaction is deposited in catalyst
In lower progress, the catalyst includes Pd/C；
Preferably, in step (2), the solvent of the reaction includes ethyl alcohol and/or methanol；
Preferably, in step (2), the time of the reaction is 2-3h.
9. the preparation method according to any one of claim 6-7, which is characterized in that in step (3), the reaction it is molten
Agent includes water and/or 1,4- dioxane；
Preferably, in step (3), the solvent of the reaction includes water and Isosorbide-5-Nitrae-dioxane, and the water and Isosorbide-5-Nitrae-dioxy six
The volume ratio of ring is 1-1.5:1；
Preferably, in step (3), the reaction carries out in the presence of a catalyst, and the catalyst includes potassium iodide and/or iodate
Sodium；
Preferably, in step (3), the reaction carries out in the presence of acid binding agent, and the acid binding agent includes potassium carbonate and/or carbonic acid
Calcium；
Preferably, in step (3), the reaction is 5-7 days in the time；
Preferably, the preparation method of the compound 7 includes the following steps:
(1 ') makes tetraethylene-glycol react to obtain compound 7 with paratoluensulfonyl chloride, and reaction equation is as follows:
Preferably, in step (1 '), the solvent of the reaction includes methylene chloride and/or acetone；
Preferably, in step (1 '), the reaction carries out in the presence of acid binding agent, the acid binding agent include sodium hydroxide and/or
Potassium hydroxide；
Preferably, in step (1 '), the time of the reaction is 3-5h.
10. a kind of application of potassium ion fluorescence probe according to claim 1 or 2 in potassium ion detection.
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| WO2021047212A1 (en) * | 2019-09-09 | 2021-03-18 | 南方科技大学 | Potassium ion fluorescent probe, preparation method and application thereof |
| CN115073311A (en) * | 2022-03-23 | 2022-09-20 | 河南大学 | High-efficiency preparation of N, N ′ Synthesis method of (2-hydroxyethyl) aniline |
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| CN106929008A (en) * | 2017-03-14 | 2017-07-07 | 南方科技大学 | A kind of potassium ion fluorescence probe and its preparation method and application |
| US20190153005A1 (en) * | 2016-07-15 | 2019-05-23 | Arizona Board Of Regents On Behalf Of Arizona State University | Mitochondria-targeting fluorescent potassium+ sensor and method of making the same |
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| CN115073311A (en) * | 2022-03-23 | 2022-09-20 | 河南大学 | High-efficiency preparation of N, N ′ Synthesis method of (2-hydroxyethyl) aniline |
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