CN107011336A - One class is using pyridine as the pH fluorescence probes and its application for protonating site - Google Patents

One class is using pyridine as the pH fluorescence probes and its application for protonating site Download PDF

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CN107011336A
CN107011336A CN201710187200.6A CN201710187200A CN107011336A CN 107011336 A CN107011336 A CN 107011336A CN 201710187200 A CN201710187200 A CN 201710187200A CN 107011336 A CN107011336 A CN 107011336A
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alkoxy
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CN107011336B (en
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金明
付鲸铭
潘海燕
万德成
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Tongji University
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
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Abstract

The present invention relates to detection technique field, more particularly to noval chemical compound of the class that represents of logical formula (I) using 4 (oxazolyl of 5 phenyl 2) pyridines as core texture, wherein { R1、R2And R3Represent halogen atom, hydrogen atom, alkyl, alkoxy or with following formula (IA) group [in formula, Y represent methylene, oxygen atom or nitrogen-atoms and following formula (IB) expression group (in formula, R5Represent hydrogen atom, alkyl or alkoxy；Z1、Z2And Z3Represent no or oxygen atom；N, o and p represent 0,1 or 2) are covalently attached the group formed；R4Represent hydrogen atom, methyl, methoxyl group or the group represented with following formula (IB)；M represents 0,1 or 2], R1、R2And R3Can not be halogen atom, hydrogen atom, alkyl or alkoxy simultaneously, X represents CH=CH or not had (i.e. biphenyl structural) }, further relate to its chemical preparating process, its detection as fluorescence probe to pH value in the aqueous solution, and the detection of its pH value in the cell, especially the fluoroscopic visualization of cell, waits the application purpose of many occasions.

Description

One class is using pyridine as the pH fluorescence probes and its application for protonating site
【Technical field】
It is more particularly to a kind of to be used for the fluorescence probe of pH value in specific detection aqueous phase the present invention relates to detection technique field And preparation method thereof and the fluorescence probe living biological cell detection in application.
【Background technology】
It is many important physiology courses of pH value and cell, enzyme and tissue such as cell propagation and apoptosis in human body cell, a variety of The activities such as drug resistance, ion transport, endocytosis and contraction of muscle are all closely related.Pass through gap connection and signal path Change, pH change also affects the nervous system activities such as cynapse transmission, neuronal excitability and iuntercellular coupling.Not just Normal cell function, growth and divide generally directly or indirectly relevant with abnormal pH value, and easily trigger as cancer and Ah The diseases such as Er Cihaimo syndromes.
Under normal circumstances, the normal value of hydrionic concentration is 7.4 in 40nmol/L or so, i.e. pH in cell liquid, greatly It there are about 5nmol/L variation (pH 7.35-7.45).The fluctuation up and down of 0.1-0.2 pH unit this may result in cardiopulmonary and nerve The disease of system, such as Alzheimer syndrome, serious possibly even threat to life.The optimal pH value of human body is in 7.35- 7.45 or so, in alkalescent, because cytoactive at this moment is most strong, organ operation is most normal.If value is less than this value, human body The activity of cell, various enzymes and hormone will greatly be suppressed, and cause tissue organ function to decline, human immunity reduction etc., Various diseases can be triggered, such as：1) human body cell is made to undergo mutation and aging；2) acidic materials are easily accumulated in the blood vessels, are formed Fatty liver, high fat of blood, gout simultaneously trigger other cardiovascular and cerebrovascular diseases；3) human body value often declines 0.1 unit, and insulin utilization rate is just Decline 30%, easily produce diabetes with triggering complication；4) acidic constitution can also make one internal free radical substantial increase, no Beneficial to the absorption of calcium, osteoporosis is caused；5) it is easily caused canceration.Tumor cell viability is most strong in pH value 6.8-6.95, and Also it could must be shifted in acid condition, so acidic constitution is the main cause for producing cancer, while it can make one The function reduction 25% or so of body immunocyte, greatly weakens the ability to inhibiting tumor cell.In addition, having inside some organelles It is normal be acidity, between 4-6, such as endosome and Vacuoles of Plants.In cell biology, when pH value is 7.0, albumen Qualitative change or the effect of enzyme and protein function are slow, and low ph value, which can be played, makes protein denaturation or kinase and protein function Effect.For example, the sour environment (pH 4.5-5.5) in lysosome, can promote drop of the protein in cellular process Solution.Therefore cell dysfunction is often extremely relevant with pH value in organelle.
At present, many methods can be used for detection pH.Such as microelectrode, nuclear-magnetism, absorption and fluorescence spectrum method.In these sides In method, fluorescence method is being determined due to the property of its non-intrusive, high sensitivity and selectivity, and widely available fluorescent dye It is more more superior than other method during pH.Moreover, Induced Fluorescence Microscopy can capture cell by using fluorescent pH probe Interior hydrionic time-space resolution.
Generally, two classes are more suitable for the report of the pH fluorescence probes of different pH scopes.One class probe a (J as follows Am Chem Soc.2007；129:1894-1895) with b (Org Lett. 2004；6:2757-2760) it is used in cytoplasm, Suitable for pH scopes in 6.80-7.40, an also class such as probe c (New J Chem.2010；34:656), it is used for acid thin The use of pH scopes is 4.50-6.00 in born of the same parents' device (such as lysosome).
However, almost not on suitable for (pH under the acid condition of pole<4) research of pH probes.Although most of work Species can hardly survive under conditions of highly acidic, but substantial amounts of microorganism such as acidophilia bacterium, enteropathogen and Helicobacter pylori misses potter severe sour environment.Therefore, develop effective suitable for being detected under high acid condition The pH fluorescence probes of intracellular ph value are highly significant and practical value.
【The content of the invention】
The problem of the present invention is to provide has larger dissolubility and can be as highly sensitive pH fluorescence in aqueous phase Probe and the compound being used.Specifically, problem of the invention is to provide a kind of compound, and the compound can be in water Complex compound differs more obvious with the fluorescent characteristic of the compound before complexing and has rule after specific capture hydrogen ion in phase, seizure Rule, can be used as pH fluorescence probes.Furthermore, the other problem of the present invention is to provide containing as characterized above Compound pH fluorescence probes and using the pH fluorescence probes aqueous phase in pH value assay method.
Present inventor is in order to solve above-mentioned problem, by research, it was found that using 4- (2- oxazolyls) pyridine as substituent Compound has high specificity to hydrogen ion, captures hydrogen ion, and the fluorescent characteristic of complex compound has obvious change before not being complexed Change.Present inventor further study show that, it was found that the compound represented with following logical formula (I)s can rapidly form with hydrogen from Significant change occurs for the complex compound of son, fluorescent characteristic.In addition flexible group in compound as shown in formula (IA) is very big to be increased Strong dissolubility of the compound in aqueous phase, significantly increases its actual application value that pH value is detected in aqueous phase.
That is, the invention provides the compound represented with following logical formula (I)s：
In formula, R1、R2And R3Separately represent halogen atom, hydrogen atom, alkyl, alkoxy or with following formula (IA) Group
[in formula, m represents 0,1 or 2, R4Represent hydrogen atom, alkyl, alkoxy or the base represented with following formula (IB) Group；Y represents the group for the formation that the group that methylene, oxygen atom or nitrogen-atoms and following formula (IB) are represented is connected
(in formula, R5Represent hydrogen atom, alkyl or alkoxy；Z1、Z2And Z3Separately represent that no or oxygen is former Son, n, o and p separately represent that 0,1 or 2), Y represent what methylene, oxygen atom or nitrogen-atoms and formula (IB) were represented The group for the formation that group is connected], R1、R2And R3Can not be halogen atom, hydrogen atom, alkyl or alkoxy simultaneously；X is represented CH=CH (i.e. with both sides phenyl ring formation talan structure) does not have (being biphenyl structural) }.
As the preferred mode of foregoing invention, there is provided the compound represented with following logical formula (II)s
In formula, R6And R7Separately represent halogen atom, hydrogen atom, alkyl or alkoxy；R8Expression hydrogen atom, Alkyl or alkoxy；X1Represent CH=CH (i.e. with both sides phenyl ring formation talan structure) or do not have (to be biphenyl knot Structure).According to the preferred embodiment of the present invention, R can be provided6And R7It is simultaneously methyl, R8It is the compound of methoxyl group.
In addition, according to the present invention it is possible to providing the compound represented with following logical formula (III)s
[in formula, R9And R10Separately represent halogen atom, hydrogen atom, alkyl or alkoxy；R11And R12Independently Ground represents hydrogen atom, alkyl, alkoxy or the group represented with following formula (IIIA)
(in formula, R13Represent hydrogen atom, alkyl or alkoxy；Z4、Z5And Z6Separately represent that no or oxygen is former Son, r, s and t separately represent 0,1 or 2), X2Represent CH=CH (i.e. with both sides phenyl ring formation talan structure) Or there is no (being biphenyl structural)；Q represents 1 or 2].According to preferred embodiment of the present invention, R can be provided9And R10It is simultaneously Hydrogen atom, R13For the compound of methoxyl group.
More, according to the present invention it is possible to provide what is represented containing above-mentioned logical formula (I), logical formula (II) or logical formula (III) The pH fluorescence probes of compound；And the compound that is represented by above-mentioned logical formula (I), logical formula (II) or logical formula (III) and hydrogen from The complex compound that son is formed.The pH fluorescence probes can be used for determining the pH value in strongly acidic aqueous solution, cell and tissue.
Further, according to the present invention, the assay method of pH value in aqueous phase can be both provided, also providing will be led to above-mentioned The compound that formula (I), logical formula (II) or logical formula (III) are represented is used as the method for pH fluorescence probes；PH value must be determined in aqueous phase Method, it is characterised in that include following process：(a) chemical combination for representing above-mentioned logical formula (I), logical formula (II) or logical formula (III) Thing and the process of hydrogen ion reaction, and the process that (b) determines the fluorescence intensity of the hydride-complex generated in above-mentioned operation；And And the compound for representing above-mentioned logical formula (I), logical formula (II) or logical formula (III) is used as pH fluorescence probes.
The compound represented with above-mentioned formula (I), logical formula (II) or logical formula (III) is as manufacturing above-mentioned pH fluorescence The intermediate of probe is useful.
In this specification, the moieties of " alkyl " or " alkoxy " refer to that such as carbon number is 1-10, preferably The alkyl that straight chain, side chain, ring-type or their combinations that carbon number is 1-6, preferably carbon number 1-4 are formed.More specifically Ground is said, is used as alkyl, preferably low alkyl group (alkyl that carbon number is 1-6).As low alkyl group, for example, it can include first Base, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, Cvclopropvlmethvl, n-pentyl, n-hexyl, ring Hexyl etc..In this manual, in the case of having halogen atom, fluorine atom, chlorine atom, bromine atoms or iodine atom can, It is preferred that fluorine atom or chlorine atom.
In the compound represented with above-mentioned formula (I), X is preferably CH=CH (i.e. with both sides phenyl ring formation talan Structure) or do not have (i.e. with both sides phenyl ring formation biphenyl structural).In the compound represented with above-mentioned formula (I), preferably R1、 R2And R3One of be with formula (IA) represent group, two other be halogen atom, hydrogen atom, alkyl or alkoxy.R2In X tables When the group contraposition shown, preferably R1And R3It is simultaneously halogen atom, hydrogen atom, alkyl or alkoxy.With formula (IA) table In the group shown, m is preferably 0,1 or 2, R4Preferably alkyl, alkoxy or by formula (IB) represent group.In living cells radiography In, R4The group preferably represented by formula (IB).For Y, preferably oxygen atom or nitrogen-atoms and the base represented with formula (IB) Group's covalent bond and the group formed.It is preferred that when Y is oxygen atom, in the group represented with formula (IB), Z1And Z2Preferably oxygen is former Son, preferably n and o are that 2, p is 1；It is preferred that when Y is nitrogen-atoms and the radicals covalent bonds represented with formula (IB) and the group formed, R4It is preferred that formula (IB) represent group in, Z1And Z2Preferably oxygen atom, preferably n be 2, o be 1, p be contain in 0, Y use formula (IB) in the group represented, Z1And Z2Preferably oxygen atom, Z3Do not have preferably, preferably n and o are that 2, p is 1. R5Preferably alkane Base or alkoxy, in addition in the purposes of live cell fluorescent radiography, preferably R5For methoxyl group.
In the compound represented with above-mentioned (II) simultaneously, preferably R6And R7It is simultaneously methyl, R8It is methoxyl group.
In the compound represented with above-mentioned formula (III), preferably R9And R10It is simultaneously hydrogen atom, R11And R12For with formula (IIIA) group represented.In preferred R11In the group represented for formula (IIIA), preferably r is that 2, s is that 1, t is 0, Z4And Z5It is excellent Elect oxygen atom as；It is preferred that R12In the group represented for formula (IIIA), preferably r is that 2, s is that 1, t is 1, Z4、Z5And Z6Preferably Oxygen atom；In the group that formula (IIIA) is represented, preferably R13For alkyl or alkoxy, in addition in live cell fluorescent radiography In purposes, preferably R5For methoxyl group.It is preferred that X2For CH=CH (i.e. with both sides phenyl ring formation talan structure) or do not have (i.e. With both sides phenyl ring formation biphenyl structural).
The compound of the invention represented with above-mentioned formula (I), (II) and (III) has with 1 according to the species of substituent Individual or more than 2 asymmetric carbon atoms situation, be based not only on 1 or more than 2 asymmetric carbon atom optically active body or Give any mixing of the stereoisomer and stereoisomer of the diastereoisomer of more than 2 asymmetric carbon atoms etc. Thing, racemic modification etc. are intended to be included within.
Set out from the alpha-brominated acetophenone (HaI is halogen) of halo, by known references method (Angew. Chem.2012； 51(11):2673-6), via Dare shore reaction generation benzylamine, then with isonicotinic acid POCl3 backflow under conditions of clasp, shape Into 4- (5- phenyl -2- oxazolyls) pyridine compounds of halo, further according to literature method, such as Suzuki and Heck reactions, and take Phenyl boric acid or distyryl compound the formation biphenyl in generation (3,4 and No. 5 position) or the substitution of styrene group, that is, obtain part Logical formula (I) product；Or, demethylation prepares the intermediate with hydroxyl on the basis of product, then carries out into ether, epoxy and adds Into, Michael's conjugate addition reaction etc., obtain another part and lead to formula (I) product.
As the preferred embodiment to the logical formula (I), the preferable for leading to compound described in formula (II) and logical formula (III) embodies Leading to the R in compound synthesis method described in formula (I) in substitution phenyl boric acid and substituted phenylethylene as described above2The otherness of group, According to the substitution reaction with amido and the flexible chain of hydroxyl, logical formula (II) and (III) institute can be more prepared easily The substitution phenyl boric acid and styrene intermediate needed, follow-up synthesis mode is with reference to logical formula (I), you can obtain logical formula (II) and formula (III) compound.
In addition, in the embodiment of this specification, in more detail and it specifically show and record in this scenario exemplary The manufacture method of compound.Thus, those skilled in the art according to these illustrate, suitably select reaction raw materials, reaction condition and Reaction reagent etc., more needs, by the way that these synthetic methods are modified or changed, and can all manufacture above-mentioned formula table The compound of the invention shown.
The exemplary compounds for meeting logical formula (I) structure are listed below：
The compound of the invention represented with above-mentioned formula (I), logical formula (II) and logical formula (III) is to have as fluorescence probe Effect.The compound of the invention that is represented with above-mentioned formula (I), logical formula (II) and logical formula (III) and hydrionic complex compound Photoluminescent property is varied widely compared with the photoluminescent property of itself, and their photoluminescent properties are complexed the difference of degree with hydrogen ion Show regular change.Above-claimed cpd has larger dissolubility and has and specific can capture in aqueous Hydrogen ion and the feature for forming complex compound.The complex compound of formation also has the feature that fluorescence is produced in cell living.Therefore, use The compound of the invention that above-mentioned logical formula (I), logical formula (II) and logical formula (III) are represented is biological thin as determining in physiological conditions The pH fluorescence probes of pH value in born of the same parents and biological tissue are exceedingly useful.In addition, so-called " measure " that is used in this specification Belong to including qualitative and quantitative determination, it should make broadest explanation.
There is no particular limitation for the application method of the pH fluorescence probes of the present invention, can be same with known pH probes Sample is used.Generally, it will be selected from and be dissolved in the aqueous mediums such as physiological saline or buffer solution or second with above-mentioned (I) compound represented Immiscible material of the miscible organic solvents such as alcohol, acetone, ethylene glycol, dimethyl sulfoxide (DMSO), dimethylformamide and aqueous medium etc. In, add the solution in the appropriate buffer solution containing cell and tissue, just can be with as long as determining its fluorescence emission spectrum.
【Brief description of the drawings】
Fig. 1：(a) uv-visible absorption spectra of the probe 1 in embodiment one in aqueous under various concentrations；(b) visit The absorbance of the maximum absorption wave strong point of pin 1 with concentration situation of change.
Fig. 2：(a) uv-visible absorption spectra of the probe 2 in embodiment two in aqueous under various concentrations；(b) visit The absorbance of the maximum absorption wave strong point of pin 2 with concentration situation of change.
Fig. 3：(a) uv-visible absorption spectra of the probe 3 in embodiment three in aqueous under various concentrations；(b) visit The absorbance of the maximum absorption wave strong point of pin 3 with concentration situation of change.
Fig. 4：(a) uv-visible absorption spectra of the probe 4 in example IV in aqueous under various concentrations；(b) visit The absorbance of the maximum absorption wave strong point of pin 4 with concentration situation of change.
Fig. 5：Probe 1 in embodiment one in the aqueous solution of the different pH value of in vitro with various Action of Metal Ions Fluorescence column diagram.
Fig. 6：Fluorescence spectrum of the middle probe 1 of embodiment one in the different pH value aqueous solution；Insertion figure：Probe 1 is in pH 2.0- Fluorescence intensity ratio I in the range of 5.5405/I450With the change curve of pH value.
Fig. 7：Fluorescence spectrum of the middle probe 2 of embodiment two in the different pH value aqueous solution；Insertion figure：Probe 2 is in pH 3.0- Fluorescence intensity ratio I in the range of 4.0390/I520With the change curve of pH value.
Fig. 8：Fluorescence spectrum of the three kinds of probes 3 of embodiment in the different pH value aqueous solution；Insertion figure：Probe 3 is in pH 2.4- In the range of 6.0 at 500nm fluorescence intensity and pH value change curve.
Fig. 9：Fluorescence spectrum of the example IV kind probe 4 in the different pH value aqueous solution；Insertion figure：Probe 4 is in pH 2.0- In the range of 5.17 at 450nm fluorescence intensity and pH value change curve.
Figure 10：Fluorescent images of the middle probe 1 of embodiment one in Hela cells living；(a) with pH=6.6 lemon Acid buffer culture 30min fluorescence picture；(d) bright field image of (a)；(b) with pH=4 citrate buffer solution culture 30min's Fluorescence picture；(e) bright field image of (b)；(c) with pH=3 citrate buffer solution culture 30min fluorescence picture；(f) light field of (c) Picture.
Figure 11：Fluorescent images of the middle probe 2 of embodiment two in Hela cells living.
Figure 12：Fluorescent images of the middle probe 3 of embodiment three in Hela cells living.
Figure 13：Fluorescent images of the example IV middle probe 4 in Hela cells living.
【Embodiment】
Embodiment one：Probe Probe 1 synthesis
It is raw material from triethylene glycol monomethyl ether, according to literature method, by three steps, is readily apparent compound 3, is brown Color thick liquid nano product.Yield 79.9%.1H NMR(400MHz,CDCl3, δppm):7.14 (t, J=7.8Hz, 2H), 7.01 (d, J=8.9Hz, 4H), 6.92 (d, J=7.9Hz, 2H), 6.84 (s, 1H), 6.82 (d, J=8.9Hz, 4H), 4.11-4.08 (m, 4H), 3.85-3.82 (m, 4H), 3.73 (dd, J=5.9,3.5Hz, 4H), 3.69-3.63 (m, 8H), 3.55 (dd, J= 5.6,3.6Hz,4H),3.37 (s,6H).
In 250mL round-bottomed flask, DMF (1.15g, 16mmol) is added, at 0 DEG C (ice-water bath) Under conditions of with syringe inject POCl3 (2.5g, 16mmol), stirring reaction 1h, by intermediate 3 (3.6g, 11mmol) It is dissolved in 100mL chloroforms, adds reaction system, be warming up to 100 DEG C, react 5h, reaction is cooled to room temperature after terminating, will Reactant is poured into frozen water, in the 20%NaOH aqueous solution and pH to 7, to be extracted with dichloromethane (50mL × 3), anhydrous sodium sulfate Dry, filtering is evaporated removing solvent, with ethyl acetate/petroleum ether (2:1) as solvent, chemical combination is obtained through silica gel column chromatography Thing 4 (2.8g).Faint yellow viscous product.Yield 48.8%.1H NMR(400 MHz,CDCl3,δppm):9.75(s,1H),7.62 (d, J=8.5Hz, 2H), 7.11 (d, J=8.7Hz, 4H), 6.90 (d, J=8.7Hz, 4H), 6.84 (d, J=8.4Hz, 2H), 4.13 (t, J=4.3Hz, 4H), 3.87 (t, J=4.8Hz, 4H), 3.76-3.73 (m, 4H), 3.71-3.65 (m, 8H), 3.57-3.53(m,4H), 3.38(s,6H).
In 250mL single-necked flasks, intermediate 3 (4.6g, 11mmol), N- bromo-succinimides are sequentially added (1.96g, 11mmol) and 50mL DMFs, are stirred at room temperature reaction 4h.Frozen water is added, ethyl acetate is used Extraction, anhydrous sodium sulfate drying, filtering revolves solvent evaporated, with ethyl acetate/petroleum ether (1:1) as solvent, through silicagel column Chromatography obtains compound 5 (2.2g).Weak yellow liquid product.Yield 30.9%.1H NMR(400MHz,CDCl3,δppm):7.26- 7.18 (m, 2H), 7.00 (d, J=8.8Hz, 4H), 6.83 (d, J=8.8Hz, 4H), 6.78 (d, J=8.8Hz, 2H), 4.13-4.07(m,4H),3.87-3.82(m,4H),3.76-3.71(m,4H),3.71-3.63(m,8H),3.57- 3.54(m, 4H),3.38(s,6H).
In 500mL single-necked flasks, 2,4'- dibromos acetophenone (32.57g, 117.2mmol), six methines are sequentially added Tetramine (16.5g, 117.9mmol) and 300mL chloroforms, stirring reaction 24h, filtering, smash filter cake to pieces, use three chloromethanes at room temperature Alkane washing is multiple, takes solid phase to place vacuum drying oven and dries 12h, obtains 47.38g white solids.Extracting waste solid is in tri- mouthfuls of burnings of 500ml In bottle, a glass three-way joint (joint connection nitrogen ball) is connect, flask is vacuumized with oil pump, nitrogen is then passed through by joint Gas, is so repeated twice, and air in flask is removed as far as possible.It is dispersed in 200mL ethanol, is then stirring under the conditions of 0 DEG C Mix down and add 150mL concentrated hydrochloric acids (injecting 10mL every time, be spaced 2min) by several times with syringe.Then stir anti-under the conditions of 0 DEG C 1h is answered, then is placed in room temperature reaction 24h.After reaction terminates, suction filtration removes white depositions, takes filtrate, is spin-dried for obtaining pale yellow colored solid Body, is dried in a vacuum and obtains compound 6 (15.74g).Faint yellow solid.Yield 53.6%.1H NMR (400MHz,d6- DMSO,δppm):8.51 (d, J=43.0Hz, 3H), 7.98 (d, J=8.4Hz, 2H), 7.83 (d, J=8.4Hz, 2H), 4.62 (d, J=5.3Hz, 2H)
In 500mL three-necked flasks, sequentially add intermediate 6 (15.74g, 62.7mmol) and isonicotinic acid (11.75g, 95.5mmol), dried condenser pipe is connected, a glass three-way joint (joint connection nitrogen ball) is connect in the condensation mouth of pipe, with oil Pump is vacuumized to flask, is then passed through nitrogen by joint, is so repeated twice, and air and moisture in flask are removed as far as possible. POCl is added with syringe3(70mL), is warming up to reflux temperature reaction 6h.After reaction terminates, room temperature is cooled to, residue is rotated POCl3.EtOH is added into flask：H2O=2:1 (v/v) mixing liquid, makes it be all dispersed in liquid, pours into 500mL beakers, are aided with NaHCO with mass ratio for the 20% NaOH aqueous solution3Neutralize solution pH to 10 or so, during note Anticipate temperature control, temperature rise higher (30 DEG C -40 DEG C) when by beaker insert in frozen water cool.Extracted with dichloromethane (70mL × 3), Merge organic phase, use anhydrous Na2SO4Dry and then filter, collect filtrate, crude product, crude product post layer are obtained after filtrate is rotated (eluant, eluent is the mixed solvent of ethyl acetate and petroleum ether to the purification of analysis method, and volume ratio is 1:3) compound 7 (1.20g) is obtained.It is light Yellow solid product, yield 6.7%.1H NMR(400MHz,d6-DMSO,δppm):8.79 (d, J=5.9Hz, 2H), 8.03 (s, 1H), (d, J=8.5Hz, the 2H) of 8.01 (dd, J=4.7,1.3Hz, 2H), 7.85 (d, J=8.5Hz, 2H), 7.73
In 100mL three-necked flasks, sequentially add intermediate 9 (60mg, 0.20mmol), molecule QS- 1 (90mg, 0.15mmol), Anhydrous potassium carbonate (70mg, 0.51mmol), methyl tricapryl ammonium chloride (0.4mL) and 25mL N, N- dimethyl Formamide, connects dried condenser pipe, a glass three-way joint (joint connection nitrogen ball) is connect in the condensation mouth of pipe, with oil pump pair Flask is vacuumized, and is then passed through nitrogen by joint, is so repeated twice, and encasing flask with masking foil ensures lucifuge condition, fast Speed weighs double (triphenylphosphine) palladium chlorides (30mg, 0.043mmol), pours into flask rapidly, flask is taken out very with oil pump Sky, is passed through nitrogen by joint, is so repeated twice.160 DEG C are heated to, 24h is reacted, is cooled to room temperature, vacuum distillation is removed Most of DMF is removed, (eluant, eluent is ethyl acetate) is purified with column chromatography and obtains probe 1 (80.0mg).Palm fibre Brown viscous oily liquid.Yield 65.6%.1H NMR(400MHz,CDCl3,δppm):8.67 (d, J=4.7Hz, 2H), 7.86 (d, J=5.8Hz, 2H), 7.61 (d, J=8.3Hz, 2H), 7.47 (d, J=8.4Hz, 2H), 7.42 (s, 1H), 7.26 (d, J =8.6Hz, 2H), 7.02 (d, J=16.3Hz, 1H), 6.97 (d, J=8.9Hz, 4H), 6.86 (d, J=16.7Hz, 1H), 6.82 (d, J=8.6Hz, 2H), 6.77 (d, J=8.9Hz, 4H), 4.07-3.98 (m, 4H), 3.80-3.74 (m, 4H), 3.67 (dd, J=5.8,3.4Hz, 4H), 3.64-3.55 (m, 8H), 3.48 (dd, J=5.6,3.6Hz, 4H), 3.30 (s, 6H) .HRMS(M+H)for C48H53N3O9:816.3860 (calculated),816.3866(experimental)；(M+Na)for C48H53N3O9:838.3680 (calculated),838.3675(experimental)。
Embodiment two：Probe probe 2 synthesis
In 250mL single-necked flasks, intermediate 3 (4.6g, 11mmol), N- bromo-succinimides are sequentially added (1.96g, 11mmol) and 50mL DMFs, are stirred at room temperature reaction 4h.Frozen water is added, ethyl acetate is used Extraction, anhydrous sodium sulfate drying, filtering revolves solvent evaporated, with ethyl acetate/petroleum ether (1:1) as solvent, through silicagel column Chromatography obtains probe 1 (2.2g).Weak yellow liquid product.Yield 30.9%.1H NMR(400MHz,CDCl3,δppm):7.26- 7.18 (m, 2H), 7.00 (d, J=8.8Hz, 4H), 6.83 (d, J=8.8Hz, 4H), 6.78 (d, J=8.8Hz, 2H), 4.13- 4.07(m,4H),3.87-3.82(m,4H),3.76-3.71(m,4H),3.71-3.63(m,8H),3.57-3.54 (m,4H), 3.38(s,6H).
In 100mL single-necked flasks, the tetrahydrofuran for taking 50mL to dry dissolves intermediate 8 (2.0g, 3.1mmol) and will It adds flask, and system temperature is down into -78 DEG C, and n-butyllithium solution (8mL, 2.5M) is added under nitrogen protection, stirs 2h, Add triisopropyl borate ester (0.88g, 4.7mmol), stirring reaction 8h.After reaction terminates, reaction solution is poured into 100mL frozen water, It is acidity to add hydrochloric acid guarantee system, is extracted with dichloromethane, and revolving removes solvent, obtains crude product.Use ethyl acetate/methanol (20:1) as solvent, compound 9 (1.3g) is obtained through silica gel column chromatography.Light yellow viscous liquid.Yield 68.8%.1H NMR(400MHz,d6-DMSO,δppm):7.76 (s, 2H), 7.59 (d, J=8.5Hz, 2H), 7.01 (d, J=8.9Hz, 4H), 6.92 (d, J=9.0Hz, 4H), 6.68 (d, J=8.5Hz, 2H), 4.08-4.04 (m, 4H), 3.77-3.69 (m, 4H), 3.59 (dd, J=5.8,3.2Hz, 4H), 3.56-3.50 (m, 8H), 3.43 (dd, J=5.8,3.6Hz, 4H), 3.23 (s, 6H)
In 100mL three-necked flasks, compound 7 (200mg, 0.67mmol), compound 9 (400mg, 0.67mmol), nothing Aqueous carbonate potassium (300mg, 2.2mmol), methyl tricapryl ammonium chloride (0.4mL), toluene, second and water each 7.5mL, 4.5mL and 1.5mL.The dried condenser pipe of connection, connects a glass three-way joint (joint connection nitrogen ball), with oil pump pair in the condensation mouth of pipe Flask is vacuumized, and is then passed through nitrogen by joint, is so repeated twice, and encasing flask with masking foil ensures lucifuge condition, fast Speed weighs tetrakis triphenylphosphine palladium (30mg, 0.026mmol), pours into flask rapidly, flask is vacuumized with oil pump, by connecing Head is passed through nitrogen, is so repeated twice.100 DEG C are heated to, 24h is reacted, is cooled to room temperature, reaction solution is poured into 100mL water In, extracted with acetic acid ethyl ester, revolving organic phase removes solvent, obtains crude product.With ethyl acetate/petroleum ether (3:1) as exhibition Agent is opened, post is walked and obtains probe 2 (280mg).Light yellow viscous liquid.Yield 52.8%.1H NMR(400MHz,d6- DMSO, δppm):8.78 (dd, J=4.6,1.5Hz, 2H), 8.01 (dd, J=4.6,1.5Hz, 2H), 7.98 (s, 1H), 7.92 (d, J= 8.4Hz, 2H), 7.76 (d, J=8.5Hz, 2H), 7.59 (d, J=8.7Hz, 2H), 7.05 (d, J=8.9Hz, 4H), 6.95 (d, J=9.0Hz, 4H), 6.85 (d, J=8.7Hz, 2H), 4.11- 4.05 (m, 4H), 3.77-3.71 (m, 4H), 3.59 (dd, J=5.9,3.2Hz, 4H), 3.57-3.50 (m, 8H), 3.45-3.41 (m, 4H), 3.24 (s, 6H) .HRMS (M+H) for C46H51N3O9:790.3703 (calculated),790.3705(experimental)；(M+Na)for C46H51N3O9: 812.3523 (calculated),812.3519(experimental)。
Embodiment three：Probe probe 3 synthesis
With the identical synthetic method of above-described embodiment one, with 3,5- dimethyl -4- hydroxy benzaldehydes for raw material, probe 3 is obtained (light yellow viscous liquid).Yield 66.0%.
1H NMR(400MHz,CDCl3,δppm):8.76 (d, J=6.0Hz, 2H), 8.02-7.89 (m, 2H), 7.74- 7.68(m,2H),7.60-7.54(m,2H),7.52(s,1H),7.20(s,2H),7.12-6.96 (m,2H),4.01-3.94 (m,2H),3.90-3.81(m,2H),3.79-3.75(m,2H),3.74-3.65(m, 4H),3.61-3.52(m,2H),3.41- 3.37 (m, 3H), 2.34 (d, J=11.2Hz, 6H) .HRMS (M+H) for C31H34N2O5:515.2546(calculated), 515.2549(experimental)；(M+Na) for C31H34N2O5:537.2366(calculated),538.2363 (experimental)。
Example IV：Probe probe 4 synthesis
With the identical synthetic method of above-described embodiment two, with 2,5- dimethyl -4- bromophenols for raw material, probe 4 is obtained (yellowish Color viscous oil-like liquid).Yield 90.1%.
1H NMR(400MHz,d6-DMSO,δppm):8.79 (d, J=5.5Hz, 2H), 8.02 (d, J=7.4Hz, 3H), 7.94 (d, J=8.2Hz, 2H), 7.78 (d, J=8.2Hz, 2H), 7.41 (s, 2H), 3.96- 3.89 (m, 2H), 3.77-3.71 (m,2H),3.66-3.60(m,2H),3.60-3.52(m,4H),3.48- 3.42(m,2H),3.25(s,3H),2.31(s, 6H).HRMS(M+H)for C29H32N2O5:489.2389 (calculated),489.2383(experimental)；(M+Na) for C29H32N2O5:512.2209 (calculated),512.2212(experimental)。
Embodiment five：Water solubility experiment
Using being obtained in the probe 3, embodiment three obtained in the probe 1, embodiment two obtained in above-described embodiment one Probe 3 and example IV in obtained probe 4, its solvability is evaluated according to absorbance method.First respectively by probe 1, Probe 2, probe 3 and probe 3, which are dissolved in match somebody with somebody in dimethyl sulfoxide, is prepared into 1.0 × 10-3M mother liquor, then progressively dilutes, and obtains one The different mother liquor of series.Then it is added to by micro syringe in the quartz colorimetric utensil of the distilled water containing 3mL.In all situations In, amount of the dimethyl sulfoxide in water is 0.2% (i.e. the probe molecule mother liquor of 6 μM of injection every time).It can so ensure that diformazan is sub- The presence of sulfone does not interfere with dissolubility of the probe molecule in pure water.Probe 1, probe 2, the result of probe 3 and probe 4 are shown respectively In Fig. 1, Fig. 2, Fig. 3 and Fig. 4.In figure, (a) figure represents the ultraviolet visible absorption spectra of corresponding compound under various concentrations； (b) figure represents the absorbance of corresponding compound maximum absorption wave strong point with the situation of change of the concentration of corresponding compound, For probe 1, probe 2, probe 3 and probe 4, this wavelength is respectively 413nm, 393nm, 358nm and 358nm.
The concentration of each (b) the figure linear region maximum into Fig. 4 of view 1 is solubility, probe 1, probe 2, the and of probe 3 Solubility of the probe 4 in water is respectively 30 μM, 20 μM, 13.3 μM and 13.3 μM.So there is flexible hydrophilic poly- second two The compound of alcohol chain has very big solubility in aqueous, the pH value that is used to detect in aqueous environment for them and to work Cell or the dyeing of biological tissue be very favorable.
Embodiment six：Ion selectivity is tested
Using the probe 1 obtained in above-described embodiment one, it is evaluated to hydrionic selectivity, 5 μM of probes 1 are distinguished It is added to containing each metal ion species (25mM Na+, 5mM K+, Ca2+；0.1mM Mg2+, Mn2+, Fe2+, Ni2+, Pb2+, Cu2+, Cr2+) Different pH value (pH be 6.6 or 3.0) the aqueous solution in, determine fluorescence emission spectrum.As a result it is shown in Fig. 5.
In figure, the longitudinal axis is probe 1 in different pH value and the aqueous solution containing different metal ions in emission spectra at 405nm With the ratio of fluorescent emission intensity at 450nm.The probe 1 of the present invention has high selectivity to hydrogen ion, i.e. the probe pair Hydrogen ion has extremely strong selectivity, even if the sodium ion largely existed in vivo, potassium ion, calcium ion, magnesium ion are with height Under conditions of concentration is present, fluorescence intensity ratio value changes are also minimum.Alternatively, it is also possible to see other metal ions to the probe The photoluminescent property of molecule influences also very little.
The compound of the present invention is using 4- (5- phenyl -2- oxazolyls) pyridines as protonation site, to hydrionic selection Property should show similar property, be the pH probes of high selectivity.
Embodiment seven：Fluorescence titration is tested
The detection of probe 1, probe 2, probe 3 and probe 4 to pH value can pass through fluorescence titration experiment and its photoluminescent property (it is the fluorescent emission intensity ratio at two wavelength for probe 1, is at a certain wavelength for probe 2, probe 3 and probe 4 Fluorescent emission intensity, this wavelength is near maximum emission wavelength) studied with the change curve of pH value, as a result it is shown in figure 6th, Fig. 7, Fig. 8 and Fig. 9.As a result show that probe 1 is suitable for detecting that pH scopes are the pH value in 3.5-4.4 environment.According to Henderson-Hasselbatch Type equations (log [(Imax-I)/(I-Imin)]=pKa-pH), calculate probes probes 1 PKa value be 3.95；Probe 2 is suitable for detecting that pH scopes are the pH value under the conditions of 3.0-4.0 and its pKa value is 3.35；Probe 3 are suitable for detecting that pH scopes are the pH value under the conditions of 3.2-4.8 and its pKa value is 4.00；Probe 4 is suitable for detecting pH scopes For the pH value under the conditions of 3.1-4.1 and its pKa value is 3.65.Thus, the photoluminescent property of compound of the invention is in a certain pH models In enclosing, the change of regularity can be embodied with pH change, can be used for detecting the pH value under acid condition.
Embodiment eight：Living biological cells fluorescence imaging
The fluoroscopic visualization in living cells is carried out using above-mentioned probe 1, probe 2, probe 3 and probe 4.Hela cells are pressed Cultivated according to regulation (ATCC, Manassas, VA, USA).Cell culture adds 10% in DMEM culture mediums in culture medium FBS buffer solutions, add the units/ml of penicillin 100, the μ g/mL of streptomysin 100, in 37 DEG C of 5%CO2In incubator.Imaging two Before it, Hela cells, which are seeded on the sterile cover slips in culture dish, to be made after its adherent 24h, removes non-attached cell.Experiment Before the storing solution that concentration is 5mM is obtained with DMSO dissolvings probe Ai.Take 0.5 μ L probes (5mM, DMSO) to add respectively to contain The culture medium (500 μ L) of attached cell makes its final concentration of 5 μM, is placed in 37 DEG C of 5%CO2 incubators and cultivates after 30min, uses Citrate buffer (pH=6.6) is gently cleaned 3 times, to remove the probe for being introduced into cell excessive in culture medium.Will be thin After born of the same parents' fixation under laser confocal microscope, pass through linear scan and carry out fluorescence photoimaging.
The living cells of above-mentioned probe 1, probe 2, probe 3 and probe 4 under the conditions of different pH value (6.6,4.0 and 3.0) is glimmering Light figure is respectively as shown in Figure 10, Figure 11, Figure 12 and Figure 13.Cell sends blue-fluorescence, with the decline of pH value residing for cell, The blue-fluorescence intensity sent shows obvious decrease, shows that pH change of the above-claimed cpd to living cells environment is very quick Sense, so being very useful as the fluorescence probe of measure pH value.
It is emphasized that the above-mentioned embodiment enumerated only is some exemplary tests, limited examination is not considered as Test or condition.The innovation scope that the present patent application is covered should be recorded by claims and is defined.

Claims (8)

1. a kind of compound, it is characterised in that the compound represented with following logical formula (I)s：
In formula, R1、R2And R3Separately represent halogen atom, hydrogen atom, alkyl, alkoxy or the base with following formula (IA) Group
In formula, m represents 0,1 or 2, R4Represent hydrogen atom, alkyl, alkoxy or the group represented with following formula (IB)；Y tables Show the group for the formation that the group that methylene, oxygen atom or nitrogen-atoms and following formula (IB) are represented is connected
In formula, R5Represent hydrogen atom, alkyl or alkoxy；Z1、Z2And Z3Separately represent no or oxygen atom, n, o 0,1 or 2 are separately represented with p,
R1、R2And R3Can not be halogen atom, hydrogen atom, alkyl or alkoxy simultaneously；X represents CH=CH (i.e. with both sides phenyl ring shape Into talan structure) or do not have (being biphenyl structural).
2. compound as claimed in claim 1, it is characterised in that the preferred mode of the logical formula (I), with 4- (5- phenyl -2- Oxazolyl) pyridine is core texture, by diglycol chain by alkyl chain (R8-CH2-CH2-) and phenyl ring bonding, under State the compound that logical formula (II) is represented：
In formula, R6And R7Separately represent halogen atom, hydrogen atom, alkyl or alkoxy；R8Represent hydrogen atom, alkyl Or alkoxy；X1Represent CH=CH (i.e. with both sides phenyl ring formation talan structure) or do not have (being biphenyl structural).
3. compound as claimed in claim 1, it is characterised in that the preferred mode of the logical formula (I), with 4- (5- phenyl -2- Oxazolyl) pyridine is core texture, introduces N in No. 4 positions of phenyl ring, the substituted amidos of N- bis- represent with following logical formula (III)s Compound：
In formula, R9And R10Separately represent halogen atom, hydrogen atom, alkyl or alkoxy；X2Represent CH=CH (i.e. and both sides Phenyl ring formation talan structure) or do not have (being biphenyl structural)；R11And R12Separately represent hydrogen atom, alkyl, Alkoxy or the group represented with following formula (IIIA)
In formula, R13Represent hydrogen atom, alkyl or alkoxy；Z4、Z5And Z6Separately represent no or oxygen atom, r, s Separately represented with t 0,1 or 2, q represent 1 or 2.
4. a kind of prepare the method for leading to compound shown in formula (I) described in claim 1, it is characterised in that the alpha-brominated benzene of halo Ethyl ketone (HaI is halogen) sets out, by known references method (Angew.Chem.2012；51(11):2673-6), via Dare shore Reaction generation benzylamine, then with isonicotinic acid POCl3 backflow under conditions of clasp, formed halo 4- (5- phenyl -2- oxazoles Base) pyridine compounds,
Reacted further according to such as Suzuki and Heck, and substitution (3,4 and No. 5 position) phenyl boric acid or distyryl compound formation connection The substitution of benzene or styrene group, that is, obtain partial Formula (I) product；
Or, demethylation prepares the intermediate with hydroxyl on the basis of product, then carries out into ether, epoxy addition, mikey Your conjugate addition reaction etc., obtains another part and leads to formula (I) product.
The preferred embodiment of the logical formula (I), the preferable of compound is embodied in described in logical formula (II) and logical formula (III) leads to as described above Replace the R in phenyl boric acid and substituted phenylethylene in formula (I) the compound synthesis method2The otherness of group, according to amine The substitution reaction of the flexible chain of base and hydroxyl, the substituted benzene needed for logical formula (II) and (III) can be more prepared easily Boric acid and styrene intermediate, follow-up synthesis mode is with reference to logical formula (I), you can obtain the chemical combination of logical formula (II) and logical formula (III) Thing.
5. a kind of application for the compound recorded containing claim 1-3 any one claim, it is characterised in that for pH Fluorescence probe.
6. application as claimed in claim 5, it is characterised in that be applied particularly in aqueous phase (in vitro living biological cell, in vitro life In thing living tissue, living biological cell or biopsy) measure of pH value.
7. application as claimed in claim 6, it is characterised in that
The assay method, including following process：
(a) compound that claim 1-3 any one claim is recorded and the process that hydrogen ion reacts are made, and
(b) process for determining the fluorescence intensity of the hydride-complex generated in above-mentioned operation.
8. application as claimed in claim 5, the compound that claim 1-3 any one claim is recorded is used as pH fluorescence Application in fluorescence imaging detection of the probe in vitro living cells or in vitro biopsy.
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