CN106565606B - Compound and its preparation method and application with aggregation-induced emission property - Google Patents
Compound and its preparation method and application with aggregation-induced emission property Download PDFInfo
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Abstract
The invention discloses compounds with aggregation-induced emission property and preparation method thereof and the application in fat drips targeting photoactivation fluorescence imaging, for the structure of the compound and its intermediate product respectively as shown in Formulas I and Formula II, Formulas I can be converted into Formula II under illumination condition.Compound of formula I is made by following steps: formula III compound and formula IV compound is dissolved in acetonitrile under nitrogen protection, are protected from light, 1, the 2- dihydro -2- azepine fluorenes ketone compounds of production I.Novel compound of present invention has aggregation-induced emission advantage, the defect that can effectively overcome the aggregation inducing of conventional fluorescent dyestuff to quench, to realize the specific photoactivation fluorescence imaging of fat drips targeting in living cells, and have many advantages, such as that photoactivation is high-efficient, signal-to-noise ratio is high, cytotoxicity is small, stoke shift is big, strong into cell ability, it can effectively distinguish cancer cell and normal cell.
Description
Technical field
The invention belongs to field of medical materials, and in particular to compound and its preparation side with aggregation-induced emission property
Method and the application in fat drips targeting photoactivation fluorescence imaging.
Background technique
Gathering induced luminescence material has strong anti-light bleaching power, the high-incidence light efficiency of state of aggregation as fluorescent material of new generation
The advantages that rate, big stoke shift and hypotoxicity, the defect that can effectively overcome aggregation inducing to quench, in bio-imaging and detection
Field is increasingly widely applied, and the imaging and physiological function especially suitable for organelle are probed into.
Fat drips are not only the important storage house of lipid molecule and protein, and are the multi-functional thin of a dynamic change
Born of the same parents' device.Fat drips size and number difference in different cells is very big.Since fat drips can be used as energy reservoir, and in film
The physiological activities such as synthesis, protein degradation in play an important role, fat drips and many diseases are closely related, including inflammation,
Virus infection and fat relevant disease.
Cancer cell has the characteristics that fast breeding, therefore has high demand to the lipid molecules such as fatty acid and phosphine rouge, accordingly
Cancer cell in the contents of fat drips also obviously increase, therefore high expression of the fat drips content in cancer cell can be used as the label of cancer
Object.Increasingly important role is played in the research of biological field in view of the Imaging-PAM with photoactivation ability,
There is an urgent need to develop the specific photoactivation fluorescence probe of fat drips targeting to probe into the physiological function of fat drips.
In order to realize the controllable fluorescence imaging of fat drips targeting space-time, need to solve following two critical issue: (1) for reality
The high brightness fluorescent imaging of existing fat drips, fluorescent material needs high concentration to be gathered in fat drips, however the aggregation of conventional fluorescent material
The defect of induction quenching seriously limits their applications in high brightness fat drips fluorescence imaging；(2) in order to realize that space-time is controllable
Fat drips fluorescence imaging, need to establish photoactivation fat drips targeting fluorescence probe.However, traditional photoactivation fluorescence probe institute
Based on photochemical reaction type it is limited, and be difficult to introduce the corresponding official targeted with photoactivation reactive functionality and fat drips
It can group.
Summary of the invention
In order to overcome the defect (i.e. aggregation inducing quenching and photochemical reaction type are limited) of above-mentioned existing fluorescent material, this
The primary and foremost purpose of invention is to provide a kind of 1,2- dihydro -2- azepine fluorenes ketone compounds with aggregation-induced emission property,
The compound can realize the photoactivation fluorescence imaging of fat drips targeting, can be based on fat drips content in cancer cell and normal cell not
Together, it is effectively distinguished.
Another object of the present invention is to provide the preparation methods of above-mentioned 1,2- dihydro -2- azepine fluorenes ketone compounds.
A further object of the present invention is to provide a kind of 2- azepine fluorenes ketone compounds, which is in above-mentioned 1,2- bis-
It is generated after hydrogen -2- azepine fluorenes ketone compounds generation photooxidation dehydrogenation reaction, aggregation-induced emission (AIE) can be shown
Property.
Fourth object of the present invention is to provide the preparation method of above-mentioned 2- azepine fluorenes ketone compounds.
Of the invention the 5th is designed to provide above-mentioned 1,2- dihydro -2- azepine fluorenes ketone compounds and 2- azepine Fluorenone
Application of the class compound in fat drips targeting photoactivation fluorescence imaging.
The purpose of the invention is achieved by the following technical solution:
One kind 1,2- dihydro -2- azepine fluorenes ketone compounds, structure are shown in formula I:
Wherein R1、R4It independently is hydrogen, halogen, C1-30Alkyl, C1-30Alkyl oxy, C1-30Alkyl amino, C1-30Alkyl sulfide
Base, aryl, heteroaryl；
R2For C1-30Alkyl oxy, C1-30Alkyl amine group, C1-30Alkyl sulfenyl, aryloxy, arylamino, artyl sulfo,
Heteroaryl oxygroup, heteroaryl amino, Heteroarylthio；
R3For hydrogen, halogen, ester group, alkyl-carbonyl, aryl carbonyl, Heteroarylcarbonyl, cyano, nitro；
The alkyl can be linear or branched alkyl group；For example, methyl, ethyl, propyl, butyl, isobutyl group, tert-butyl；
The aryl refers to monocycle or polycyclic aromatic group with 6-20 carbon atom, and representative aryl includes: benzene
Base, naphthalene, anthryl, pyrenyl；
The heteroaryl refers to 1-20 carbon atom, 1-4 selected from the heteroatomic monocycle of N, S, O or polycyclic hetero-aromatic
Group, representative heteroaryl include: pyrrole radicals, pyridyl group, pyrimidine radicals, imidazole radicals, thiazolyl, indyl, azepine naphthalene, nitrogen
Miscellaneous anthryl, azepine pyrenyl；
Preferably, R1For 4- (hexichol amido) phenyl or 9- Ethy-Carbazole -3- base；R2For morpholinyl, amino or replace amine
Base；R3For cyano；R4For hydrogen.
The preparation methods of above-mentioned 1,2- dihydro -2- azepine fluorenes ketone compounds the following steps are included:
The definition of each substituent group is identical as Formulas I in formula III, formula IV；
Formula III compound and formula IV compound that molar ratio is 1:1~1:2 are dissolved in acetonitrile；Temperature be 50~
It 60 DEG C, under nitrogen protection, is protected from light, 1, the 2- dihydro -2- azepine fluorenes ketone compounds of production I；
Preferably, the molar ratio is 1:1, and temperature is 50~55 DEG C.
Unexpectedly, inventor is the study found that photooxidation is occurring for 1, the 2- dihydro -2- azepine fluorenes ketone compounds of Formulas I
2- azepine fluorenes ketone compounds can be generated after fluidized dehydrogenation reaction, structure is as shown in Formula II.The 2- azepine fluorenes ketone compounds of Formula II
It can show the property of aggregation-induced emission (AIE).
In Formula II, the definition of each substituent group is identical as Formulas I；
2- azepine fluorenes ketone compounds are de- in addition to that can be occurred under light illumination by 1,2- dihydro -2- azepine fluorenes ketone compounds
Except hydroxide reaction generates, it can also be made by following steps:
Formula III compound and formula IV compound that molar ratio is 1:1~1:2 are dissolved in acetonitrile, in dry air
In, it under illumination, is reacted under counterflow condition, the 2- azepine fluorenes ketone compounds of production II；
Above-mentioned reaction carries out that effect is more preferable in oxygen, but in view of the source of air is more wider than the source of pure oxygen
It is general and more economical；On the other hand in view of the source for using air as oxygen in the reaction can obtain preferably
Reaction yield, therefore, above-mentioned reaction carries out in air；It is preferred that the content of oxygen is greater than in the air
21%；The content of oxygen is greater than 40% in further preferred air；The content of oxygen is greater than 60% in further preferred air；Into
The content of oxygen is greater than 80% in the preferred air of one step；Further preferred above-mentioned reaction carries out in oxygen；
Preferably, the molar ratio is 1:1, and temperature is 80~90 DEG C.
Above-mentioned 1,2- dihydro -2- azepine fluorenes ketone compounds and 2- azepine fluorenes ketone compounds can be used as fat drips dyestuff
For the photoactivation fluorescence imaging of cell fat drips targeting, based on the difference of fat drips content, cancer cell and normal thin can be effectively distinguished
Born of the same parents；
The cell refers to lung carcinoma cell and normal pneumonocyte；
Above-mentioned 1,2- dihydro -2- azepine fluorenes ketone compounds and 2- azepine fluorenes ketone compounds can also be in many cells ring
Photoactivation fluorescence imaging selectively is realized for individual cells or cell mass under border.
After 1,2- dihydro -2- azepine fluorenes ketone compounds dye fat drips as photoactivation fat drips dyestuff, in purple
Under outer light irradiation, photooxidation dehydrogenation reaction occurs, generates 2- azepine fluorenes ketone compounds, 2- azepine fluorenes ketone compounds have poly-
Collect induced luminescence effect, to carry out fluorescence imaging to fat drips.By by 1,2- dihydro -2- azepine fluorenes ketone compounds and commercial
Fat drips dyestuff BODIPY493/503 Green carries out total dye experiment and confirms that 1,2- dihydro -2- azepine fluorenes ketone compounds have
Good dyeing effect.
It is worth noting that, under ultraviolet light, light occurs for 1,2- dihydro -2- azepine fluorenes ketone compounds of the invention
Oxidation reaction, shining for the 2- azepine fluorenes ketone compounds of generation are different from traditional fluorescence imaging, but show aggregation and lure
Optronic property, it means that even if under a high concentration condition, 1,2- dihydro -2- azepine fluorenes ketone compounds can also carry out
Photoactivation fluorescence imaging, and traditional fluorescent dye then has the phenomenon that aggregation inducing is quenched under a high concentration condition, therefore passes
The fluorescent dye of system is unfavorable for carrying out fluorescence imaging under a high concentration condition.
In addition, 1,2- dihydro -2- azepine fluorenes ketone compounds itself and do not have fluorescence imaging or aggregation-induced emission
Property, why showing the property of aggregation-induced emission is because translate into 2- azepine Fluorenone class under illumination condition
Object is closed, and 2- azepine fluorenes ketone compounds have the property of aggregation-induced emission.It is emphasized that in the prior art, not having
Document report 1,2- dihydro -2- azepine fluorenes ketone compounds excessively of the invention and 2- azepine fluorenes ketone compounds can show to gather
Collect the property of induced luminescence, also not having document report to cross them can be used as fat drips dyestuff.
In the present invention, " aggregation-induced emission " refers to that fluorescent chemicals hardly shine in weak solution, but is assembling
The phenomenon that state or solid-state issue hyperfluorescence.For example, in the present invention, due to the intramolecular charge that internal molecular motion is limited and distorts
Metastasis, 2- azepine fluorenes ketone compounds solution state do not issue fluorescence or shine it is very weak, but state of aggregation issue hyperfluorescence.
In the present invention, the molecule that " photoactivation fluorescence probe " refers to a kind of photoresponse, chemically reacts under light illumination,
The molecule with fluorescent emission ability is generated, has in bio-imaging and is easy to regulate and control and the advantages such as high-spatial and temporal resolution.
The present invention has the following advantages and effects with respect to the prior art:
1, novel compound of present invention can realize the specific photoactivation fluorescence imaging that fat drips target in living cells, and have
Have the advantages that photoactivation is high-efficient, signal-to-noise ratio is high, cytotoxicity is small, stoke shift is big, strong into cell ability, it can effective district
Divide cancer cell and normal cell.
2, novel compound of present invention has aggregation-induced emission advantage, can effectively overcome the aggregation of conventional fluorescent dyestuff to lure
Lead the defect of quenching.
Detailed description of the invention
Fig. 1 is the crystal structure figure of compound II-2；A is the single-molecule crystals structure chart of compound II-2；B is compound
The crystal accumulation figure of II-2.
Fig. 2 is the UV absorption and fluorescence emission spectrogram of compound of compound II-1；(A) compound II-1 is in tetrahydrofuran
Normalization uv absorption spectra (left side) and the fluorescence hair that water content is continuously increased in the mixed solution of tetrahydrofuran and water
Penetrate spectrogram (10-5mol·L-1, right side)；(B) compound II-1 is continuously increased water in the mixed solution of tetrahydrofuran and water
The ratio variation diagram of maximum fluorescence emission intensity in the maximum fluorescence emission intensity and tetrahydrofuran solution of content.
Fig. 3 is UV absorption and fluorescence emission spectrogram of compound of the compound II-1 in different solvents；(A) compound II-1 exists
Normalization uv absorption spectra (10 in different solvents-5mol·L-1)；(B) fluorescence of the compound II-1 in different solvents
Launching light spectrogram.
Fig. 4 is the highest occupied molecular orbital and lowest unoccupied molecular orbital energy diagram of compound II-1~II-3.
Fig. 5 is fluorescence emission spectrogram of compound of the compound II-1 in ethyl alcohol and glycerol.
Fig. 6 is the UV absorption and fluorescence emission spectrogram of compound of compound II-2；(A) compound II-2 is in tetrahydrofuran
Normalization uv absorption spectra (left side) and the fluorescence hair that water content is continuously increased in the mixed solution of tetrahydrofuran and water
Penetrate spectrogram (10-5mol·L-1, right side)；(B) compound II-1 is continuously increased water in the mixed solution of tetrahydrofuran and water
The ratio variation diagram of maximum fluorescence emission intensity in the maximum fluorescence emission intensity and tetrahydrofuran solution of content.
Fig. 7 is the UV absorption and fluorescence emission spectrogram of compound of compound II-3；(A) compound II-3 is in tetrahydrofuran
Normalization uv absorption spectra (left side) and the fluorescence hair that water content is continuously increased in the mixed solution of tetrahydrofuran and water
Penetrate spectrogram (10-5mol·L-1, right side)；(B) compound II-1 is continuously increased water in the mixed solution of tetrahydrofuran and water
The ratio variation diagram of maximum fluorescence emission intensity in the maximum fluorescence emission intensity and tetrahydrofuran solution of content.
Fig. 8 is the UV absorption and fluorescence emission spectrogram of compound of compound II-4；(A) compound II-4 is in tetrahydrofuran
Normalization uv absorption spectra (left side) and the fluorescence hair that water content is continuously increased in the mixed solution of tetrahydrofuran and water
Penetrate spectrogram (10-5mol·L-1, right side)；(B) compound II-1 is continuously increased water in the mixed solution of tetrahydrofuran and water
The maximum fluorescence emission intensity of content and the variation diagram of maximum emission wavelength.
Fig. 9 be compound I-1 in the mixed solution of dimethyl sulfoxide and water (dimethyl sulfoxide: volume ratio=1 of water:
99,10-4mol·L-1), it is glimmering with the fluorescence emission spectrogram of compound (A) and maximum of irradiation time variation under the portable UV lamp irradiation of 365nm
Light emitting Strength Changes figure (B).
Figure 10 be compound I-1 in the mixed solution of dimethyl sulfoxide and water (dimethyl sulfoxide: volume ratio=1 of water:
99,10-4mol·L-1), under 365nm portable UV lamp irradiation with the UV-Vis spectra figure (A) of irradiation time variation and
The ratio variation diagram (B) of absorption intensity at 413nm and 530nm.
Figure 11 be compound I-2 in the mixed solution of dimethyl sulfoxide and water (dimethyl sulfoxide: volume ratio=1 of water:
99,10-4mol·L-1), it is glimmering with the fluorescence emission spectrogram of compound (A) and maximum of irradiation time variation under the portable UV lamp irradiation of 365nm
Light emitting Strength Changes figure (B).
Figure 12 be compound I-2 in the mixed solution of dimethyl sulfoxide and water (dimethyl sulfoxide: volume ratio=1 of water:
99,10-4mol·L-1), under 365nm portable UV lamp irradiation with the UV-Vis spectra figure (A) of irradiation time variation and
The ratio variation diagram (B) of absorption intensity at 432nm and 545nm.
Figure 13 be compound I-3 in the mixed solution of dimethyl sulfoxide and water (dimethyl sulfoxide: volume ratio=1 of water:
99,10-4mol·L-1), it is glimmering with the fluorescence emission spectrogram of compound (A) and maximum of irradiation time variation under the portable UV lamp irradiation of 365nm
Light emitting Strength Changes figure (B).
Figure 14 be compound I-3 in the mixed solution of dimethyl sulfoxide and water (dimethyl sulfoxide: volume ratio=1 of water:
99,10-4mol·L-1), under 365nm portable UV lamp irradiation with the UV-Vis spectra figure (A) of irradiation time variation and
The ratio variation diagram (B) of absorption intensity at 424nm and 547nm.
Figure 15 is the nucleus magnetic hydrogen spectrum stacking chart of compound I-1 and II-1.
Figure 16 is compound I-1 and II-1 to HCC827 cell (A), A549 cell (C) and HLF cell (E) and chemical combination
Cytotoxicity result figure of the object II-1 to HCC827 cell (B), A549 cell (D) and HLF cell (F).
Figure 17 is compound I-1 in HCC827 cell, increases (22.4s/ times) with scanning times under 405nm laser irradiation
(A) confocal fluorescent photo variation diagram and (B) statistics figure of fluorescence intensity changes.
Figure 18 is compound I-1 in HCC827 cell, with fat drips dyestuff BODIPY493/503 Green and nuclei dyeing
Expect the total dye figure of Hoechst 33342；Wherein, (A) is the nuclei dyeing chromatic graph of Hoechst 33342；It (B) is II-1 in illumination
Colored graph after activation；(C) the fat drips colored graph for being BODIPY493/503 Green；It (D) is the superposition of (A), (B) and (C)
Figure.
Figure 19 is compound I-1 in A549 cell, increases (22.4s/ times) with scanning times under 405nm laser irradiation
Confocal fluorescent photo variation diagram.
Figure 20 is compound I-1 in A549 cell, with fat drips dyestuff BODIPY493/503 Green and nucleus dyestuff
The total dye figure of Hoechst 33342；Wherein, (A) is the nuclei dyeing chromatic graph of Hoechst 33342；(B) swash for II-1 in illumination
Colored graph after work；(C) the fat drips colored graph for being BODIPY493/503 Green；It (D) is (A), the stacking chart of (B) and (C).
Figure 21 is compound I-1 in lung cancer HCC827 cell, lung cancer A549 cell and normal pneumonocyte HLF after photoactivation
Fluorescence photo.
Figure 22 is the compound I-1 in the cell that gradually successively photoactivation is selected under the visual field of multiple HCC827 cells
Fluorescence realizes light-operated time-space resolution fluorescence imaging.
Figure 23 is compound I-2 in HCC827 cell, increases (22.4s/ times) with scanning times under 405nm laser irradiation
Confocal fluorescent photo variation diagram.
Figure 24 is compound I-3 in HCC827 cell, increases (22.4s/ times) with scanning times under 405nm laser irradiation
Confocal fluorescent photo variation diagram.
Figure 25 is compound I-2 in A549 cell, increases (22.4s/ times) with scanning times under 405nm laser irradiation
Confocal fluorescent photo variation diagram.
Figure 26 is compound I-3 in A549 cell, increases (22.4s/ times) with scanning times under 405nm laser irradiation
Confocal fluorescent photo variation diagram.
Figure 27 is total dye figure of the compound I-2 in HCC827 cell, with fat drips dyestuff BODIPY493/503 Green；
Wherein, (A) is the light field figure of HCC827 cell；It (B) is colored graph of the II-2 after lighting activation；It (C) is BODIPY493/503
The fat drips colored graph of Green；It (D) is (A), the stacking chart of (B) and (C).
Figure 28 is total dye figure of the compound I-3 in HCC827 cell, with fat drips dyestuff BODIPY493/503 Green；
Wherein, (A) is the light field figure of HCC827 cell；It (B) is colored graph of the II-2 after lighting activation；It (C) is BODIPY493/503
The fat drips colored graph of Green；It (D) is (A), the stacking chart of (B) and (C).
Figure 29 is total dye figure of the compound I-2 in A549 cell, with fat drips dyestuff BODIPY493/503 Green；Its
In, (A) is the light field figure of HCC827 cell；It (B) is colored graph of the II-2 after lighting activation；It (C) is BODIPY493/503
The fat drips colored graph of Green；It (D) is (A), the stacking chart of (B) and (C).
Figure 30 is total dye figure of the compound I-3 in A549 cell, with fat drips dyestuff BODIPY493/503 Green；Its
In, (A) is the light field figure of HCC827 cell；It (B) is colored graph of the II-2 after lighting activation；It (C) is BODIPY493/503
The fat drips colored graph of Green；It (D) is (A), the stacking chart of (B) and (C).
Specific embodiment
Present invention will now be described in further detail with reference to the embodiments and the accompanying drawings, but embodiments of the present invention are unlimited
In this.
Embodiment 1
Synthesize three kinds of compound of formula I:
(1) compound I-1:1- (4- (hexichol amido) phenyl)-morpholinyl -9- oxo -2,9- dihydro -1H- indeno [2,
1-c] pyridine -4- nitrile synthesis (R1=4- (hexichol amido) phenyl, R2=morpholinyl)
2- ((Z) -2- (4- diphenyl amino)-benzylidene) -1,2- dihydro -1- benzofuran -3- subunit)-malononitrile
(225mg, 0.5mmol) and morpholine (43.5mg, 0.5mmol) are dissolved in 10mL acetonitrile, then under 50 DEG C of nitrogen protections, reaction
12 hours.To the end of reacting, restore to room temperature, reaction solution rotates under reduced pressure removes solvent, and residue passes through silica gel column layer
Analyse isolated red solid product 1- (4- (hexichol amido) phenyl)-morpholinyl -9- oxygen -2,9- dihydro -1H- indeno [2,
1-c] pyridine -4- nitrile (126mg, yield 47%).Related structural characterization data are as follows:
1H NMR(CD2Cl2, 500MHz): δ 7.79 (d, J=7.5Hz, 1H), 7.33 (td, J1=7.0Hz, J2=2.0Hz,
1H), 7.26-7.18 (m, 8H), 7.03-7.00 (m, 6H), 6.95 (d, J=8.5Hz, 2H), 6.25 (d, J=4.5Hz, 1H),
5.61 (d, J=4.5Hz, 1H), 3.83-3.74 (m, 6H), 3.49-3.46 (m, 2H)；13C NMR(CD2Cl2,125MHz):
190.6,162.3,155.8,149.2,148.8,140.8,136.8,136.0,133.1,130.9,130.6,128.5,
125.9,124.5,122.1,121.8,120.8,113.5,67.7,62.9,50.6.HRMS(ESI):m/z[M+Na]+calcd
for C35H28N4NaO2,559.2110；found,559.2161.
(2) compound I-1:1- (4- (hexichol amido) phenyl) -3- diethylin -9- oxo -2,9- dihydro -1H- indeno
Synthesis (the R of [2,1-c] pyridine -4- nitrile1=4- (hexichol amido) phenyl, R2=diethylin)
2- ((Z) -2- (4- diphenyl amino)-benzylidene) -1,2- dihydro -1- benzofuran -3- subunit)-malononitrile
(225mg, 0.5mmol) and diethylamine (36.5mg, 0.5mmol) are dissolved in 10mL acetonitrile, then under 50 DEG C of nitrogen protections, instead
It answers 12 hours.To the end of reacting, restore to room temperature, reaction solution rotates under reduced pressure removes solvent, and residue passes through silicagel column
Chromatography obtains red solid product 1- (4- (hexichol amido) phenyl) -3- diethylin -9- oxygen -2,9- dihydro -1H- indeno
[2,1-c] pyridine -4- nitrile (115mg, yield 44%).Related structural characterization data are as follows:
1H NMR(CD2Cl2, 500MHz): δ 7.89 (d, J=7.5Hz, 1H), 7.31 (td, J1=7.0Hz, J2=2.0Hz,
1H), 7.27-7.20 (m, 8H), 7.02-6.95 (m, 8H), 6.02 (d, J=4.0Hz, 1H), 5.59 (d, J=4.0Hz, 1H),
3.60 (q, J=6.5Hz, 4H), 1.28 (t, J=6.5Hz, 6H)；13C NMR(CD2Cl2,125MHz):189.9,156.0,
156.3,149.0,148.9,141.1,137.5,136.5,132.7130.7,130.6,128.4,125.8,124.7,124.4,
122.2,121.5,112.6,61.2,46.3,14.7；HRMS(ESI):m/z[M+Na]+calcd for C35H30N4NaO,
545.2317；found,545.2379.
(3) compound I-3:3- amino -1- (4- (hexichol amido) phenyl) -9- oxo -2,9- dihydro -1H- indeno [2,1-
C] pyridine -4- nitrile synthesis (R1=4- (hexichol amido) phenyl, R2=amino)
2- ((Z) -2- (4- diphenyl amino)-benzylidene) -1,2- dihydro -1- benzofuran -3- subunit)-malononitrile
(225mg, 0.5mmol) and ammonium hydroxide (140mg, 25wt.%, 0.5mmol) are dissolved in 10mL acetonitrile, then in 50 DEG C of nitrogen protections
Under, it reacts 12 hours.To the end of reacting, restore to room temperature, reaction solution rotates under reduced pressure removes solvent, and residue passes through silicon
The isolated red solid product 1- of plastic column chromatography (4- (hexichol amido) phenyl) -3- diethylin -9- oxygen -2,9- dihydro -1H-
Indeno [2,1-c] pyridine -4- nitrile (121mg, yield 52%).Related structural characterization data are as follows:
1H NMR(DMSO-d6, 500MHz): 8.19 (d, J=3.0Hz, 1H), 7.70 (d, J=7.0Hz, 1H), 7.42 (br
s,2H),7.39(td,J1=7.5Hz, J2=1.0Hz, 1H), 7.32 (td, J1=8.0Hz, J2=1.0Hz, 1H), 7.29-
7.26(m,4H),7.22–7.21(m,3H),7.02(tt,J1=7.5Hz, J2=1.0Hz, 2H), 6.97-6.95 (m, 6H),
5.51 (d, J=3.0Hz, 1H)；13C NMR(DMSO-d6,125MHz):δ186.3,158.9,153.0,147.1,146.6,
138.5,137.9,135.3,131.0,129.8,129.5,127.5,123.7,122.9,119.8,119.7,118.7,
107.9,57.8,52.3；HRMS(ESI):m/z[M+Na]+calcd for C31H23N4NaO,489.1691；found,
489.1845.
Embodiment 2
Synthesize 4 kinds of Formula II compounds:
(1) compound II-1:1- (4- (hexichol amido) phenyl)-morpholinyl -9- oxo -9H- indeno [2,1-c] pyrrole
Synthesis (the R of pyridine -4- nitrile1=4- (hexichol amido) phenyl, R2=morpholinyl)
2- ((Z) -2- (4- diphenyl amino)-benzylidene) -1,2- dihydro -1- benzofuran -3- subunit)-malononitrile
(225mg, 0.5mmol) and morpholine (43.5mg, 0.5mmol) are dissolved in 10mL acetonitrile, then under dry air, 7W white section
Energy light irradiation, back flow reaction 12 hours.To the end of reacting, restore to room temperature, reaction solution rotates under reduced pressure removes solvent, residual
Excess passes through the isolated Orange red solid product 1- of silica gel column chromatography (4- (hexichol amido) phenyl)-morpholinyl -9- oxygen -
9H- indeno [2,1-c] pyridine -4- nitrile (162mg, yield 61%).Related structural characterization data are as follows:
1H NMR(CD2Cl2, 500MHz): δ 8.39 (d, J=7.5Hz, 1H), 7.88 (td, J1=9.0Hz, J2=2.0Hz,
2H),7.71(dt,J1=7.5Hz, J2=0.5Hz, 1H), 7.64 (td, J1=7.5Hz, J2=1.0Hz, 1H), 7.56 (dt, J1
=7.5Hz, J2=1.0Hz, 1H), 7.35-7.32 (m, 4H), 7.20-7.19 (m, 4H), 7.14 (dt, J1=7.5Hz, J2=
1.0Hz,1H),7.12(dt,J1=7.5Hz, J2=1.0Hz, 1H), 7.04 (dt, J1=9.0Hz, J2=2.5Hz, 2H), 4.00
(t, J=5.0Hz, 4H), 3.85 (t, J=5.0Hz, 4H)；13C NMR(CD2Cl2,125MHz):189.4,162.2,161.9,
159.5,151.7,148.3,139.7,136.8,135.5,133.6,132.8,130.8,130.2,127.0,125.5,
125.0,124.5121.2,118.5,117.1,85.6,68.0,49.9.HRMS(ESI):m/z[M+Na]+calcd for
C35H26N4NaO2,557.1953；found,557.1946.
(2) compound II-2:3- diethylin -1- (4- (hexichol amido) phenyl) -9- oxo -9H- indeno [2,1-c] pyrrole
Synthesis (the R of pyridine -4- nitrile1=4- (hexichol amido) phenyl, R2=diethylin)
2- ((Z) -2- (4- diphenyl amino)-benzylidene) -1,2- dihydro -1- benzofuran -3- subunit)-malononitrile
(225mg, 0.5mmol) and diethylamine (36.5mg, 0.5mmol) are dissolved in 10mL acetonitrile, then under dry air, 7W white
Energy saving light irradiation, back flow reaction 12 hours.To the end of reacting, restoring to room temperature, reaction solution rotates under reduced pressure removes solvent,
Residue passes through the isolated Orange red solid product 3- diethylin -1- of silica gel column chromatography (4- (hexichol amido) phenyl) -9-
Oxo -9H- indeno [2,1-c] pyridine -4- nitrile (II-2) (177mg, yield 68%).Related structural characterization data are as follows:
1H NMR(CDCl3, 500MHz): δ 8.39 (d, J=8.0Hz, 1H), 7.89 (d, J=8.5Hz, 2H), 7.71 (d, J
=7.0Hz, 1H), 7.60 (td, J1=7.5Hz, J2=1.0Hz, 1H), 7.51 (td, J1=7.5Hz, J2=1.0Hz, 1H),
7.32-7.29 (m, 4H), 7.21-7.19 (m, 4H), 7.11-7.06 (m, 4H), 3.90 (q, J=7.0Hz, 4H), 1.39 (t, J
=7.0Hz, 6H)；13C NMR(CDCl3,125MHz):188.1,161.1,158.6,158.3,150.1,147.0,138.4,
135.7,133.8,131.9,131.3,129.4,129.3,125.6,123.9,123.5,123.3,120.2,118.1,
114.2,81.2,45.0,13.8.HRMS(ESI):m/z[M+Na]+calcd for C35H28N4NaO,543.2161；found,
543.2218.
(3) compound II-3:3- amino -1- (4- (hexichol amido) phenyl) -9- oxo -9H- indeno [2,1-c] pyridine -
Synthesis (the R of 4- nitrile1=4- (hexichol amido) phenyl, R2=amino)
2- ((Z) -2- (4- diphenyl amino)-benzylidene) -1,2- dihydro -1- benzofuran -3- subunit)-malononitrile
(225mg, 0.5mmol) and ammonium hydroxide (140mg, 25wt.%, 0.5mmol) are dissolved in 10mL acetonitrile, then under dry air,
The energy saving light irradiation of 7W white, back flow reaction 12 hours.To the end of reacting, restore to room temperature, reaction solution rotates remove under reduced pressure
Solvent is removed, residue passes through the isolated Orange red solid product 3- amino -1- of silica gel column chromatography (4- (hexichol amido) phenyl) -
9- oxo -9H- indeno [2,1-c] pyridine -4- nitrile (153mg, yield 66%).Related structural characterization data are as follows:
1H NMR(CDCl3, 500MHz): 8.18 (d, J=8.0Hz, 1H), 8.03 (br s, 2H), 7.78-7.77 (m,
3H), 7.66-7.65 (m, 2H), 7.38 (t, J=8.0Hz, 4H), 7.16-7.12 (m, 6H), 6.95 (d, J=8.0Hz, 2H)；13C NMR(DMSO-d6,125MHz):δ187.3,161.6,160.4,158.4,149.8,147.0,137.8,135.6,
134.8,133.1,131.8,130.2,129.6,125.5,124.5,124.0,122.7,120.2,115.9,113.8,81.9；
HRMS(ESI):m/z[M+H]+calcd for C31H21N4O,465.1715；found,465.1785.
(4) compound II-4:1- (9- ethyl -9H- carbazole -3-) -3- morpholino -9- oxo -9H- indeno [2,1-c] pyrrole
Pyridine -4- nitrile
Malononitrile (200mg, 0.5mmol) and morpholine (43.5mg, 0.5mmol) are dissolved in 10mL acetonitrile, then in drying
Under air, the energy saving light irradiation of 7W white, back flow reaction 12 hours.To the end of reacting, restore to room temperature, reaction solution is under reduced pressure
Revolving removes solvent, and residue passes through the isolated Orange red solid product 1- of silica gel column chromatography (9- ethyl -9H- carbazole -3-) -
3- morpholino -9- oxo -9H- indeno [2,1-c] pyridine -4- nitrile (II-5) (138mg, yield 57%).Related structural characterization number
According to as follows:
1H NMR(CDCl3, 500MHz): δ 8.79 (s, 1H), 8.43 (d, J=7.5Hz, 1H), 8.43 (d, J=7.5Hz,
1H), 8.18 (d, J=7.5Hz, 1H), 8.12 (d, J=8.5Hz, 1H), 7.78 (d, J=7.0Hz, 1H), 7.65 (t, J=
7.5Hz, 1H), 7.57 (t, J=7.5Hz, 1H), 7.51-7.44 (m, 2H), 7.29-7.26 (m, 1H), 4.42 (q, J=
7.5Hz, 2H), 4.07 (s, 4H), 3.93 (s, 4H), 1.48 (t, J=7.5Hz, 2H)；HRMS(ESI):m/z[M+Na]+calcd
for C31H24N4NaO2,507.1797；found,507.1795.
Embodiment 3
The single crystal structure analysis of compound II-2:
In the mono-crystalline structures (see Fig. 1) of compound II-2, the dihedral angle of 2- azepine Fluorenone and 1- aromatic ring is 41.9 (6) °,
And triphenylamine segment is propeller conformation, the dihedral angle between corresponding aromatic ring is respectively 61.3 (2) °, 67.9 (1) ° and 73.3
(6)°.The molecular conformation of the distortion facilitates the solution state luminous energy absorbed by Internal Rotations of Molecules dissipation, to not issue glimmering
Light.In addition, there is a variety of C-H π, C-HO and model ylid bloom action power facilitate in crystalline substance in crystal structure
Movement in state or state of aggregation restriction molecule, prevents nonradiative transition, is conducive to issue fluorescence by radiation transistion.
Embodiment 4
The photophysical property of compound II characterizes:
By tetrahydrofuran and water according to different volume ratio (tetrahydrofuran: water=100:0,90:10,80:20,70:30,
60:40,50:50,40:60,30:70,20:80,10:90,1:99) mixing, the different mixed liquor of water content is formed, by compound
II-1 is dissolved into these mixed liquors, makes the concentration 10 of compound-5mol·L-1, fluorescence emission spectrum is then detected, as a result
See Fig. 2.
When the water content being continuously increased in mixed solution system to (tetrahydrofuran: water=30:70), compound II-1's
Fluorescence weakens first, this is because caused by the Intramolecular electron transfer effect of distortion.By taking compound II-1 as an example, by it
The measurement of UV absorption and fluorescence emission spectrum in different solvents finds the increase with solvent polarity, compound II-1's
Fluorescence emission spectrum occurs apparent red shift and weakens (see Fig. 3), this is the change of the Intramolecular electron transfer property with distortion
Close characteristic feature possessed by object.
It is further found by theoretical calculation, the electronics of the highest occupied molecular orbital (HOMO) of compound II-1~II-3
Cloud is mainly distributed on triphenylamine segment, and the electron cloud for not accounting for molecular orbit (LUMO) most is mainly distributed on 2- azepine Fluorenone segment
(see Fig. 4), it was confirmed that Formula II compound has the structure feature of typical donor-receiver (D-A).
Further in the mixed solvent system of tetrahydrofuran and water increase water ratio to (tetrahydrofuran: water=10:
90) when, the solubility of compound II-1 reduces to assemble, and fluorescence intensity enhances rapidly, this is because after forming aggregation, point
In son caused by limitation of movement.Further when water content reaches 99%, fluorescence intensity is declined slightly, this is because it is dissolved
Caused by loose aggregate caused by degree quickly reduces.
By taking compound II-1 as an example, by it in ethyl alcohol (viscosity coefficient η=1.2mPa S) and glycerol (viscosity coefficient η
=945mPa S) in fluorescence emission spectrum measurement, with the increase of solvent viscosity, internal molecular motion is restricted, fluorescence
Emissive porwer is remarkably reinforced (see Fig. 5).
By measurement compound II-1~II-3 tetrahydrofuran solution neutralized film state quantum yield and fluorescence lifetime,
It was found that compound II-1 increases 20 times in the quantum yield of thin-film state, and fluorescence lifetime increases relative in tetrahydrofuran solution state
Add 3.4 times, clearly demonstrated its aggregation-induced emission property.And compound II-1 is in the stoke shift of thin-film state
200nm is very beneficial for it in bio-imaging much larger than traditional fluorescent material (stoke shift is usually less than 40nm)
Using.Compound II-2, II-3, II-4 show similar photophysical property.
1 compound II-1~II-3 of table is characterized in the photophysical property of tetrahydrofuran solution state and thin-film state
Fig. 6~Fig. 8 is uv absorption spectra in tetrahydrofuran of compound II-2, II-3, II-4, in tetrahydrofuran
With the fluorescence emission spectrogram of compound and maximum fluorescence emission intensity and emission maximum for being continuously increased water content in the mixed solution of water
The variation diagram of wavelength, they show typical aggregation-induced emission property.
Embodiment 5
Compound I-1~I-3 is converted into compound II-1~II-3 with aggregation-induced emission property under light illumination:
Fig. 9 is compound I-1 in water: in the solution of dimethyl sulfoxide (99:1, v/v), portable ultraviolet (UV) lamp of 365nm shines
Fluorescent emission under penetrating changes spectrum.As can be seen from Figure, under UV lamp irradiation, as the irradiation time increases, compound
The fluorescence intensity of I-1 gradually increases, and causes this is because compound I-1 generates compound II-1 by photooxidation dehydrogenation reaction
's.In addition, from the uv-visible absorption spectra of compound I-1 it can also be seen that with UV illumination extension, in 530nm
Characteristic absorption peak, the gradually 413nm of blue shift to the characteristic absorption peak for belonging to compound II-1 (see Figure 10).
Compound I-2~I-3 is under UV lamp irradiation, fluorescence emission spectrum, uv-visible absorption spectroscopy and nuclear-magnetism spectrum
Figure also has similar variation (see Figure 11~Figure 14).In order to confirm the conversion of photooxidation fluidized dehydrogenation, from the stacking chart of nucleus magnetic hydrogen spectrum
As can be seen that the signal of the hydrogen in compound I-1 on C-N singly-bound in 6.25 and 5.61ppm completely disappears in compound II-1,
Confirmed the reaction mechanism of photooxidation fluidized dehydrogenation (see Figure 15).
Embodiment 6
The cytotoxicity experiment of compound I-1 and II-1:
Figure 16 is that compound I-1 and II-1 are directed to lung carcinoma cell HCC827, the cytotoxicity of A549 and normal pneumonocyte HLF
Experimental result.Should the result shows that, (10,20,40,60,80,100 μM) all almost under various concentration by compound I-1 and II-1
There is no cytotoxicity.
Embodiment 7
Application of the compound I-1 in the photoactivation fluorescence imaging that fat drips target:
Figure 17 is dyeing effect of the compound I-1 to lung carcinoma cell HCC827.As a result, it has been found that compound I-1 is in HCC827
It is intracellular just to start not issue fluorescence, by the way that by the laser active of 405nm, fluorescent emission intensity increases sharply.In 405nm
Under the scanning of laser, as scanning times increase to 5 times (sweep time is 22.4 seconds/time), fluorescence intensity increases to initial
265 times of value, show that compound I-1 has high photoactivation efficiency and very high signal-to-noise ratio in HCC827 into the cell.
In order to confirm the compound I-1 after photoactivation the location of in cell, contaminate with the fat drips of commercialization
Expect the total dye experiment of BODIPY493/503 Green and nucleus dyestuff Hoechst 33342.As a result, it has been found that after photoactivation
Compound I-1 can have with fat drips dyestuff BODIPY493/503 Green good common location (overlap coefficient is up to 0.92) (see
Figure 18), show that compound I-1 can be used as the photoactivation fluorescence probe of fat drips targeting.
Compound I-1 can also realize the specific photoactivation fluorescence imaging (see Figure 19) to fat drips in lung cancer A549 cell,
And pass through the total dye of fat drips dyestuff BODIPY493/503 Green and nucleus dyestuff Hoechst 33342 with commercialization reality
Testing is confirmed (see Figure 20).
Embodiment 8
The photoactivation fluorescence imaging that compound I-1 is targeted by fat drips is distinguishing answering in lung carcinoma cell and normal pneumonocyte
With:
Figure 21, by with the fat drips imaging contrast in HCC827 and A549 lung carcinoma cell, as a result, it has been found that thin in HLF normal lung
Fat drips content in born of the same parents significantly reduces.Show that compound I-1 as photoactivation fluorescence probe, can also effectively distinguish lung carcinoma cell
With normal pneumonocyte.
Embodiment 9
Compound I-1 is selectively realized in photoactivation fluorescence imaging for individual cells or cell mass under many cells environment
Application:
It can be used for the cell imaging of high time-space resolution to verify compound I-1, by taking HCC827 cell as an example, discovery exists
In the environment of many cells, compound I-1 can pass through light-operated realization successively lighting one by one (see Figure 22) to different cells.Chemical combination
This property of object I-1 is particularly conducive to it and moves in the tissue in the motion change monitoring of fat drips subgroup and individual cells
The research of variation monitoring.
Embodiment 10
The application of compound I-2, I-3 in the photoactivation fluorescence imaging that fat drips target:
By taking HCC827 and A549 lung carcinoma cell as an example, compound I-2 and I-3 is further demonstrated to intracellular fat drips
Specificity photoactivation fluorescence imaging can be achieved.As a result, it has been found that fat drips target can be achieved to HCC827 and A549 lung carcinoma cell in they
To photoactivation fluorescence imaging (see Figure 23-26), and being total to by the fat drips dyestuff BODIPY493/503 Green with commercialization
Dye experiment is confirmed (see Figure 27-30).The fluorescence of activated compounds I-2 and I-3 under 405nm laser irradiation, discovery exist
It with the overlap coefficient of fat drips dyestuff BODIPY493/503 Green is 0.85 and 0.88 in HCC827 cell, and in A549 cell
In overlap coefficient be 0.83 and 0.85.The total dye is the experiment proves that compound I-2 and I-3 can realize spy to intracellular fat drips
Anisotropic photoactivation fluorescence imaging.
The present invention establishes the simple and effective of 1,2- dihydro -2- azepine fluorenes ketone compounds and 2- azepine fluorenes ketone compounds
Preparation method.Under light illumination, photooxidation dehydrogenation reaction can occur for 1,2- dihydro -2- azepine fluorenes ketone compounds, generation has
The 2- azepine fluorenes ketone compounds of aggregation-induced emission property.Due to the Intramolecular electron transfer that internal molecular motion is limited and distorts
Mechanism, 2- azepine fluorenes ketone compounds solution state do not issue fluorescence or shine it is very weak, but state of aggregation issue hyperfluorescence.1,2-
For dihydro -2- azepine fluorenes ketone compounds as photoactivation fluorescence probe, the light-operated high-spatial and temporal resolution for realizing fat drips targeting is glimmering
Light imaging, and it can effectively be distinguished based on the difference of fat drips content in cancer cell and normal cell.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention,
It should be equivalent substitute mode, be included within the scope of the present invention.
Claims (8)
1. one kind 1,2- dihydro -2- azepine fluorenes ketone compounds, it is characterised in that structure is shown in formula I:
Wherein R1For 4- (hexichol amido) phenyl or 9- Ethy-Carbazole -3- base；R2For amino, morpholinyl；R3For cyano；R4For hydrogen.
2. one kind 1,2- dihydro -2- azepine fluorenes ketone compounds, it is characterised in that be following compound:
3. the preparation method of 1,2- dihydro -2- azepine fluorenes ketone compounds of any of claims 1 or 2, it is characterised in that including
Following steps:
Formula III compound and formula IV compound that molar ratio is 1:1~1:2 are dissolved in acetonitrile；It is 50~60 DEG C in temperature,
It under nitrogen protection, is protected from light, 1, the 2- dihydro -2- azepine fluorenes ketone compounds of production I.
4. the preparation method of 1,2- dihydro -2- azepine fluorenes ketone compounds according to claim 3, it is characterised in that: institute
Stating molar ratio is 1:1, and temperature is 50~55 DEG C.
5. a kind of 2- azepine fluorenes ketone compounds, it is characterised in that structure is as shown in Formula II:
Wherein R1For 4- (hexichol amido) phenyl or 9- Ethy-Carbazole -3- base；R2For amino, morpholinyl；R3For cyano；R4For hydrogen.
6. a kind of 2- azepine fluorenes ketone compounds, it is characterised in that be following compound:
7. the preparation method of 2- azepine fluorenes ketone compounds described in claim 5 or 6, it is characterised in that comprise the steps of:
Under light illumination by compound of formula I, it is reacted in the presence of oxygen, the 2- azepine fluorenes ketone compounds of production II.
8. the preparation method of 2- azepine fluorenes ketone compounds described in claim 5 or 6, it is characterised in that the following steps are included:
Formula III compound and formula IV compound that molar ratio is 1:1~1:2 are dissolved in acetonitrile, in dry air, light
It according under, is reacted under counterflow condition, the 2- azepine fluorenes ketone compounds of production II.
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