CN107501104A - A kind of formaldehyde fluorescent nano probe intermediate of dual signal turn on outputs and its preparation and application - Google Patents

A kind of formaldehyde fluorescent nano probe intermediate of dual signal turn on outputs and its preparation and application Download PDF

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CN107501104A
CN107501104A CN201710650693.2A CN201710650693A CN107501104A CN 107501104 A CN107501104 A CN 107501104A CN 201710650693 A CN201710650693 A CN 201710650693A CN 107501104 A CN107501104 A CN 107501104A
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朱勍
谢振达
朱伸
赵成艳
应莎莎
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Zhejiang University of Technology ZJUT
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Abstract

The invention discloses a kind of preparation method and application of Mitochondrially targeted dual signal turn on formaldehyde fluorescent nano probe intermediate (III), method is using parahydroxyben-zaldehyde as initiation material, in the presence of acid binding agent, it is to be activated at 60 70 DEG C in temperature, then using 3 propargyl bromides as nucleopilic reagent, at 60 70 DEG C of temperature, nucleophilic substitution occurs in acetone solvent, obtains compound (II)；Compound (II) carries out ammonification using methanolic ammonia solution at 0 DEG C, adjacent two tertiary alcohol esters of propylene ylboronic acid is added at 0 DEG C, temperature control is reacted at 25 35 DEG C after mixing, obtains the compound shown in the formula (III).Compound shown in formula (III) can be as the formaldehyde fluorescent nano probe intermediate for preparing dual signal turn on.The nano-probe does not almost have fluorescence in water, and two free fluorescent materials are obtained after being reacted with formaldehyde, so as to realize double turn on effect, so as to improve the accuracy of testing result.

Description

A kind of the formaldehyde fluorescent nano probe intermediate and its system of dual signal turn-on outputs It is standby with application
Technical field
The present invention relates to a kind of formaldehyde fluorescent nano probe intermediate of dual signal turn-on outputs and its prepare and answer With.
Background technology
1st, formaldehyde is to carry gas molecule minimum in carbonyls as carcinogen.On the one hand, formaldehyde is to human body Respiratory system and eye there is strong impulse effect, be chronically exposed to the PFT that people can be reduced under formaldehyde environment.It is another Aspect, formaldehyde have pathogenic to human body.Too high formaldehyde can cause the various cancers such as Alimentary System, lung cancer, god in vivo Through degenerative disease, stages alzheimer's disease etc..Nowadays, the technology of most of detection formaldehyde is only able to detect in air or in water Formaldehyde, live body or the intracellular effect monitored in real time can not be realized.Therefore, it is necessary to which developing one kind can detect in cell in real time Concentration of formaldehyde technology.
2nd, fluorescence probe, as it is a kind of with efficient, sensitive, selectivity it is strong, can monitoring and other advantages in real time detection technique, Applied by numerous researchers.In numerous fluorescence probes that can detect intracellular formaldehyde, also realized not over self assembly Namo fluorescence probe is so as to reaching the report of dual signal turn-on effects.Present invention aims at one dual signal turn- of exploitation The midbody compound of the formaldehyde fluorescent nano probe of on outputs, the compound has two features, and one end has alkynes, can be with Click chemistry is carried out with azido, it is convenient to be reacted with other compounds；The other end has homoallylic alcohol ammonia, and the group can Aldehyde radical is exclusively generated with formaldehyde.
The content of the invention
The present invention seeks to formaldehyde fluorescent nano probe intermediate of a kind of dual signal turn-on outputs and preparation method thereof With application.
The present invention uses following technical scheme to achieve the above object：
A kind of compound shown in formula (III)：
A kind of preparation method of compound shown in formula (III), the preparation method are：(1) using parahydroxyben-zaldehyde as Initiation material, it is to be activated at 60-70 DEG C in temperature in the presence of acid binding agent, then using 3- propargyl bromides as nucleopilic reagent, At 60-70 DEG C of temperature, nucleophilic substitution occurs in acetone solvent, post-treated A obtains compound (II)；(2) by step (1) compound (II) obtained carries out ammonification using methanolic ammonia solution at 0 DEG C, and adjacent two uncles of propylene ylboronic acid are added at 0 DEG C Alcohol ester, temperature control is reacted at 25-35 DEG C after mixing, and post-treated B obtains the compound shown in the formula (III)；
Further, the acid binding agent described in above-mentioned preparation method is potassium carbonate.The amount dosage of the material of the acid binding agent is 1.5 times of equivalents of parahydroxyben-zaldehyde.
Further, in above-mentioned preparation method the material of parahydroxyben-zaldehyde described in step (1) and 3- propargyl bromides amount ratio For 1:1.5~3, preferably 1:2.
Further, the ammonia density in above-mentioned preparation method described in step (2) in methanolic ammonia solution is 7mol/L.
Further, compound (II) described in above-mentioned preparation method and the amount ratio of the theoretical material of the ammonia in methanolic ammonia solution For 1：6~20, preferably 1：10.
Further, compound (II) described in above-mentioned preparation method and the theoretical material of adjacent two tertiary alcohol esters of propylene ylboronic acid Amount is than being 1：1.2~2, preferably 1:1.5.
Further, A is post-processed described in above-mentioned preparation method is：Reaction solution vacuum rotary steam adds water, second after removing solvent Acetoacetic ester extracts, and merges organic phase, takes organic phase water and saturated common salt water washing for several times, anhydrous sodium sulfate drying, filtering, Solvent is spin-dried for, target product is obtained after column chromatography for separation, eluant, eluent is volume ratio 1:10 ethyl acetate and petroleum ether；
The post processing B is：Reaction solution vacuum rotary steam removes solvent, and crude product obtains target production after carrying out chromatography post separation Thing, eluant, eluent are volume ratio 40:1 dichloromethane and methanol.
In addition, the compound that the present invention is also provided shown in a kind of formula (III) is glimmering as the formaldehyde for preparing dual signal turn-on The application of light nano-probe intermediate.
Further, the formaldehyde fluorescence nano that described dual signal turn-on is prepared by the compound shown in formula (III) is visited The preparation method of pin is as follows：
Compound (III) in acid condition, generates schiff bases intermediate product with compound (IV), and its carbon-to-nitrogen double bon is gone back Former agent sodium triacetoxy borohydride reduction generation compound (V)；Compound (VI) occurs acid amides reaction with 3- nitrine propylamine and given birth to Into compound (VII)；Finally, by compound (V) and compound (VII) under cupprous catalysis, compound (I) is generated；Again Compound (I) is dissolved in DMSO as mother liquor, diluted with ultra-pure water or PBS or cell culture fluid, several minutes of ultrasound, so Acutely concussion, compound (I) self assembly obtain the formaldehyde fluorescent nano probe of the dual signal turn-on afterwards；
The formaldehyde fluorescent nano probe reaction scheme of the dual signal turn-on is as follows：
Further, described dual signal turn-on formaldehyde fluorescence nano is prepared by the compound shown in formula (III) Probe preparation method is specially：
(1) compound (IV) presses the amount of theoretical material than 1 with compound (III), sodium triacetoxy borohydride:1.2:4 Room temperature reaction is gone to after 0 DEG C of mixing in acid condition, post-treated C is prepared into compound (V)；Reaction time is 12 hours, Reaction dissolvent is tetrahydrofuran；
(2) compound (VI) presses the amount of material than 1 with 3- nitrine propylamine:1.2 reactions, post-treated D are prepared into compound (VII)；Reaction temperature is room temperature, and the reaction time is 10 hours, and reaction dissolvent is dichloromethane；
(3) compound (V) and compound (VII) are pressed into the amount of theoretical material than 1:1 reacts under monovalence copper catalysis, is evaporated Solvent, crude product obtain compound (I) using high-efficient liquid phase chromatogram purification；Reaction temperature is room temperature, and the reaction time is 6 hours, Reaction dissolvent is tetrahydrofuran and water；
(4) compound (I) is dissolved in DMSO and is configured to the probe mother liquor that concentration is 0.1~2mM, delayed with ultra-pure water or PBS Fliud flushing or DMEM culture mediums are diluted to 99 times of original mother liquor volume, and several minutes of ultrasound, then acutely concussion, compound (I) is certainly Assembling obtains the fluorescent nano probe.
The compounds of this invention (IV) is disclosed compound, and its preparation method refers to document [H.Park, S.- K.Chang,Signaling of water content in organic solvents bysolvatochromism of a hydroxynaphthalimide-based merocyanine dye,DyesPigm.122(2015)324–330.]。
Further, acid condition described in above method step (1) is realized using acetic acid, acetic acid and the thing of compound (IV) The amount ratio of matter is 8~20：1, preferably 10:1.
Further, 1- hydroxy benzo triazoles, 1- ethyls-(3- dimethylaminos third can be added in above method step (2) Base) carbodiimide hydrochloride reacts condensing agent as acid amides, and triethylamine is recommended as 3 as acid binding agent, the amount ratio of three's material:3: 4。
C is post-processed described in the above method is：Reaction solution vacuum rotary steam removes solvent, after crude product carries out chromatography post separation Target product is obtained, eluant, eluent is volume ratio 20:1 dichloromethane and methanol；
The post processing D is：Reaction solution is separated using thin-layer chromatography, and solvent is volume ratio 20:1 dichloromethane And methanol, obtain target compound.
In addition, dual signal turn-on of the present invention formaldehyde fluorescent nano probe can be used for detecting concentration of formaldehyde.
Further, formaldehyde of the present invention exists as an aqueous solution, and concentration is 0~5mmol/L, and the concentration is 0 Implication is to be infinitely close to 0 but not equal to 0.
Further, formaldehyde of the present invention is preferably intracellular formaldehyde, and concentration is 0~1mmol/L.
Further, cell of the present invention is human breast cancer cell line Bcap-37.
The above-mentioned dual signal turn-on of present invention formaldehyde fluorescent nano probe is Mitochondrially targeted dual signal Turn-on formaldehyde fluorescent nano probe nano-MTDF, abbreviation nano-probe nano-MTDF.
It is of the present invention by compound (I) self assembly as a kind of Mitochondrially targeted dual signal turn-on first Aldehyde fluorescent nano probe, it can be applied to the fluorogenic quantitative detection of formaldehyde.The fluoroscopic examination principle of described Quant Formaldehyde concentration is： Using nano-probe nano-MTDF as fluorescence probe, after being reacted with formaldehyde, intermediate product, subsequent 2- azepines-Ke Pu are generated Reset and hydrolyze, generate fluorescent material compound VIII and compound IX, determine and exciting as under 440nm and 535nm Fluorescence intensity change, so as to obtain concentration of formaldehyde.
It is dense using formaldehyde in the new Mitochondrially targeted dual signal turn-on of present invention formaldehyde fluorescence probe detection water The principle of degree is as follows：
The Mitochondrially targeted dual signal turn-on of present invention formaldehyde fluorescent nano probe is almost not have fluorescence in water , that is, two fluorogens 1 in probe, the fluorescence of 8- naphthalimides and rhodamine B is all quenched, principle therein It is 1,8- naphthalimides because FRET causes fluorescent quenching, while the causing of hydrophobicity of 1,8- naphthalimide Compound (I) independently dresses up nano particle in water, and rhodamine B causes fluorescent quenching because principle is quenched in aggregation inducing.Work as nanometer After probe nano-MTDF and formaldehyde react, the fluorogens of two separation are discharged, nano-probe self assembly removes, 1,8- naphthoyl Imines and the fluorescence of rhodamine B recover simultaneously, it is achieved thereby that dual signal turn-on effect.Wherein in rhodamine B structure N+Also there is targetted mitochondria.
Compared with prior art, beneficial effect of the present invention is mainly reflected in：First, the present invention is using parahydroxyben-zaldehyde as original Beginning raw material, title intermediate compound is synthesized by two steps.Reaction condition is gentle, without inflammable and explosive reagent, easily industrialization Production scale.Secondly, the invention provides a kind of formaldehyde fluorescent nano probe intermediate of new dual signal turn-on outputs, The compound one end has alkynes, easily carries out addition reaction with other compounds with azido；The other end has high alkene Propyl alcohol amine groups, the group is first and formaldehyde generation schiff bases, subsequent cope reset and hydrolyzed generation aldehyde radical, and this kind of reaction is to first Aldehyde selectivity is strong.In summary, the compound provides a kind of effective conjunction to dual signal turn-on formaldehyde fluorescent nano probe Into intermediate.
Brief description of the drawings
Fig. 1 is the nucleus magnetic hydrogen spectrum of compound (I) prepared by embodiment 1 in the present invention.
Fig. 2 is the nuclear-magnetism carbon spectrum of compound (I) prepared by embodiment 1 in the present invention.
Fig. 3 is the nano-probe nano-MTDF (1 μM) of the preparation of embodiment 1 in the present invention at DMSO/ water (v/v=1/99) Under the conditions of use dynamic optical diffraction test particle particle diameter, and pass through transmission electron microscope (1 μm of gauge) and carry out nano particle Imaging.
Fig. 4 is the nano-probe nano-MTDF (1 μM) of the preparation of embodiment 1 in the present invention in the glimmering of different DMSO/ water ratios Optical emission spectroscopy figure.Figure a is fluorescence emission spectrogram of compound, excitation wavelength 440mm.Figure b is fluorescence emission spectrogram of compound, excitation wavelength 535nm。
Fig. 5 is the nano-probe nano-MTDF (1 μM) of the preparation of embodiment 1 in the present invention in DMSO/PBS buffer solutions (pH= 7.4, v/v=1/99) fluorescence emission spectrogram of compound added under the conditions of under different equivalent of formaldehyde.Figure a is fluorescence emission spectrogram of compound, is swashed Send out wavelength 440mm.Figure b is fluorescence emission spectrogram of compound, excitation wavelength 535mm.
Fig. 6 is the nano-probe nano-MTDF (1 μM) of the preparation of embodiment 1 in the present invention in DMSO/PBS buffer solutions (pH= 7.4, v/v=1/99) under the conditions of with the fluorogram changed over time in formaldehyde (1mM) mechanism.Scheme a excitation wavelengths 440nm, launch wavelength 540nm.Scheme b excitation wavelength 535nm, launch wavelength 585nm.
Fig. 7 is the nano-probe nano-MTDF (1 μM) of the preparation of embodiment 1 in the present invention in DMSO/PBS buffer solutions (pH= 7.4, v/v=1/99) fluorogram of selective result under the conditions of.1-17 be respectively PBS, formaldehyde, acetaldehyde, pyroracemic aldehyde, benzaldehyde, Paranitrobenzaldehyde, parahydroxyben-zaldehyde, acetone, formic acid, Sodium Pyruvate, glucose, glutathione, homocysteine, half Cystine, niter cake, hydrogen peroxide, TBHP.Scheme a excitation wavelength 440nm, launch wavelength 540nm.Figure b is excited Wavelength 535nm, launch wavelength 585nm.
Fig. 8 is the nano-probe nano-MTDF (1 μM) of the preparation of embodiment 1 in the present invention in DMSO/ difference pH buffer solutions (v/v=1/99) fluorogram front and rear with formaldehyde reaction under the conditions of.Scheme a excitation wavelength 440nm, launch wavelength 540nm.Figure b swashs Send out wavelength 535nm, launch wavelength 585nm.
Fig. 9 be the present invention in embodiment 1 prepare nano-probe nano-MTDF DMSO/PBS buffer solutions (pH=7.4, V/v=1/99 the high-efficient liquid phase chromatogram and mass spectrogram added under the conditions of) before and after formaldehyde.
Figure 10 is the nano-probe nano-MTDF of the preparation of embodiment 1 in the present invention to formaldehyde fluorescence imaging in cell.
Embodiment
With reference to specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in This.
The preparation of embodiment 1 (1) compound (II)
1.22g parahydroxyben-zaldehydes (10mmol) are dissolved in 50mL acetone solns, then add 2.07g (15mmol) carbon Sour potassium, at 60-70 DEG C after half an hour, 2.37g 3- propargyl bromides (20mmol) are added, are stopped after being reacted 2 hours at 60-70 DEG C, Decompression steams solvent.Water is added into mixture, ethyl acetate extraction, merges organic phase, water and saturated common salt water washing number It is secondary, anhydrous sodium sulfate drying, filtering, it is spin-dried for solvent, column chromatography for separation (ethyl acetate：Petroleum ether=1:10 be eluant, eluent), obtain To compound as white solid (II) (1.53g, 95% yield).1H NMR(500MHz,CDCl3)δ9.88(s,1H),7.95–7.75 (m, 2H), 7.18-6.98 (m, 2H), 4.77 (d, J=2.4Hz, 2H), 2.58 (t, J=2.4Hz, 1H)13C NMR(126MHz, CDCl3)δ190.69,162.30,131.81,130.51,115.11,77.51,76.35,55.87.ESI calcd.for C10H8O2[M+H]+161.05,found 161.18。
(2) preparation of compound (III)
0.64g compounds (II) (4mmol) are dissolved in 40mL methanol, ice bath adds 6mL methanolic ammonia solutions to 0 DEG C (7mol/L, 42mmol), half an hour being reacted at 0 DEG C, then adding adjacent two tertiary alcohol esters (6mmol) of 1g propylene ylboronic acid, reaction turns To 25-35 DEG C and reaction is stayed overnight.Vacuum rotary steam removes solvent, and crude product carries out chromatography post separation (dichloromethane：Methanol=40:1 For eluant, eluent), obtain colourless oil liquid compound (III) (0.613g, 76% yield).1H NMR(500MHz,CDCl3)δ 7.32-7.25 (m, 2H), 6.99-6.91 (m, 2H), 5.79-5.71 (m, 1H), 5.16-5.05 (m, 2H), 4.69 (d, J= 2.4Hz, 2H), 3.98-3.95 (m, 1H), 2.53 (t, J=2.4Hz, 1H), 2.49-2.41 (m, 1H), 2.40-2.29 (m, 1H).13C NMR(126MHz,CDCl3)δ156.51,138.87,135.46,127.35,117.56,114.75,78.65, 75.42,55.82,54.71,44.17.ESI calcd.for C13H15NO[M+H]+202.12,found 202.29。
(3) preparation of compound (V)
0.15g compounds (IV) (0.5mmol) are added in 15mL anhydrous tetrahydro furans, are cooled to 0 DEG C, are then added successively Enter 0.18g compounds (III) (0.6mmol), 0.3g acetic acid (5mmol) and 0.42g sodium triacetoxy borohydrides (2mmol). Reaction goes to 20-30 DEG C and reaction is stayed overnight.Vacuum rotary steam removes solvent, and crude product carries out chromatography post separation (dichloromethane：Methanol =20:1) orange solid chemical compound (V) (0.14g, 59% yield), is obtained.1H NMR(500MHz,CDCl3) δ 8.38 (t, J= 7.2Hz, 2H), 7.93 (s, 1H), 7.53 (t, J=7.8Hz, 1H), 7.30 (d, J=8.6Hz, 2H), 7.03 (d, J=8.6Hz, 2H), 5.81-5.73 (m, 1H), 5.22-5.13 (m, 2H), 4.71 (d, J=2.4Hz, 2H), 4.13-4.05 (m, 2H), 4.02 (d, J=14.2Hz, 1H), 3.91 (d, J=14.2Hz, 1H), 3.81 (t, J=7.0Hz, 1H), 2.70-2.59 (m, 2H), 2.56 (t, J=2.3Hz, 1H), 1.70-1.64 (m, 2H), 1.49-1.37 (m, 2H), 0.97 (q, J=7.8Hz, 3H)13C NMR(126MHz,CDCl3)δ164.60,163.76,162.42,157.39,133.86,132.93,132.48,131.08, 128.81,128.29,124.93,123.02,121.68,118.77,115.34,111.71,78.39,75.74,61.41, 55.85,49.83,41.43,39.98,30.21,24.81,20.39,13.85.ESI calcd.For C30H30N2O4[M–H]- 481.22,found 481.27。
(4) preparation of compound (VII)
0.06g compounds (VI) (0.1mmol) are dissolved in 5mL dichloromethane, then sequentially add 1- hydroxy benzos three Nitrogen azoles (0.02g, 0.15mmol), 0.03g 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride (0.15mmol)), 0.02g triethylamines (0.2mmol) and 0.01g 3- nitrine-propylamine (0.12mmol), at room temperature reaction are stayed overnight, After question response terminates, crude product is with preparing thin-layer chromatography (dichloromethane：Methanol=20:1) separated, obtain dark red solid Compound (VII) (0.057g, 82% yield).1H NMR(400MHz,DMSO)δ7.89(s,1H),7.83–7.66(m,3H), 7.54 (s, 1H), 7.13 (dt, J=9.7,5.6Hz, 4H), 6.95 (d, J=1.7Hz, 2H), 3.66 (dd, J=13.6, 6.5Hz, 8H), 3.56-3.16 (m, 10H), 3.08 (dd, J=12.2,6.2Hz, 2H), 2.50 (d, J=1.5Hz, 3H), 2.29 (s, 2H), 1.73-1.49 (m, 2H), 1.21 (t, J=6.9Hz, 12H)13C NMR(75MHz,DMSO)δ171.70,170.45, 166.94,159.23,158.77,158.30,157.83,157.44,155.95,155.51,135.64,132.13,131.05, 130.76,130.14,127.87,118.34,114.63,113.41,96.29,48.73,47.13,45.75,44.63, 41.44,36.12,30.59,28.80,28.07,12.76.ESI calcd.for C39H49N8O4[M]+693.39,found 693.48。
(5) preparation of compound (I)
0.027g compounds (VII) (0.04mmol) and compound (V) (0.04mmol) are dissolved in 3mL tetrahydrofurans, The aqueous solution (3mL) of 0.004g vitamin Cs (0.02mmol) and 0.003g cupric sulfate pentahydrates (0.02mmol) is added above-mentioned In mixed liquor, normal-temperature reaction 6 hours.Solvent evaporated, crude product purify to obtain kermesinus Guization using preparative high-performance liquid chromatographic Compound (I) (0.03g, 65% yield).Vitamin C plays herein is reduced into cupprous effect by cupric.
1H NMR (300MHz, DMSO) δ 8.43 (d, J=7.9Hz, 1H), 8.26 (t, J=3.5Hz, 2H), 7.98 (s, 2H), 7.72 (ddd, J=13.2,7.3,4.6Hz, 3H), 7.46 (ddd, J=28.1,12.0,6.5Hz, 4H), 7.18-7.01 (m, 6H), 6.91 (d, J=11.8Hz, 2H), 5.56 (td, J=17.0,6.8Hz, 1H), 5.16 (s, 2H), 5.04 (t, J= 12.8Hz, 2H), 4.38 (t, J=6.8Hz, 2H), 4.24 (dd, J=9.2,5.5Hz, 2H), 3.96 (dd, J=20.2, 13.1Hz, 6H), 3.63 (d, J=6.9Hz, 18H), 3.25 (dd, J=33.1,17.3Hz, 10H), 3.04 (d, J=5.9Hz, 3H), 2.94-2.58 (m, 3H), 2.30 (s, 2H), 1.93 (dd, J=11.2,4.5Hz, 2H), 1.63-1.43 (m, 2H), 1.30 (dd, J=14.8,7.4Hz, 2H), 1.19 (dd, J=12.5,5.8Hz, 12H), 0.90 (t, J=7.3Hz, 3H)13C NMR (75MHz,DMSO)δ175.28,171.87,170.47,166.91,164.51,163.03,158.72,157.38,155.91, 155.46,142.82,135.74,135.61,133.43,132.07,131.86,131.05,130.88,130.77,130.67, 130.18,130.08,130.03,128.28,127.86,126.90,125.00,122.23,121.37,119.09,115.27, 114.60,114.28,113.37,100.35,96.26,61.61,60.13,48.00,47.57,47.05,45.75,41.46, 38.96,37.95,36.03,30.59,30.35,30.29,29.33,28.79,28.10,20.20,14.13,12.78.HRMS (ESI)calcd.for C69H79N10O8[M]+1175.6082,found1175.6067。
(6) nano-probe nano-MTDF preparation
Compound (I) is dissolved in DMSO as mother liquor, mother liquor is added to ultra-pure water, PBS or cell culture fluid, surpasses Several minutes of sound, then acutely concussion, obtains nano-probe nano-MTDF.
The nano-probe nano-MTDF of embodiment 2 is under the conditions of DMSO/ water buffer solution (pH=7.4, v/v=1/99) with dynamic State optical diffraction test particle particle diameter and pass through transmission electron microscope carry out nano particle imaging.
Compound (I) prepared by a certain amount of embodiment 1 is accurately weighed, it is female to be configured to the probe that concentration is 0.1mM with DMSO Liquid, liquid-transfering gun are drawn 0.02mL and are added in 1.98mL water, several minutes of ultrasound, and then acutely concussion, obtains nano-probe nano- MTDF, particle sizes of the nano-MTDF in water then is determined with nano-zs90particle analyzer, while take the above Mixed liquor drop on copper mesh, 37 DEG C drying carry out projection electron microscope imagings, as a result see Fig. 3.
Referring to Fig. 3 (a) it can be found that the average grain diameter that the result that dynamic optical diffraction is tested to obtain is particle is 161.9nm, Polydispersity coefficient PDI indexes are 0.262.Referring to Fig. 3 (b), from transmission electron microscope (gauge：1 μm) obtained nanoparticle Footpath and the data that dynamic optical diffraction obtains are basically identical, so as to prove that compound (I) forms nano material in water.
Fluorescence spectrum detections of the nano-probe nano-MTDF of embodiment 3 (1 μM) under different DMSO/ water ratios.
Compound (I) prepared by a certain amount of embodiment 1 is accurately weighed, it is 0.1mM's to be configured to concentration with dimethyl sulfoxide (DMSO) Probe mother liquor, liquid-transfering gun draw 0.02mL be added to the different DMSO/ water ratios of 1.98mL (DMSO 1%, 5%, 10%, 20%th, 40%, 60%, 70%, 80%, 90%), several minutes of ultrasound, then acutely concussion, then determines the glimmering of compound (I) Light spectrum.
Test result indicates that the raising of the ratio with DMSO, the Fluorescence Increasing of compound (I), so as to prove with The reduction of DMSO ratios, the congregational rate of compound (I) strengthen, and the fluorescence under different excitation wavelengths all weakens, and shows rhodamine B Fluorescence be due to that aggregation causes to be quenched.Simultaneously can also be observed that no matter DMSO ratios height, excitation wavelength be 440nm under Probe only has an emission peak, and the fluorescence for illustrating naphthalimide is strictly to be quenched by FRET by rhodamine B. Fluorescence pattern is shown in Fig. 4.
Nano-probe nano-MTDF (1 μM) is in DMSO/PBS buffer solutions (pH=7.4, v/v=1/ in the present invention of embodiment 4 99) the fluorescence spectrum detection added under the conditions of under different equivalent of formaldehyde.
Probe (I) prepared by a certain amount of embodiment 1 is accurately weighed, the mother that concentration is 0.1mM is configured to dimethyl sulfoxide (DMSO) Liquid, liquid-transfering gun are drawn 0.02mL and are added in 1.96mL PBSs, several minutes of ultrasound, and then acutely concussion, obtains nanometer Probe nano-MTDF, 396 μ L nano-probe nano-MTDF solution are drawn every time, are separately added into 4 μ L difference equivalent of formaldehyde solution (concentration of the final formaldehyde in water is respectively 0,0.0025,0.0075,0.01,0.025,0.04,0.05,0.06,0.075, 0.1st, 0.15,0.25,0.4,0.5,0.6,0.75,1,2,5mM), after reacting 3h at 37 DEG C, determine its fluorescent value.Excitation wavelength To be respectively 440nm or 535nm, fluorogram is shown in Fig. 5.
Test result indicates that with the increase of formaldehyde equivalent, two free fluorogens caused by nano-probe nano-MTDF Increase, the fluorescence intensity of the fluorogen of two increases respectively.
Nano-probe nano-MTDF (1 μM) is in DMSO/PBS buffer solutions (pH=7.4, v/v=1/ in the present invention of embodiment 5 99) under the conditions of with the fluorogram changed over time in formaldehyde (1mM) mechanism.
A certain amount of probe (I) is accurately weighed, is configured to the mother liquor that concentration is 0.1mM with dimethyl sulfoxide (DMSO), liquid-transfering gun is inhaled 0.02mL is taken to be added in 1.96mL PBSs, several minutes of ultrasound, then acutely concussion, obtains nano-probe nano- MTDF, 396 μ L nano-probe nano-MTDF solution are drawn every time, adding 4 μ L formalins, (final formaldehyde is dense in water Spend for 1mM), react at 37 DEG C, different time points (be respectively 0,0.5,1,1.5,2,2.5,3,4h) determine its fluorescent value.It is glimmering Spectrogram 6 (a)：Excitation wavelength is 440nm, launch wavelength 540nm, and fluorogram is shown in Fig. 6 (b)：Excitation wavelength is 535nm, Launch wavelength is 585nm.
It is demonstrated experimentally that increasing over time, the fluorescence intensity of two fluorogens can also strengthen therewith, meet probe in detecting The effect of formaldehyde.
Nano-probe nano-MTDF (1 μM) is in DMSO/PBS buffer solutions (pH=7.4, v/v=1/ in the present invention of embodiment 6 99) the fluorescence spectrum detection of selective result under the conditions of.
A certain amount of probe (I) is accurately weighed, is configured to the mother liquor that concentration is 0.1mM with dimethyl sulfoxide (DMSO), liquid-transfering gun is inhaled 0.02mL is taken to be added in 1.96mL PBSs, several minutes of ultrasound, then acutely concussion, obtains nano-probe nano- MTDF, 396 μ L nano-probe nano-MTDF solution is drawn every time, being separately added into 4 μ L formalins, (final formaldehyde is in water The equal 1mM of concentration) to biology related the active small molecular aqueous solution (acetaldehyde, pyroracemic aldehyde, acetone, formic acid, 4- hydroxy benzaldehydes, 4- Nitrobenzaldehyde, benzaldehyde, hydrogen peroxide, TBHP, NaHS, glutathione, cysteine, high half Guang ammonia Acid, Sodium Pyruvate, glucose, ultimate density are 1mM), 3h is reacted at 37 DEG C, determines its fluorescent value.Fluorogram 7 (a)：Swash Hair wavelength is 440nm, launch wavelength 540nm, and fluorogram is shown in Fig. 7 (b)：Excitation wavelength is 535nm, launch wavelength 585nm.
Test result indicates that except formaldehyde, nano-probe nano-MTDF are glimmering in the presence of other relevant biological activity molecules Luminous intensity does not change substantially, shows that its antijamming capability is very good, i.e. the selectivity of PARA FORMALDEHYDE PRILLS(91,95) is relatively good.
Nano-probe nano-MTDF (1 μM) is in DMSO/ difference pH buffer solutions (v/v=1/99) bar in the present invention of embodiment 7 The fluorescence spectrum front and rear with formaldehyde reaction detects under part.
A certain amount of probe (I) is accurately weighed, is configured to the mother liquor that concentration is 0.1mM with dimethyl sulfoxide (DMSO), liquid-transfering gun is inhaled Take 0.02mL be added to 1.96mL difference pH buffer solutions (pH is respectively 3.5,4,4.5,5,5.5,6,6.5,7,7.5,8,8.5,9, 9.5th, 10, in 10.5), several minutes of ultrasound, then acutely concussion, obtains nano-probe nano-MTDF, draws 396 μ L every time and receives Rice probe nano-MTDF solution, is separately added into 4 μ L formalins (concentration of the final formaldehyde in water is 0 and 1mM), 37 DEG C Lower reaction 3h, determines its fluorescent value.Fluorogram 8 (a)：Excitation wavelength is 440nm, launch wavelength 540nm, and fluorogram is shown in Fig. 8 (b)：Excitation wavelength is 535nm, launch wavelength 585nm.
It is demonstrated experimentally that in the range of pH is from 5 to 7.5, the influence of pH change to nano-MTDF is little, i.e. nano-MTDF It is adapted to the concentration for detecting formaldehyde in vivo.
Nano-probe nano-MTDF (1 μM) is in DMSO/PBS buffer solutions (pH=7.4, v/v=1/ in the present invention of embodiment 8 99) the reacted mechanism of formaldehyde is added under the conditions of to be proved.
A certain amount of probe (I) is accurately weighed, is configured to the mother liquor that concentration is 2mM with dimethyl sulfoxide (DMSO), liquid-transfering gun is drawn 0.02mL is added in 1.96mL PBSs, several minutes of ultrasound, and then acutely concussion, obtains nano-probe nano-MTDF, 0.99mL nano-probe nano-MTDF solution is drawn, is separately added into 10 μ L formalins, reaction overnight, then utilizes efficient Liquid-phase chromatographic analysis.Efficient liquid phase spectrogram is shown in Fig. 9.
It is demonstrated experimentally that the nano-probe nano-MTDF of our descriptions is correct with the mechanism that formaldehyde reacts.nano- MTDF generates two free fluorescent material compound VIII and compound IX with formaldehyde, so as to test dual signal turn-on effects Fruit.
Formaldehyde imaging analysis of the nano-probe nano-MTDF in cancer cell in the present invention of embodiment 9
A certain amount of probe (I) is accurately weighed, is configured to the mother liquor that concentration is 0.5mM with dimethyl sulfoxide (DMSO), liquid-transfering gun is inhaled 0.02mL is taken to be added in 1.98mL DMEM culture mediums, several minutes of ultrasound, then acutely concussion, obtains nano-probe nano- MTDF.The nutrient solution for taking 1mL to contain nano-probe nano-MTDF is added in MCF-7 cells, hatches 0.5h at 37 DEG C, with new Fresh DMEM culture mediums wash twice, and are then hatched 3 hours with different concentration of formaldehyde (final concentration of formaldehyde is respectively 0,1), fresh DMEM culture mediums wash twice, and add commercializationWherein, 37 DEG C hatch 20min to Deep Red FM, PBS is washed twice, and finally uses PerkinElmer UltraView Vox Spinning Disk confocal microscope Fluorescence imaging.Figure 10 is cell confocal fluorescent imaging effect figure.(a1、a2、a3)：Formaldehyde (0mM), (a1, a2, a3):Formaldehyde (1mM)。Na-channel(a1,b1):λex=440nm, λem=455-515nm；Rho-channel(a2,b2):λex= 514nm,λem=524.5-649.5nm；Deep red-channel(a3,b3):λex=640nm, λem=660-750nm.c1: B1 and b3 coincidence；c2:Na-channel and Deep red-channel overlap coefficient；c3:B2and b3 coincidence；c4: Rho-channel and Deep red-channel overlap coefficient station meters, 20 μm of
Test result indicates that in the case where concentration of formaldehyde improves, it can be seen that the fluorescence signal in cell also exists Become strong, illustrate that our material can detect intracellular formaldehyde.Meanwhile by with commercializationDeep Red FM imaging is compared, and it is respectively 0.81 (λ to obtain Pearson correlation coefficientex=440nm) and 0.85 (λex=514nm), this As a result prove that nano-MTDF can detect the formaldehyde in intracellular mitochondrial.

Claims (10)

  1. A kind of 1. compound shown in formula (III)：
  2. 2. a kind of preparation method of compound as claimed in claim 1, it is characterised in that the preparation method is：(1) with right Hydroxy benzaldehyde is initiation material, is to be activated at 60-70 DEG C in temperature, then with 3- bromines third in the presence of acid binding agent Alkynes is nucleopilic reagent, at 60-70 DEG C of temperature, nucleophilic substitution occurs in acetone solvent, post-treated A obtains compound (II)；(2) compound (II) that step (1) obtains is subjected to ammonification using methanolic ammonia solution at 0 DEG C, third is added at 0 DEG C Ene boric acid two tertiary alcohol esters of neighbour, temperature control is reacted at 25-35 DEG C after mixing, and post-treated B obtains the formula (III) Shown compound；
  3. 3. the preparation method of compound as claimed in claim 2, it is characterised in that：Described acid binding agent is potassium carbonate, described The amount dosage of the material of acid binding agent is 1.5 times of equivalents of parahydroxyben-zaldehyde.
  4. 4. the preparation method of compound as claimed in claim 2, it is characterised in that：Parahydroxyben-zaldehyde described in step (1) Amount ratio with the material of 3- propargyl bromides is 1:1.5~3.
  5. 5. the preparation method of compound as claimed in claim 2, it is characterised in that：Described in step (2) in methanolic ammonia solution Ammonia density be 7mol/L.
  6. 6. the preparation method of compound as claimed in claim 2, it is characterised in that：The compound (II) and methanolic ammonia solution In ammonia theoretical material amount ratio be 1：6~20.
  7. 7. the preparation method of compound as claimed in claim 2, it is characterised in that：The compound (II) and propylene ylboronic acid The amount ratio of the theoretical material of adjacent two tertiary alcohol esters is 1：1.2~2.
  8. 8. the preparation method of compound as claimed in claim 2, it is characterised in that：
    The post processing A is：Reaction solution vacuum rotary steam adds water after removing solvent, ethyl acetate extraction, merges organic phase, has taken Machine mutually uses water and saturated common salt water washing for several times, anhydrous sodium sulfate drying, filtering, is spin-dried for solvent, after column chromatography for separation To target product, eluant, eluent is volume ratio 1:10 ethyl acetate and petroleum ether；
    The post processing B is：Reaction solution vacuum rotary steam removes solvent, and crude product obtains target product after carrying out chromatography post separation, Eluant, eluent is volume ratio 40:1 dichloromethane and methanol.
  9. 9. the compound described in a kind of claim 1 is as the formaldehyde fluorescent nano probe intermediate for preparing dual signal turn-on Application.
  10. 10. application as claimed in claim 9, it is characterised in that：The formaldehyde fluorescent nano probe of the dual signal turn-on is used In detection concentration of formaldehyde.
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