CN117820415A - Dendronized fluorescence sensor molecule based on F-rster resonance energy transfer mechanism and preparation and application thereof - Google Patents
Dendronized fluorescence sensor molecule based on F-rster resonance energy transfer mechanism and preparation and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000002165 resonance energy transfer Methods 0.000 title claims description 29
- 230000007246 mechanism Effects 0.000 title claims description 27
- 238000005886 esterification reaction Methods 0.000 claims abstract description 11
- 108010016626 Dipeptides Proteins 0.000 claims abstract description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 8
- 150000004702 methyl esters Chemical class 0.000 claims abstract description 7
- 239000004471 Glycine Substances 0.000 claims abstract description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 6
- 238000007112 amidation reaction Methods 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 29
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
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- 229940125782 compound 2 Drugs 0.000 claims description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- 229940126214 compound 3 Drugs 0.000 claims description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
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- 235000010378 sodium ascorbate Nutrition 0.000 claims description 5
- 229960005055 sodium ascorbate Drugs 0.000 claims description 5
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 5
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical group Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 4
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 claims description 4
- 125000003827 glycol group Chemical group 0.000 claims description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 3
- 230000009435 amidation Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 2
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- 230000007704 transition Effects 0.000 claims description 2
- 239000007809 chemical reaction catalyst Substances 0.000 claims 1
- JEDHEXUPBRMUMB-UHFFFAOYSA-N n,n-dimethylpyridin-3-amine Chemical compound CN(C)C1=CC=CN=C1 JEDHEXUPBRMUMB-UHFFFAOYSA-N 0.000 claims 1
- -1 alkoxy ether Chemical compound 0.000 abstract description 13
- 238000000034 method Methods 0.000 abstract description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 7
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract description 4
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- 239000000543 intermediate Substances 0.000 abstract description 3
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 abstract description 2
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- 230000008878 coupling Effects 0.000 abstract 1
- 238000010168 coupling process Methods 0.000 abstract 1
- 238000005859 coupling reaction Methods 0.000 abstract 1
- 239000007864 aqueous solution Substances 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 238000012546 transfer Methods 0.000 description 10
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- JLZUZNKTTIRERF-UHFFFAOYSA-N tetraphenylethylene Chemical compound C1=CC=CC=C1C(C=1C=CC=CC=1)=C(C=1C=CC=CC=1)C1=CC=CC=C1 JLZUZNKTTIRERF-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
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- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 3
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
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- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
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- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
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- 239000012043 crude product Substances 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 230000005283 ground state Effects 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
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- PMRORUJSYPHHBC-UHFFFAOYSA-N 3-methyl-n-propan-2-ylbutan-2-amine Chemical compound CC(C)NC(C)C(C)C PMRORUJSYPHHBC-UHFFFAOYSA-N 0.000 description 1
- 101001018064 Homo sapiens Lysosomal-trafficking regulator Proteins 0.000 description 1
- 102100033472 Lysosomal-trafficking regulator Human genes 0.000 description 1
- 235000010703 Modiola caroliniana Nutrition 0.000 description 1
- 244000038561 Modiola caroliniana Species 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
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- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention relates to the field of fluorescence sensors, in particular to a fluorescent sensor based onThe preparation method comprises the steps of modifying dipeptide (alanine-glycine) methyl ester (TFA-AG-OMe) to a methyl/ethyl end capped dendronized alkoxy ether element through amidation reaction, then covalently coupling tetraphenylethylene propyne and azido spiropyran through click reaction, and finally preparing the fluorescent sensor molecule MG/EG-TPE-SP with a dendritic structure through esterification reaction by the two intermediates. And at presentCompared with the prior art, the invention has the advantages of meeting various responses, along with simple and feasible method, low cost and the like.
Description
Technical Field
The invention relates to the field of fluorescence sensors, in particular to a fluorescent sensor based onDendronized fluorescence sensor molecule of resonance energy transfer mechanism, and preparation and application thereof.
Background
Fluorescent sensors have found wide application in biological, physiological, medical, pharmacological and other fields. The detection method based on the fluorescence sensor has the advantages of simplicity, low cost, high sensitivity, easiness in automatic analysis, support of spatial resolution imaging, provision of various signal output modes and the like. More broadly, fluorescence sensors provide a unique method of detecting biologically or environmentally important analytes and help reveal the physiological and pathological functions of these analytes. In fluorescent sensors, the fluorescent sensor is based onFluorescence sensors for fluorescence resonance energy transfer FRET (involving changes in electron interactions between donor and acceptor) have broad application prospects, particularly small molecule fluorescent probes based on FRET are commonly used as chemical sensors and imaging agents, as they can be rapidly taken up by cells, allowing the use of non-destructive visualization techniques, and the potential for in situ detection with little interference with the structure and function of key biomacromolecules, as well as their easily-tuned structural features. FRET is the process of non-radiative energy transfer through long Cheng Ouji-dipole interactions between donor-acceptor pairs. Upon photoexcitation, the electron excitation energy of the donor in the excited state can be transferred to the acceptor in the ground state. When donor and acceptorIn the case of fluorophores, FRET is commonly referred to as "fluorescence resonance energy transfer".
Today, smart stimulus-responsive materials are receiving attention because of their sensitivity to a wide variety of physical stimuli from the outside world (e.g., light, pH, temperature, and pressure). Among them, the novel stimulus-responsive fluorescent molecules are very much demanded in practical applications due to their functions, and materials exhibiting single stimulus responses have become quite popular and cannot meet the needs of practical applications, so materials with multiple stimulus responses are an important direction of current research. However, a challenge is often faced with conventional fluorescent dye molecules in that luminescence is observed only in specific organic solvents or dilute solutions. Under aqueous or solid state conditions, most planar fluorescent molecules tend to have a strong pi-pi stacking effect, resulting in aggregation-induced quenching (ACQ) phenomenon. Tang Benzhong institution team has proposed the concept of Aggregation Induced Emission (AIE) which effectively solves the problem of efficient emission in aqueous solutions because it does not emit light in dilute solutions, but has strong fluorescence in aggregate or solid state. Thus, a fluorescent light-emitting device with high efficiency in aqueous solution and multiple stimulus responsiveness is designedThe fluorescent sensor molecules constructed by the resonance energy transfer (FRET) mechanism have wide application value in fluorescent sensors and biomedical technologies.
Disclosure of Invention
The invention provides a base onDendronized fluorescence sensor molecule of resonance energy transfer mechanism, preparation and application thereof, and can regulate and control assembly, fluorescence color change and fluorescence color change in aqueous solution through solvation, temperature, ultraviolet and visible lightResonance energy transfer behavior, multiple response realization, and wide development prospect in the fields of fluorescence sensors and biomedical technology.
The aim of the invention can be achieved by the following technical scheme:
based onThe dendronized fluorescence sensor molecule of the resonance energy transfer mechanism has a structural formula shown in a formula I:
wherein, in formula I: r is R 1 Is a dendronized alkoxy ether motif containing methyl or ethyl terminated three-arm oligoethylene glycol chain, and has a structure shown as a formula II or a formula III:
R 2 the structure of the Spiropyran (SP) molecule which is covalently connected through a triazole spacer is shown as formula IV:
based onThe preparation method of the dendronized fluorescence sensor molecule of the resonance energy transfer mechanism comprises the following steps:
s1: amidation and hydrolysis reactions:
dissolving compound 1 and N, N-diisopropylethylamine in reflux-dried Dichloromethane (DCM), stirring the reaction mixture in an ice-salt bath under nitrogen atmosphere for 10min, then adding a catalyst to displace nitrogen, stirring the reaction mixture under ice-salt bath for 30min to prepare an active ester,
adding dipeptide (alanine-glycine) methyl ester into active ester, replacing nitrogen again, naturally cooling to room temperature, reacting overnight to obtain compound 2, and passing compound 2 through LiOH H 2 The O catalyst hydrolyzes to intermediate compound 3;
s2: "click chemistry:
dissolving Compound 4 (tetraphenylethylene propyne) and Compound 5 (azidospirane) in tert-butanol and Water (t-BuOH/H) 2 Adding sodium ascorbate and copper sulfate pentahydrate into the mixed solution of the O) in sequence, replacing nitrogen, reacting, and drying to obtain a compound 6;
s3: esterification reaction:
dissolving a compound 6 (tetraphenyl ethylene (TPE) and Spiropyran (SP) double dye molecules) and a compound 3 and 4-dimethylaminopyridine in 15mL of dry dichloromethane, replacing nitrogen, stirring the reaction mixture for 30min under the ice salt bath condition, adding an esterification catalyst, replacing nitrogen again, and naturally cooling to room temperature to react to obtain a compound with a structural formula shown in a formula I;
wherein R is 1 Is a dendronized alkoxy ether motif containing methyl or ethyl terminated three-arm oligoethylene glycol chain, X is OMe, Y is OH, Z is propyne, R 2 Is a Spiropyran (SP) molecule covalently linked through a triazole spacer.
Further, the temperature of the ice salt bath is-8-0 ℃.
Further, in the step S1, the molar ratio of the compound 1, N-diisopropylethylamine, the catalyst and the dipeptide (alanine-glycine) methyl ester is 1:3:3 (1-1.2).
Further, in the step S1, the catalyst is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCI) and 1-hydroxybenzotriazole (HOBt), and the molar ratio of the two is 1:1-1.1.
Further, in the step S2, the molar ratio of the compound 4 to the compound 5 to the sodium ascorbate to the copper sulfate pentahydrate is 1:1.2:1.2 (1-1.3).
Further, in the step S3, the molar ratio of the compound 3, the compound 6, the 4-dimethylaminopyridine and the esterification catalyst is 1 (1-1.2): 0.2:1.5.
Further, in step S3, the esterification catalyst is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride.
The basis is thatThe dendronized fluorescent sensor molecules of the resonance energy transfer mechanism can be used in the field of fluorescent sensors.
Furthermore, the molecule has temperature sensitive property and photosensitive property, wherein the phase transition temperature is 10-30 ℃.
According to the invention, dipeptide (alanine-glycine) methyl ester (TFA-AG-OMe) is modified to a methyl/ethyl end capped dendronized alkoxy ether element through amidation reaction, then tetraphenyl ethylene propyne and azido spiropyran are covalently coupled through click reaction, and finally the two intermediates are subjected to esterification reaction to prepare the fluorescent sensor molecule MG/EG-TPE-SP with dendritic structure. The fluorescent nano aggregate is assembled in aqueous solution through the drive of hydrophobic, hydrogen bond and pi-pi stacking action, has better fluorescence emission, takes tetraphenyl ethylene TPE as an energy donor, and takes ring-opened spiropyran SP as an energy acceptor to construct a fluorescent nano aggregate based onDendronized fluorescent sensor molecules of resonant energy transfer mechanism and can be modulated in their assembly, fluorescence discolouration and +.>Resonant energy transfer efficiency.
Compared with the prior art, the invention has the following advantages:
1. the invention introduces the tetraphenyl ethylene TPE fluorescent molecule with aggregation-induced emission AIE property, so that the tetraphenyl ethylene TPE fluorescent molecule can emit stronger fluorescence in aqueous solution, and the aggregation-induced quenching (ACQ) effect of the traditional fluorescent molecule is avoided.
2. The invention introduces hydrophilic dendron alkoxy ether element to improve water solubility, which endows application potential in biomedical field, dendron alkoxy ether also endows temperature sensitive property, and can regulate fluorescence and control fluorescent molecule by temperatureResonance energy transfer.
3. The invention introduces Spiropyran (SP) dye molecules with photochromic property, endows the spiropyran with photosensitive property, and can regulate and control spiropyran ring-opening isomerization, fluorescent switch and fluorescent color change through visible light and ultraviolet light.
4. The invention is based onDendronized fluorescence sensor molecule of resonance energy transfer mechanism, TPE is taken as energy donor, open-loop SP is taken as energy acceptor to construct a fluorescent sensor molecule based on +.>The dendronized fluorescence sensor molecule of the resonance energy transfer mechanism can regulate and control FRET energy transfer efficiency and a switch through temperature and ultraviolet light. Endows the fluorescent sensor with application potential in the technical fields of fluorescence sensor, biomedicine and the like. In addition, the method is simple and feasible, has low cost and is suitable for popularization and application.
Drawings
FIG. 1 is a diagram of Compound 2 prepared in example 1 1 H NMR spectrum;
FIG. 2 is a diagram of Compound 6 prepared in example 1 1 H NMR spectrum;
FIG. 3 shows MG-TPE-SP prepared in example 1 1 H NMR spectrum;
FIG. 4 shows the MG-TPE-SP prepared in example 1 with THF/H having different water contents 2 Fluorescence spectrum in O mixed solution;
FIG. 5 shows the MG-TPE-SP prepared in example 1 with THF/H having different water contents 2 Fluorescence trend graph in O mixed solution;
FIG. 6 shows the MG-TPE-SP prepared in example 1 at a moisture content of0% and 90% THF/H 2 Fluorescence photograph in O mixed solution;
FIG. 7 is a graph showing the ultraviolet absorption spectrum of MG-TPE-SP prepared in example 1 in an aqueous solution as the irradiation time of ultraviolet light increases;
FIG. 8 is a photograph showing fluorescence of MG-TPE-SP prepared in example 1 before and after ultraviolet irradiation in an aqueous solution;
FIG. 9 is a graph showing fluorescence spectra of MG-TPE-SP prepared in example 1 in aqueous solution as a function of UV irradiation time;
FIG. 10 is a graph showing the trend of fluorescence intensity at 480nm and 635nm in an aqueous solution of MG-TPE-SP prepared in example 1;
FIG. 11 is a photograph showing fluorescence of MG-TPE-SP prepared in example 1 before and after irradiation with ultraviolet light;
FIG. 12 is a graph showing fluorescence spectra of MG-TPE-SP prepared in example 1 at various temperatures in aqueous solution;
FIG. 13 is a graph showing the change in fluorescence intensity at 480nm and 635nm in an aqueous solution with respect to temperature of MG-TPE-SP prepared in example 1.
Detailed Description
The invention will now be described in detail with reference to the drawings and specific examples.
The following examples are given with the above technical solutions of the present invention as a premise, and detailed embodiments and specific operation procedures are given, but the scope of protection of the present invention is not limited to the following examples.
The following are more detailed embodiments, by which the technical solutions of the invention and the technical effects that can be obtained are further illustrated.
In the following examples, unless otherwise specified, starting materials or processing techniques are indicated as being conventional commercial products or conventional processing techniques in the art.
Example 1
The embodiment provides a method based onThe dendronized fluorescence sensor molecule of the resonance energy transfer mechanism and a preparation method thereof are as follows:
(1) Amidation and hydrolysis reactions:
2.13g,3.49mmol of Compound 1 (R in this example 1 Dendronized alkoxyl ether carboxylic acids blocked with methyl groups, prepared by published literature, li W, zhang A.Amphilic dendronized homopolymers [ J]Science China Chemistry,2010,53 (12): 2509-19.) and N, N-Diisopropylethylamine (DiPEA) (1.35 g,10.48 mmol) were dissolved in 30mL of reflux-dried DCM, the reaction mixture was stirred under nitrogen at-6deg.C for 10min in an ice-salt bath, EDC. HCI (1.00 g,5.24 mmol) and 1-hydroxybenzotriazole (HOBt) (707.91 mg,5.24 mmol) were then added, nitrogen was replaced, the reaction mixture was continued to be stirred under an ice-salt bath for 30min to prepare an active ester,
TFA-AG-OMe (1.00 g,3.84mmol, see C in patent CN 110078932A) dissolved in 5mL of dry DCM 3 Preparation of molecules) the mixed solution was added to the active ester obtained above, nitrogen was replaced again, and the reaction was allowed to cool to room temperature overnight. The completion of the reaction was detected by TLC plate, followed by washing with saturated sodium hydrogencarbonate solution and 10wt% potassium hydrogensulfate solution, extraction, and collection of the organic layer using anhydrous Na 2 SO 4 Drying, filtration and evaporation of the solvent, finally further purification of the crude product by silica gel column chromatography (DCM: meoh=40:1, v/v) afforded compound 2 (1.84 g, yield: 85%) as a colourless oil;
compound 2 was structurally characterized (nuclear magnetic resonance diagram is shown in fig. 1):
1 h NMR (500 mhz, chloro form-d) delta 7.13 (s, 2H), 7.08 (d, j=7.4 hz, 1H), 6.93 (t, j=5.6 hz, 1H), 4.72 (p, j=7.1 hz, 1H), 4.20 (td, j=5.1, 1.7hz, 6H), 4.04 (t, j=5.3 hz, 2H), 3.84 (dd, j=5.7, 4.1hz, 4H), 3.79 (dd, j=5.8, 4.2hz, 2H), 3.74 (s, 3H), 3.73-3.70 (m, 6H), 3.68-3.61 (m, 12H), 3.56-3.52 (m, 6H), 3.36 (d, j=9.9 hz, 9H), 1.50 (d, j=7.0 hz); the product was identified as compound 2;
preparation of compound 3:
compound 2 methyl-capped dendronized alkoxyether dipeptide methyl ester (2 g,2.66 mmol) was dissolved in 15mL of a mixed solvent of methanol (MeOH) and water (MeOH: H) 2 O=4:1, v/v) and then LiOH H is added under ice salt bath conditions 2 O (1.12 g,26.64 mmol) to the reaction mixtureThe reaction was stirred at room temperature for 3 hours. TLC plate was used to check the completion of the reaction, after which 10wt% KHSO was used 4 The pH of the reaction mixture was adjusted to 5-6 with aqueous solution, followed by extraction with ethyl acetate, and the organic layer was collected using anhydrous Na 2 SO 4 Drying, filtration and evaporation of the solvent gave compound 3 as a colourless oil: methyl capped branched alkoxy ether dipeptide carboxylic acid (1.76 g, yield: 90%).
(2) "click chemistry reaction progress:
compound 4 (200.00 mg, 496.90. Mu. Mol) and compound 5 (225.04 mg, 596.28. Mu. Mol) were dissolved in 7.5mL of t-BuOH/H 2 To the O (v/v=1:1) mixed solution, sodium ascorbate (NaSAC) (118.13 mg, 596.28. Mu. Mol) and CuSO were added in this order 4 ·5H 2 O (148.88 mg, 596.28. Mu. Mol), replacing nitrogen, and the reaction mixture was stirred at room temperature for 24 hours. TLC plate was used to detect completion of the reaction, after completion of the reaction, the mixed solvent was distilled off under reduced pressure, followed by washing and extraction with saturated NaCl and ethyl acetate, and the organic layer was collected using anhydrous Na 2 SO 4 Drying, filtration and evaporation of the solvent, and finally further purification of the crude product by silica gel column chromatography (Hex: etoac=3:4, v/v) afforded compound 6 (310 mg, yield: 81%) as a pale red solid;
compound 6 was structurally characterized (nuclear magnetic resonance diagram is shown in fig. 2):
1 h NMR (500 mhz, chloro form-d) delta 8.00 (dd, j=9.0, 2.7hz, 1H), 7.92 (d, j=2.7 hz, 1H), 7.49 (s, 1H), 7.20 (td, j=7.7, 1.3hz, 1H), 7.13-7.04 (m, 8H), 7.01 (dt, j=7.6, 1.7hz, 4H), 6.97-6.92 (m, 3H), 6.89-6.85 (m, 2H), 6.73-6.62 (m, 4H), 6.54 (dd, j=8.1, 5.7hz, 3H), 5.11 (q, j=12.2 hz, 2H), 4.96 (d, j=10.3 hz, 1H), 4.60-4.54 (m, 2H), 3.68 (dt, j=14.9, 7.85 (m, 2H), 6.73-6.62 (m, 4H), 6.54 (dd, j=8.1, 5.7hz, 3H), 5.11 (q, j=12.2 hz, 1H), 4.60-4.54 (d, 3.15). The product was found to be compound 6.
(3) Esterification reaction:
compound 6 (300.00 mg,384.67 μmol), compound 3: methyl-capped dendronized alkoxyl ether dipeptide carboxylic acid (311.77 mg, 423.13. Mu. Mol) and 4-Dimethylaminopyridine (DMAP) (9.40 mg, 76.93. Mu. Mol) were dissolved in 15mL of dry DCM, replaced with nitrogen, and the reaction mixture was stirred in a hot water bathStirring for 30min in ice salt bath, adding EDC & HCl (110.61 mg, 577.00. Mu. Mol), replacing nitrogen again, and naturally cooling to room temperature for reaction overnight. The completion of the reaction was detected by TLC plate, after the completion of the reaction, saturated NaHCO was used in sequence 3 Solution and 10wt% KHSO 4 Washing and extracting with solution, collecting organic layer, and using anhydrous Na 2 SO 4 Drying, filtering and evaporating the solvent. Finally the crude material was further purified by column chromatography (DCM/MeOH, 30/1, v/v) to give MG-TPE-SP: pale red solid (450 mg, yield: 78%);
structural characterization of the target product (MG-TPE-SP) (nuclear magnetic resonance diagram is shown in FIG. 3):
1 h NMR (500 mhz, chloroform-d) delta 8.00 (dt, j=9.0, 2.3hz, 1H), 7.92 (d, j=2.8 hz, 1H), 7.49 (s, 1H), 7.21 (t, j=7.7 hz, 1H), 7.14 (s, 2H), 7.10 (td, j=7.3, 3.0hz, 7H), 6.99 (ddd, j=13.9, 9.5,4.8hz, 7H), 6.95-6.90 (m, 3H), 6.84-6.78 (m, 2H), 6.71 (dd, j=11.0, 8.6hz, 3H), 6.65 (dd, j=10.4, 4.4hz, 1H), 6.55 (d, j=7.8 hz, 1H), 5.11 (q, j=12.3 hz), 4.94 (dd, 4.9, 4.8 hz), 6.9 (d, 7H), 6.84-6.78 (m, 3H), 6.84-6.78 (m, 2H), 6.71 (dd, j=11.0, 8.6hz, 3H), 6.55 (j=4.6 hz, 1H), 6.11 (d, 4.6H), 6.55 (j=4.7, 4 hz), 6.7, 1H), 5.11 (q (d, 4, 4.4H), 4.7 hz), 6.7, 3H), 6.9.9.9 (3 hz, 3H), 6.7.7.7H), 6.7 (3H), 3.7.7H (j=3.7, 3H), 3.7, 1H), 3.7.7.7H (J, 1H); the product was known as MG-TPE-SP.
And (3) performance detection: the target product MG-TPE-SP prepared in example 1 was used as a sample, and experimental analysis and test were performed:
(1) Aggregation of MG-TPE-SP in aqueous solution induces luminescent AIE behavior:
the concentration of the preparation is 0.2 mg.mL -1 THF/H at different water contents 2 The O-mixed solution was monitored for the effect of solvation at different water contents on the fluorescence of the assembly using a fluorescence spectrometer, and aggregation-induced emission AIE properties were explored. As shown in fig. 4 and 5, the fluorescence is very weak with little emission at a moisture content below 80%, whereas the emission (bluish fluorescence) corresponding to TPE increases abruptly at 480nm when the moisture content exceeds 80%, and reaches a maximum at a moisture content of 90%, indicating that the basis is thatThe dendronized fluorescent sensor molecules of the resonant energy transfer mechanism inherit the aggregation-induced emission AIE properties typical of TPEs.
(2) Photochromic behavior of MG-TPE-SP in aqueous solution:
the concentration of the preparation is 0.2 mg.mL -1 THF/H with a water content of 90% 2 The solution was mixed with O and monitored for its photochromic/isomerisation process using an ultraviolet spectrophotometer (fig. 7). As shown in the figure, as the irradiation time of ultraviolet light increases, a new absorption peak appears at 556nm, which corresponds to the absorption of the ring-opened spiropyran SP, the color of the solution is changed from colorless to purple, and the solution can be reversibly recovered after the irradiation of visible light, and has better fatigue resistance. Description of the basisThe dendronized fluorescence sensor molecule of the resonance energy transfer mechanism has better photochromic/isomerization property.
(3) Fluorescence discoloration of MG-TPE-SP in aqueous solutionResonant energy transfer behavior:
the concentration of the preparation is 0.2 mg.mL -1 The THF/H2O mixed solution with 90% water content was monitored for changes in fluorescence spectrum and color of the assembly with increasing uv exposure time using a fluorescence spectrometer. As shown in fig. 9, 10 and 11, the emission at 480nm was gradually decreased corresponding to TPE and the emission at 635nm was gradually increased corresponding to ring-opened spiropyran with the increase of the ultraviolet irradiation time, and the fluorescence color was also gradually changed from blue to mauve. While TPE is illustrated as an energy donor to transfer energy to the ground state dye acceptor ring-opened spiropyran SP via triazole spacer and long Cheng Ouji-dipole interaction. The description is based onThe resonance energy transfer mechanism successfully constructs a dendronized fluorescence sensor molecule and has better photochromic property.
(4) MG-TPE-SP atTemperature regulation in aqueous solutionsResonant energy transfer behavior:
the concentration of the preparation is 0.2 mg.mL -1 The THF/H2O mixed solution with the water content of 90 percent is irradiated by ultraviolet light for 40 seconds to lead most of the spiropyran molecules to be in an open-loop state, thereby ensuring that the FRET energy transfer process can be carried out, and the fluorescence spectrum change of the assembly body at different temperatures is monitored by a fluorescence spectrometer. As shown in fig. 12 and 13, the fluorescence intensity of TPE gradually becomes weaker as the temperature increases, and the fluorescence of open-loop spiropyran gradually becomes weaker as the temperature increases, and it is hypothesized that the reason is that the open-loop spiropyran gradually becomes a closed-loop structure as the temperature increases, the fluorescence color gradually changes from red to pink, and thusThe resonance energy transfer efficiency also decreases with increasing temperature. Explaining the basis +.>Dendronized fluorescent sensor molecules of the resonance energy transfer mechanism can be regulated by temperature>Resonant energy transfer efficiency.
In summary, tetraphenyl ethylene (TPE) was used as the energy donor and Spiropyran (SP) as the energy acceptor based onThe dendronized fluorescence sensor molecule with intelligent stimulus response property is successfully constructed by a resonance energy transfer mechanism, can be well dissolved in aqueous solution and can emit light with high efficiency, has good photochromic/photochromic property in the aqueous solution, and can be regulated and controlled by temperature>Resonance energy transfer efficiency and fluorescence color change.
Therefore, the dendronized fluorescent sensor molecule can be used as a fluorescent sensor with good biocompatibility in aqueous solution even in a cell environment, the fluorescent intensity or color can be changed by responding to temperature (the response range is 10-30 ℃) or ultraviolet light, and then the cell state can be well monitored by changing the fluorescent intensity or color, so that the dendronized fluorescent sensor molecule has wide application value in fluorescent sensors and biomedical technology.
The previous description of the embodiments is provided to facilitate a person of ordinary skill in the art in order to make and use the present invention. It will be apparent to those skilled in the art that various modifications can be readily made to these embodiments and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments, and those skilled in the art, based on the present disclosure, should make improvements and modifications without departing from the scope of the present invention.
Claims (10)
1. Based onThe dendronized fluorescence sensor molecule of the resonance energy transfer mechanism is characterized by having a structural formula shown in a formula I:
wherein, in formula I: r is R 1 Is a dendronized alkoxy ether motif containing methyl or ethyl terminated three-arm oligoethylene glycol chain, and has a structure shown as a formula II or a formula III:
R 2 the structure of the Spiropyran (SP) molecule which is covalently connected through a triazole spacer is shown as formula IV:
2. a base according to claim 1The preparation method of the dendronized fluorescence sensor molecule of the resonance energy transfer mechanism is characterized by comprising the following steps:
s1: amidation and hydrolysis reactions:
dissolving the compound 1 and N, N-diisopropylethylamine in dichloromethane, stirring the reaction mixture in an ice salt bath under nitrogen atmosphere for 10min, then adding a catalyst to replace nitrogen, stirring the reaction mixture in the ice salt bath for 30min to prepare active ester,
adding dipeptide (alanine-glycine) methyl ester into active ester, replacing nitrogen again, naturally cooling to room temperature, reacting overnight to obtain compound 2, and passing compound 2 through LiOH H 2 The O catalyst hydrolyzes to intermediate compound 3;
s2: "click chemistry:
dissolving a compound 4 and a compound 5 in a mixed solution of tert-butanol and water, sequentially adding sodium ascorbate and copper sulfate pentahydrate, replacing nitrogen, reacting, and drying to obtain a compound 6;
s3: esterification reaction:
dissolving a compound 6 and compounds 3 and 4-dimethylaminopyridine in 15mL of dry dichloromethane, replacing nitrogen, stirring the reaction mixture for 30min under the ice salt bath condition, adding an esterification reaction catalyst, replacing nitrogen again, and naturally cooling to room temperature to react to obtain a compound with a structural formula shown in a formula I;
wherein R is 1 Is a dendronized alkoxy ether motif containing methyl or ethyl terminated three-arm oligoethylene glycol chain, X is OMe, Y is OH, Z is propyne, R 2 Is a Spiropyran (SP) molecule covalently linked through a triazole spacer.
3. The base of claim 2The preparation method of the dendronized fluorescence sensor molecule of the resonance energy transfer mechanism is characterized in that the temperature of the ice salt bath is-8-0 ℃.
4. The base of claim 2The preparation method of the dendronized fluorescence sensor molecule of the resonance energy transfer mechanism is characterized in that in the step S1, the mol ratio of the compound 1 to N, N-diisopropylethylamine to the dipeptide (alanine-glycine) methyl ester is 1:3:3 (1-1.2).
5. The base of claim 2The preparation method of the dendronized fluorescence sensor molecule of the resonance energy transfer mechanism is characterized in that in the step S1, the catalyst is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole, and the molar ratio of the two is 1:1-1.1.
6. The base of claim 2The preparation method of the dendronized fluorescence sensor molecule of the resonance energy transfer mechanism is characterized in that in the step S2, the molar ratio of the compound 4 to the compound 5 to the sodium ascorbate to the copper sulfate pentahydrate is 1:1.2:1.2 (1-1.3).
7. The base of claim 2The preparation method of the dendronized fluorescence sensor molecule of the resonance energy transfer mechanism is characterized in that in the step S3, the molar ratio of the compound 3 to the compound 6 to the 4-dimethylaminopyridine to the esterification catalyst is 1 (1-1.2): 0.2:1.5.
8. The base of claim 2The preparation method of the dendronized fluorescence sensor molecule of the resonance energy transfer mechanism is characterized in that in the step S3, the esterification catalyst is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride.
9. A base according to claim 1Use of a dendronized fluorescent sensor molecule of a resonance energy transfer mechanism, characterized in that the molecule is used for the preparation of a fluorescent sensor.
10. The base of claim 9The application of the dendronized fluorescence sensor molecule of the resonance energy transfer mechanism is characterized in that the molecule has temperature sensitive property and photosensitive property, wherein the phase transition temperature is 10-30 ℃.
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