CN116514767B - Chemiluminescent probe based on adamantine-1, 2-dioxetane and preparation method and application thereof - Google Patents
Chemiluminescent probe based on adamantine-1, 2-dioxetane and preparation method and application thereof Download PDFInfo
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- 239000000523 sample Substances 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title abstract description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims abstract description 17
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 claims abstract description 15
- 229940125782 compound 2 Drugs 0.000 claims abstract description 14
- 229940125904 compound 1 Drugs 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 12
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 claims abstract description 11
- MCPLVIGCWWTHFH-UHFFFAOYSA-L methyl blue Chemical compound [Na+].[Na+].C1=CC(S(=O)(=O)[O-])=CC=C1NC1=CC=C(C(=C2C=CC(C=C2)=[NH+]C=2C=CC(=CC=2)S([O-])(=O)=O)C=2C=CC(NC=3C=CC(=CC=3)S([O-])(=O)=O)=CC=2)C=C1 MCPLVIGCWWTHFH-UHFFFAOYSA-L 0.000 claims abstract description 11
- AXKGIPZJYUNAIW-UHFFFAOYSA-N (4-aminophenyl)methanol Chemical compound NC1=CC=C(CO)C=C1 AXKGIPZJYUNAIW-UHFFFAOYSA-N 0.000 claims abstract description 9
- RREPYIWLDJQENS-UHFFFAOYSA-N 4-nitrophenylglyoxylic acid Chemical compound OC(=O)C(=O)C1=CC=C([N+]([O-])=O)C=C1 RREPYIWLDJQENS-UHFFFAOYSA-N 0.000 claims abstract description 9
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 claims abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 238000010898 silica gel chromatography Methods 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 241001274216 Naso Species 0.000 claims description 5
- 229940126214 compound 3 Drugs 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 238000005187 foaming Methods 0.000 claims description 2
- 230000001678 irradiating effect Effects 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims description 2
- 238000001514 detection method Methods 0.000 abstract description 7
- 238000006862 quantum yield reaction Methods 0.000 abstract description 5
- 239000007821 HATU Substances 0.000 abstract description 4
- 239000000203 mixture Substances 0.000 abstract description 4
- CMFNMSMUKZHDEY-UHFFFAOYSA-N peroxynitrous acid Chemical compound OON=O CMFNMSMUKZHDEY-UHFFFAOYSA-N 0.000 abstract 1
- CMFNMSMUKZHDEY-UHFFFAOYSA-M peroxynitrite Chemical compound [O-]ON=O CMFNMSMUKZHDEY-UHFFFAOYSA-M 0.000 description 27
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000007792 addition Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000005587 bubbling Effects 0.000 description 3
- 230000004907 flux Effects 0.000 description 3
- 238000009413 insulation Methods 0.000 description 3
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 3
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- 102000004452 Arginase Human genes 0.000 description 1
- 108700024123 Arginases Proteins 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 238000004435 EPR spectroscopy Methods 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- IYKFYARMMIESOX-SPJNRGJMSA-N adamantanone Chemical compound C([C@H](C1)C2)[C@H]3C[C@@H]1C(=O)[C@@H]2C3 IYKFYARMMIESOX-SPJNRGJMSA-N 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- 150000001449 anionic compounds Chemical class 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000840 electrochemical analysis Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001917 fluorescence detection Methods 0.000 description 1
- 238000002189 fluorescence spectrum Methods 0.000 description 1
- VGGRCVDNFAQIKO-UHFFFAOYSA-N formic anhydride Chemical compound O=COC=O VGGRCVDNFAQIKO-UHFFFAOYSA-N 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 235000003969 glutathione Nutrition 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- -1 lithium aluminum hydride Chemical compound 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- KMFJVYMFCAIRAN-UHFFFAOYSA-N methyl 3-bromobenzoate Chemical compound COC(=O)C1=CC=CC(Br)=C1 KMFJVYMFCAIRAN-UHFFFAOYSA-N 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000000626 neurodegenerative effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 235000013930 proline Nutrition 0.000 description 1
- 238000006479 redox reaction Methods 0.000 description 1
- 238000011896 sensitive detection Methods 0.000 description 1
- 235000004400 serine Nutrition 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00
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- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6486—Measuring fluorescence of biological material, e.g. DNA, RNA, cells
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- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
- G01N21/76—Chemiluminescence; Bioluminescence
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- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
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- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1088—Heterocyclic compounds characterised by ligands containing oxygen as the only heteroatom
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02B—CLIMATE CHANGE MITIGATION TECHNOLOGIES RELATED TO BUILDINGS, e.g. HOUSING, HOUSE APPLIANCES OR RELATED END-USER APPLICATIONS
- Y02B20/00—Energy efficient lighting technologies, e.g. halogen lamps or gas discharge lamps
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Abstract
The invention discloses a chemiluminescent probe based on adamantine-1, 2-dioxetane and a preparation method and application thereof. The probe has the following molecular formula, and the preparation method comprises the following steps: reacting 2- (4-nitrophenyl) -2-oxoacetic acid and 4-aminobenzyl alcohol in the presence of HATU, N-diisopropylethylamine to produce compound 1; mixing and dissolving the compound 2a, the compound 2b and piperidine, and then reacting to obtain a compound 2c; the compound 2c and the methyl blue are mixed in a solvent and then irradiated with white light, and meanwhile, the mixture is strongly foamed by air to generate a compound 2; reacting the compound 1 with the compound 2 under alkaline conditions to generate the probe. The chemiluminescent probe applied to detection of peroxynitrite has the advantages of good light stability, large Stokes shift, high quantum yield, capability of generating near infrared fluorescence and the like.
Description
Technical Field
The invention relates to a fluorescent probe, in particular to a chemiluminescent probe based on adamantine-1, 2-dioxetane, and a preparation method and application thereof.
Background
Both redox reactions and oxidative stress are involved in the etiology of many diseases and in the aging process, endogenous peroxynitrite (ONOO-) has been recognized as a strong oxidant in vivo. This chemical nature of peroxynitrite makes it a central biological causative agent of a variety of diseases, such as cardiovascular, neurodegenerative and inflammatory diseases. Knowing the important role of peroxynitrite in biological systems, it is quite valuable and interesting to develop sensitive and selective techniques for detecting peroxynitrite. To date, several methods for detecting peroxynitrite have been developed, including ultraviolet/visible spectroscopy, electrochemical analysis, electron spin resonance, and immunohistochemistry. However, the exact pathogenic role of peroxynitrite in biological systems is still not clear due to its short life span in vivo, high activity, low concentration, elusive nature. In contrast, fluorescence for peroxynitrite detection has evolved over the past decades because of its many advantages such as: high measurement efficiency, non-invasive detection, excellent spatial and temporal resolution, etc. Many fluorescent peroxynitrite sensors have been reported and applied to in vitro and in vivo imaging of peroxynitrite, which further facilitates the study of peroxynitrite behavior in biological processes. However, these probes may suffer from problems such as lower quantum yields and smaller stokes shifts.
Disclosure of Invention
In order to solve the technical problems, the invention firstly provides a chemiluminescent probe based on adamantene-1, 2-dioxetane. The invention adopts adamantine-1, 2-dioxetane as a luminous group to improve the optical performance of the probe, solves the problems of low quantum yield and small Stokes shift, and simultaneously discovers that the probe has the advantages of good light stability, large Stokes shift, high quantum yield, capability of generating enhanced fluorescence and the like when being used for detecting peroxynitrite.
Based on the second aspect of the invention, a preparation method of a chemiluminescent probe based on adamantine-1, 2-dioxetane is also provided, and a feasible process route is provided for industrial application of the product.
Based on the third aspect of the invention, the application of the chemiluminescent probe based on adamantene-1, 2-dioxetane in detecting endogenous peroxynitrite is also provided. The chemiluminescent probe can specifically react with peroxynitrite and generate a change of a fluorescent signal of turn on, and the content of peroxynitrite is detected by detecting the change of the fluorescent signal.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a chemiluminescent probe based on adamantene-1, 2-dioxetane, having the molecular structural expression:
a method for preparing a chemiluminescent probe based on adamantene-1, 2-dioxetane, comprising the steps of:
s1, dissolving 2- (4-nitrophenyl) -2-oxo acetic acid and 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate in anhydrous dichloromethane, then adding N, N-diisopropylethylamine, stirring at room temperature for 10-30min, finally adding 4-amino benzyl alcohol, and stirring at room temperature for reacting for 12-24h; after the reaction, methylene chloride was added to dilute the reaction solution, which was washed several times with saturated brine, and anhydrous NaSO 4 Drying, performing silica gel column chromatography, and purifying to obtain a compound 1;
s2, adding the compound 2a, the compound 2b and piperidine into a flask, and then adding acetonitrile as a solvent; placing the reaction solution in an oil bath at 90-120 ℃ for heat preservation reaction for 1-5h, and purifying by silica gel column chromatography to obtain a compound 2c;
s3, adding the compound 2c and methyl blue into a double-neck flask, taking anhydrous dichloromethane as a solvent, stirring, placing the flask in an ice bath, irradiating white light above the flask, and simultaneously, strongly foaming for 2-4 hours by using air; after the reaction is finished, purifying by silica gel column chromatography to obtain an orange solid compound 2;
s4, dissolving potassium carbonate in N, N-dimethylformamide, adding the compound 1 and the compound 2, stirring and reacting for 10-36h, and purifying by silica gel column chromatography to obtain the compound 3, namely the chemical fluorescent probe.
In a preferred embodiment of the invention, in step S1, the molar ratio of 2- (4-nitrophenyl) -2-oxoacetic acid, 4-aminobenzyl alcohol, 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine is 1 (1-1.5): (1-2): (20-50), for example, when the molar equivalent of 2- (4-nitrophenyl) -2-oxoacetic acid is 1, the molar equivalent of 4-aminobenzyl alcohol may be 1, 1.1, 1.2, 1.3, 1.4, 1.5, etc., the molar equivalent of 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate may be 1, 1.2, 1.4, 1.6, 1.8, etc., and the molar equivalent of N, N-diisopropylethylamine may be 20, 25, 30, 35, 40, 45, 50, etc.
In a preferred embodiment of the invention, in step S2, the molar ratio of compound 2a, compound 2b, piperidine is 1 (0.8-1.2): (2-3), for example, when the molar equivalent of compound 2a is 1, the molar equivalent of compound 2b may be 0.8, 0.9, 1, 1.1, 1.2, etc., and the molar equivalent of piperidine may be 2, 2.2, 2.4, 2.6, 2.8, 3, etc.
In a preferred embodiment of the invention, in step S3, methyl blue is used in an amount of 1 to 10% by mole of compound 2c, for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% by mole of compound 2c, etc.
In a preferred embodiment of the invention, in step S3, the white light is emitted as 150-300W LED light.
In a preferred embodiment of the invention, in step S4, the molar ratio of compound 1 to compound 2 is 1 (1-1.5), for example 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, etc.
In a preferred embodiment of the invention, in step S4, potassium carbonate is used in an amount of 10 to 20 times, for example 10 times, 12 times, 14 times, 16 times, 18 times, 20 times, etc., the amount of 1 mole of the compound.
Use of an adamantene-1, 2-dioxetane based chemiluminescent probe as described herein and an adamantene-1, 2-dioxetane based chemiluminescent probe prepared by the method as described herein in the field of detection of endogenous peroxynitrite.
The chemiluminescent probe uses adamantine-1, 2-dioxetane as a luminescent group, and has the advantages of good light stability, large Stokes shift, high quantum yield, capability of generating enhanced fluorescence and the like when being applied to detection of peroxynitrite.
Drawings
FIG. 1 is a graph of chemiluminescent probe as a function of fluorescence intensity.
Detailed Description
The invention will now be further illustrated by means of specific examples which are given solely by way of illustration of the invention and do not limit the scope thereof.
Unless otherwise specified, the starting materials and reagents in the examples of the present invention are all commercially available. Wherein, the compound 2a can be custom synthesized in Chongqing FuTENG medical Co., ltd, and also can be prepared by itself according to the following method:
0.1mmol of adamantanone and 0.25mmol of methyl 3-bromobenzoate were dissolved in 30ml of dimethyl sulfoxide, reacted for 24 hours in the presence of 0.01mmol of titanium trichloride catalyst and 0.01mmol of lithium aluminum hydride, extracted by adding water and dichloromethane, and the organic layer was purified by silica gel column chromatography to obtain an intermediate 2a'.
0.1mmol of intermediate 2a' and 0.3mmol of formic anhydride are mixed with 20ml of anhydrous dichloromethane solvent, friedel-crafts acylation reaction is carried out under the action of 0.01mmol of anhydrous aluminum trichloride catalyst, the reaction is finished after 12 days, water and dichloromethane are added for extraction, and an organic layer is purified by silica gel column chromatography to obtain the compound 2a.
[ example 1 ]
The chemiluminescent probe is prepared according to the following steps, and the reaction process expression is as follows:
(1) 1mmol of 2- (4-nitrophenyl) -2-oxoacetic acid and 1.2mmol of 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) were dissolved in 15ml of anhydrous dichloromethane, 36.3mmol of N, N-diisopropylethylamine was then added, stirring was carried out at room temperature for 20min, and finally 1.1mmol of 4-aminobenzyl alcohol was added, and the reaction was carried out at room temperature with stirring for 12h. After the completion of the reaction, 10ml of methylene chloride was added to dilute the reaction mixture, which was washed 3 times with saturated brine, and anhydrous NaSO 4 And (3) performing silica gel column chromatography after drying, and purifying to obtain the compound 1.
1H NMR(500MHz,Chloroform-d):δ9.25(s,1H),8.45–8.36(m,2H),8.02–7.96(m,2H),7.91–7.83(m,2H),7.49–7.38(m,2H),4.46(s,2H),1.43(s,1H).
(2) 1.6mmol of compound 2a, 1.8mmol of compound 2b [ i.e., (3, 5-trimethylcyclohex-2-eneylene) malononitrile ] and 3.2mmol of piperidine were added to the flask, followed by addition of 20ml of acetonitrile as a solvent. The reaction solution was placed in an oil bath at 90℃and reacted for 2 hours under thermal insulation. Purifying by silica gel column chromatography to obtain compound 2c.
1H NMR(500MHz,Chloroform-d):δ7.48–7.43(m,2H),7.04(dd,J＝11.2,9.6Hz,2H),6.65(d,J＝15.0Hz,1H),6.35(s,1H),3.57(s,3H),2.79(p,J＝3.1Hz,2H),2.65(s,2H),2.57(d,J＝0.9Hz,2H),1.92–1.78(m,7H),1.61(t,J＝3.1Hz,4H),1.05(t,J＝3.1Hz,1H),0.94(s,6H).
(3) 0.4mmol of compound 2c, 0.025mmol of Methyl Blue (MB) were added to a two-necked flask, anhydrous methylene chloride was used as a solvent, and after stirring, the flask was placed in an ice bath, and white light (LED 150W) was irradiated over the flask while strongly bubbling with air for 2 hours. After the reaction, silica gel column chromatography purification was performed to obtain orange solid compound 2.
1H NMR(500MHz,Chloroform-d):δ7.66–7.53(m,2H),7.25–7.07(m,1H),7.01(s,1H),6.65(d,J＝30.2Hz,1H),6.38(t,J＝2.0Hz,1H),3.46(s,3H),2.70(s,2H),2.60(d,J＝2.0Hz,2H),2.23–2.15(m,4H),2.08(t,J＝6.4Hz,2H),2.01–1.84(m,2H),1.75(t,J＝6.2Hz,1H),1.06(t,J＝6.2Hz,1H),0.97(s,6H),0.82(dt,J＝10.0,6.3Hz,4H).
(4) Will 3.6mmol K 2 CO 3 Dissolving in 10ml DMF, adding 0.3mmol of compound 1 and 0.4mmol of compound 2, stirring for reaction for 12h, and purifying by silica gel column chromatography to obtain compound 3, namely the chemofluorescent probe.
1H NMR(500MHz,Chloroform-d):δ9.51(s,1H),8.34(m,2H),8.16(m,2H),7.69(m,2H),7.35(dt,J＝7.8,1.0Hz,2H),7.31(d,J＝14.2Hz,1H),7.24(d,J＝8.0Hz,1H),7.08(dd,J＝14.3,1.3Hz,1H),6.95(dd,J＝8.0,2.3Hz,1H),6.88(d,J＝2.3Hz,1H),6.45(q,J＝1.1Hz,1H),4.99(q,J＝0.8Hz,2H),3.48(s,2H),2.62(p,J＝5.3Hz,2H),2.39(m,3H),2.33(m,1H),2.02(dq,J＝9.6,4.7Hz,2H),1.74(m,8H),1.69(t,J＝5.2Hz,2H),1.06(s,2H),1.01(s,2H).
[ example 2 ]
The chemiluminescent probe was prepared according to the following steps:
(1) 1mmol of 2- (4-nitrophenyl) -2-oxoacetic acid and 1.5mmol of 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) were dissolved in 20ml of anhydrous dichloromethane, 25mmol of N, N-diisopropylethylamine was added thereto, and the mixture was stirred at room temperature for 20 minutes, and finally 1.3mmol of 4-aminobenzyl alcohol was added thereto, and the mixture was stirred at room temperature for 20 hours. After the completion of the reaction, 10ml of methylene chloride was added to dilute the reaction mixture, which was washed 3 times with saturated brine, and anhydrous NaSO 4 And (3) performing silica gel column chromatography after drying, and purifying to obtain the compound 1.
(2) 1.6mmol of compound 2a, 1.6mmol of compound 2b [ i.e., (3, 5-trimethylcyclohex-2-eneylene) malononitrile ] and 4.8mmol of piperidine were added to the flask, followed by addition of 20ml of acetonitrile as a solvent. The reaction solution was placed in an oil bath at 100℃for a thermal insulation reaction for 4 hours. Purifying by silica gel column chromatography to obtain compound 2c.
(3) 0.4mmol of compound 2c, 0.005mmol of Methyl Blue (MB) were added to a two-necked flask, anhydrous methylene chloride was used as a solvent, and after stirring, the flask was placed in an ice bath, and white light (LED 150W) was irradiated over the flask while strongly bubbling with air for 4 hours. After the reaction, silica gel column chromatography purification was performed to obtain orange solid compound 2.
(4) Will 5.5mmol K 2 CO 3 Dissolving in 10ml DMF, adding 0.3mmol of compound 1 and 0.3mmol of compound 2, stirring for reaction for 36h, and purifying by silica gel column chromatography to obtain compound 3, namely the chemofluorescent probe.
[ example 3 ]
The chemiluminescent probe was prepared according to the following steps:
(1) 1mmol of 2- (4-nitrophenyl) -2-oxoacetic acid and 1.8mmol of 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) were dissolved in 20ml of anhydrous dichloromethane, 46.4mmol of N, N-diisopropylethylamine was added thereto, and the mixture was stirred at room temperature for 20 minutes, and finally 1.5mmol of 4-aminobenzyl alcohol was added thereto, and the reaction was stirred at room temperature for 24 hours. After the completion of the reaction, 10ml of methylene chloride was added to dilute the reaction mixture, which was washed 3 times with saturated brine, and anhydrous NaSO 4 And (3) performing silica gel column chromatography after drying, and purifying to obtain the compound 1.
(2) 1.6mmol of compound 2a, 1.3mmol of compound 2b [ i.e., (3, 5-trimethylcyclohex-2-enylidene) malononitrile ] and 4mmol of piperidine were added to the flask, followed by addition of 20ml of acetonitrile as a solvent. The reaction solution was placed in an oil bath at 120℃for 5 hours of thermal insulation reaction. Purifying by silica gel column chromatography to obtain compound 2c.
(3) 0.4mmol of Compound 2c, 0.015mmol of Methyl Blue (MB) was added to a two-necked flask, anhydrous methylene chloride was used as a solvent, and after stirring, the flask was placed in an ice bath, and white light (LED 150W) was irradiated over the flask while strongly bubbling with air for 2.5 hours. After the reaction, silica gel column chromatography purification was performed to obtain orange solid compound 2.
(4) Will be 4.5mmol K 2 CO 3 Dissolving in 10ml DMF, adding 0.3mmol of compound 1 and 0.4mmol of compound 2, stirring, reacting for 24h, and purifying by silica gel column chromatography to obtain compound 3, namely the chemofluorescent probe.
[ application example ]
(1) Sensitive detection of peroxynitrite
Firstly, preparing 1mmol/L of the chemiluminescent probe aqueous solution prepared in the example 1, then reacting sodium nitrite and hydrogen peroxide in a dilute hydrochloric acid medium to obtain a peroxynitrite solution containing 1 mu mol/L of ONOO-free radicals, adding the peroxynitrite solution into the probe solution, and detecting the maximum absorption wavelength, the maximum emission wavelength and the Stokes shift before and after the adding, wherein the test results are shown in Table 1:
TABLE 1 test results
From the above test results, it can be seen that the maximum absorption wavelength, the maximum emission wavelength, and the Stokes shift of the solution, in particular, the Stokes shift was changed from 41nm to 98nm, by adding peroxynitrite to the aqueous solution of the chemiluminescent probe prepared in example 1. The larger the Stokes shift, the smaller the energy absorption, the smaller the overlapping of the two peaks, the smaller the interference and the higher the accuracy.
Meanwhile, the change of fluorescence flux before and after the peroxynitrite solution is added is recorded, wherein the initial fluorescence flux phi=0.03 of the solution, and after the peroxynitrite solution is added, the fluorescence flux of the solution is increased by 20-30 times within 10-30min, which indicates that the fluorescence detection intensity of the chemical fluorescence probe provided by the invention on peroxynitrite is high.
(2) Relationship between substance concentration and fluorescence intensity
Aqueous solutions of chemiluminescent probes were prepared at different concentrations according to the data in Table 2, and peroxynitrite solutions containing 1. Mu. Mol/L ONOO-radicals were added, respectively, and the fluorescence intensity was measured under 365nm ultraviolet light and the standard intensity (F/F) was recorded 0 ) Wherein F 0 The fluorescence intensity before the peroxynitrite is added, and F is the fluorescence intensity 30min after the peroxynitrite is added. The results are shown in Table 2:
TABLE 2 relationship between substance concentration and fluorescence intensity
| Concentration (mu mol/L) | 0 | 5 | 10 | 15 | 20 | 25 | 30 |
| Standard intensity (F/F) 0 ) | 0.95 | 1.46 | 1.92 | 2.48 | 3.02 | 3.39 | 3.92 |
The test data in Table 2 are plotted as a function, as shown in FIG. 1, and it can be seen that the fluorescence intensity of the chemiluminescent probe aqueous solution at a concentration is linearly and positively correlated with the probe concentration.
(3) Detection sensitivity test:
the chemiluminescent probe solutions (final concentration: 1. Mu. Mol/L) were added to peroxynitrite solutions (final concentrations: 5, 10, 25, 50, 100, 250 nmol/L) of different ONO-concentrations, respectively, to react, and the fluorescence spectra of the reacted solutions were measured. The results show that the chemiluminescent probes generate a change of a turn on type fluorescent signal during the ONO-reaction (within the range of 5-250 nmol/L) with different concentrations, which shows that the fluorescent detection sensitivity is high and the application range is wide.
(4) Fluorescence selectivity test:
adding the following anionic compounds which are common in nature or human body and comprise H into 1mmol/L chemiluminescent probe aqueous solution respectively 2 S、KCl、NaI、MgSO 4 、KNO 3 、NaNO 2 、Na 2 CO 3 、NaHCO 3 NaOAc, and commonly active small molecules, including aqueous solutions of glutathione, cysteine, glutamic acid, proline, serine, 5-aminolevulinic acid, arginase (1 μmol/L), found that the fluorescence emission intensity of these solution samples was not significantly changed compared to that of the fluorescence probe alone (Φ=0.03), indicating that the fluorescence probe was highly responsive and selective to ONOO-only.
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and additions may be made to those skilled in the art without departing from the method of the present invention, which modifications and additions are also to be considered as within the scope of the present invention.
Claims (8)
1. A chemiluminescent probe based on adamantene-1, 2-dioxetane, wherein the chemiluminescent probe has a molecular structural expression as follows:
2. a method for preparing a chemiluminescent probe based on adamantene-1, 2-dioxetane, comprising the steps of:
s1, dissolving 2- (4-nitrophenyl) -2-oxo acetic acid and 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate in anhydrous dichloromethane, then adding N, N-diisopropylethylamine, stirring at room temperature for 10-30min, finally adding 4-amino benzyl alcohol, and stirring at room temperature for reacting for 12-24h; after the reaction, methylene chloride was added to dilute the reaction solution, which was washed several times with saturated brine, and anhydrous NaSO 4 Drying, performing silica gel column chromatography, and purifying to obtain a compound 1;
s2, adding the compound 2a, the compound 2b and piperidine into a flask, and then adding acetonitrile as a solvent; placing the reaction solution in an oil bath at 90-120 ℃ for heat preservation reaction for 1-5h, and purifying by silica gel column chromatography to obtain a compound 2c;
s3, adding the compound 2c and methyl blue into a double-neck flask, taking anhydrous dichloromethane as a solvent, stirring, placing the flask in an ice bath, irradiating white light above the flask, and simultaneously, strongly foaming for 2-4 hours by using air; after the reaction is finished, purifying by silica gel column chromatography to obtain an orange solid compound 2;
s4, dissolving potassium carbonate in N, N-dimethylformamide, adding the compound 1 and the compound 2, stirring and reacting for 10-36h, and purifying by silica gel column chromatography to obtain the compound 3, namely the chemiluminescent probe.
3. The method for preparing a chemiluminescent probe based on adamantene-1, 2-dioxetane of claim 2 wherein the molar ratio of 2- (4-nitrophenyl) -2-oxoacetic acid, 4-aminobenzyl alcohol, 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine in step S1 is 1 (1-1.5): 1-2): 20-50.
4. The method for preparing a chemiluminescent probe based on adamantene-1, 2-dioxetane of claim 2 wherein the molar ratio of compound 2a, compound 2b and piperidine in step S2 is 1 (0.8-1.2): 2-3.
5. The method for preparing a chemiluminescent probe based on adamantene-1, 2-dioxetane of any one of claims 2-4 wherein the amount of methyl blue used in step S3 is 1-10% of the molar amount of compound 2c.
6. The method for preparing a chemiluminescent probe based on adamantene-1, 2-dioxetane of claim 5 wherein in step S3 the white light is 150-300W LED light.
7. The method for preparing a chemiluminescent probe based on adamantene-1, 2-dioxetane of any one of claims 2-4 wherein the molar ratio of compound 1 to compound 2 in step S4 is 1 (1-1.5).
8. The method for preparing a chemiluminescent probe based on adamantene-1, 2-dioxetane of claim 7 wherein the amount of potassium carbonate used in step S4 is 10-20 times the amount of compound 1 by mole.
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