CN107868050A - A kind of fluorescence probe and its synthesis and application - Google Patents
A kind of fluorescence probe and its synthesis and application Download PDFInfo
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- CN107868050A CN107868050A CN201610848330.5A CN201610848330A CN107868050A CN 107868050 A CN107868050 A CN 107868050A CN 201610848330 A CN201610848330 A CN 201610848330A CN 107868050 A CN107868050 A CN 107868050A
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- carbon atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- 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
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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
Abstract
The present invention relates to a kind of fluorescence probe available for hepatic lesion diagnosis.The structure of the probe is:
Description
Technical field
The present invention relates to a kind of fluorescence probe for diagnosing hepatic lesion
Background technology
Liver is the important metabolic organ of human body.Synthesis, decomposition and the conversion of various nutriments are more to be carried out in liver.
Hepatic lesion can cause general metabolism obstacle and dysfunction.Therefore, hepatic lesion is made in time and diagnoses and then provide corresponding place
Manage significant.However, it is an easy process that the diagnosis of hepatic lesion, which is not,.Existing Liver function test, including enzyme
Diagnosis and other biochemical analysis are learned, its diagnostic result is suffered from from the dry of cardiac muscle, the skeletal muscle even lesion tissue such as colon
Disturb.Therefore, be badly in need of development has specific diagnostic method to hepatic lesion disease.
The content of the invention
The present invention is aiming above mentioned problem, there is provided a species specificity is good, fluorescence available for quick diagnosis hepatic lesion
Probe.This kind of probe is used to diagnose hepatic lesion, and itself fluorescence is in 460nm or so, after the serum effect of hepatic lesion patient,
460nm or so fluorescence intensity reduces, while 510nm or so fluorescence intensity enhancing, so as to indicate the generation of hepatic lesion.
The present invention adopts the following technical scheme that:Using 1,8- aphthalimides as fluorescent parent, introduced on its naphthalene nucleus
Carbamate structures are as the group reacted with hepatic lesion patients serum.When probe and the serum of hepatic lesion patient act on,
Carbamate structures are destroyed, so as to cause the change of fluorescence probe.
The structure of the probe is as follows:
Wherein:
R1 is hydrogen atom, or the alkyl with 1-10 carbon atom, the cycloalkyl and 6-10 carbon original of 3-10 carbon atom
The aryl of son;
R2 is hydrogen atom, chlorine atom, bromine atoms, hydroxyl, amino, or the alkyl with 1-10 carbon atom, 3-10 carbon
The cycloalkyl of atom, the aryl of 6-10 carbon atom, alkoxy and substituted-amino;
R3 is hydrogen atom, or the alkyl with 1-10 carbon atom, the cycloalkyl and 6-10 carbon original of 3-10 carbon atom
The aryl of son;
R4 is the alkyl with 1-10 carbon atom, the cycloalkyl of 3-10 carbon atom and the aryl of 6-10 carbon atom;
R5 is hydrogen atom, or the alkyl with 1-10 carbon atom, the cycloalkyl and 6-10 carbon original of 3-10 carbon atom
The aryl of son;
R6 is hydrogen atom, or the alkyl with 1-10 carbon atom, the cycloalkyl and 6-10 carbon original of 3-10 carbon atom
The aryl of son;
N represents carbon atom number in parantheses, numerical value 0-3;
The aryl of the 6-10 carbon atom is phenyl, or is aminomethyl phenyl, 3,5-dimethylphenyl, trimethylphenyl, and
Methylethyl phenyl;
The alkoxy substituent is methoxyl group, ethyoxyl, propoxyl group, isopropoxy or butyl;
The substituted-amino is methylamino, dimethylamino, ethylamino- and diethylin.
R1 is preferably the alkyl with 1-10 carbon atom;
R2 is preferably hydrogen atom, chlorine atom, bromine atoms, hydroxyl, amino, or the alkyl with 1-10 carbon atom;
R3 is preferably the alkyl with 1-10 carbon atom;
R4 is preferably the alkyl with 1-10 carbon atom;
R5 is preferably the alkyl with 1-10 carbon atom;
R6 is preferably the alkyl with 1-10 carbon atom.
It is using the compound with structure III or structure I V as Material synthesis
Wherein, R3 is hydrogen atom or alkyl or the cycloalkyl or 6-10 of 3-10 carbon atom with 1-10 carbon atom
The aryl of individual carbon atom;Preferably there is the alkyl of 1-10 carbon atom;
R5 is hydrogen atom or alkyl or the cycloalkyl or 6-10 carbon of 3-10 carbon atom with 1-10 carbon atom
The aryl of atom;Preferably there is the alkyl of 1-10 carbon atom;
R6 is hydrogen atom or alkyl or the cycloalkyl or 6-10 carbon of 3-10 carbon atom with 1-10 carbon atom
The aryl of atom;Preferably there is the alkyl of 1-10 carbon atom.
When using the compound with structure III for raw material, its synthesis step includes:
Compound with structure III reacts to obtain corresponding carbamoyl chloride compounds with phosgene or solid phosgene;
Gained carbamoyl chloride compounds react to obtain the compound with structure I with corresponding hydroxy compounds;
Or, when using the compound with structure I V for raw material, compound and phosgene or solid light with structure I V
Solid/liquid/gas reactions obtain the compound with structure I I.
Compound with structure III or structure I V, at -5~8 DEG C, is carried out, three second with phosgene reaction in the presence of triethylamine
The mol ratio of the dosage of amine and the compound with structure III is 0.8~3.
Compound with structure I and structure I I, this kind of compound can be used for the diagnosis of hepatic lesion disease.
Compound with structure I and structure I I is used for the diagnosis of hepatic lesion disease, and the serum of itself and hepatic lesion patient are made
After (contact), it is reduced in 460nm or so fluorescence, while is strengthened in 510nm or so fluorescence, so as to pass through measure
Change in fluorescence diagnoses hepatic lesion.
Beneficial effects of the present invention:
Fluorescence probe of the present invention, which is used for hepatic lesion diagnosis, has selectivity well.The probe and non-hepatic lesion
Patient, such as the serum of the patient such as heating, diarrhoea, hemorrhage of digestive tract act on no obvious change in fluorescence.In view of liver is to people
The importance of body, and threat of the hepatic lesion to health, probe provided by the invention find and diagnosed hepatic lesion timely,
It is significant to assist in the therapeutic scheme of hepatic lesion and the therapeutic effect of tracking hepatic lesion etc..
Brief description of the drawings
Fig. 1:Probe A and change in fluorescence figure after the effect of various concentrations serum.
Fig. 2:Fluorescence ratio is mapped after probe A responds to various concentrations serum;Ordinate:Relative intensity of fluorescence;Abscissa,
Serum-concentration.
Fig. 3:Probe A and probe B are to the fluorescence response of different patients serums, ordinate:Relative intensity of fluorescence.
Fig. 4:Probe A structures hydrogen is composed.
Fig. 5:Probe B structure hydrogen is composed.
Embodiment
Embodiment 1:Probe A synthesis
1g solid phosgenes are added into the reaction bulb full of nitrogen, 10ml dichloromethane, ice-water bath cools down after dissolved clarification, instills
2 drop DMF stirring reaction half an hour.The formyl butylamine of 2.5g 4- amino -1,8- naphthalene two, 1ml triethylamines and 10ml dichloromethanes is added dropwise
The mixed solution of alkane.It is added dropwise, continues stirring reaction 3 hours, TLC detection substrates convert completely, add 2ml chlorethanols, after
Continuous reaction 3 hours, TLC detection reactions are complete, and filtering, filtrate is spin-dried for, and column chromatography obtains product 2.3g.
Characterization of The Products data MS (API-ES):m/z C19H19ClN2O4[M+H]+375.10,found375.10.1HNMR
(400MHz,CHLOROFORM-D)δ(ppm):δ=8.64 (d, 1H, J=7.2 Hz), 8.60 (d, 1H, J=8.4Hz), 8.34
(d, 1H, J=8.0Hz), 8.19 (d, 1H, J=8.4Hz), 7.80 (t, 1H, J=7.6Hz), 7.49 (s, 1H), 4.55 (t, 2H,
), J=5.2Hz 4.18 (t, 2H, J=7.6Hz), 3.81 (t, 2H, J=5.6Hz), 1.72 (m, 2H), 1.46 (m, 2H), 0.98
(t, 3H, J=8.0Hz)
Embodiment 2:Probe B synthesis
1g solid phosgenes are added into the reaction bulb full of nitrogen, 10ml dichloromethane, ice-water bath cools down after dissolved clarification, instills
2 drop DMF stirring reaction half an hour.The mixed solution of 3g hydroxy compounds 1,1ml triethylamines and 10ml dichloromethane is added dropwise.Drop
Add complete, continue stirring reaction 3 hours, TLC detection substrates convert completely, continue reaction 3 hours, TLC detection reactions are complete, mistake
Filter, filtrate are spin-dried for, and column chromatography obtains product 2.8g.
MS(API-ES):m/z C19H18N2O4[M+H]+339.13,found 339.13.1HNMR(400MHz,
Chloroform-d)δ(ppm):δ=8.64 (d, 1H, J=7.2Hz), 8.61 (d, 1H, J=8.0Hz), 8.28 (d, 1H, J=
8.6Hz), 7.80 (t, 1H, J=7.8Hz), 7.69 (d, 1H, J=7.6Hz), 4.71 (t, 2H, J=8.2Hz), 4.20 (m,
4H), 1.72 (m, 2H), 1.45 (m, 2H), 0.98 (t, 3H, J=7.2Hz)13CNMR(100MHz,Chloroform-d)δ
(ppm):163.90,163.44,156.59,140.13,131.11,129.32,127.78,127.36,123.35,123.29,
122.22,62.77,48.68,40.34,30.18,20.37,13.85.
Embodiment 3:Fluorescence responses of the probe A to various concentrations hepatic lesion patients serum
Configure the serial dilutions solution of serum.Configure probe A (2mM) DMSO solution.Each react in 178ul
Add 2ul probes A (2mM) and 20ul series concentration serum in 100mM PBS, it is multi-functional using full wavelength scanner formula
Readout instrument and 96 hole elisa Plates measure, and the final concentration of probe and enzyme is respectively 20uM.Measure the fluorescent emission of the working solution
Spectrum, λ ex1=350nm, raster width 5nm, transmitting boundary is from 370nm-600nm.λ ex2=450nm, raster width are
5nm, transmitting boundary is from 470nm-700nm.After NACL and HSA effects, with the increase of HSA concentration, 460nm fluorescence reduces (a),
512nm fluorescence raises (b), as shown in Figure 1.Fluorescence intensity ratio is as shown in Figure 2.
Embodiment 4:Fluorescence responses of the probe A and probe B to different patients serums
Configure probe A/B (2mM) DMSO solution.Each react in 178ul 100mM PBS plus 2ul is visited
Pin A (2mM) and 20ul difference patients serums, are surveyed using the multi-functional readout instrument of full wavelength scanner formula and 96 hole elisa Plates
Amount.The fluorescence emission spectrum of the working solution is measured, λ ex1=350nm, raster width 5nm, it is strong to detect 460nm wavelength fluorescents
Degree.λ ex2=450nm, raster width 5nm, detect 510nm wavelength fluorescent intensity.Accompanying drawing 3 shows probe A and probe B to liver
The serum response of infringement patient is sensitive, and fluorescence has significant change;To the serum of other patients then without obvious responsing to.
Claims (9)
1. a kind of fluorescence probe, it is characterised in that there is the fluorescence probe following structures I and/or Structure Structure to be:
Wherein:
R1 is hydrogen atom or alkyl or the cycloalkyl or 6-10 carbon atom of 3-10 carbon atom with 1-10 carbon atom
Aryl;
R2 is hydrogen atom, chlorine atom, bromine atoms, hydroxyl, amino or alkyl or 3-10 carbon original with 1-10 carbon atom
The cycloalkyl of son or aryl, alkoxy or the substituted-amino of 6-10 carbon atom;
R3 is hydrogen atom or alkyl or the cycloalkyl or 6-10 carbon atom of 3-10 carbon atom with 1-10 carbon atom
Aryl;
R4 is the cycloalkyl of alkyl with 1-10 carbon atom or 3-10 carbon atom or the aryl of 6-10 carbon atom;
R5 is hydrogen atom or alkyl or the cycloalkyl or 6-10 carbon atom of 3-10 carbon atom with 1-10 carbon atom
Aryl;
R6 is the cycloalkyl or 6-10 carbon atom of hydrogen atom or alkyl with 1-10 carbon atom, 3-10 carbon atom
Aryl;
N represents carbon atom number in parantheses, numerical value 0-3.
2. fluorescence probe according to claim 1, it is characterised in that
The aryl of the 6-10 carbon atom is phenyl or is aminomethyl phenyl, 3,5-dimethylphenyl, trimethylphenyl or methyl second
Base phenyl;
The alkoxy substituent is methoxyl group, ethyoxyl, propoxyl group, isopropoxy or butyl;
The substituted-amino is methylamino, dimethylamino, ethylamino- and diethylin.
3. fluorescence probe according to claim 1 or 2, it is characterised in that
R1 is preferably the alkyl with 1-10 carbon atom;
R2 is preferably hydrogen atom, chlorine atom, bromine atoms, hydroxyl, amino, or the alkyl with 1-10 carbon atom;
R3 is preferably the alkyl with 1-10 carbon atom;
R4 is preferably the alkyl with 1-10 carbon atom;
R5 is preferably the alkyl with 1-10 carbon atom;
R6 is preferably the alkyl with 1-10 carbon atom.
A kind of 4. synthetic method of any described fluorescence probes of claim 1-3, it is characterised in that:It is with structure
III or structure I V compound are Material synthesis
Wherein, R3 is hydrogen atom or alkyl or the cycloalkyl or 6-10 carbon of 3-10 carbon atom with 1-10 carbon atom
The aryl of atom;Preferably there is the alkyl of 1-10 carbon atom;
R5 is hydrogen atom or alkyl or the cycloalkyl or 6-10 carbon atom of 3-10 carbon atom with 1-10 carbon atom
Aryl;Preferably there is the alkyl of 1-10 carbon atom;
R6 is hydrogen atom or alkyl or the cycloalkyl or 6-10 carbon atom of 3-10 carbon atom with 1-10 carbon atom
Aryl;Preferably there is the alkyl of 1-10 carbon atom.
5. the synthetic method of fluorescence probe according to claim 4, it is characterised in that:
When using the compound with structure III for raw material, its synthesis step includes:
1) compound with structure III reacts to obtain corresponding carbamoyl chloride compounds with phosgene or solid phosgene;
2) gained carbamoyl chloride compounds react to obtain the compound with structure I with corresponding hydroxy compounds;
Or, when using the compound with structure I V for raw material, compound and phosgene or solid phosgene with structure I V are anti-
The compound with structure I I should be obtained.
6. the synthetic method of fluorescence probe according to claim 5, it is characterised in that:Change with structure III or structure I V
Compound, at -5~8 DEG C, is carried out with phosgene reaction in the presence of triethylamine, the dosage of triethylamine and the compound with structure III
Mol ratio is 0.8~3.
7. application of the fluorescence probe in the detection reagent for preparing hepatic lesion disease, its feature exist described in a kind of claim 1-3
In:The fluorescence probe can be as the active component for preparing hepatic lesion disease detection reagent, the diagnosis for hepatic lesion disease.
8. the application of fluorescence probe according to claim 7, it is characterised in that:By containing with structure I and/or structure I I
The hepatic lesion disease detection reagent of compound is acted on the serum of hepatic lesion patient, and it is reduced in 460nm or so fluorescence, while
510nm or so fluorescence strengthens.
9. according to the application of the fluorescence probe of claim 7 or 8, it is characterised in that:Excited in 300-450nm wave-length coverages
The probe, the detection of fluorescence emission spectrum is carried out in the range of 400-550nm.
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN109608414A (en) * | 2018-12-26 | 2019-04-12 | 山东师范大学 | Detect the fluorescence probe and its preparation method and application of peroxynitrite |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20130043922A (en) * | 2011-10-21 | 2013-05-02 | 고려대학교 산학협력단 | Thiol-targeting chemodosimetric fluorescent probe, method for preparing the same, and method for bioimaging of thiol using the same |
CN106833615A (en) * | 2015-12-04 | 2017-06-13 | 中国科学院大连化学物理研究所 | A kind of fluorescence probe NACL and its preparation and application |
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2016
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20130043922A (en) * | 2011-10-21 | 2013-05-02 | 고려대학교 산학협력단 | Thiol-targeting chemodosimetric fluorescent probe, method for preparing the same, and method for bioimaging of thiol using the same |
CN106833615A (en) * | 2015-12-04 | 2017-06-13 | 中国科学院大连化学物理研究所 | A kind of fluorescence probe NACL and its preparation and application |
Non-Patent Citations (1)
Title |
---|
JUN FENG ZHANG ET AL.: "A Highly Selective Colorimetric and Ratiometric Two-Photon Fluorescent Probe for Fluoride Ion Detection", 《ORG.LETT.》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN109608414A (en) * | 2018-12-26 | 2019-04-12 | 山东师范大学 | Detect the fluorescence probe and its preparation method and application of peroxynitrite |
CN109608414B (en) * | 2018-12-26 | 2020-09-29 | 山东师范大学 | Fluorescent probe for detecting peroxynitrite and preparation method and application thereof |
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Application publication date: 20180403 |