CN108864052A - A kind of synthesis and application of the fluorescence probe for GC33-3-1 antibody with specific recognition - Google Patents
A kind of synthesis and application of the fluorescence probe for GC33-3-1 antibody with specific recognition Download PDFInfo
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- CN108864052A CN108864052A CN201810577436.5A CN201810577436A CN108864052A CN 108864052 A CN108864052 A CN 108864052A CN 201810577436 A CN201810577436 A CN 201810577436A CN 108864052 A CN108864052 A CN 108864052A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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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
- G01N21/6428—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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- 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
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
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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
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms
Abstract
The present invention discloses the synthesis and application of a kind of fluorescence probe for GC33-3-1 antibody with specific recognition.The probe synthetic route is simple, and reaction condition is mild, post-processes simple and convenient.The fluorescence probe marks human albumin（HSA）Fluorescence intensity greatly enhances afterwards, is used for identification GC33-3-1 antibody again after fluorescence probe label HSA.Compared with the method for other detection antibody, this method has easy to operate, responds sensitive, and has many advantages, such as selectivity, have preferable application prospect in biological field；。
Description
Technical field
The invention belongs to bioanalysis detection fields, and in particular to one kind is used for specific recognition GC33-3-1 antibody fluorescence
The synthesis and its application of probe.
Background technique
Human albumin（HSA）It is the most abundant protein and most important pharmaceutical carrier albumen in serum.It for
The transhipment of many endogenous and exogenous lipid, distribution and metabolism, including fatty acid, amino acid, metal ion and many drugs,
And there is middle important role to the mixing osmotic pressure of blood.Human serum albumins（HSA）It is a kind of high molecular weight blood plasma egg
It is white.The single chain that it is made of 585 amino acid.As other mammal albumin, human albumin contains 17
Disulphide bridges and a free mercaptan Cys34.In most cases, the effect of be combineding with each other of protein and drug can significantly affect
The apparent volume of distribution of drug also will affect the clearance rate of drug.Therefore, drug can provide related with protein bound research
The information of medicines structure feature determines the therapeutic effect of drug, in chemistry and clinical research area research drug and the white egg of serum
White interaction is all very important.
Glypican-3（GCP3）It is cell surface glycoprotein, belongs to one of glypican family, is that liver is thin
Born of the same parents' cancer（Heptocellular carcinoma, HCC）Surface specific marker.GCP3 can be expressed highly in HCC, just
Without expression in normal hepatic tissue, so GCP3 can be used as the ideal marker of liver cancer treatment.The missing of GCP3 function will lead to
Undue growth and distortion（Simpson-Golabi-Behmel）Syndrome, this is a kind of disease of X chromosome exception.GCP3 is lacked
Lose the phenotype that mouse shows undue growth and some distortion.GCP3 overexpression can inhibit hepatocyte growth and liver in mouse
Regeneration.GC33-3-1 antibody is the anti-GCP3 antibody of high-affinity, has very strong anti-tumor activity.Therefore, by synthesizing benzo
Imidazolone fluorescence probe marks human albumin（HSA）, then identify GC33-3-1 antibody, thus the liver cancer of detection into the human body
Cell.The fluorescence probe has high sensitivity, good, the simple operation and other advantages of selectivity.
Summary of the invention
An object of the present invention is to provide a kind of fluorescence probe for specific recognition GC33-3-1 antibody, the fluorescence
Probe and ultra-pure water solution, Tris-HCl solution are according to 1：1：Fluorescence signal is fainter when 1 ratio is made into mixed solution, when this
Fluorescence probe and human albumin's solution, Tris-HCl solution are according to 1：1：It is obvious that 1 ratio is made into mixed solution fluorescence signal
Enhancing.
An object of the present invention provides a kind of synthesis of fluorescence probe that can be used for specific recognition GC33-3-1 antibody
Methods and applications, this method have it is easy to operate, raw material is easy to get, and purifies the advantages that simple.
All technical solutions of the present invention are：
The present invention provides a kind of fluorescence probes that can be used for specific recognition GC33-3-1 antibody, and the structural formula of the probe is such as
Under：
The present invention provides the preparation methods of the fluorescence probe, and the method steps are as follows：
Specific synthesis step is as follows：
（1）The synthesis of midbody compound F1
4,6- dichloro pyrimidine and o-phenylenediamine are dissolved in isopropanol, and n,N-diisopropylethylamine is added into the reaction solution,
Reaction solution is added in microwave reaction, 150 DEG C of 10 min of reaction are removed under reduced pressure isopropanol, obtain compound F1.
（2）The synthesis of midbody compound F2
Compound F1 and carbonyl -2- imidazoles are dissolved in tetrahydrofuran solution, pyridine is added and makees catalyst, under nitrogen protection 65
DEG C oil bath reflux is removed under reduced pressure solvent, through silica gel post separation, obtains compound F2 overnight.
（3）The synthesis of fluorescence probe F3
Compound F2 and 2-aminopyridine are dissolved in isopropanol, p-methyl benzenesulfonic acid is added and makees catalyst, reaction solution is added micro-
In wave reaction, solvent is removed under reduced pressure in 150 DEG C of 10 min of reaction, is extracted with saturated sodium bicarbonate/dichloromethane solution, and collection has
Machine layer, is spin-dried for, and through silica gel post separation, obtains fluorescence probe F3.
Step（1）The synthesis of middle compound F1 directly obtains product without post-processing；
Step（2）Middle silicagel column is with petroleum ether：Ethyl acetate volume ratio is 4:1--1:1 solvent；
Step（3）Middle silicagel column is with petroleum ether：Ethyl acetate volume ratio is 1:1 solvent；
Step（1）The molal weight ratio of middle 4,6- dichloropyridine and o-phenylenediamine is 1：1.
Step（2）The mass ratio of middle compound F2 and carbonyl -2- imidazoles and pyridine is 1:2:1.
Step（3）Compound F2 and 2-aminopyridine and the molal weight of p-methyl benzenesulfonic acid are than 1:1:2.5；
Human albumin the present invention also provides above-mentioned fluorescence probe for label（HSA）GC33-3-1 for identification is anti-
Body.
The present invention has following beneficial effect：The simple synthetic method of the probe molecule, raw material are easy to get, post-processing letter
It is single；It combines and is not obvious after the probe Direct Recognition antibody, fluorescence signal is weak, when probe first marks human blood protein（HSA）Exist afterwards
After identifying antibody, fluorescence signal is under fluorescence inverted microscope it can clearly be seen that fluorescence signal；Such probe can be by anti-
Body identification technology, is marked target antibody, is applied to the fields such as bioluminescence imaging.
Detailed description of the invention
Fig. 1 is the uv absorption spectra of fluorescence probe of the present invention.
Fig. 2 is the fluorescence spectra of fluorescence probe of the present invention.
Fig. 3 is fluorescence probe of the present invention and human albumin（HSA）In conjunction with the fluorescence spectra of front and back.
Fig. 4 is the fluorescence imaging figure under fluorescence probe fluorescence inverted microscope of the present invention.
Fig. 5 is that fluorescence of the present inventor's haemocyanin in conjunction with antibody is inverted micro-imaging figure.
Fig. 6 is fluorescence probe of the present invention and the fluorescence imaging figure after antibody identification under fluorescence inverted microscope.
Fig. 7 is that fluorescence probe of the present invention marks human blood protein（HSA）Identification antibody is glimmering under fluorescence inverted microscope afterwards
Light image.
Fig. 8 be fluorescence probe of the present invention in the Tris-HCl solution of different PH with the fluorescence signal of independent fluorescence probe
The photoluminescent property of comparison.
Fig. 9 is that fluorescence probe of the present invention marks human albumin（HSA）It is incubated for the variation of different time fluorescence signal afterwards.
Specific embodiment
The following examples will be further described the present invention, but not thereby limiting the invention.
Embodiment 1：The synthesis of small-molecule fluorescent probe for antibody label
（1）The synthesis of midbody compound F1：
Respectively weigh 15.7 mmol4,6- dichloro pyrimidine and o-phenylenediamine, 17.5 mmolN, N-- diisopropylethylamine is anti-in microwave
The dissolution of 10 ml isopropanols, 150 DEG C of 10 min of reaction in microwave are added in Ying Guanzhong.Post-processing：Thin-layered chromatography monitoring reaction
As a result, reaction solution vacuum rotary steam is removed solvent, yellow oil F1, yield 100%, MS (m/z) are obtained:220.5.
（2）The synthesis of midbody compound F2：
The F1 of 1.6 mmol, 4.4 mmol carbonyls -- 2-- imidazoles are weighed, in a round bottom flask, tetrahydro is added in 4.4 mmol pyridines
Furans is stayed overnight as solvent, nitrogen protection, 65 DEG C of oil bath reflux.Post-processing：Thin-layered chromatography monitors reaction result, will react
Liquid vacuum rotary steam removes solvent, crosses silica gel post separation, obtains pink solid, yield 50%, MS (m/z):246.03.
（3）The synthesis of fluorescence probe F3：
0.41mmol F2,0.41 mmol2- aminopyridine are weighed, 1 mmol p-methyl benzenesulfonic acid is added 10 in microwave reaction pipe
The dissolution of ml isopropanol, 150 DEG C of 10 min of reaction in microwave, thin-layered chromatography monitor reaction result, reaction solution are spin-dried for, and use
Several times, collected organic layer, vacuum rotary steam removes solvent, crosses silicagel column point for saturated sodium bicarbonate aqueous solution and ethyl acetate extraction
From obtaining faint yellow solid, MS (m/z):304.11, fluorescence probe spectrogram is shown in that Fig. 1 and Fig. 2, Fig. 1 are fluorescence probe of the present invention
Uv absorption spectra, Fig. 2 are the fluorescence spectra of fluorescence probe of the present invention.Fig. 4 is that fluorescence probe fluorescence of the present invention inversion is aobvious
Fluorescence imaging figure under micro mirror.
Embodiment 2：Fluorescence probe marks human albumin（HSA）Change in fluorescence after reaction
Sample solution：Fluorescence probe made from a certain amount of embodiment 1 is dissolved in suitable methanol solution and is diluted with ultrapure water
It is 1.5X10 at concentration-5 mol/L；By human serum albumins（HSA）Being diluted to concentration with ultrapure water is 1X10-5 mol/L；
Tris-HCl solution is formulated as 0.05mol/LPH=7.4（Include the NaCl that concentration is 0.1mol/L）；Add in the EP pipe of 4 ml
Enter 1ml Tris-HCl solution, the HSA solution of the fluorescent chemicals of 1ml and 1 ml mixes.Contrast solution：1 ml fluorescence probe
Solution, 1 ml Tris-HCl solution, the ultrapure water of 1 ml are hybridly prepared into contrast solution.Measurement fluorescence spectra obtains Fig. 3.
Embodiment 3：Fluorescence probe Direct Recognition antibody
（1）Coating：Antibody is diluted to 1 μ g/ml, with coating buffer（Carbonate buffer solution）It is mixed to join in enzyme mark version, 37 DEG C
2 h are incubated for, 4 DEG C overnight；
（2）Washing：It takes 40 ml PBS that 20 μ l polysorbas20s are added, is configured to PBST solution and is configured to PBST solution, it is molten with PBST
Liquid detersive enzyme mark version, every 300 μ l of hole, 3 min, is washed 3 times every time；
（3）Closing：Bovine serum albumin is configured to 0.02 mg/ml, is added in ELISA Plate, 37 DEG C of 2 h of incubation；
（4）Washing：With PBST solution detersive enzyme mark version, every 300 μ l of hole, 3 min, is washed 3 times every time；
（5）In conjunction with：Fluorescent probe compounds made from a certain amount of embodiment 1 are dissolved in suitable methanol solution and use ultrapure water
Being diluted to concentration is 1.5X10-5 mol/L；Tris-HCl solution is formulated as 0.05 PH=7.4 mol/L（Including concentration is 0.1
The NaCl of mol/L）；1 ml Tris-HCl solution is added in the EP pipe of 4 ml, the fluorescent chemicals of 1 ml mix, at 37 DEG C
2 h of lower incubation.
（6）Label：The mixed solution of above-mentioned preparation is added on 96 orifice plates, every hole adds 100 μ l, is incubated for 2 at 37 DEG C
H, with PBST solution detersive enzyme mark version, every 300 μ l of hole, 3 min, is washed 3 times every time.
（7）Whether specifically bound with fluorescence inverted microscope observation antigen-antibody, obtains Fig. 5.
Embodiment 4：Fluorescence probe marks human blood protein（HSA）Antibody for identification afterwards
（1）Coating：Antibody is diluted to 1 μ g/ml, with coating buffer（Carbonate buffer solution）It is mixed to join in enzyme mark version, 37 DEG C
2 h are incubated for, 4 DEG C overnight；
（2）Washing：It takes 40 ml PBS that 20 μ l polysorbas20s are added, is configured to PBST solution and is configured to PBST solution, it is molten with PBST
Liquid detersive enzyme mark version, every 300 μ l of hole, 3 min, is washed 3 times every time；
（3）Closing：Bovine serum albumin is configured to 0.02 mg/ml, is added in ELISA Plate, 37 DEG C of 2 h of incubation；
（4）Washing：With PBST solution detersive enzyme mark version, every 300 μ l of hole, 3 min, is washed 3 times every time；
（5）In conjunction with：Fluorescent probe compounds made from a certain amount of embodiment 1 are dissolved in suitable methanol solution and use ultrapure water
Being diluted to concentration is 1.5X10-5 mol/L；By human serum albumins（HSA）Being diluted to concentration with ultrapure water is 1X10-5 mol/L；
Tris-HCl solution is formulated as PH=7.4 0.05mol/L（Include the NaCl that concentration is 0.1 mol/L）；In the EP pipe of 4 ml
1 ml Tris-HCl solution is added, the HSA solution of the fluorescent chemicals of 1 ml and 1 ml mixes, 2 h are incubated at 37 DEG C.
（6）Label：The fluorescent antigen mixture of above-mentioned preparation is added on 96 orifice plates, every hole adds 100 μ l, at 37 DEG C
2 h of lower incubation, with PBST solution detersive enzyme mark version, every 300 μ l of hole, 3 min, is washed 3 times every time.
（7）Whether specifically bound with fluorescence inverted microscope observation antigen-antibody, obtains Fig. 6.
Embodiment 5：Photoluminescent property of the fluorescence probe in the Tris-HCl solution of different PH
Prepare changing value of the Tris-HCl of different PH as fluorescence intensity before and after buffer solution comparative determination.Embodiment 1 is made
The individual fluorescence intensity of the fluorescence probe obtained is stablized, and will not substantially change with the variation of pH value, prepares PH=6.4-12.4
Tris-HCl buffer solution, the change in fluorescence between measurement.Wherein fluorescence intensity fluorescence intensity difference in PH=7.4 is maximum,
Fluorescence probe preferably obtains Fig. 7 in PH=7.4 in conjunction with protein.
Embodiment 6：Different incubation times mark human albumin to fluorescence probe（HSA）Photoluminescent property variation
1ml Tris-HCl solution, fluorescent probe compounds and 1 made from the embodiment 1 of 1 ml are added in the EP pipe of 4 ml
The HSA solution of ml mixes, 0 min, 20 min, 40 min, 60 min, 80 min, 100min, 120 is incubated at 37 DEG C
Min, 140 min, 160 min, fluorescence intensity change is maximum when being incubated for 120 min i.e. 2 h, therefore selects incubation time for 2 h.
Obtain Fig. 8.Fig. 9 is that fluorescence probe of the present invention marks human albumin（HSA）It is incubated for the variation diagram of different time fluorescence signal afterwards
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, it is all in spirit of the invention and
Made any modification within principle, equivalent replacement and improvement etc., should all be included in the protection scope of the present invention.
Claims (7)
1. a kind of fluorescence probe for GC33-3-1 antibody with specific recognition, it is characterised in that：The knot of the fluorescence probe
Structure formula is as follows：
。
2. there is described in a kind of claim 1 for GC33-3-1 antibody the synthetic method of the fluorescence probe of specific recognition,
It is characterized in that：Include the following steps：
（1）The synthesis of midbody compound F1
4,6- dichloro pyrimidine and o-phenylenediamine are dissolved in isopropanol, and n,N-diisopropylethylamine is added into the reaction solution,
Reaction solution is added in microwave reaction, 150 DEG C of 10 min of reaction are removed under reduced pressure isopropanol, obtain compound F1；
（2）The synthesis of midbody compound F2
Compound F1 and carbonyl -2- imidazoles are dissolved in tetrahydrofuran solution, pyridine is added and makees catalyst, under nitrogen protection 65
DEG C oil bath reflux is removed under reduced pressure solvent, through silica gel post separation, obtains compound F2 overnight；
（3）The synthesis of fluorescence probe F3
Compound F2 and 2-aminopyridine are dissolved in isopropanol, p-methyl benzenesulfonic acid is added and makees catalyst, reaction solution is added micro-
In wave reaction, solvent is removed under reduced pressure in 150 DEG C of 10 min of reaction, is extracted with saturated sodium bicarbonate/dichloromethane solution, and collection has
Machine layer, is spin-dried for, and through silica gel post separation, obtains fluorescence probe F3.
3. synthetic method as claimed in claim 2, it is characterised in that：
Step（1）The synthesis of middle compound F1 directly obtains product without post-processing；
Step（2）Middle silicagel column is with petroleum ether：Ethyl acetate volume ratio is 4:1--1:1 solvent；
Step（3）Middle silicagel column is with petroleum ether：Ethyl acetate volume ratio is 1:1 solvent.
4. synthetic method as claimed in claim 2, it is characterised in that：Step（1）Middle 4,6- dichloropyridine and o-phenylenediamine
Molal weight ratio is 1：1.
5. synthetic method as claimed in claim 2, it is characterised in that：Step（2）Middle compound F2 and carbonyl -2- imidazoles and
The mass ratio of pyridine is 1:2:1.
6. the synthetic method as described in claim 2-5 is any, it is characterised in that：Step（3）Compound F2 and 2-aminopyridine
And the molal weight of p-methyl benzenesulfonic acid is than 1:1:2.5.
7. a kind of fluorescence probe described in claim 1 is used for specific recognition GC33-3-1 antibody.
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| CN1429222A (en) * | 2000-02-17 | 2003-07-09 | 安姆根有限公司 | Kinase inhibitors |
| CN102791131A (en) * | 2010-01-13 | 2012-11-21 | 葛兰素史密斯克莱有限责任公司 | Compounds and methods |
| CN105112046A (en) * | 2015-09-29 | 2015-12-02 | 南通大学 | Method for preparing quantum dots with nuclear shell structures, fluorescent nanometer probe for target tumor markers GPC-3 and method for preparing fluorescent nanometer probe |
-
2018
- 2018-06-07 CN CN201810577436.5A patent/CN108864052A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001025220A1 (en) * | 1999-10-07 | 2001-04-12 | Amgen Inc. | Triazine kinase inhibitors |
| CN1429222A (en) * | 2000-02-17 | 2003-07-09 | 安姆根有限公司 | Kinase inhibitors |
| CN102791131A (en) * | 2010-01-13 | 2012-11-21 | 葛兰素史密斯克莱有限责任公司 | Compounds and methods |
| CN105112046A (en) * | 2015-09-29 | 2015-12-02 | 南通大学 | Method for preparing quantum dots with nuclear shell structures, fluorescent nanometer probe for target tumor markers GPC-3 and method for preparing fluorescent nanometer probe |
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| Title |
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