CN107488144A - A kind of molecule that can be specifically bound and the aggregation of Tau albumen can be suppressed and its preparation method and application - Google Patents
A kind of molecule that can be specifically bound and the aggregation of Tau albumen can be suppressed and its preparation method and application Download PDFInfo
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- 230000002776 aggregation Effects 0.000 title claims abstract description 32
- 238000004220 aggregation Methods 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims description 8
- 102000013498 tau Proteins Human genes 0.000 claims abstract description 60
- 108010026424 tau Proteins Proteins 0.000 claims abstract description 60
- 239000000523 sample Substances 0.000 claims abstract description 18
- 239000000178 monomer Substances 0.000 claims abstract description 10
- 125000001033 ether group Chemical group 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 claims 2
- 150000001924 cycloalkanes Chemical class 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 5
- 230000001575 pathological effect Effects 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 230000008859 change Effects 0.000 description 5
- JADVWWSKYZXRGX-UHFFFAOYSA-M thioflavine T Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C1=[N+](C)C2=CC=C(C)C=C2S1 JADVWWSKYZXRGX-UHFFFAOYSA-M 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- OFUFXTHGZWIDDB-UHFFFAOYSA-N 2-chloroquinoline Chemical compound C1=CC=CC2=NC(Cl)=CC=C21 OFUFXTHGZWIDDB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000004896 high resolution mass spectrometry Methods 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 238000011085 pressure filtration Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 102000009664 Microtubule-Associated Proteins Human genes 0.000 description 1
- 108010020004 Microtubule-Associated Proteins Proteins 0.000 description 1
- 230000004308 accommodation Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- -1 by compound 3 Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000002189 fluorescence spectrum Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- CMQCNTNASCDNGR-UHFFFAOYSA-N toluene;hydrate Chemical compound O.CC1=CC=CC=C1 CMQCNTNASCDNGR-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
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- 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
-
- 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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- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Materials Engineering (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention belongs to suppress albumen aggregation technique field, and in particular to a kind of pathologic mark Tau albumen that can be specifically bound in Alzheimer disease and the probe molecule that can suppress its aggregation.Such probe molecule with specific combination Tau albumen and can suppress the aggregation of Tau albumen, and its inhibitory action shows concentration dependant.The advantage of the invention is that the affinity to Tau protein monomers and aggregation can be realized by the length of ether chain among adjusting, while the length of ether chain also has a significant impact to the rejection ability that Tau albumen is assembled.
Description
Technical field
The invention belongs to suppress albumen aggregation technique field, and in particular to one kind can specifically bind Alzheimer disease
In pathologic mark Tau albumen and can suppress its aggregation probe molecule.
Background technology
Alzheimer disease (Alzheimer ' s Disease, AD) is most commonly seen a kind of nerve degenerative diseases, sternly
The health of elderly population is endangered again, and brings heavy burden to social medical industry and patient home.Alzheimer disease has
Two important pathologic marks, one is senile plaque expelling that amyloid-beta (A β) is formed in nerve cell external sediment；Separately
One is the NFT for assembling to be formed in nerve cell by the Tau albumen of Hyperphosphorylationof.Research finds Tau eggs
There is more preferable correlation than A β between AD morbidities property in vain.Therefore, the fluorescent probe molecule of the Tau albumen of high specific is set
Meter also just becomes more and more urgent with exploitation.
Tau albumen is a kind of microtubule associated protein, is largely existed in nerve cell.Typically have on normal Tau albumen
The amino acid in two to three sites carries out phosphorylation.When Tau albumen occur Hyperphosphorylationof after, will the depolymerization from micro-pipe, solution
The very easy aggregation of Tau albumen for gathering the Hyperphosphorylationof to get off forms NFT (NFTs).Tau albumen is in intracerebral
Unusual aggregation be increasingly proved to AD morbidity play an important role.But up to the present, although there is some Tau albumen
PET probe molecules be reported, but the specificity of itself is not high, and can not all suppress its aggregation.Therefore, design synthesis energy
Enough targetings, which combine Tau albumen and can suppress its probe molecule assembled, turns into instantly very urgent demand.
The content of the invention
It is an object of the invention to provide a kind of synthetic method of new Tau albumen probe, the probe can be with specific knot
Close Tau albumen.
It is a further object of the present invention to provide a kind of method that can suppress the aggregation of Tau albumen, this inhibitory action is in
Reveal concentration dependant.
Targeted inhibition probe structure formula involved in the present invention is as follows：
R1 and R2 can be each independently selected from hydrogen atom, the alkyl or cycloalkyl below 6 carbon, the alkyl or ring of substitution
Alkyl；
Wherein R1 can be identical with R2, can also differ；
N is 1-6 half-integer or integer, specially 1,1.5,2,2.5, and so on to 6.
The specific building-up process of the targeted inhibition probe of Tau albumen is as follows：
Preparation process is as follows：
(1) prepare compound 2：
Weigh 1eq compound 1 and 2.5eq 2- chloroquinoline -6- alcohol be dissolved in 5.0mL drying N, N- dimethyl methyls
In acid amides, reaction, which is maintained at 70 DEG C, is reacted overnight, and after reaction terminates, reaction solution is extracted with the system of toluene-water, filter
Liquid is dried with magnesium sulfate, column chromatography for separation.
(2) prepare compound DT
Under nitrogen atmosphere, by compound 3, potassium carbonate, tetrakis triphenylphosphine palladium, the mixed solvent of dimethyl ether and water is added
In, first stirred under normal temperature 20 minutes, add compound 2, be heated to reflux, gained solid is first washed with deionized, Ran Houzai
Washed three times with cold absolute ethyl alcohol, column chromatography obtains final compound；
Whether we have combination with the Research on Methods of fluorescence spectrum between probe molecule DT and Tau albumen.If
Tau albumen can be combined, the fluorescence of probe molecule will strengthen, and if being not bound with, fluorescence intensity does not have too big substantially
Change.
We weigh whether compound can suppress Tau with the change of thioflavine-T (ThT) fluorescence intensity herein
The aggregation of albumen and corresponding inhibition level.ThT be it is a kind of be widely used can target the business with reference to Tau aggregations
Industry dyestuff, ThT can only combine the Tau albumen of aggregation, so as to produce fluorescence.If compound can suppress the aggregation of Tau albumen,
Then ThT fluorescence intensity can decrease compared to the fluorescence intensity of no addition compound, and rejection ability is stronger, then fluorescence is strong
Degree is lower.Experiment finds that as n=1, the toxicity of compound is relatively low, has good binding ability with Tau albumen, and has most strong
Rejection ability.
The cytotoxicity of probe is detected by MTT method, by the experiment of cytotoxicity, even if working as chemical combination
Thing at concentrations up to 100 μM, incubation time is 24 hours, the survival rate of cell also more than 90% (accompanying drawing 1), and and control group
Compared to there is no statistical significant difference relatively.This illustrates that the cytotoxicity of such probe is relatively low.
The involved compound of the present invention, it is expected to treat A Er by suppressing the aggregation of Tau albumen as one kind is new
The drug candidate of Ci Haimo diseases or be the fluorescence probe etc. for indicating Tau albumen.
Brief description of the drawings
Fig. 1 is influences of the DT1 and DT2 to HeLa ability of cell proliferation, incubation time 6 hours, 12 hours and 24 hours, is changed
0-100 μM of the concentration of compound.
Fig. 2 is that compound DT1 mixes front and rear change in fluorescence with Tau monomers and aggregation.
Fig. 3 is that compound DT2 mixes front and rear change in fluorescence with Tau monomers and aggregation.
Fig. 4 is Tau albumen when being 1 μM, and compound DT1 and DT2 tests to its inhibition.
Fig. 5 is Tau albumen when being 2 μM, and compound DT1 and DT2 tests to its inhibition.
Fig. 6 is Tau albumen when being 10 μM, and compound DT1 and DT2 tests to its inhibition.
Embodiment
We taken different length ether chain two compound DT1 (n=1) and DT2 (n=1.5) be case do it is detailed
Explanation.
Embodiment 1 (n=1)：
The preparation of compound 5：The bromo- 2- of 1- (2- bromines methoxyl group) ethane (37.0 μ L, 0.3mmol), 2- chloroquinoline -6- alcohol
(116mg, 0.65mmol) and potassium carbonate (96.7mg, 0.7mmol) are dissolved in DMF (2.5mL), are maintained at 70 DEG C of reaction 4h,
TLC tracking reactions, until reaction is complete.After reaction terminates, reaction solution is extracted with toluene-aqueous systems, and filtrate is dried with magnesium sulfate,
Be concentrated under reduced pressure, column chromatography for separation purification can be obtained by compound 10 (red solid, 95.8%；Ethyl acetate：Petroleum ether=1：
2)。
1H NMR(400MHz,CDCl3):δ=7.96-7.90 (m, 4H)；7.41(dd,J1=2.4Hz, J2=9.2Hz,
2H)；7.32 (d, J=8.4Hz, 2H)；7.07 (d, J=2.4Hz, 2H)；4.29 (t, J=4.4Hz, 4H)；4.04-4.02(m,
4H).
13C NMR:(125MHz,CDCl3), δ=157.2,148.2,143.8,137.6,130.0,127.8,123.2,
122.6,106.3,69.9,67.9.
HR-MS(ESI,m/z):calcd for C22H9N2O3Cl2[M+H]+,429.0773,found 429.0773.
Compound DT1 preparation：Compound 5 (123mg, 0,26 mmol), Pd are added into 50mL round-bottomed flask
(PPh3)4(30mg, 0.026mmol), 4- dimethylaminos phenyl boric acid (82,6mg, 0.5mmol), K2CO3(69.1g,0,
5mmol), under the atmosphere of nitrogen, solvent DME/H is added20(5mL/100μL).Reaction solution carried out at 100 DEG C reaction until
Reaction is complete.After reaction terminates, reaction solution is cooled to room temperature, pressure filtration, and gained solid is first washed with deionized, Ran Houzai
Washed three times with cold absolute ethyl alcohol.This solid is dried under reduced pressure to the target compound for just having obtained crude product.Then quick
(ethyl acetate on column chromatography：Petroleum ether=1：2) it is further proposed that final product DTI (bright yellow solid, 31%) can be obtained.
1H NMR(400MHz,CDCl3):δ=8.06-7,96 (m, 4H)；7.74 (d, J=4.4Hz, 2H)； 7.39-7.36
(m,2H)；7.07(s,2H)；6.83 (d, J=8.8Hz, 4H)；4.30 (t, J=4.4Hz, 4H)；4.04 (t, J=4.4Hz,
4H)；3.04(s,12H).
13C NMR:(125MHz,CDCl3), δ=156.1,151.1,135.2,130.8,128.1,127.4,125.0,
122.0,118.6,112.3,106.3,70.0,67.8,40.4.
HR-MS(ESI,m/z):calcd for C38H39N4O3[M+H]+,599.3022,found 599.3026.
Embodiment 2 (n=1.5)：
The preparation of compound 6：By 2- chloroquinoline -6- alcohol, ((253mg, 1.1mmol) is dissolved in dry THF, then to it
In sequentially add PPh3(393mg, 1.5mmol), triethylene glycol (68.3 μ L, 0.5mmol) and DIAD
(diisopropylazodicarboxylate, 294 μ L, 1.5mmol).It is anti-that reaction is kept at room temperature reaction 4h, TLC tracking
Should, until reaction is complete.Reaction terminate after, be concentrated under reduced pressure, column chromatography for separation purification can be obtained by compound 6 (red solid,
95.8%；Ethyl acetate：Dichloromethane=1：1).1H NMR (400MHz,CDCl3):δ=7.94-7,88 (m, 4H)；7.39
(dd,J1=2.8Hz, J2=9.2Hz, 2H)；7.30 (d, J=8.8Hz, 2H)；7.03 (s, d, J=2.8Hz, 2H)；4.21(t,
J=4.8Hz, 4H)； 3.94-3.92(s,4H)；3.79(s,4H).
Preparation of the compound without DT2：Compound 6 (255mg, 0,54 mmol), Pd are added into 50mL round-bottomed flask
(PPh3)4(116mg, 0.1mmol), 4- dimethylaminos phenyl boric acid (162.1mg, 1.62mmol), K2CO3(138.2g,
1.7mmol), under the atmosphere of nitrogen, solvent DME/H is added20(5mL/100μL).Reaction solution carries out reacting straight at 100 DEG C
It is complete to reaction.After reaction terminates, reaction solution is cooled to room temperature, pressure filtration, and gained solid is first washed with deionized, then
Washed three times with cold absolute ethyl alcohol again.This solid is dried under reduced pressure to the target compound for just having obtained crude product.Then fast
(ethyl acetate on fast column chromatography：Petroleum ether=1：2) it is further proposed that final product DT2 (bright yellow solid, 80%) can be obtained.
1H NMR(400MHz,CDCl3):δ=8.05-8.02 (m, 4H)；8.00 (d, J=9.2Hz, 2H)； 7.93(d,J
=8.4Hz, 2H)；7.71 (d, J=8.8Hz, 2H)；7.36(dd,J1=2.8Hz, J2=9.2Hz, 2H)；7.02 (d, J=
2.8Hz,2H)；6.82 (d, J=8.8Hz, 4H)；4.23 (t, J=4.8Hz, 4H)；4.94 (t, J=4.8Hz, 4H)；3.81
(s,4H)；3.03(s,12H).
13C NMR:(125MHz,CDCl3), δ=156.2,155.2,151.2,144.4,135.2,130.7,128.1,
127.4,122.1,118.5,112.3,106.2,70.9,69.8,67.7,40.4.
HR-MS(ESI,m/z):calcd for C40H43N4O4[M+H]+,643.3284,found 643.3281.
The compound DT1 being synthesized by case study on implementation can combine the aggregation of Tau albumen, but for Tau albumen
Monomer does not show affinity (accompanying drawing 2) then.And compound DT2 can then combine the monomer and aggregation (accompanying drawing of Tau albumen
3)
We employ three kinds of different concentration Tau albumen and made to study suppression of the two probe molecules to Tau albumen
With：1 μM, 2 μM and 10 μM.When Tau protein concentrations are at 1 μM, DT1 and DT2 can not suppress the aggregation (accompanying drawing of Tau albumen
4)；When Tau protein concentrations are 2 μM, DT1 shows the inhibitory action to Tau albumen, and DT2 is not shown to Tau then
The inhibitory action (accompanying drawing 5) of albumen；When Tau protein concentrations are 10 μM, DT1 and DT2 show the suppression to Tau albumen
Acting on (accompanying drawing 6), the fluorescence intensity containing DT1 is less than DT2, so, DT1 shows more preferable inhibitory action relative to DT2.
In summary, DT1 and DT2 shows concentration dependant to the inhibitory action of Tau albumen, when the concentration of Tau albumen is too low, two
Compound is not without all showing inhibitory action, and compound DT1 rejection ability is better than DT2.
The advantage of the invention is that it can be realized by the length of ether chain among adjusting to Tau protein monomers and aggregation
Affinity, and it was found that the probe of different length ether chain shows different affinity to the monomer and aggregation of Tau albumen,
The length of ether chain also has a significant impact to the rejection ability that Tau albumen is assembled simultaneously.
Above-described embodiment is the preference of the present invention, is not intended to limit the present invention, all within the principle of the present invention, institute
Any modification, change, accommodation or the alternative made, within protection scope of the present invention.
Claims (4)
1. a kind of molecule that can be specifically bound and the aggregation of Tau albumen can be suppressed, it is characterised in that structural formula is：
R1 and R2 can be each independently selected from hydrogen atom, the alkyl or cycloalkyl below 6 carbon, the alkyl or cycloalkanes of substitution
Base；
Wherein R1 can be identical with R2, can also differ；
Half-integer or the integer that n is 1~6, specially 1,1.5,2,2.5, and so on to 6.
2. a kind of preparation method for the molecule that can be specifically bound as claimed in claim 1 and the aggregation of Tau albumen can be suppressed,
Characterized in that, synthetic route and method are as follows：
3. a kind of application for the molecule that can be specifically bound as claimed in claim 1 and can suppress the aggregation of Tau albumen, it is special
Sign is, by adjusting the ether chain length among probe molecule, shows to the Bu Tong affine of Tau protein monomers and aggregation
Power, as n=1, the molecule can combine Tau albumen aggregation, but for Tau albumen monomer do not show then it is affine
Power；As n=1.5, then the monomer and aggregation of Tau albumen can be combined.
4. a kind of application for the molecule that can be specifically bound as claimed in claim 1 and can suppress the aggregation of Tau albumen, it is special
Sign is, adjusts the ether chain length among probe molecule, shows the different rejection abilities to the aggregation of Tau albumen.
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| WO2021105497A1 (en) * | 2019-11-29 | 2021-06-03 | University Of Copenhagen | Small-molecule nadph oxidase 2 inhibitors |
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| CN102438660A (en) * | 2009-03-23 | 2012-05-02 | 美国西门子医疗解决公司 | Imaging agents for detecting neurological disorders |
| EP2567954A1 (en) * | 2010-04-29 | 2013-03-13 | Universidad De Chile | Method for inhibiting tau protein aggregation and treatment of alzheimer's disease with a compound derived from quinoline |
| CN103380118A (en) * | 2010-10-29 | 2013-10-30 | 克林诺株式会社 | Tau imaging probe |
| CN105814023A (en) * | 2013-10-22 | 2016-07-27 | 克林诺株式会社 | Tau imaging probe |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2010011964A2 (en) * | 2008-07-24 | 2010-01-28 | Siemens Medical Solutions Usa, Inc. | Imaging agents useful for identifying ad pathology |
| CN102438660A (en) * | 2009-03-23 | 2012-05-02 | 美国西门子医疗解决公司 | Imaging agents for detecting neurological disorders |
| EP2567954A1 (en) * | 2010-04-29 | 2013-03-13 | Universidad De Chile | Method for inhibiting tau protein aggregation and treatment of alzheimer's disease with a compound derived from quinoline |
| CN103380118A (en) * | 2010-10-29 | 2013-10-30 | 克林诺株式会社 | Tau imaging probe |
| CN105814023A (en) * | 2013-10-22 | 2016-07-27 | 克林诺株式会社 | Tau imaging probe |
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| WO2021105497A1 (en) * | 2019-11-29 | 2021-06-03 | University Of Copenhagen | Small-molecule nadph oxidase 2 inhibitors |
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