Molecule specifically bind to Tau protein and capable of inhibiting Tau protein aggregation, preparation method and application thereof

A technology for protein aggregation and specificity, applied in chemical instruments and methods, analytical materials, drug combinations, etc., can solve problems such as low specificity and inability to inhibit aggregation

Active Publication Date: 2017-12-19
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But so far, although some PET probe molecules of Tau protein have been reported, their specificity is not high, and none of them can inhibit its aggregation.

Method used

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  • Molecule specifically bind to Tau protein and capable of inhibiting Tau protein aggregation, preparation method and application thereof
  • Molecule specifically bind to Tau protein and capable of inhibiting Tau protein aggregation, preparation method and application thereof
  • Molecule specifically bind to Tau protein and capable of inhibiting Tau protein aggregation, preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1 (n=1):

[0031] Preparation of compound 5: 1-bromo-2-(2-bromomethoxy)ethane (37.0 μL, 0.3 mmol), 2-chloroquinolin-6-ol (116 mg, 0.65 mmol) and potassium carbonate (96.7 mg, 0.7 mmol) was dissolved in DMF (2.5 mL), kept at 70° C. for 4 h, followed by TLC until the reaction was complete. After the reaction, the reaction liquid was extracted with toluene-water system, the filtrate was dried with magnesium sulfate, concentrated under reduced pressure, separated and purified by column chromatography to obtain compound 10 (red solid, 95.8%; ethyl acetate:petroleum ether=1:2 ).

[0032] 1 H NMR (400MHz, CDCl 3 ): δ=7.96-7.90 (m, 4H); 7.41 (dd, J 1 =2.4Hz,J 2 =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 ).

[0033] 13 C NMR: (125MHz, CDCl 3 ), δ=157.2, 148.2, 143.8, 137.6, 130.0, 127.8, 123.2, 122.6, 106.3, 69.9, 67.9.

[0034] HR-MS(ESI,m / z):calcd for C 22 h 9 N 2 o 3 Cl 2 [M+H] + ,429.0773,found 42...

Embodiment 2

[0039] Embodiment 2 (n=1.5):

[0040] Preparation of compound 6: 2-chloroquinolin-6-alcohol ((253mg, 1.1mmol) was dissolved in dry THF, and then PPh was added successively thereto 3(393mg, 1.5mmol), triethylene glycol (68.3μL, 0.5mmol) and DIAD (diisopropylazodicarboxylate, 294μL, 1.5mmol). The reaction was kept at room temperature for 4 h, followed by TLC until the reaction was complete. After the reaction, concentrated under reduced pressure, separated and purified by column chromatography to obtain compound 6 (red solid, 95.8%; ethyl acetate:dichloromethane=1:1). 1 H NMR (400MHz, CDCl 3 ):δ=7.94-7,88(m,4H); 7.39(dd,J 1 =2.8Hz,J 2 =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).

[0041] Preparation of compound without DT2: Add compound 6 (255 mg, 0,54 mmol), Pd(PPh 3 ) 4 (116mg, 0.1mmol), 4-dimethylaminophenylboronic acid (162.1mg, 1.62mmol), K 2 CO 3 (138.2g, 1.7mmol), under nitrogen atmosphere, add s...

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Abstract

The invention belongs to the technical field of protein aggregation inhibition, and concretely relates to a probe molecule specifically bind to a pathological marker Tau protein in Alzheimer disease and capable of inhibiting Tau protein aggregation. The probe molecule specifically binds to the Tau protein and is capable of inhibiting Tau protein aggregation, and the inhibition effect presents concentration dependence. The probe molecule has the advantages that by adjusting length of intermediate ether chain, affinity to a Tau protein monomer and aggregation is realized, and the probe molecule has great influence on the inhibition capability of the Tau protein aggregation by the length of the ether chain.

Description

technical field [0001] The invention belongs to the technical field of inhibiting protein aggregation, and specifically relates to a probe molecule that can specifically bind to the pathological marker Tau protein in Alzheimer's disease and inhibit its aggregation. Background technique [0002] Alzheimer's disease (Alzheimer's Disease, AD) is the most common type of neurodegenerative disease, which seriously endangers the health of the elderly and brings a heavy burden to social medical services and patients' families. There are two important pathological markers of Alzheimer's disease, one is senile plaques formed by the deposition of β-amyloid protein (Aβ) outside nerve cells; the other is formed by the accumulation of hyperphosphorylated Tau protein in nerve cells of neurofibrillary tangles. Studies have found that Tau protein has a better correlation with AD pathogenesis than Aβ. Therefore, the design and development of fluorescent probe molecules with high specificity...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/20C09K11/06G01N21/64A61P25/28
CPCC07D215/20C09K11/06C09K2211/1029G01N21/6486
Inventor 易涛吕光磊魏鹏李若涵
Owner FUDAN UNIV
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