CN107488144B - Molecule capable of specifically binding and inhibiting Tau protein aggregation and preparation method and application thereof - Google Patents
Molecule capable of specifically binding and inhibiting Tau protein aggregation and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of inhibiting protein aggregation, and particularly relates to a probe molecule capable of specifically binding to a pathological marker Tau protein in Alzheimer's disease and inhibiting aggregation of the pathological marker Tau protein. The probe molecules can specifically bind to Tau protein and can inhibit the aggregation of Tau protein, and the inhibition effect of the probe molecules is concentration-dependent. The method has the advantages that the affinity to Tau protein monomers and aggregates can be realized by adjusting the length of the intermediate ether chain, and the length of the ether chain also has great influence on the inhibition capability of Tau protein aggregation.
Description
Technical Field
The invention belongs to the technical field of inhibiting protein aggregation, and particularly relates to a probe molecule capable of specifically binding to a pathological marker Tau protein in Alzheimer disease and inhibiting aggregation of the pathological marker Tau protein.
Background
Alzheimer's Disease (AD) is the most common neurodegenerative Disease, seriously harms the health of the elderly, and places a heavy burden on the social medical industry and the patient's home. There are two important pathological markers of alzheimer's disease, one is senile plaque formed by deposition of beta-amyloid (a β) outside nerve cells; the other is the neurofibrillary tangles formed by the aggregation of hyperphosphorylated Tau protein in nerve cells. The research finds that the Tau protein has better correlation with the pathogenesis of AD than A beta. Therefore, the design and development of highly specific fluorescent probe molecules for Tau protein are becoming more and more urgent.
Tau protein is a microtubule-associated protein and is present in large amounts in nerve cells. The normal Tau protein is generally phosphorylated at two to three amino acids. When Tau protein is hyperphosphorylated, it is depolymerized from microtubules, and the depolymerized hyperphosphorylated Tau protein is very likely to aggregate to form neurofibrillary tangles (NFTs). The abnormal aggregation of Tau protein in the brain is increasingly being demonstrated to play an important role in the pathogenesis of AD. However, although some PET probe molecules for Tau protein have been reported so far, their specificity is not high and their aggregation cannot be inhibited. Therefore, the design and synthesis of probe molecules capable of targeting and binding to Tau protein and inhibiting its aggregation is an urgent need.
Disclosure of Invention
The invention aims to provide a method for synthesizing a novel Tau protein probe, which can be specifically combined with Tau protein.
Another object of the present invention is to provide a method for inhibiting Tau protein aggregation, which exhibits concentration dependence.
The structural formula of the targeted inhibition probe is as follows:
r1 and R2 may each be independently selected from a hydrogen atom, an alkyl or cycloalkyl group of 6 carbons or less, a substituted alkyl or cycloalkyl group;
wherein R1 may be the same as or different from R2;
n is a half-integer or integer from 1 to 6, specifically 1, 1.5, 2, 2.5, and so on to 6.
The specific synthesis process of the targeted inhibition probe of Tau protein is as follows:
the preparation process comprises the following steps:
(1) preparation of compound 2:
weighing 1eq of compound 1 and 2.5eq of 2-chloroquinolin-6-ol, dissolving in 5.0mL of dry N, N-dimethylformamide, reacting at 70 ℃ overnight, after the reaction is finished, extracting the reaction solution with a toluene-water system, drying the filtrate with magnesium sulfate, and separating by column chromatography.
(2) Preparation of Compound DT
Adding a compound 3, potassium carbonate and tetrakis (triphenylphosphine) palladium into a mixed solvent of dimethyl ether and water under the nitrogen atmosphere, stirring for 20 minutes at normal temperature, adding a compound 2, heating and refluxing, washing the obtained solid with deionized water, then washing with cold absolute ethyl alcohol for three times, and carrying out column chromatography to obtain a final compound;
we explore whether there is binding between the probe molecule DT and Tau protein by fluorescence spectroscopy. If the Tau protein can be bound, the fluorescence of the probe molecule is enhanced, and if not bound, the fluorescence intensity does not change substantially.
Here we use the change in the fluorescence intensity of thioflavin-T (ThT) to determine whether a compound inhibits Tau protein aggregation and the corresponding degree of inhibition. ThT is a widely used commercial dye that can target Tau aggregates, and only binds aggregated Tau proteins, thereby producing fluorescence. If the compound can inhibit the aggregation of Tau protein, the fluorescence intensity of ThT will be reduced compared to that without the compound added, and the stronger the inhibition, the lower the fluorescence intensity. Experiments show that when n ═ 1, the compound has low toxicity, good binding capacity with Tau protein and strongest inhibition capacity.
The cytotoxicity of the probe was measured by the MTT method, and it was found from the cytotoxicity test that the survival rate of the cells was more than 90% even when the concentration of the compound was as high as 100 μ M and the incubation time was 24 hours (fig. 1), and there was no statistically significant difference compared with the control group. This indicates that the cytotoxicity of this type of probe is low.
The compound of the invention is expected to be a novel candidate drug for treating Alzheimer disease by inhibiting Tau protein aggregation, a fluorescent probe indicating Tau protein and the like.
Drawings
FIG. 1 shows the effect of DT1 and DT2 on the proliferation capacity of HeLa cells at concentrations of 0-100. mu.M for 6 hours, 12 hours and 24 hours.
FIG. 2 shows the change in fluorescence before and after mixing of compound DT1 with Tau monomers and aggregates.
FIG. 3 shows the change in fluorescence before and after mixing of compound DT2 with Tau monomers and aggregates.
FIG. 4 shows the inhibition of Tau protein by compounds DT1 and DT2 at 1. mu.M.
FIG. 5 shows the inhibition of Tau protein by compounds DT1 and DT2 at 2. mu.M.
FIG. 6 shows the inhibition of Tau protein by compounds DT1 and DT2 at 10. mu.M.
Detailed Description
We take two compounds DT1(n ═ 1) and DT2(n ═ 1.5) of different length ether chains as examples for detailed description.
Example 1(n ═ 1):
preparation of compound 5: 1-bromo-2- (2-bromomethoxy) ethane (37.0. mu.L, 0.3mmol), 2-chloroquinolin-6-ol (116mg,0.65mmol) and potassium carbonate (96.7mg, 0.7mmol) were dissolved in DMF (2.5mL) and kept at 70 ℃ for 4h and the reaction was followed by TLC until complete. After the reaction, the reaction mixture was extracted with toluene-water system, the filtrate was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 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.
Preparation of compound DT 1: to a 50mL round bottom flask was added compound 5(123mg,0,26 mmol), Pd (PPh)3)4(30mg,0.026mmol) 4-Dimethylaminophenylboronic acid (82,6mg,0.5mmol), K2CO3(69.1g,0,5mmol) solvent DME/H was added under nitrogen atmosphere20(5 mL/100. mu.L). The reaction solution was reacted at 100 ℃ until the reaction was complete. After the reaction is finished, the reaction liquid is cooled to room temperature, pressure filtration is carried out, and the obtained solid is washed by deionized water firstly and then washed by cold absolute ethyl alcohol for three times. The solid was dried under reduced pressure to obtain the crude target compound. Further extraction on flash column chromatography (ethyl acetate: petroleum ether ═ 1: 2) afforded the final product, DTI (bright yellow solid, 31%).
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.
Example 2(n ═ 1.5):
preparation of compound 6: 2-chloroquinolin-6-ol ((253mg,1.1mmol) was dissolved in dry THF, to which PPh was then added successively3(393mg,1.5mmol), triethylene glycol (68.3. mu.L, 0.5mmol) and DIAD (diisopyrophyllodicarbylate, 294. mu.L, 1.5 mmol). The reaction was kept at room temperature for 4h and followed by TLC until the reaction was complete. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and purified by column chromatography to obtain compound 6 (red solid, 95.8%; ethyl acetate: dichloromethane: 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 compound without DT 2: to a 50mL round bottom flask was added compound 6(255mg,0,54 mmol), Pd (PPh)3)4(116mg,0.1mmol), 4-Dimethylaminophenylboronic acid (162.1mg,1.62mmol), K2CO3(138.2g,1.7mmol) solvent DME/H was added under nitrogen atmosphere20(5 mL/100. mu.L). The reaction solution was reacted at 100 ℃ until the reaction was complete. After the reaction is finished, the reaction liquid is cooled to room temperature, pressure filtration is carried out, and the obtained solid is washed by deionized water firstly and then washed by cold absolute ethyl alcohol for three times. The solid was dried under reduced pressure to obtain the crude target compound. Further extraction on flash column chromatography (ethyl acetate: petroleum ether ═ 1: 2) afforded the final product DT2 (bright yellow solid, 80%).
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.
Compound DT1 synthesized by the examples can bind to aggregates of Tau protein, but shows no affinity for monomers of Tau protein (fig. 2). While DT2 can bind to monomers and aggregates of Tau protein (FIG. 3)
We used three different concentrations of Tau protein to study the inhibitory effect of these two probe molecules on Tau protein: 1. mu.M, 2. mu.M and 10. mu.M. Neither DT1 nor DT2 inhibited Tau protein aggregation at Tau protein concentrations of 1. mu.M (FIG. 4); DT1 showed inhibition of Tau protein at Tau protein concentration of 2. mu.M, whereas DT2 showed no inhibition of Tau protein (FIG. 5); both DT1 and DT2 showed inhibition of Tau protein at Tau protein concentration of 10 μ M (fig. 6), and the fluorescence intensity with DT1 was lower than DT2, so DT1 showed better inhibition than DT 2. In conclusion, the inhibitory effect of DT1 and DT2 on Tau protein showed concentration dependence, and when the concentration of Tau protein was too low, neither compound showed inhibitory effect, and compound DT1 had stronger inhibitory ability than DT 2.
The invention has the advantages that the affinity to Tau protein monomers and aggregates can be realized by adjusting the length of the middle ether chain, and the probes with different length ether chains are found to present different affinities to the Tau protein monomers and aggregates, and meanwhile, the length of the ether chain also has great influence on the inhibition capability of Tau protein aggregation.
The above-mentioned embodiments are preferred examples of the present invention, and are not intended to limit the present invention, and any modification, change, alteration or substitution made within the principle of the present invention is within the protection scope of the present invention.
Claims (4)
1. A molecule that specifically binds and inhibits Tau protein aggregation, characterized by the structural formula:
r1 and R2 may each be independently selected from a hydrogen atom, an alkyl group of 6 carbons or less, or a cycloalkyl group; wherein R1 may be the same as or different from R2.
2. A method for preparing the molecule according to claim 1, wherein the synthesis route and method are as follows:
wherein the content of the first and second substances,
compound 1 is
Compound 2 is
DT of
R1 and R2 may each be independently selected from a hydrogen atom, an alkyl group of 6 carbons or less, or a cycloalkyl group; wherein R1 may be the same as or different from R2.
3. Use of the molecule according to claim 1, wherein the compound ether chain is selected from the group consisting of
The molecule may bind to aggregates of Tau protein, but does not show affinity for monomers of Tau protein; when the compound ether chain is
When this occurs, monomers and aggregates of the Tau protein can be bound.
4. Use of the molecule of claim 1 which specifically binds to and inhibits Tau protein aggregation for the preparation of a small molecule inhibitor for inhibiting Tau protein aggregation when the compound ether chain is
When this molecule is boundAggregates of Tau-containing proteins, but no affinity for monomers of Tau proteins; when the compound ether chain is
When this occurs, monomers and aggregates of the Tau protein can be bound.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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