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Alpha-synuclein targeting compound as well as preparation method and application thereof

A technology of synuclein and compound, which is applied to α-synuclein targeting compound and preparation method and application field thereof, can solve the problem of inability to directly degrade α-synuclein, etc. Apply foreground, lower level effect

Active Publication Date: 2022-06-03
SUN YAT SEN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved by the present invention is to overcome the defects and deficiencies that existing drugs targeting α-synuclein cannot directly degrade α-synuclein, and provide a class of α-synuclein-directly clearing α-synuclein Synuclein Targeting Compounds

Method used

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  • Alpha-synuclein targeting compound as well as preparation method and application thereof
  • Alpha-synuclein targeting compound as well as preparation method and application thereof
  • Alpha-synuclein targeting compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1 Synthesis and structure confirmation of APD-A series compounds

[0042] The synthetic route and condition of described APD-A series compound are as follows:

[0043]

[0044] (a) NaOH, Ba(OH) 2 ·8H 2 O, MeOH, RT, 24h; (b) H 2 O 2 , NaOH, MeOH, 0°C to RT, 24h; (c) NH 2 NH 2 ·H 2 O, p-TsOH, toluene, 90℃, 4h; (d) DHP, p-TsOH, THF, flux, 24h; (e) H 2 , Pd / C, RT, 24h; (f) (Boc 2 )O, Et 3 N, MeOH, flux, 3h; (g) p-TsCl, DMAP, DCM, RT, 1h+1h; (h) (Boc 2 )O, NaOH, H 2 O / acetone, RT, 24h; (i) DIEA, DMF, 90°C, 24h; (j) TFA, DCM, RT, 2h; (k) EDC·HCl, HOBT, DIEA, DMF, RT, 24h.

[0045] Specific methods and structure confirmation:

[0046] General method one (deprotection):

[0047] Dissolve about 1 mmol of the reactant in 10 mL of a mixed solvent of dichloromethane / trifluoroacetic acid (1:1), and react at room temperature for 2 h under vigorous stirring; after the reaction is completed, remove the solvent under reduced pressure for several times, and dry in...

Embodiment 2

[0089] Example 2 Synthesis and structure confirmation of APD-B series compounds

[0090] The synthetic route and condition of described APD-B series compound:

[0091]

[0092] (a) DIEA, DMF, 90℃, 24h; (b) TFA, DCM, RT, 2h; (c) EDC·HCl, HOBT, DIEA, DMF, RT, 24h.

[0093] Specific synthesis method and structure confirmation:

[0094] Synthesis of compound 18:

[0095] Dissolve 0.5 mmol of compound 7 (182 mg) and 1 mmol of N,N-diisopropylethylamine (164 μL) in 5 mL of N,N-dimethylformamide, then add 0.5 mmol of tert-butyl bromoacetate (compound 16, 75 μL ), reacted at room temperature or heated to 90 °C for 24 h; after the reaction was completed, cooled to room temperature, diluted with water, extracted with ethyl acetate, combined the organic phases, washed with water and brine respectively, and dried with anhydrous magnesium sulfate, the obtained crude product was subjected to flash column Purified by chromatography (petroleum ether / ethyl acetate, 2:1), and dried in vacu...

Embodiment 3

[0109] Example 3 Synthesis and structure confirmation of APD-C series compounds

[0110] The synthetic route and condition of described APD-C series compound:

[0111]

[0112] (a) CBr 4 , PPh 3 , DCM, 0°C to RT, 12h; (b) DIEA, DMF, 90°C, 24h; (c) TFA, DCM, RT, 2h; (d) EDC·HCl, HOBT, DIEA, DMF, RT, 24h.

[0113] Specific preparation method and structure confirmation:

[0114] Synthesis of compound 24a:

[0115] Dissolve 1 mmol of carboxyl tripolyethylene glycol tert-butyl ester (compound 23a, 234 mg) in 10 mL of dichloromethane, cool to 0 °C, and then add 1 mmol of carbon tetrabromide (331 mg) and 1 mmol of triphenylphosphine in portions under stirring (262mg), reacted at room temperature for 12h; after the reaction was completed, the solvent was removed under reduced pressure, resuspended with water, extracted with ethyl acetate, the organic phases were combined, washed with water and brine respectively, and dried with anhydrous magnesium sulfate. Purification by flas...

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Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to an alpha-synuclein targeting compound as well as a preparation method and application thereof. The compound simultaneously contains an alpha-synuclein ligand, a connexon and an E3 ligase ligand structural fragment, and can recruit E3 ligase in cells to carry out ubiquitination modification on alpha-synuclein, so that chemical induced degradation of the alpha-synuclein is realized by virtue of UPS (Uninterrupted Power Supply); and tests prove that the compounds can achieve the effects of remarkably reducing the intracellular alpha-synuclein aggregate level and improving the cell viability by targeting alpha-synuclein and inducing ubiquitination of the alpha-synuclein, and have better application prospects in the field of treatment of alpha-synuclein related diseases.

Description

technical field [0001] The invention belongs to the technical field of biomedicine. More specifically, it relates to a class of α-synuclein targeting compounds and preparation methods and applications thereof. Background technique [0002] Studies have found that α-synuclein (α-Synuclein) plays a central role in the occurrence and development of a series of neurodegenerative diseases, including but not limited to Parkinson's disease (PD) , dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), which are collectively referred to as synucleopathies. The imbalance of intracellular protein homeostasis in patients with these diseases, excessive aggregation of α-synuclein, the formation of characteristic Lewy bodies, and then the death of dopaminergic neurons. Therefore, drug regulation of intracellular α-synuclein levels will become an effective and novel strategy in the treatment of these diseases. [0003] For example, Chinese patent application CN110891565A dis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14C07D401/14C07K5/062A61K31/454A61K38/05A61P25/16A61P25/28A61P25/00
CPCC07D405/14C07D401/14C07K5/06034A61P25/16A61P25/28A61P25/00A61K38/00Y02P20/55
Inventor 庞冀燕佟奕辰林焕怀
Owner SUN YAT SEN UNIV
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