Proteolytic targeting chimera, and preparation method and application thereof

A technology of protein degradation and chimera, which is applied in the direction of drug combination, pharmaceutical formula, medical preparations containing active ingredients, etc., can solve the problem that there is no small molecule protein degradation targeting chimera, etc.

Active Publication Date: 2020-01-03
XIANGYA HOSPITAL CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, there is no small molecule protein

Method used

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  • Proteolytic targeting chimera, and preparation method and application thereof
  • Proteolytic targeting chimera, and preparation method and application thereof
  • Proteolytic targeting chimera, and preparation method and application thereof

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Experimental program
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preparation example Construction

[0069] The preparation method of the above-mentioned protein degradation targeting chimera is as follows.

[0070] The first case: (1) when the linking group of the protein degradation targeting chimera is (a), and n 1 When =1, the preparation method of the above-mentioned protein degradation targeting chimera includes the following steps S11-S12.

[0071] S11. Substitution reaction between apeticoacetic acid (PAB) and chloromethyl chlorosulfonate to obtain compound 1.

[0072] Wherein, the structure of compound 1 is as follows:

[0073]

[0074] Further, in step S11, the substitution reaction is carried out under the action of a phase transfer catalyst and a base.

[0075] Wherein, the phase transfer catalyst is preferably a quaternary ammonium salt phase transfer catalyst, and the base is an inorganic base.

[0076] In one of the embodiments, in step S11, the phase transfer catalyst is Bu 4 N + HSO 4 - , the inorganic base is K 2 CO 3 .

[0077] The reaction is ...

Embodiment 1

[0152] The structural formula of protein degradation targeting chimera 1 is as follows:

[0153]

[0154] The synthesis steps are as follows:

[0155] (1) Weigh 22mg Bu 4 N + HSO 4 - (0.06mmol), 468mg K 2 CO 3 (3.38mmol) was added to a 50mL three-necked bottle, and dissolved in 10mL of water; weighed 212mg of Vitex acetic acid (0.49mmol), and 135mg of chloromethyl chlorosulfonate (0.82mmol) were dissolved in 10mL of DCM, and the DCM solution Slowly added to the reaction flask within 10 minutes, and reacted at room temperature for 10h. TLC monitored that the PAB reaction was complete. After stopping the reaction, 15 mL of water was added, and then extracted with dichloromethane (DCM). The combined organic layers were dried over anhydrous magnesium sulfate, filtered with suction, and rotary evaporated to obtain 288 mg of a crude light yellow intermediate.

[0156] (2) Weigh 76 mg of the crude intermediate (0.16 mmol) obtained in step (1), 121 mg of 2-(2,6-dioxo-piperid...

Embodiment 2

[0161] The structural formula of protein degradation targeting chimera 2 is as follows:

[0162]

[0163] (1) Weigh 110mg 2-(2,6-dioxo-piperidin-3-yl)-4-hydroxy-isoindole-1,3-dione (0.4mmol), 167mg 3-bromopropanol (1.2mmol), 60mg NaI (0.4mmol), 168mg sodium bicarbonate (0.8mmol), put into a 10mL eggplant-shaped bottle, add 1mL DMF to dissolve, react under argon at 70°C for 24h, and remove most of the DMF by rotary evaporation. Add 5mL of water, then extract with ethyl acetate, the ethyl acetate layer is light green, combine the ethyl acetate layers and extract with sodium carbonate aqueous solution until the solution is colorless, then wash with saturated saline until the solution is neutral, anhydrous sodium sulfate Drying, suction filtration, rotary evaporation, and recrystallization gave 109 mg of the intermediate.

[0164] The intermediate structure is as follows:

[0165]

[0166] The characterization results of the intermediate are as follows:

[0167] 1 H NMR(50...

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Abstract

The invention relates to a proteolytic targeting chimera, and a preparation method and application thereof. The structure of the proteolytic targeting chimera is as in the description, wherein L is aconnecting group containing at least one heteroatom of N and O, and can be used to connect a pseudolaric acid part capable of being specifically combined with a target CD147 protein and a thalidomidepart capable of being connected with E3 ubiquitin ligase. Through simultaneous action on the target protein and the E3 ubiquitin ligase, activated ubiquitin is transferred to the target protein, so that selective ubiquitination on the target protein is realized, and finally the ubiquitinated target protein is recognized and degraded by a proteasome. The preparation method of the compound is simpleand is easy to realize, and the proteolytic targeting chimera can obviously reduce the level of the CD147 protein, and has high application value in preparation of medicaments for treating or preventing cancers, in particular in preparation of antitumor medicaments taking CD147 as a target point.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a protein degradation targeting chimera and its preparation method and application. Background technique [0002] CD147 protein is a single transmembrane glycoprotein with a relative molecular weight of 50-60kDa, and is a member of the immunoglobulin superfamily; it is highly expressed on various tumor cells and participates in tumor cell proliferation, invasion, metastasis, metabolism, Differentiation, anti-apoptosis and other important biological functions are effective drug targets. [0003] The ubiquitin-proteasome system is the main pathway of intracellular protein degradation, and participates in the degradation of more than 80% of intracellular proteins. The ubiquitin-proteasome system is a multi-step reaction process involving many different proteins. First, ubiquitin (polypeptide) is activated by ubiquitin activating enzyme E1 and passed to ubiq...

Claims

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Application Information

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IPC IPC(8): C07D405/14A61P35/04A61P35/00A61K31/454
CPCA61P35/00A61P35/04C07D405/14
Inventor 龙菁陈翔彭聪周哲王媛李乾斌胡高云唱祺
Owner XIANGYA HOSPITAL CENT SOUTH UNIV
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