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Protein degradation targeting chimeric body as well as preparation method and application thereof

A protein degradation and chimera technology, applied in the fields of drug combination, organic chemistry, anti-tumor drugs, etc., can solve problems such as the advent of protein degradation targeted chimeras

Active Publication Date: 2020-02-28
XIANGYA HOSPITAL CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, there is no protein degradation targeting chimera with CD147 protein as the linker part of the target protein containing a heterocyclic structure

Method used

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  • Protein degradation targeting chimeric body as well as preparation method and application thereof
  • Protein degradation targeting chimeric body as well as preparation method and application thereof
  • Protein degradation targeting chimeric body as well as preparation method and application thereof

Examples

Experimental program
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preparation example Construction

[0051] One embodiment of the present invention further provides a preparation method of the above protein degradation targeting chimera, and the preparation method includes the following steps S11-S14.

[0052] S11. Compound 1 is provided; wherein, compound 1 contains a heterocycle and at least two primary or secondary amine groups, and the heterocycle contains at least one N atom;

[0053] In one of the embodiments, the above compound 1 contains two secondary amine groups.

[0054] In one of the embodiments, the above-mentioned compound 1 contains a primary amino group and a secondary amino group.

[0055] In one embodiment, the aforementioned heterocycle is an aliphatic heterocycle.

[0056] In one of the embodiments, the above-mentioned heterocycle is a five-membered ring or a six-membered ring

[0057] In one embodiment, the above-mentioned compound 1 contains a heterocycle, and the heterocycle is a five-membered ring or a six-membered ring. Further, in one of the embodim...

Embodiment 1

[0124] The structural formula of protein degradation targeting chimera (c) is as follows:

[0125]

[0126] The synthesis steps are as follows:

[0127] (1) Weigh 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (55mg, 0.2mmol) and 4-Boc -Aminopiperidine (44mg, 0.22mmol), added into a reactor equipped with 2mL NMP, stirred and dissolved, then added 66uL N,N-diisopropylethylamine (DIEA) to the reactor, and heated to The reaction was carried out at 100°C for 4 hours. After cooling, the solvent was spin-dried to obtain a crude product. The crude product was subjected to column chromatography to obtain 78 mg of an intermediate with a yield of 86%. The structure of the intermediate is shown below.

[0128]

[0129] The characterization results of the intermediate are as follows:

[0130] 1 H NMR (500MHz, DMSO) δ: 11.10(s, 1H), 7.71-7.65(m, 1H), 7.33(d, J=7.9Hz, 2H), 6.92(d, J=7.7Hz, 1H), 5.09 (dd,J=12.8,5.5Hz,1H),3.68-3.60(m,2H),3.51-3.40(m,1H),2.98-2.83(m,3H),2...

Embodiment 2

[0136] The structural formula of the protein degradation targeting chimera (b) is as follows:

[0137]

[0138] The synthesis steps are basically the same as in Example 1, except that the 4-Boc-aminopiperidine in the step (1) of Example 1 is replaced with 1-Boc-4-aminopiperidine, and the structure of the obtained intermediate is as follows Show.

[0139]

[0140] The characterization results of the intermediate are as follows.

[0141] 1 H NMR (500MHz, DMSO) δ: 11.11(s, 1H), 7.60(dd, J=8.4, 7.2Hz, 1H), 7.22(d, J=8.7Hz, 1H), 7.06(d, J=7.0Hz ,1H),6.27(d,J=8.4Hz,1H),5.06(dd,J=12.8,5.4Hz,1H),3.97-3.85(m,2H),3.79-3.72(m,1H),3.02- 2.81(m,3H),2.62-2.46(m,4H),2.06-1.99(m,1H),1.95-1.88(m,2H),1.41(s,9H).

[0142] HRMS(ESI)m / z:calcd for C 23 h 28 N 4 NaO 6 (M+Na) + 479.1901,found 479.1904.

[0143] The characterization results of the protein degradation targeting chimera (b) are as follows.

[0144] 1 H NMR (500MHz, DMSO) δ: 8.31(s, 1H), 7.57-7.49(m, 1H), 7.24-7.20(m, 1...

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Abstract

The present invention relates to a protein degradation targeting chimeric body, a preparation method and application thereof, the protein degradation targeting chimeric body has a structure represented by the formula shown in the specification, the protein degradation targeting chimeric body is a heterocyclic ring-containing linking group, and the heterocyclic ring contains at least one N atom. The protein degradation targeting chimeric body connects a Pseudolaric Acid B part which can be specifically combined with a target CD147 protein and a thalidomide part which can be combined with E3 ubiquitin ligase; the protein degradation targeting chimeric body is capable of simultaneously acting on a target protein and the E3 ubiquitin ligase; activated ubiquitin is transferred to the target protein, selective ubiquitination of the target protein is achieved, finally, the ubiquitinated target protein is recognized and degraded by proteasome, and the protein degradation targeting chimeric body has very high application value in preparation of drugs for treating or preventing cancer, especially in preparation of anti-tumor drugs with the 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] Protein degradation targeting chimeras (PROTACs) are a class of compounds that can lead to the degradation of target proteins by inducing polyubiquitination of target proteins. They mainly include three parts: Ligand 1, Ligand 2 and the intermediate linker . [0003] The linker organically connects the ligand 1 acting on the target protein and the ligand 2 acting on the E3 ubiquitin ligase. When the protein degradation targeting chimera acts on the target protein, it can form the target protein-PROTACs-E3 ubiquitinase The ternary complex transfers the activated ubiquitin to the target protein to achieve its selective ubiquitination, and finally the ubiquitinated target protein is recognized and degraded by the proteasome, thereby achieving tar...

Claims

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Application Information

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IPC IPC(8): C07D405/14A61P35/00
CPCA61P35/00C07D405/14Y02P20/55
Inventor 龙菁陈翔彭聪周哲唱祺胡高云李乾斌胡维稳邓广通李雅芸王媛
Owner XIANGYA HOSPITAL CENT SOUTH UNIV
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