Dimer ester micromolecule PROTACs for inducing MDM2 to self-degrade E3 ubiquitin ligase

A technology of enzyme dimer and MDM2, applied in the direction of organic active ingredients, medical preparations containing active ingredients, organic chemistry, etc., to achieve the best anti-tumor effect

Active Publication Date: 2018-10-02
SHAOXING UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The first purpose of the present invention is to provide a small molecule PROTACs that induces MDM

Method used

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  • Dimer ester micromolecule PROTACs for inducing MDM2 to self-degrade E3 ubiquitin ligase
  • Dimer ester micromolecule PROTACs for inducing MDM2 to self-degrade E3 ubiquitin ligase
  • Dimer ester micromolecule PROTACs for inducing MDM2 to self-degrade E3 ubiquitin ligase

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0096] The preparation method of PROTACs of any structure as above comprises the following steps:

[0097] (a) piperazin-2-one is substituted after group protection, and then deprotected to obtain

[0098] In this step, the imino group at the 4-position of the raw material piperazin-2-one is first protected, and common protecting agents such as Cbz, Boc, Fmoc, Alloc, Teoc, or Tos and TMB can be used for group protection;

[0099] Then, the group-protected product was combined with BrCH 2 COOR 14 Reaction to replace the amino group at position 1;

[0100] Then, deprotection is carried out, and the protecting group is removed to obtain compound (i);

[0101] In step (a), R 14 C1-C6 straight chain or branched chain alkyl with or without substituents, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, Isopentyl, neopentyl, or hexyl, etc.

[0102] (b) Substitution of 2,4-dihydroxybenzaldehyde to give

[0103] In this step, the target product i...

Embodiment 1

[0135] Taking the preparation of 15 with a symmetrical structure as an example, the preparation method of PROTACs of the present invention is introduced as follows:

[0136] Synthesis of tert-butyl 3-oxopiperazine-1-carboxylate (1)

[0137] Piperazin-2-one (1.0 g, 10 mmol) was suspended in 10 mL of DCM, Boc was added slowly 2 O. After the addition was complete, it was left overnight at room temperature. After the reaction, wash three times with 0.1N dilute hydrochloric acid, 20ml each time, and wash three times with saturated potassium carbonate 20ml each time. Finally the dichloromethane was dried over anhydrous sodium sulfate and the solution was removed in vacuo to give a white solid.

[0138] Product melting point: 161-162°C, 1 H NMR (400MHz, CDCl 3 )δ7.66(s,1H),4.07(s,2H),3.62(t,J=5.3Hz,2H),3.37(s,2H),1.47(s,9H).

[0139] Synthesis of tert-butyl 4-(2-methoxy-2-oxoethyl)-3-oxopiperazine-1-carboxylate (2)

[0140] In a 500 mL three-necked flask, 12.70 g (63.0 mmol, 1...

experiment example 1

[0171] In order to test the effect of the compound of the present invention, the inventors conducted experimental tests on the effect of compound 15a in A549 cells.

[0172] The specific experimental method is as follows: A549 cells were treated with 20 μM compound 15a for 12 hours; at the same time, a sample without compound was prepared as a negative control.

[0173] After treatment, cells were lysed and subjected to immunoblot analysis to monitor changes in the levels of endogenous MDM2 and p53.

[0174] The results of the WesternBolt experiment are as follows: image 3 shown, by image 3 The experimental results showed that after the compound 15a was intervened in A549 cells at a concentration of 5 μM for 12 hours, the p53 protein began to be up-regulated and MDM2 began to be weakened. After the compound 15a was intervened at a concentration of 20 μM for 12 hours, the p53 protein was significantly up-regulated and the MDM2 protein was significantly weakened.

[0175]At ...

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Abstract

The invention provides dimer ester micromolecule PROTACs for inducing MDM2 to self-degrade E3 ubiquitin ligase. The structure of the PROTACs is shown in the specification, wherein in a compound (I), L1 is C1-C30 linear or branched alkyl with or without a substituent group, and any carbon atom in L1 is optionally replaced by heteroatom; R1, R2, R3 and R4 are C1-C30 linear or branched alkyl with orwithout a substituent group, C1-C30 aryl with or a without substituent group, C1-C30 linear or branched alkylaryl with or without a substituent group or C1-C30 linear or branched aryl alkyl with or without a substituent group respectively and independently; X1, X2, X3 and X4 are halogen respectively and independently.

Description

technical field [0001] The invention relates to the field of anticancer drugs, in particular to inducing MDM2 to self-degrade E3 ubiquitin ligase dimer ester small molecule PROTACs. Background technique [0002] As a disease with high morbidity and mortality worldwide, tumor seriously threatens human health and has become one of the important social problems faced by countries all over the world. Among many tumor-related gene networks, the p53 gene is the tumor suppressor gene with the highest correlation with human malignant tumors. It plays an important role in DNA transcription, cell growth and proliferation, and many metabolic processes. It can effectively inhibit tissue proliferation, promote Apoptosis has the function of maintaining genome stability, inhibiting or preventing cell transformation, thereby inhibiting the occurrence and development of malignant tumors. The p53 gene is regulated by many downstream factors, among which MDM2 protein plays the most important ...

Claims

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Application Information

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IPC IPC(8): C07D403/14A61K31/496A61P35/00
CPCA61P35/00C07D403/14
Inventor 胡纯琦李歆施亚茹杜文婷童洁苏婉婷夏玮琪
Owner SHAOXING UNIVERSITY
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