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Induction of mdm2 self-degradation E3 ubiquitin ligase dimer amide-like small molecule protacs

An enzyme dimer amide, MDM2 technology, applied in the field of tumor prevention and treatment drugs, to achieve the best anti-tumor effect

Active Publication Date: 2020-04-03
SHAOXING UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The first purpose of the present invention is to provide a kind of small molecule PROTACs that can induce MDM2 to self-degrade E3 ubiquitin ligase dimer amides, so as to solve the shortcomings of existing compounds

Method used

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  • Induction of mdm2 self-degradation E3 ubiquitin ligase dimer amide-like small molecule protacs
  • Induction of mdm2 self-degradation E3 ubiquitin ligase dimer amide-like small molecule protacs
  • Induction of mdm2 self-degradation E3 ubiquitin ligase dimer amide-like small molecule protacs

Examples

Experimental program
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Effect test

preparation example Construction

[0092] The preparation method of PROTACs of any structure as above comprises the following steps:

[0093] (a) piperazin-2-one is substituted after group protection, and then deprotected to obtain

[0094] 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;

[0095] Then, the group-protected product was combined with BrCH 2 COOR 14 Reaction to replace the amino group at position 1;

[0096] Then, deprotection is carried out, and the protecting group is removed to obtain compound (i);

[0097] 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.

[0098] (b) Substitution of 2,4-dihydroxybenzaldehyde to give

[0099] In this step, the target product i...

Embodiment 1

[0133] Taking the preparation of 15a and 15b whose products are symmetrical structures as an example, the preparation method of PROTACs of the present invention is introduced as follows:

[0134] Synthesis of tert-butyl 3-oxopiperazine-1-carboxylate (1)

[0135] 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, the reaction was left overnight at room temperature. After the reaction, wash with 0.1N dilute hydrochloric acid three times, 20 ml each time, and wash with saturated potassium carbonate three times, 20 ml each time. Finally anhydrous sodium sulfate was added and the solution was removed in vacuo to give a white solid.

[0136] Product melting point: 161-162°C, 1 H NMR (400MHz, CDCl 3 ) δ 7.66 (s, 1H), 4.07 (s, 2H), 3.62 (t, J=5.3Hz, 2H), 3.37 (s, 2H), 1.47 (s, 9H).

[0137] Synthesis of tert-butyl 4-(2-methoxy-2-oxoethyl)-3-oxopiperazine-1-carboxylate (2)

[0138] In a 500mL three-necked fl...

experiment example 1

[0170] In order to test the effect of the compounds of the present invention, the inventors conducted experimental tests on the effects of compounds 15a and 15b in A549 cells.

[0171] The specific experimental method is as follows: A549 cells were treated with 5 μM or 20 μM compound 15a and 15b for 12 hours; meanwhile, a sample without compound was prepared as a negative control.

[0172] After treatment, cells were lysed and subjected to immunoblot analysis to monitor changes in the levels of endogenous MDM2 and p53.

[0173] The results of the WesternBolt experiment are as follows: image 3 shown by image 3 The experimental results showed that after the intervention of compounds 15a and 15b at a concentration of 5 μM for 12 hours in A549 cells, the p53 protein began to be up-regulated and MDM2 began to be weakened, and after the concentration of 20 μM for 12 hours, the p53 protein was significantly up-regulated and the MDM2 protein was significantly weakened.

[0174] At...

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Abstract

The invention provides dimer amide 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 without a 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 tumor prevention and treatment drugs, in particular to inducing MDM2 self-degradation E3 ubiquitin ligase dimer amide small molecule PROTACs. Background technique [0002] Malignant tumors are one of the major high-incidence diseases that seriously threaten human health. The outline of my country's science and technology development plan has listed the basic and applied research of malignant tumors as a key scientific issue of public health and important disease prevention and control. Therefore, the research of new anti-tumor drugs is not only a compelling need for clinical tumor treatment and improving the health of our people, but also has great significance for the development of my country's pharmaceutical industry and society. [0003] 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 tr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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