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miRNA biosynthesis inhibitor

A compound, -COOR9 technology, applied in the field of chemical medicine, can solve the problems of drug clinical development failure, high cost, unclear understanding of protein signaling network, etc.

Active Publication Date: 2019-05-28
CHENGDU INST OF BIOLOGY CHINESE ACAD OF S
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although our country regards the research and development of anticancer drugs as a priority project, the current research on anticancer drugs mainly has the following two difficulties: First, there are too few drug targets: the targets of more than 2,000 clinically marketed drugs are only About 300, mainly distributed in seven types of gene families such as hormone receptors and GPCRs
The second is that the understanding of the occurrence of the disease and the protein signaling network is not clear, which leads to the failure of the clinical development of the drug and the high cost
[0004] However, the inhibitory effect of miRNA inhibitors currently available is far from meeting clinical requirements.

Method used

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Embodiment 1, the synthesis of compound of the present invention

[0062]

[0063] Ethyl 2-(4-methoxyphenyl)-4-methylthiazole-5-carboxylate (T2): Add 4-methoxybenzamide (152.2mg, 1mmol) in a 25mL round bottom flask, Lawson's reagent (485.4mg, 1.2 mmol) and THF (20 mL). After reacting for 4 hours at room temperature, Lawson's reagent and solvent were removed, and the intermediate thiobenzamide was separated and purified by column chromatography, and then mixed with ethyl 3-bromo-2-oxobutanoate (209 mg, 1 mmol) in ethanol (10 mL) was used as a solvent, refluxed at 70°C for 4 h under reaction conditions, after the reaction was completed, the solvent was removed, and compound T2 was obtained by separation and purification by column chromatography. Yield 92%, white solid, developing system PE / EA 10:1 (Rf=0.5, PE / EA=3:1), 1 H NMR (400MHz, CDCl 3 )7.91(d, J=8.8Hz, 2H), 6.96(d, J=8.8Hz, 2H), 4.37(q, J=7.1Hz, 2H), 3.86(s, 3H), 2.76(s, 3H) ,1.68(s,1H),1.40(t,J=7.1Hz,3H); ...

experiment example 1

[0238] Experimental Example 1. Analysis of the Inhibitory Activity of Compounds on miRNA-21

[0239] 1. Experimental method:

[0240] (1) Experimental materials and instruments

[0241] a. Main reagents: DMEM / high glucose medium, PBS buffer, EDTA-0.25% trypsin, penicillin streptomycin (double antibody), BIOMYC-3Antibiotic Solution, etc. were purchased from Hyclone Company; fetal bovine serum was purchased from Gibco Company; Coenzyme A sodium salt hydrate and D-Luciferin sodium salt were purchased from Sigma; DMSO and G418 were purchased from Amresco.

[0242] b. Main instrument: CO 2 Constant temperature cell incubator, ultra-clean workbench, full-wavelength scanning multi-function reader, cell operation table, optical inverted microscope, pressure steam sterilizer, micro centrifuge, electronic constant temperature water bath, horizontal shaker, etc.

[0243] (2) Establishment of cell model

[0244] Construction of a cell screening model for small molecule inhibitors of m...

experiment example 2

[0259] Experimental example 2. Affinity analysis of compound docking with TRBP-related binding protein in the process of miRNA biosynthesis 1. Experimental method:

[0260] In our previous study, we combined 7 reported TRBP-related binding proteins in miRNA biosynthesis (from the PDB database, 4 from mammalian and 2 from Drosophila genes and 1 from plant) Molecular docking was carried out with compound 3b, and it was found that only two protein crystal models from mammals (4WYQ: Dicer-TRBP and 3LLH: TRBP (dsRBD2)) could form an active pocket with 3b.

[0261] TRBP acts as a Dicer partner in animal cells. TRBP can affect the malignant metastasis of cancer cells by affecting the miRNA maturation mediated by Dicer and Ago2. TRBP has been proved to be indispensable in the process of RNA interference (RNAi); TRBP and Dicer Or Ago2 interacts and combines with dsRNA to form a RISC complex (RNA induced silencing complex) to perform gene silencing function, which can process pre-miRNA ...

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Abstract

The invention provides a compound shown as a formula I, or a conformational isomer thereof, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The compound can be tightly combined with related binding proteins in an miRNA biosynthesis process and can effectively inhibit the synthesis of miRNA-21. The prepared active compound provided by the invention can be used as an miRNA-21 inhibitor, and further as a potential drug for treating malignant tumors. The formula I is shown in the description.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and in particular relates to an inhibitor of miRNA biosynthesis. Background technique [0002] Cancer has become the first cause of death in Chinese cities and the second cause of death in rural areas. Although our country regards the research and development of anticancer drugs as a priority project, the current research on anticancer drugs mainly has the following two difficulties: First, there are too few drug targets: the targets of more than 2,000 clinically marketed drugs are only There are about 300 genes, mainly distributed in seven types of gene families such as hormone receptors and GPCRs. The second is that the understanding of the occurrence of the disease and the protein signaling network is not clear, which leads to the failure of the clinical development of the drug and the high cost. [0003] miRNA has important functions in the body, and abnormal expression of miRNA can lead to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/34C07D277/56A61P35/00
Inventor 王飞卢晓霞张国林王涛彭婷
Owner CHENGDU INST OF BIOLOGY CHINESE ACAD OF S
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