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PLK1 inhibitor, and preparation method and application thereof

A cutting agent and condensation reaction technology, which is applied in the direction of pharmaceutical formulations, medical preparations containing active ingredients, organic active ingredients, etc., can solve the problem of difficulty in penetrating cell membranes, decreased binding force, and transmembrane transport of oligonucleotides and small RNA molecules Difficult to solve and other problems, to achieve the effect of overcoming the problem of drug resistance

Active Publication Date: 2017-06-20
SHENZHEN INST OF ADVANCED TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, antisense oligonucleotides are easily hydrolyzed by nucleases and have a short effective time; small molecule RNA interference technology also has safety and stability issues
In addition, oligonucleotides and small molecule RNAs are difficult to penetrate the cell membrane, and the problem of transmembrane transport has been difficult to solve
However, the small-molecule kinase inhibitors that are currently successfully marketed for tumor therapy all have a common weakness—drug resistance
Since tumor cells can quickly mutate during treatment, the binding ability of kinases to small molecule inhibitors is reduced, making them insensitive to small molecule inhibitors, resulting in drug resistance. Chemical small molecule inhibition of PLK1 Drugs have the same problem of drug resistance

Method used

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  • PLK1 inhibitor, and preparation method and application thereof
  • PLK1 inhibitor, and preparation method and application thereof
  • PLK1 inhibitor, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] Example 1 Preparation of Compound 1

[0095] (a) Resin swelling: Add 400mg Fmoc protected phenylhydrazine resin (0.66mmol / g, 0.264mmol) and 3mL CH to a 10mL solid phase reactor 2 Cl 2 , Swell the resin for 30 minutes, and remove CH 2 Cl 2 ,spare;

[0096] (b) Removal of Fmoc protecting group: Add 3 mL of 20% piperidine / DMF solution to the swelled resin in step (a), N 2 Mix well by bubbling. After 10 minutes, remove the solvent and add 3 mL of 20% piperidine / DMF solution, N 2 Mix well by bubbling. After 10 minutes, wash the resin with DMF (4×3mL), and then wash the resin with 3mL of anhydrous DMF for later use;

[0097] (c) Amino acid condensation: 4-tert-butoxycarbonylamino-1-methyl-1H-pyrrole-2-carboxylic acid (254mg, 1.056mmol) and triphosgene (BTC, 128mg, 0.433mmol) were dissolved in 2mL of anhydrous THF, slowly dropwise add collidine (collidine, 488μL, 3.696mmol) to the solution, the reaction immediately produces a large amount of white precipitate, after adding the reacti...

Embodiment 2

[0113] Example 2 Preparation of Compound 2

[0114] The peptide of formula (5) supported on phenylhydrazine resin was prepared according to the same steps of Example 1, and the step (b) in Example 1 was used to remove the peptide of formula (5) supported on phenylhydrazine resin. Fmoc protecting group in the above peptide;

[0115] The Hester acid derivative Ht-1 (539 mg, 1.056 mmol) and PyBOP (550 mg, 1.056 mmol) were dissolved in 3 mL of anhydrous DMF, DIEA (350 μL, 2.112 mmol) was added, and the reaction was carried out for 5 min. The reaction solution was transferred to the In addition to Fmoc, the peptide represented by formula (5) supported on phenylhydrazine resin, N 2 Bubbling and mixing, condensation reaction for 1h, aspirate the reaction liquid, wash the resin with DMF (4×3mL); take out the resin, add 1mL DMF, 200μL dimethylaminopropylamine and 10mg Cu(OAc) 2 , Shake the reaction at room temperature for 12h, filter out the resin, and use 20mL CH 2 Cl 2 Wash the resin; con...

Embodiment 3

[0119] Example 3 Preparation of Compound 3

[0120] The peptide of formula (5) supported on phenylhydrazine resin was prepared according to the same steps of Example 1, and the step (b) in Example 1 was used to remove the peptide of formula (5) supported on phenylhydrazine resin. Fmoc protecting group in the above peptide;

[0121] Will Boc 2 O (243 μL, 1.056 mmol) was dissolved in 3 mL anhydrous DMF, DIEA (350 μL, 2.112 mmol) was added, and the reaction solution was transferred to the Fmoc-removed peptide represented by formula (5) supported on phenylhydrazine resin, N 2 Bubbling and mixing, condensation reaction for 20min. The reaction solution was removed, and the resin was washed with DMF (4×3 mL) to obtain the Boc-protected peptide represented by formula (6) supported on the phenylhydrazine resin;

[0122]

[0123] Take out the resin obtained above, add 1mL DMF, 200μL N,N-bis(3-aminopropyl)methylamine, shake the reaction at 90℃ for 1h, cool to room temperature, filter out the ...

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PUM

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Abstract

The invention provides a PLK1 inhibitor, and a preparation method and an application thereof. The PLK1 inhibitor is a compound represented by general formula (I) shown in the description, and stereoisomers or pharmaceutically acceptable salts thereof. All groups in the formula (I) are defined as in the description. The PLK1 inhibitor can specifically bind to a DNA sequence in a PLK1 gene transcription promoter region, represented by SEQ: NO:1, in a high strength manner, inhibits transcription of the PLK1 gene, inhibits the expression of a PLK1 protein, causes tumor cell growth inhibition or apoptosis, can traverse through a cell membrane and a nuclear membrane and resist nuclease hydrolysis, and also solves the drug resistance problem of micro-molecular kinases inhibitors.

Description

Technical field [0001] The invention relates to a PLK1 inhibitor and a preparation method and application thereof, and belongs to the field of medicinal chemistry. Background technique [0002] PLK1 is a member of the Polo-like kinase family and a highly conserved serine / threonine protein kinase. It participates in centrosome maturation, spindle formation and chromosome separation during cell division, and plays an important role in the regulation of cell mitosis. effect. Studies have found that PLK1 is abnormally highly expressed in various malignant tumors such as lung cancer, breast cancer, and gastric cancer. Its overexpression is also one of the signs of poor prognosis of tumors, but its expression level in normal cells is very low, and sometimes even impossible to detect. Therefore, PLK1 is a target of widespread attention in tumor diagnosis and treatment. [0003] The application of antisense technology, small molecule RNA interference technology or small molecule inhibito...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14A61K31/4178A61K31/497A61K31/4184A61P35/00
CPCC07D403/14A61K31/4178A61K31/4184A61K31/497Y02P20/55
Inventor 粟武李红昌房丽晶刘科张建超潘正银
Owner SHENZHEN INST OF ADVANCED TECH
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