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Hydroxyproline peptoid derivative and preparation method and application thereof

A peptide derivative, hydroxyproline technology, used in drug combination, organic chemistry, anti-tumor drugs, etc., can solve problems such as adverse reactions and drug resistance, and achieve improved affinity, improved inhibitory activity, and good spatial matching. Effect

Inactive Publication Date: 2019-05-24
XIAN CENT HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Small molecule tyrosine kinase inhibitors targeting Bcr-Abl are currently on the market, but there are problems such as drug resistance and other clinical adverse reactions.

Method used

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  • Hydroxyproline peptoid derivative and preparation method and application thereof
  • Hydroxyproline peptoid derivative and preparation method and application thereof
  • Hydroxyproline peptoid derivative and preparation method and application thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0035] see figure 1 , as the preparation method of the hydroxyproline peptide derivatives of the above structure, comprising the following steps:

[0036] 1) 5-bromo-2-aminopyridine is acylated with an acid chloride compound to prepare acylated 5-bromo-2-aminopyridine;

[0037] 2)N 2 Under protection, 5-bromo-nicotinic acid reacts with thionyl chloride and amine compounds to prepare ammoniated 5-bromo-nicotinic acid;

[0038]3) Under the catalysis of tetrakistriphenylphosphine palladium, acylated 5-bromo-2-aminopyridine or ammoniated 5-bromonicotinic acid undergoes Suzuki coupling reaction with m-carboxyphenylboronic acid to obtain biphenyl compounds;

[0039] 4) Condensation of Boc-protected hydroxyproline with 3-trifluoromethyl-4-chloroaniline to generate tert-butyl-(2R,4S)-2-((4-chloro-3-(trifluoromethyl)benzene Base) carbamoyl)-4-hydroxypyrrolidinyl-1-carboxylate;

[0040] 5) tert-butyl-(2R,4S)-2-((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)-4-hydroxypyrrolidinyl-1-c...

Embodiment 1

[0055] A hydroxyproline peptide derivative, characterized in that R is , the preparation method is as follows:

[0056] 1) Synthesis of N-(5-bromopyridin-2-yl)acetamide: 5-bromo-2-aminopyridine (5.19 g, 30 mmol) was dissolved in 100 ml of anhydrous dichloromethane, and 20 ml of triethylamine was added. Under the condition of ice bath, acetyl chloride (2.54ml) was slowly added dropwise to the above solution. After the dropwise addition was completed, the ice bath was removed, and the mixture was raised to room temperature to react overnight. After the reaction was finished, dichloromethane was added for dilution, washed with water (30ml×3), saturated NaHCO 3 Solution washing (30ml×3), saturated NaCl washing (30ml), organic phase anhydrous NaCl 2 SO 4 dry. Column chromatography separated 5.65 g of white solid with a yield of 88%. Mp 78-81℃; EI-MS(m / z):214[M] + .

[0057] 2) Synthesis of 4-(6-(acetylamino)pyridin-3-yl)benzoic acid: N-(5-bromopyridin-2-yl)acetamide (4.30g,...

Embodiment 2

[0064] A hydroxyproline peptide derivative, characterized in that R is , the preparation method is as follows:

[0065] 1) Synthesis of 5-bromo-N-cyclopropyl nicotinamide: in N 2 Under protection, add thionyl chloride (36ml, 494mmol) dropwise to 5-bromonicotinic acid (5.00g, 24.7mmol). After the dropwise addition, heat to reflux for 2-3h until the solution is clear, and spin off the chloride under reduced pressure. Sulfoxide, a light yellow solid was obtained. The solid was dissolved in 30ml of anhydrous dichloromethane, and the reactive intermediate solution was slowly added dropwise to a solution of cyclopropylamine (3.77ml) in dichloromethane (30ml) in an ice bath. After the dropwise addition, it was raised to room temperature and reacted overnight. After the reaction, add 2mol / L K to the reaction system 2 CO 3 Solution 20ml. Separate the liquid to take the dichloromethane phase, extract the aqueous phase with dichloromethane (15ml × 3), combine the organic phases, a...

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Abstract

Disclosed are a hydroxyproline peptoid derivative and a preparation method and application thereof. With biphenyl pyridine as a hinge region binding fragment, by adopting a design strategy of a fragment drug and introducing L-hydroxyproline as a flexible Linker, a peptoid micromolecule-like compound library with kinase inhibition activity is constructed, and through screening of ADP-Glo and otheractivity tests, a peptoid tyrosine-like kinase inhibitor which has Bcr-Abl kinase inhibition activity and prevents the proliferation of tumor cells is found. The compound can be used for preparing anti-tumor drugs and has the activity of inhibiting Bcr-Abl and Bcr-AblT315I kinases and activity of inhibiting the cell proliferation of K562 cells. By introducing the L-hydroxyproline, the structural diversity of the Bcr-Abl inhibitor is expanded, the activity result shows that the introduction of proline has a certain effect on the inhibition activity of the compound, and the proline can serve asa novel pharmacological-effect fragment of the Bcr-Abl tyrosine kinase inhibitor.

Description

technical field [0001] The present invention relates to a kind of hydroxyproline peptide derivative and its preparation method and application Background technique [0002] Chronic myeloid leukemia (CML) is a malignant clonal proliferative disease that occurs in bone marrow hematopoietic stem cells, accounting for 15% to 20% of adult leukemia patients. It is characterized by the detection of Ph chromosomes in CML patients. The Ph chromosome is a breakpoint aggregation cluster-Alberson (BCR-ABL) fusion gene formed by the reciprocal translocation of normal chromosome 22 and chromosome 9 in the human body. This fusion gene encodes Bcr that produces continuous activation of tyrosine kinase activity -Abl fusion protein. Small molecule tyrosine kinase inhibitors targeting Bcr-Abl are currently on the market, but they all have problems such as drug resistance and other clinical adverse reactions. Subsequently, the research and development of novel Bcr-Abl tyrosine kinase inhibito...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61P35/00A61P35/02
Inventor 张杰潘晓艳梁丽媛卢闻王嗣岑贺浪冲司茹王瑾
Owner XIAN CENT HOSPITAL
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