Hydroxamic acid compound, and preparation method and application thereof

A compound, hydroxamic technology, applied in the field of hydroxamic acid, can solve the problems of toxic reaction, HDACs subtype selectivity, poor bioavailability, etc., to achieve mild reaction conditions, affect cell cycle arrest, and few steps Effect

Inactive Publication Date: 2013-06-19
GUANGDONG PHARMA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The more successful representative of this type of HDACi, SAHA, was approved by the US FDA in October 2006 as the first HDACi for the treatment of metastatic cutaneous T-cell lymphoma. However, in recent studies, it

Method used

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  • Hydroxamic acid compound, and preparation method and application thereof
  • Hydroxamic acid compound, and preparation method and application thereof
  • Hydroxamic acid compound, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1 Preparation of N-(2,5-dimethoxyphenyl)-N′-hydroxysuberamide (abbreviation: N25)

[0061] The reaction scheme is as follows:

[0062]

[0063] S1. Weigh 3.158g (20mmol) of 2,5-dimethoxyaniline and 9.031g (20mmol) of Carter’s condensing agent BOP into a 250ml round bottom flask, add 130ml of anhydrous dichloromethane, stir and mix, and then Add 3.670ml (20mmol) of monomethyl suberate and 12.440ml (70.67mmol) of DIEA, mix well, put it at room temperature, and stir it with magnetic force. The reaction time is 24h, and TLC detection is carried out during the period. The developer is ethyl acetate : Petroleum ether=1:2. Remove the solvent by rotary evaporation, use 100-200 mesh silica gel column for chromatography, and carry out separation and purification on the silica gel column. Reobtain 2.124g brown oil, productive rate: 32.88%;

[0064] S2. Weigh NH 2 OH·HCl 3.712g was dissolved in 20mL methanol, NaOH 5.261g was dissolved in methanol, and the two were mi...

Embodiment 2

[0067] Example 2 Preparation of N-(2-phenoxyphenyl)-N'-hydroxysuberamide

[0068] The reaction scheme is as follows:

[0069]

[0070] S1. Weigh 0.561g (3mmol) of 2-phenoxyaniline and 0.576g (3mmol) of Carter’s condensing agent BOP into a 50ml round bottom flask, add 20ml of anhydrous dichloromethane, stir and mix well, then add octane Acid monomethyl ester 0.550ml (3mmol), DIEA 1.865ml (10.6mmol), after mixing, put it at room temperature, stir with a magnetic force, the reaction time is 24h, TLC detection is carried out during this period, the developer is ethyl acetate: petroleum ether =1:2. The solvent was removed by rotary evaporation, and the silica gel column used for chromatography of 100-200 mesh was used for separation and purification of the silica gel column. The eluent was ethyl acetate:petroleum ether=1:20, and a yellow-brown oily solution was obtained. Weighed to obtain 0.689g, yield: 64.69%.

[0071] S2. Weigh NH 2 1.095 g of OH·HCl was dissolved in 20 mL...

Embodiment 3

[0073] Example 3 Anti-proliferation effect of N25 on tumor cells

[0074] Three glioma cell lines: U251, U87, T98G and three other lung cancer cell lines: H460, A549, H1299 were selected, and the anti-proliferation experiments were conducted on the cells by CCK-8 method. Cells in good growth state were inoculated in 96-well plates at a cell density of 10 4 Each well, N25 and the control drug SAHA were pre-acted on the same cell, and each concentration of each drug was set to 3 replicate holes. After the cells adhered to the wall, the drug treatment was performed. : 0.5umol / L, 1.0umol / L, 2.0umol / L, 4.0umol / L, 8.0umol / L, 16.0umol / L, 32.0umol / L, after administration for 48 hours, add 10ul CCK-8 solution to each well , shake well, put into the cell incubator and incubate for 1 h, and measure the absorbance value at 450nm on a microplate reader. The results are shown in Table 1 and Table 2.

[0075] The results showed that the sensitivity of N25 to different tumor cell lines was...

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Abstract

The invention relates to the application areas of organic chemistry, pharmaceutical chemistry and medicine, and particularly discloses hydroxamic acid. The hydroxamic acid compound has a structure shown in Formula I, wherein R is selected from a substituted benzene ring, a heterocyclic ring, a substituted heterocyclic ring, a benzoheterocyclic ring or a substituted benzoheterocyclic ring, wherein the substitution refers to that 1-n hydrogen atoms on the benzene ring, heterocyclic ring or benzoheterocyclic ring are substituted by the following groups: halogen, amino, hydroxy, nitro, cyano, alkoxy, aminoalkyl, alkylamino, sulfoalkyl, perfluoroalkyl, perfluoroalkoxy, amido or alkoxycarbonyl. According to the invention, the hydroxamic acid compound achieves the purpose of treating neoplastic diseases by regulating histone deacetylase; the hydroxamic acid compound has anti-proliferation effect on tumor cells, influences cell cycle arrest and induces cell apoptosis; and above all, the anti-proliferation effect on lung cancer cell strains is obviously improved in comparison with the effect of a positive control drug SAHA (suberoylanilide hydroxamic acid).

Description

technical field [0001] The present invention relates to the field of organic chemistry, medicinal chemistry and medical application, more specifically, relates to a kind of isohydroxy [0002] Oxymesic acid compounds and their preparation methods and applications. Background technique [0003] In recent years, histone deacetylase inhibitors (histone deacetylase inhibitors, HDACi) have become one of the research hotspots of anti-tumor drugs. Currently, HDACi mainly include hydroxamic acids, cyclic tetrapeptides, short-chain fatty acids, benzamides, electrophilic ketones, and trithiocarbonic acids. Among them, the hydroxamic acid HDACi is the earliest discovered and the most extensively studied so far. It has strong enzyme inhibitory effect, simple structure and easy synthesis. Understanding the structure-activity relationship of hydroxamic acids is the key to design SAHA derivatives. The structure of this type of HDACi is mostly composed of ring, aliphatic chain and hydrox...

Claims

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Application Information

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IPC IPC(8): C07C259/06C07D239/42C07D235/30C07D213/75C07D217/02C07D215/40C07D215/38A61K31/472A61K31/4706A61K31/47A61K31/167A61K31/44A61K31/4184A61K31/505A61P35/00A61P11/00
Inventor 冯冰虹吴丽叶连宝张菘
Owner GUANGDONG PHARMA UNIV
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