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Hydroxamic acid compound and application thereof

A compound and application technology, applied in the field of medicinal chemistry, can solve the problems of normal tissue cell toxicity and side effects, easy drug resistance, lack of HDAC subtype selectivity, etc., achieve good anticancer activity, high yield, and easy post-processing Effect

Active Publication Date: 2022-04-12
SOUTHERN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Although a large number of HDAC inhibitors are currently on the market or have entered the clinical research stage, these drugs lack the subtype selectivity of HDAC, resulting in a relatively high toxicity to normal tissue cells while producing good anticancer activity. Side effects and susceptibility to drug resistance

Method used

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  • Hydroxamic acid compound and application thereof
  • Hydroxamic acid compound and application thereof
  • Hydroxamic acid compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0062] Preparation of intermediates

[0063] Intermediate: Preparation of methyl 2-(2,4-dimethoxyphenyl)thiazole-5-carboxylate

[0064] Dissolve 0.2g of 2-bromo-5-carboxylate thiazole in 10mL of toluene, add 0.2g of 2,4-dimethoxyphenylboronic acid, then add 0.11g of tetrakistriphenylphosphine palladium and 0.5g of potassium phosphate, in React at 90°C for 10 hours under a nitrogen atmosphere. After the reaction is complete as monitored by thin-layer chromatography, the reaction solution is extracted with ethyl acetate (20mL×3), allowed to stand for liquid separation, and the organic phase is washed with saturated brine (5mL×3) , then dried with anhydrous sodium sulfate, suction filtered, and removed ethyl acetate under reduced pressure to obtain a white solid, which was subjected to column chromatography with petroleum ether: ethyl acetate to obtain 0.218 g of white solid powder with a yield of 86%. The white solid powder obtained by column chromatography was identified by th...

Embodiment 3

[0091] Example 3 In vitro antitumor activity research

[0092] The in vitro antitumor activity of the compound of the present invention is proved by the following method test. These effects suggest that the compounds of the present invention are useful in the treatment of cancer. The specific test method is as follows:

[0093] 2-(2,4-dimethoxyphenyl)-N-(7-(hydroxylamino)-7-oxoheptyl)thiazole-5-carboxamide prepared by MTT method detection embodiment 1 and implementation In vitro antitumor activity of 2-(2,4-dimethoxyphenyl)-N-(7-(hydroxyamino)-7-oxoheptyl)imidazole-5-carboxamide prepared in Example 2. Tumor cell lines were purchased from ATCC in the United States, and the standard MTT method was used to determine the effect of the test compound on human colorectal cancer cell line HCT-116, human non-small cell lung cancer cell A549, human breast cancer cell MCF-7, melanoma cell B16-F10 and The anti-proliferation activity of gastric cancer cell line YCC resistant to HDAC inh...

Embodiment 4

[0098] Example 4 Research on Inhibition of HDAC in Vitro

[0099] The in vitro antitumor activity of the compounds VIII and IX of the present invention is demonstrated by the following method. These effects indicate that compounds VIII, IX of the present invention can be used to effectively inhibit HDAC6. The specific test method is as follows:

[0100] The enzyme inhibitory activity of compounds VIII and IX was determined by fluorescence analysis, wherein HDAC1 (#ab101661) and HDAC6 (#ab42632) enzymes were purchased from Abcam, HDAC3 (#BML-SE515-0050) was purchased from Enzo, HDAC8 (# H90-30H-05) was purchased from SignalChem. The buffer contains 25mmol / L Tris (pH 8.0), 1mmol / L MgCl 2, 0.1mg / mL BSA, 137mmol / L NaCl, 2.7mmol / L KCl, of which HDAC (HDAC1, 7.2ng / well; HDAC3, 3.4ng / well; HDAC6, 15ng / well; HDAC8, 22ng / well), total volume 40 μL. The compound to be tested (10 dilution concentrations, followed by 500μM, 125μM, 31.25μM, 7.81μM, 1.95μM, 0.49μM, 0.12μM, 0.03μM, 7.6nM...

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Abstract

The invention relates to the field of medical chemistry, in particular to a hydroxamic acid compound containing substituted 2-phenylthiazole-5-formamide or 2-phenylimidazole-5-formamide and application of the hydroxamic acid compound, the compound has a structure as shown in a formula (I), can selectively act on HDAC6, inhibit cancer cell proliferation and enhance tumor immunity, and can be used for preparing an HDAC6 drug or an HDAC6 drug or an HDAC6 drug or an HDAC6 drug or an HDAC6 drug or an HDAC6 drug or an HDAC6 drug. The compound has efficient anti-cancer activity. Therefore, the compound can be used for preparing histone deacetylase inhibitors and drugs for treating and / or preventing cancers.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a hydroxamic acid compound and its application. Background technique [0002] Malignant tumors are a highly complex disease that seriously threatens human life and health, second only to cardiovascular and cerebrovascular diseases. Effective treatment of malignant tumors is still the focus of medicinal chemists. In recent years, a large number of studies have shown that the regulation imbalance of histone deacetylase (HDAC) can lead to the occurrence of tumors, so this target is considered to be an effective target for the treatment of tumors. The HDAC family mainly has four categories and 11 subtypes, and different subtypes have different biological significance. HDAC6 is an important subtype of HDAC, inhibition of HDAC6 has greater toxicity to tumor cells, but less toxicity to normal tissues. At the same time, HDAC6 can effectively promote tumor immunity and inc...

Claims

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Application Information

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IPC IPC(8): C07D277/30C07D233/90A61K31/426A61K31/4164A61K31/277A61P35/00
Inventor 陈建军彭孝鹏李玲陈镜玄
Owner SOUTHERN MEDICAL UNIVERSITY
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