Synthesis and application of HDAC6 inhibitor based on hydroxamic acid

A technology of inhibitors and uses, applied in the field of medicinal chemistry, can solve the problems of lack of HDAC subtype selectivity, adverse reactions, etc., and achieve the effects of good anti-cancer activity, simple post-processing, and good economy.

Pending Publication Date: 2022-07-01
佛山市晨康生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] So far, 5 HDAC inhibitors have been approved for marketing. Due to the lack of HDAC subtype selectivity of these drugs, there are many adverse reactions in the course of cancer treatment.

Method used

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  • Synthesis and application of HDAC6 inhibitor based on hydroxamic acid
  • Synthesis and application of HDAC6 inhibitor based on hydroxamic acid
  • Synthesis and application of HDAC6 inhibitor based on hydroxamic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1 synthetic method:

[0054]

[0055] Preparation of intermediates

[0056] Intermediate: Preparation of (E)-2-(1-(2-phenylhydrazinoethylidene)aniline (3)

[0057] 2-Aminoethanone (0.5 mmol), phenylhydrazine (0.5 mmol) and p-toluenesulfonic acid (0.05 mmol) were refluxed in 2 ml of ethanol at 80 degrees for 8 hours. The reactant was dried under reduced pressure and washed with n-hexane to obtain the product (E)-2-(1-(2-phenylhydrazinoethylidene)aniline, yield: 82%.

[0058] Intermediate: Preparation of 2-(1H-indol-2-yl)aniline (4)

[0059] 1ml of Eaton's reagent was stirred and heated at 80 degrees in the flask, when the temperature was constant, reactant 3 (0.5mol) was added and stirred for 30min, cooled to room temperature, and the pH was adjusted to 7 with 0.2mol / L aqueous sodium hydroxide solution under ice bath conditions, After forming a precipitate, suction filtration and washing with deionized water for 3 times to obtain the product 2-(1H-indol-...

Embodiment 2

[0071] Example 2 In vitro antitumor activity study

[0072] The in vitro antitumor activity of the compounds of the present invention was demonstrated by the following method. These effects suggest that the compounds of the present invention are useful in the treatment of cancer. The specific test method is as follows:

[0073] 4-((6-(4-Fluorophenyl)-11H indole[3,2-c]quinolin-11-yl)methyl)-N-hydroxybenzyl prepared in Example 1 was detected by MTT method In vitro antitumor activity of amides and N-hydroxy-4-((6-(pyridin-2-yl)-11H-indol[3,2-c]quinolin-11-yl)methyl)benzamide. The tumor cell lines were purchased from ATCC in the United States, and the anti-proliferative activity of the test compounds against human colorectal cancer cell line HCT-116, human breast cancer cell MCF-7, and melanoma cell B16-F10 was determined by standard MTT assay. -8 method to evaluate the cytotoxicity of human lymphoma Jurkat-T cell line. All cancer cell lines were cultured in RPMI-1640 medium s...

Embodiment 3

[0079] Example 3 In vitro study of HDAC inhibition

[0080] The in vitro anti-tumor activities of the compounds G3 and G12 of the present invention were tested by the following methods. These effects indicate that the compounds G3 and G12 of the present invention can be used to effectively inhibit HDAC6.

[0081] The specific test method is as follows:

[0082] The enzyme inhibitory activities of compounds G3 and G12 were 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 / LMgCl 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 to 40 μL. Compounds to be tested (10 dilution concentrations, followed by 500 μM, 125 μM, 31.25 μM, 7.81 μM, 1.95 μM, 0.49 μM, 0.12 ...

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Abstract

The invention relates to the field of medical chemistry, in particular to a hydroxamic acid compound with a structure shown in a formula (I) and application thereof, and the hydroxamic acid compound can selectively act on HDAC6, inhibit cancer cell proliferation and enhance tumor immunity. 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 use thereof. Background technique [0002] Histone deacetylases (HDACs) are a family of enzymes capable of catalyzing the removal of acetyl groups from N-acetyllysine residues in histones or non-histone proteins. To date, 18 HDAC subtypes have been identified and grouped into four broad categories. HDACs play important roles in gene regulation, transcription, cell proliferation, and differentiation. Therefore, the research on HDAC inhibitors has received extensive attention in the past decade. Based on this, HDAC inhibitors are considered to have therapeutic potential for diseases such as cancer, inflammation, and the nervous system. As an important HDAC subtype, HDAC6 is closely related to the occurrence and development of various diseases. At the same time, studies have shown that HDAC6 plays an important role in promoting tumor i...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61P35/00A61P35/02
CPCC07D471/04A61P35/00A61P35/02
Inventor 不公告发明人
Owner 佛山市晨康生物科技有限公司
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