Histone deacetylase inhibitor and preparation method and application thereof

A technology of deacetylase and histone, applied in the field of biomedicine, can solve the problems of uncontrollable toxic and side effects, inability to achieve therapeutic effect of chemical drugs, and drug resistance, and achieve induction of differentiation and apoptosis, and good inhibitory activity , the effect of inhibiting proliferation

Inactive Publication Date: 2014-06-11
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are still many deficiencies in antineoplastic drugs, such as uncontrollable toxic and side effects, rapid drug resistance, etc., which lead to the inability of chemical drugs to achieve the expected therapeutic effect

Method used

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  • Histone deacetylase inhibitor and preparation method and application thereof
  • Histone deacetylase inhibitor and preparation method and application thereof
  • Histone deacetylase inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] The compound is a hydroxamic acid, the R in its structural formula 1 , R 2 3,5-Ditrifluoromethyl and hydroxylamine, respectively, prepared by the following steps:

[0055] 1) Preparation of isoferulic acid from isovanillin by Knaevengel condensation reaction

[0056] Put 22.81g (150mmol) of isovanillin and 62.44g (600mmol) of malonic acid in a 500mL round bottom flask, add 150mL of anhydrous pyridine to dissolve, add 34.26g of 1,8-diazabicyclo[5.4.0] Undec-7-ene (DBU), heating to reflux reaction; after the reaction is complete, cool to room temperature, pour the reaction mixture into a mixture of 500mL of concentrated hydrochloric acid and water (V:V=1:1), A precipitate precipitated out, filtered and washed with acid water to obtain a crude product. Dissolve the crude product in 200mL of 1mol / L sodium hydroxide aqueous solution, extract with dichloromethane, adjust the pH of the aqueous solution to 1, filter the obtained precipitate, wash with acid water, and dry to ...

Embodiment 2

[0075] R in the structural formula of this compound 1 , R 2 Respectively 3-chloro-4-fluoro and hydroxylamine, the preparation method is:

[0076] The 3,5-bistrifluoromethylaniline in Example 1 was replaced with 3-chloro-4fluoromethylaniline, and the other preparation methods were the same.

[0077] The resulting intermediate is N-(3-chloro-4-fluorophenyl)-2-{2-methoxy-5-[(1E)-3-oxobutenyl]phenoxy}acetamide, which The structure of the compound is shown below:

[0078]

[0079] Physical and chemical properties: mp: 182-184 ° C, MS (EI) [M] + :m / z=393.0.

[0080] Proton NMR data: 1 H NMR (400MHz, CDCl 3 )δppm:7.80(d,J=4Hz,1H),7.63(d,J=8Hz,1H),7.45(d,J=8Hz,1H),7.26(s,1H),7.17(s,1H), 7.14(d,J=4Hz,1H),6.98(d,J=4Hz,1H),6.34(d,J=8Hz,1H),4.68(s,2H),4.00(s,3H),3.83(s ,3H).

[0081] The target compound is (2E)-3-(5-{2-[(3-chloro-4-fluorophenyl)amino]-2-oxoethoxy}-3-methoxyphenyl)-N- Hydroxyacrylamide, the structure of the compound is shown below:

[0082]

[0083] Physic...

Embodiment 3

[0086] R in the structural formula of this compound 1 , R 2 3-Bromo-5-trifluoromethyl and 2-aminoaniline, respectively, prepared by:

[0087] 1) Preparation of isoferulic acid from isovanillin by Knaevengel condensation reaction

[0088]Put 22.81g (150mmol) of isovanillin and 62.44g (600mmol) of malonic acid in a 500mL round bottom flask, add 150mL of anhydrous pyridine to dissolve, add 34.26g of 1,8-diazabicyclo[5.4.0] Undec-7-ene (DBU), heating to reflux reaction; after the reaction is complete, cool to room temperature, pour the reaction mixture into a mixture of 500mL of concentrated hydrochloric acid and water (V:V=1:1), A precipitate precipitated out, filtered and washed with acid water to obtain a crude product. Dissolve the crude product in 200mL of 1mol / L sodium hydroxide aqueous solution, extract with dichloromethane, adjust the pH of the aqueous solution to 1, filter the obtained precipitate, wash with acid water, and dry to obtain 22.56g of white crystal isoferu...

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PUM

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Abstract

The invention discloses a histone deacetylase inhibitor and a preparation method and application thereof. The histone deacetylase inhibitor comprises a hydroxamic acid compound and a benzamide compound and is a novel compound which shows activity for inhibiting histone deacetylase and also shows a good inhibiting activity for in-vitro histone deacetylase; HDACs (Histone Deacetylases) are closely related with the growth and development of cancer. The histone deacetylase inhibitor is characterized in that the activity of the HDACs can be inhibited to effectively inhibit the proliferation of cancer cells and introduce the cancer cells to differentiate and reach apoptosis, so as to realize the purpose of treating tumor. The experiment result shows that the prepared histone deacetylase inhibitor is able to inhibit the growth of tumor cells; some of the compounds show the equivalent inhabitation for tumor cells as positive SAHA (Suberoylanilide Hydroxamic Acid), which proves that the prepared histone deacetylase inhibitor can be used for preparing antineoplastic drugs.

Description

technical field [0001] The invention relates to the technical field of biomedicine, relates to an anti-tumor compound, in particular to an isoferulic acid histone deacetylase inhibitor and its preparation method and application. Background technique [0002] Malignant tumor is one of the main diseases that seriously affect human health and threaten human life. Statistics from the World Health Organization show that millions of people die from malignant tumors every year in the world, and it has become the second largest killer of human diseases after cardiovascular and cerebrovascular diseases. Chemotherapy, as one of the important means of treating tumors, has undergone tremendous development and progress in the past three decades, and a large number of clinical antitumor drugs with different mechanisms of action have been obtained. However, there are still many deficiencies in antineoplastic drugs, such as uncontrollable toxic and side effects, rapid drug resistance, etc....

Claims

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Application Information

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IPC IPC(8): A61K31/16A61K31/167A61P35/00C07C259/06C07C235/38C07C231/12
Inventor 张杰卢闻王芳贺浪冲潘晓艳王琛李鹏飞
Owner XI AN JIAOTONG UNIV
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