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Belinostat structural analogue with histone deacetylase inhibiting effect and application of belinostat structural analogue

A sirupin and belistat technology, applied in the field of belistat's structural analogues, can solve the problem of unrecorded sulfonamide bond replacement HDACIs etc.

Inactive Publication Date: 2018-02-16
XUZHOU NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After searching the existing technical literature, it is found that many HDACIs on the market or in clinical research contain amide bonds in the surface recognition region, but only belistat has a sulfonamide structure in the surface recognition region. Replacement of the sulfonamide bond in the structure of lixistat with an amide bond to obtain the content of HDACIs

Method used

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  • Belinostat structural analogue with histone deacetylase inhibiting effect and application of belinostat structural analogue
  • Belinostat structural analogue with histone deacetylase inhibiting effect and application of belinostat structural analogue
  • Belinostat structural analogue with histone deacetylase inhibiting effect and application of belinostat structural analogue

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Synthesis of 3-(2-(methoxyformyl)vinyl)benzoic acid (3)

[0025] Dissolve m-bromobenzoic acid (3.0g, 15mmol) and methyl acrylate (6.45g, 75mmol) in N,N-dimethylformamide (50mL), add triethylamine (202mg, 2mmol), palladium acetate ( 67mg, 0.3mmol) and three (o-methylphenyl) phosphorus (92mg, 0.3mmol). Under nitrogen, the temperature of the reaction solution was raised to 110° C. for 5 hours. Then cool to room temperature, adjust the pH value to about 2 with dilute hydrochloric acid, filter the precipitated solid, and recrystallize with acetone to obtain 2.15 g of white solid, with a yield of 70%. 1 H NMR (400MHz, DMSO-d 6 )δ8.20(d, J=1.8Hz, 1H), 8.02-7.95(m, 2H), 7.74(d, J=16.1Hz, 1H), 7.56(t, J=7.7Hz, 1H), 6.72( d,J=16.1Hz,1H),3.74(s,3H).

Embodiment 2

[0027] Synthesis of 3-(2-(methoxyformyl)vinyl)benzoyl chloride (4)

[0028] 3-(2-(Methoxyformyl)vinyl)benzoic acid 3 (1.03g, 5mmol) was dissolved in an appropriate amount of toluene, and thionyl chloride (1.1mL, 15mmol) and 1 drop of N,N-dimethyl Formamide. After reacting at 90°C for 1 hour, toluene and excess thionyl chloride were distilled off under reduced pressure to obtain acid chloride 4. The crude product was used directly in the next step without purification.

Embodiment 3

[0030] General Synthesis of Methyl 3-(3-(Substituted Aryl)carbamoyl)Benzacrylate (6)

[0031] Substituted arylamines 5a-o (5mmol) were dissolved in dichloromethane (20mL), cooled to 0°C in an ice-water bath, triethylamine (7mmol) was added, and then a solution of compound 4 in dichloromethane was slowly added dropwise. The reaction solution was slowly raised to room temperature and stirred for 1-2 hours until compound 4 disappeared (monitored by TLC). After the reaction, the pH value was adjusted to about 2 with dilute hydrochloric acid. The organic layer was separated, the aqueous layer was extracted with dichloromethane, the organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Separation by column chromatography (petroleum ether: ethyl acetate = 3:1) gave compounds 6a-o.

[0032] Methyl 3-(3-(2-methylphenyl)carbamoyl)benzoacrylate (6a)

[0033] White solid, yield 35%. 1 H NMR (400M...

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Abstract

The invention relates to a belinostat structural analogue with the histone deacetylase inhibiting effect and an application of the belinostat structural analogue. The active component of the belinostat structural analogue at least includes a compound of the general formula of the belinostat structural analogue and pharmaceutical salt, aquo-complex, predrugs or metabolite products formed by any forms of metabolism. The belinostat structural analogue has the remarkable histone deacetylase inhibiting effect and antitumor activity, and the compound is suggested to have potential applications in combination with preparation of pharmaceutical drugs related to histone deacetylase relevant diseases, preparation of antitumor drugs and other antitumor drugs or radiation therapy for tumor treatment.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to a structural analogue of belinostat with histone deacetylase inhibitory activity and an application thereof. Background technique [0002] Histone deacetylase (HDAC) is a family of proteases that can hydrolyze acetyl groups on histone or non-histone terminal lysine residues, which can make nuclear chromatin more compact, thereby inhibiting gene Transcription, through the deacetylation of histones and non-histones, affects various cellular functions. The mutation and abnormal expression of HDAC can lead to the occurrence of various diseases, especially tumors. HDAC is abnormally expressed in tumor cells, and most of histones are in a low acetylation state, which makes HDAC an important anti-tumor target. Inhibition of HDAC can restore normal gene expression, which can block the cell cycle of cancer cells, promote cell differentiation and apoptosis. Therefore, histone deacetylase inhibito...

Claims

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Application Information

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IPC IPC(8): C07C259/06C07D213/75C07D333/36A61P35/00
CPCC07C259/06C07D213/75C07D333/36
Inventor 赵立明张皆欢金海善
Owner XUZHOU NORMAL UNIVERSITY
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