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3-aryl coumarin derivative as well as preparation method and application thereof

A technology of aryl coumarin and hydroxy coumarin, which is applied in the directions of drug combination, pharmaceutical formulation, medical preparation containing active ingredients, etc., can solve the problems of low bioavailability, poor pharmacokinetics, poor specificity, etc. , to achieve the effect of obvious specificity, good affinity and low cost

Active Publication Date: 2021-07-16
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] At present, there are many reports on SIRT3 agonists, including natural products and honokifen, silybin and resveratrol, etc., but such SIRT3 Most agonists have problems such as broad targets and poor specificity
Oligonucleotide-based SIRT3-targeted agonists have limited their clinical application due to their low bioavailability, poor pharmacokinetics, and susceptibility to nuclease degradation.

Method used

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  • 3-aryl coumarin derivative as well as preparation method and application thereof
  • 3-aryl coumarin derivative as well as preparation method and application thereof
  • 3-aryl coumarin derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Embodiment 1: the preparation of 3-(2-hydroxyphenyl)-6-methylcoumarin (1)

[0075] 2-Hydroxyphenylacetic acid (5 g, 32.86 mmol), 2-hydroxy 5-methylbenzaldehyde (4.47 g, 32.86 mmol), acetic anhydride (20.13 g, 197.18 mmol) and triethylamine (13.30 mmol) were added to a round bottom flask. g, 131.45mmol), stirred and reacted at 120°C for 8h, and monitored the progress of the reaction by thin-layer chromatography. After the reaction is completed, according to post-processing method B, pour the reaction solution into ice water and keep stirring to obtain a viscous solid, pour out the supernatant, soak and wash the viscous material in water until the water phase is close to neutral. Add 50 mL of sodium hydroxide (2.63 g, 65.73 mmol) aqueous solution to the above viscous material, stir to dissolve, extract and wash with ethyl acetate twice, separate the liquids to obtain an aqueous layer, slowly add dilute hydrochloric acid aqueous solution dropwise to adjust pH = 2, A large...

Embodiment 2

[0076] Embodiment 2: the preparation of 3-(2-hydroxyphenyl)-6-methylcoumarin (1)

[0077] Into a round bottom flask was added 2-hydroxyphenylacetic acid (5 g, 32.86 mmol), 2-hydroxy 5-methylbenzaldehyde (4.47 g, 32.86 mmol), acetic anhydride (16.77 g, 164.31 mmol) and triethylamine (9.98 g, 98.59mmol), stirred and reacted at 110°C for 10h, and monitored the progress of the reaction by thin-layer chromatography. After the reaction is completed, according to post-processing method B, pour the reaction solution into ice water and keep stirring to obtain a viscous solid, pour out the supernatant, soak and wash the viscous material in water until the water phase is close to neutral. Add 50 mL of sodium hydroxide (2.63 g, 65.73 mmol) aqueous solution to the above viscous material, stir to dissolve, extract and wash with ethyl acetate twice, separate the liquids to obtain the water layer, slowly add dilute hydrochloric acid aqueous solution dropwise, and adjust pH=3 , a large amount...

Embodiment 3

[0078] Example 3: Preparation of 3-(2-hydroxyl-4-methoxyphenyl)-6-chlorocoumarin (2)

[0079] To a round bottom flask was added 2-hydroxy-5-methoxyphenylacetic acid (5 g, 27.45 mmol), 2-hydroxy-4-chlorobenzaldehyde (4.30 g, 27.45 mmol), acetic anhydride (16.81 g, 164.68 mmol) and triethylamine (11.11g, 109.78mmol), stirred and reacted at 120°C for 8h, and monitored the progress of the reaction by thin-layer chromatography. After the reaction is completed, according to post-processing method B, pour the reaction solution into ice water and keep stirring to obtain a viscous solid, pour out the supernatant, soak and wash the viscous material in water until the water phase is close to neutral. Add 50mL of sodium hydroxide (2.20g, 54.89mmol) aqueous solution to the above viscous material, stir to dissolve it, extract and wash with ethyl acetate twice, separate the liquids to obtain an aqueous layer, slowly add dilute hydrochloric acid aqueous solution dropwise, and adjust pH=2 , a...

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Abstract

The invention discloses a 3-aryl coumarin derivative as well as a preparation method and application thereof. The preparation method comprises the following steps of: carrying out tandem condensation-lactonization reaction on substituted phenylacetic acid and substituted 2-hydroxybenzaldehyde as raw materials in the presence of triethylamine and acetic anhydride, and after the reaction is finished, respectively and independently carrying out three post-treatment methods to obtain the 3-aryl coumarin derivative. The 3-aryl coumarin derivative provided by the invention has good affinity to SIRT3 protein, can up-regulate the deacetylase activity of the SIRT3 protein and reverse ISO (isoprenaline) stimulated and induced cardiac hypertrophy, and can be used for preparing anti-cardiovascular disease or anti-diabetes drugs.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and pharmacy, and in particular relates to a 3-aryl coumarin derivative and its preparation method and application. Background technique [0002] Protein post-translational modification is the key to the regulation of protein function. Sirtuins (silent information regulartors, silent information regulators) protein family, as important sirtuins, play an important role in regulating genome stability, energy metabolism, and responding to cellular stress (Theranostics, 2020, 10(18) ,8315). Among the seven members of the Sirtuins family, SIRT3 (Silent Information Regulator 3) protein is a class of NAD-dependent deacetylase localized in mitochondria, and is widely expressed in mitochondria-rich organs such as kidney, heart, brain and liver , whose regulated acetylation modification is critical for maintaining mitochondrial homeostasis in these organs (Cell, 2010, 143(5), 802-812). [0003] Studies...

Claims

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Application Information

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IPC IPC(8): C07D311/16C07D311/12A61K31/352A61P3/10A61P9/00
CPCC07D311/16C07D311/12A61P3/10A61P9/00
Inventor 刘培庆邹永李泽宇卢国庆沈娟张小雷
Owner SUN YAT SEN UNIV
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