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Piperlongumine derivative as well as preparation method and application thereof

A technology for longinamide and derivatives, which is applied in the field of longinamide derivatives and their preparation, can solve problems such as not obtaining clear conclusions, and achieve the effects of high yield and simple synthesis process.

Active Publication Date: 2019-11-22
NINGXIA MEDICAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The research on the intracellular mechanism mediated by its up-regula

Method used

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  • Piperlongumine derivative as well as preparation method and application thereof
  • Piperlongumine derivative as well as preparation method and application thereof
  • Piperlongumine derivative as well as preparation method and application thereof

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preparation example Construction

[0044] A method for preparing a perylene amide derivative as described in formula (I-1), including any mixture of these forms or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0045] a. Using 3-hydroxyl-4-nitrobenzaldehyde and propyne bromide as raw materials to prepare a product 1 with a propynyl group;

[0046] b. react product 1 with malonic acid and precipitate with dilute hydrochloric acid to prepare product 2 with chloroacrylic acid groups;

[0047] c. reacting the product 2 with oxalyl chloride, and reacting the resulting product with a chlorinated seven-membered lactam ring to prepare a perylene amide derivative as shown in formula (I-1).

[0048] specifically:

[0049] (1) Dissolve 3-hydroxy-4-nitrobenzaldehyde and Propargyl bromide in DMF (dimethylformamide), add potassium carbonate (K 2 CO 3 ), after several hours of reaction at room temperature, 5 times the volume of purified water was added and extracted with ethyl acetate. The o...

Embodiment 1

[0076] Embodiment 1: the preparation of the perylene amide derivative as shown in formula (I-1)

[0077] Dissolve 1.07g (1.0 equivalent) of 3-hydroxy-4-nitrobenzaldehyde and 0.9g (1.2 equivalent) of propyne bromide in 10mLDMF, add 0.2g (2.0 equivalent) of potassium carbonate, react at room temperature for 4 hours and add 5 times volume of purified water and extracted with ethyl acetate. The organic layers were combined and washed with saturated brine, dried over anhydrous sodium sulfate, mixed and loaded on the column, and the product was eluted with ethyl acetate:petroleum ether 1:4 to obtain 1.3 g of product 1 as a yellow solid, with a yield of 100%.

[0078] The obtained product 1 was dissolved in 8 mL of pyridine, 1.2 g (1.8 equivalents) of malonic acid and a catalytic amount of piperidine were added and reacted at 60° C. for 4 hours. TLC monitored until the raw material was consumed, and 1 mol / L dilute hydrochloric acid was added until the precipitate was no longer preci...

Embodiment 2

[0081] Embodiment 2: as the perylene amide derivative shown in formula (II-1) (R 3 For the preparation of nitro)

[0082] Dissolve 30 mg of product (I-1) in 5 mL of tert-butanol, add 8 mg (1.0 equivalent) of copper sulfate, add 30 mg (0.8 equivalent) of biotin-PEG4-azide, and protect with nitrogen. Dissolve 25 mg (3.0 equivalents) sodium vitamin C in 5 mL of pure water, slowly drop it into the reaction flask, react at room temperature for 4 hours, TLC monitors that the raw material is dry, add 5 times the volume of pure water and extract with ethyl acetate. The organic layers were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and separated on a thick silica gel preparative plate with dichloromethane / methanol 10:1 to obtain the crude product. D., s-5m), the mobile phase is acetonitrile / water 75:25, the flow rate: 2mL / min, and 6 mg of light yellow oily liquid is obtained, which is the perylene amide derivative shown in formula (II-1) (R 3 is n...

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Abstract

The invention discloses a piperlongumine derivative as well as a preparation method and application thereof, and belongs to the technical field of medical chemistry. The piperlongumine derivative isshown as a formula (I): the piperlongumine derivative, as well as any mixture of these forms or a pharmaceutically acceptable salt thereof, can be used as the target Keap1 molecular probe, can position and bind the Keap1 protein in a lysis solution, and can be detected in the Western-Blot at the later stage so as to provide the new means for the research of the anti-tumor effect mechanism of the piperlongumine. According to the method, 3-hydroxy-4-nitrobenzaldehyde is used as a raw material, the synthesis process is simple, efficient and rapid, and the prepared piperlongumine derivative has relatively high yield.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a perylene amide derivative and a preparation method and application thereof. Background technique [0002] Piperlongumine (Piperlongumine, PL) is an active natural product isolated and extracted from the Piper genus plant, and it has been found to have a variety of biological activities, such as anti-inflammatory, anti-fungal, treatment of anxiety and depression, anti-platelet aggregation and anti-tumor effects Wait. Studies have found that Piperamide selectively kills tumor cells and has very little toxicity to normal cells. This unique selective effect has attracted the attention of drug researchers at home and abroad, and it is used as a lead compound to research and develop new anti-tumor drugs. [0003] The anti-tumor mechanism of Piperamide is still unclear, and it is widely considered as a class of small molecules that act on multiple targets, suc...

Claims

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Application Information

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IPC IPC(8): C07D495/04G01N33/50G01N33/535G01N33/561G01N33/58
CPCC07D495/04G01N33/561G01N33/535G01N33/581G01N33/68G01N33/5011G01N2550/00
Inventor 庄春林缪震元马皓张万年曲卓张火俊余建强徐丽娟
Owner NINGXIA MEDICAL UNIV
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