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NO donor type piperlongumine derivative as well as preparation method and application thereof

A technology of perylene amide and derivatives, applied in the field of medicinal chemistry, can solve the problems of short biological half-life and limit direct application, and achieve good inhibitory effect

Active Publication Date: 2022-07-29
WUHAN UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the short biological half-life of NO limits its direct clinical application.

Method used

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  • NO donor type piperlongumine derivative as well as preparation method and application thereof
  • NO donor type piperlongumine derivative as well as preparation method and application thereof
  • NO donor type piperlongumine derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] In this example, two compounds were synthesized, which were abbreviated as TP-1 and TP-2 respectively.

[0038] The name of compound TP-1 is: 2-((5-(4-(3-(5-chloro-6-oxo-3,6-dihydropyridin-1(2H)-yl)-3-oxopropane -1-en-1-yl)-2,6-dimethoxyphenoxy)pentane(oxy)methoxy)-1-morpholinodiazene 1-oxide, the structural formula is as follows:

[0039]

[0040] The name of compound TP-2 is: 1-((5-(4-(3-(5-chloro-6-oxo-3,6-dihydropyridin-1(2H)-yl)-3-oxopropane -1-En-1-yl)-2,6-dimethoxyphenoxy)pentane(oxy)methoxy)-3,3-diethyltriazole-1-ene 2-oxide , the structure is as follows:

[0041]

[0042] The reaction scheme involved in the present embodiment of the present invention is as follows:

[0043]

[0044] Step a: Add anhydrous sodium sulfate (2.35 g, 16.54 mmol) to the flask, add 15 ml of dichloromethane, mix well, add concentrated sulfuric acid (1.63 g, 16.63 mmol), and stir at room temperature for 1 h. A mixture of 5-bromovaleric acid (1.50 g, 8.29 mmol) and tert-butan...

Embodiment 2

[0061] Example 2: Control compound (3-chloro-1-(3-(4-((5-((diethylamino)oxy)-5-oxopentyl)oxy)-3,5-di Synthesis of Methoxyphenyl)acryloyl)-5,6-dihydropyridin-2(1H)-one))(TP-3)

[0062] Compound structure:

[0063]

[0064] Take 0.2 g of intermediate 8 into a round-bottomed flask, add dichloromethane to dissolve, add 0.041 g of N,N-diethylhydroxylamine (DEHA), after mixing, add 0.094 g of EDC under an ice bath, and stir at room temperature The reaction was carried out for 8 h, and the reaction was monitored by TLC. After extraction, the organic layer was collected and washed with water and saturated sodium chloride (20 ml x 3), respectively, dried over anhydrous sodium sulfate, and concentrated. Purification by thin layer chromatography, developing solution ethyl acetate: petroleum ether = 2: 1, to obtain 18 mg of the product as a yellow paste. 1 H NMR (600MHz, CDCl 3 )δ7.72–7.65 (dd, J=15.5, 2.1Hz, 1H), 7.43–7.36 (dd, J=15.5, 2.1Hz, 1H), 7.09–7.05 (td, J=4.6, 2.0Hz, 1H) ...

Embodiment 3

[0065] Example 3: Partial pharmacological tests and results of representative compounds of the present invention

[0066] 1. In vitro anti-tumor screening

[0067] Cell viability was determined by MTT assay. The cells in the logarithmic growth phase were adjusted to a density of 5000 cells / well, seeded in a 96-well plate, placed at 37°C, 5% CO 2 Cultivated under conditions until the cells were 90% confluent, then incubated with serum-free medium (HCT-116:McCoy's 5A medium, A549:F12K medium, CCD841:EMEM medium) for 2h to synchronize the cells, using the corresponding compounds respectively. After treating the cells for 24h and 72h, carefully remove the supernatant, add 90μL of fresh culture medium, and then add 10μL of MTT solution, 37°C, 5% CO 2 Incubate for 4 h under conditions, after the incubation, aspirate the supernatant, add 110 μL of Formazan lysis solution to each well, and place on a shaker for low-speed shaking for 10 min to fully dissolve the crystals. The absorb...

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Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to NO donor type piperlongumine derivatives as well as a preparation method and application thereof. The derivative provided by the invention is specifically a compound as shown in a formula (I), an isomer or pharmaceutically acceptable salt thereof, wherein R1 is selected from morpholine, pyrazine, pyrrole, furan, pyridine, quinoline, thiophene, diethylamine and derivative structures related to the morpholine, pyrazine, pyrrole, furan, pyridine, quinoline, thiophene, diethylamine and the like. R2 is selected from H or halogen. The compound, the isomer or the pharmaceutically acceptable salt of the compound can be applied to preparation of anti-tumor drugs for treatment or prevention, and particularly has good application prospects in treatment or prevention of colon cancer and non-small cell lung cancer.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a class of NO-donating piperonamide derivatives, a preparation method and an application. Background technique [0002] Piperlongumine (PL) is a natural alkaloid compound with various pharmacological activities such as anti-tumor, anti-platelet aggregation, anti-inflammatory and anti-depression. Especially in terms of anti-tumor, piperamide can inhibit the proliferation or metastasis of lung cancer, colon cancer, gastric cancer, breast cancer, ovarian cancer and other cancer cells, but has no obvious toxic and side effects on normal cells, tissues and organs, and has certain effects. It is a highly potential antitumor compound. Longinamide can inhibit and kill tumor cells in many ways. Current research shows that longanamide exerts its anti-tumor activity mainly through the following ways: a. Inducing the level of intracellular reactive oxygen species to ...

Claims

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Application Information

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IPC IPC(8): C07D211/86A61K31/4412A61K31/5377A61P35/00
CPCC07D211/86A61P35/00
Inventor 邹瑜谭丽娟杨曦亮王婷曹晓璐程仁璋
Owner WUHAN UNIV OF SCI & TECH
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