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Nitrate NO donor type tripyridine bisoxazole compound as well as preparation method and application thereof

A technology of tripyridine bioxazole and nitrate, applied in digestive system, organic chemistry, drug combination and other directions, can solve the problems of poor selectivity, strong toxic and side effects, and achieve the effects of high selectivity, high toxic and side effects, and weak toxic and side effects

Active Publication Date: 2021-02-02
ANHUI MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chemotherapy is an important way to treat cancer, but traditional chemotherapy drugs have poor selectivity and strong side effects. This problem needs to be solved urgently

Method used

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  • Nitrate NO donor type tripyridine bisoxazole compound as well as preparation method and application thereof
  • Nitrate NO donor type tripyridine bisoxazole compound as well as preparation method and application thereof
  • Nitrate NO donor type tripyridine bisoxazole compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Synthesis of compound 1:

[0028]

[0029] Dissolve 2,6-pyridinedicarbaldehyde (14.6mmol) in 60mL of methanol, add 2 times the amount of TosMIC (24.8mmol) and 4 times the amount of K 2 CO 3 (58.4mmol), reflux reaction for 5 hours, after the reaction was finished, the solvent was evaporated, washed with water, filtered, and purified by silica gel column chromatography (petroleum ether / ethyl acetate=40:1) to obtain 2.7g yellow solid with a yield of 87%. . 1 H NMR (400MHz, CDCl 3 )8.01(s, 2H), 7.80(t, J=8.7Hz, 1H), 7.63(s, 2H), 7.56(d, J=8.6Hz, 2H). ESI-MS: m / z 214.1 [M+ H] + .

Embodiment 2

[0031] Synthesis of compound 3:

[0032]

[0033] Dissolve 4.7mmol of Intermediate 1 in 20mL of dioxane, add 3.3 times the amount of 5-bromo-2methoxypyridine (15.5mmol), and then add 0.4 times the amount of Pd(OAC) in a stirring state after dissolution 2 (1.9mmol), 4.4 times the amount of CsCO 3 (20.6mmol), 4.4 times the amount of CuI (10.8mmol) and 0.2 times the amount of PCy 3 .HBF 4 (0.94mmol), reacted at 130°C for 24 hours under the protection of argon, evaporated the solvent to obtain the black crude product 2, was dissolved in 120mL of dichloromethane after drying, N 2 Slowly drop 3 times the molar amount of BBr in a low-temperature reactor at -25°C under protective conditions 3 / CHCl 2 , slowly return to room temperature after the dropwise addition, and continue to stir for 24 hours. After the reaction is completed, the reaction system is quenched with methanol and water successively, dichloromethane is evaporated, and silica gel column chromatography (petroleum ...

Embodiment 3

[0035] Synthesis of Compound 8a:

[0036]

[0037] Concentrated sulfuric acid (20mmol) was added dropwise to fuming nitric acid (20mmol) under ice-cooling, and after stirring for 10min, a dichloromethane solution of bromoethanol (10mmol) was added dropwise. After reacting for 3 h, 10 mL of water was added to terminate the reaction. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 6, which was directly used in the next reaction.

[0038] Compound 3 (0.5mmol) in Example 2 was placed in a reaction flask, DMF (8mL) was added, stirred until the compound was completely dissolved, DBU (0.75mmol) and 6 (0.75mmol) were added to react at room temperature for 5 hours, and the reaction was monitored by TLC process, after the reaction is over, pour the reaction solution into 50ml of ice-water mixture, extract three times with 100ml of dichloromethane, wash with saturated brine, dry over anhy...

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Abstract

The invention discloses a nitrate NO donor type tripyridine bisoxazole compound as well as a preparation method and application thereof. The structural formula of the nitrate NO donor type tripyridinebisoxazole compound is shown as a formula (I) in the description, wherein in the formula (I), n is 1 or 2. The nitrate NO donor type tripyridine bisoxazole compound disclosed by the invention shows targeted combination with a G-quadruplex and basically does not generate a combination effect with double helix DNA, so that targeted release of NO in tumor cells is realized, NO and a flexible G-quadruplex ligand generate a synergistic anti-tumor effect, and only weak toxic and side effects are generated. Theoretical and experimental bases are provided for developing novel anti-tumor drugs with high selectivity, high efficiency and low toxic and side effects on the basis of double functions of targeting G-quadruplex and releasing NO.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a nitrate NO donor type tripyridyl bisoxazole compound and a preparation method and application thereof. Background technique [0002] Cancer is one of the major diseases that threaten human life and health. Chemotherapy is an important way to treat cancer, but traditional chemotherapy drugs have poor selectivity and strong side effects, which need to be solved urgently. In the past ten years, with the in-depth development of tumor molecular biology, proteins or genes closely related to tumorigenesis, growth, metastasis, and apoptosis have been used as drug design targets to develop highly efficient, low-toxic, and specific anti-tumor drugs. It has become an important direction in the research and development of anticancer drugs. [0003] The design of new anti-tumor drugs targeting G-quadruplex DNA is one of the important frontiers in the research of ta...

Claims

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Application Information

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IPC IPC(8): C07D413/14A61K31/4439A61P35/00A61P1/00
CPCC07D413/14A61P35/00A61P1/00
Inventor 李增刘治成
Owner ANHUI MEDICAL UNIV
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