ALA hybrid 3-hydroxypyridone derivative as well as preparation method and application thereof

A technology for hydroxypyridone and derivatives, which is applied in the field of ALA hybrid 3-hydroxypyridone derivatives and its preparation, and can solve the problems of decreased therapeutic effect and poor pharmacokinetic performance

Active Publication Date: 2022-07-12
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Through the analysis of the mechanism of action of ALA in vivo, ferrochelatase can catalyze the transformation of PpIX into heme without photosensitivity, resulting in a decline in the therapeutic effect. It can be seen that the activity of ferrochelatase is the key factor affecting the accumulation of PpIX in cells. Iron chelators can inhibit the activity of ferrochelatase by removing unstable iron pools in cells
[0006] Studies have found that in ALA-PDT, due to the presence of iron chelators ethylenediaminetetraacetic acid (EDTA) and deferoxamine, the level of PpIX induced by ALA can be increased, but it also shows some adverse effects on the produced PpIX and poor pharmacokinetic performance

Method used

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  • ALA hybrid 3-hydroxypyridone derivative as well as preparation method and application thereof
  • ALA hybrid 3-hydroxypyridone derivative as well as preparation method and application thereof
  • ALA hybrid 3-hydroxypyridone derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0114] (1) ALA hydrochloride (4.20 g, 25.0 mmol) and NaHCO were added to a 250 mL round-bottomed flask 3 (12.60g, 150mmol) and Boc 2 O (6.00 g, 27.5 mmol), and 75 mL of anhydrous methanol was added as a solvent, stirred at room temperature under argon protection, and the reaction progress was detected by TLC during the reaction, and the color was developed in an iodine cylinder. After 24h, the reaction was stopped, and the reaction solution was beige at this time, and the unreacted NaHCO was 3 The solid was removed by filtration with a Buchner funnel and rinsed with methanol. The filtrate was distilled under reduced pressure and dissolved in 30 mL of water, then acidified to pH=1~2 with 10% potassium hydrogen sulfate solution, and extracted with ethyl acetate for 3 times. , the organic layers were combined and washed with saturated brine (3×25 mL), dried over anhydrous sodium sulfate for 12 h, filtered to remove the solid, evaporated to remove the solvent under reduced pressu...

Embodiment 2

[0126] (1) In a 100 mL round-bottomed flask, add the yellow oil (3.30 g, 10.0 mmol) and amylamine (5.23 g, 60.0 mmol) obtained in Example 1 (6), ethanol and water (V:V=1: 1) 20 mL was used as a solvent, reacted under reflux conditions for 18 h, during which TLC was used to monitor the reaction progress, after the reaction was completed, the solvent was distilled off under reduced pressure to obtain a brown oily substance, dissolved in ethanol and adjusted to pH=1 with concentrated hydrochloric acid, continued to reflux for 4 h, TLC The reaction progress was monitored, after the reaction was completed, it was cooled to room temperature, the solvent was distilled off under reduced pressure, the residue was dissolved in water and washed twice with diethyl ether, then adjusted to pH=9 with 10 mol / L sodium hydroxide solution, extracted with dichloromethane (3 × 20 mL), combined the organic layers, dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure to re...

Embodiment 3

[0133] (1) In a 100 mL round-bottomed flask, add the yellow oil (3.30 g, 10.0 mmol) and n-hexylamine (6.07 g, 60.0 mmol) obtained in Example 1 (6), ethanol and water (V:V=1: 1) 20 mL was used as a solvent, reacted under reflux conditions for 18 h, during which TLC was used to monitor the reaction progress, after the reaction was completed, the solvent was distilled off under reduced pressure to obtain a brown oily substance, dissolved in ethanol and adjusted to pH=1 with concentrated hydrochloric acid, continued to reflux for 4 h, TLC The reaction progress was monitored, after the reaction was completed, it was cooled to room temperature, the solvent was distilled off under reduced pressure, the residue was dissolved in water and washed twice with diethyl ether, then adjusted to pH=9 with 10 mol / L sodium hydroxide solution, extracted with dichloromethane (3 × 20 mL), combined the organic layers, dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure to...

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Abstract

The invention designs and synthesizes a novel anti-tumor active compound with iron chelating property and photosensitive activity based on the principles of reasonable drug design, drug-likeness and the like. The invention aims to provide a preparation method of a series of novel active compounds of ALA hybrid 3-hydroxypyridone (HPO) derivatives with iron ion chelating ability and PDT activity and application of the novel active compounds in the anti-tumor aspect. A series of novel compounds with PDT activity synthesized by the invention have remarkable advantages in the aspect of anti-tumor activity.

Description

technical field [0001] The invention relates to the fields of organic synthesis and medicinal chemistry, in particular to a class of ALA hybrids which have both iron ion chelating ability and photosensitivity activity of 3-hydroxypyridone (HPO) and 5-aminolevulinic acid (ALA). 3-Hydroxypyridone derivatives and preparation method thereof and application in photodynamic therapy (PDT). Background technique [0002] Since the 20th century, with the acceleration of industrialization, the pollution of human living environment has become more and more serious, people have become more frequent contact with carcinogenic factors, and the incidence of cancer has also increased year by year. In high-income countries, cancer has surpassed cardiovascular disease as a The number one enemy of human health. There are three commonly used methods for tumor treatment: surgery, chemotherapy and radiotherapy. Although these three commonly used treatment methods have good curative effect on the t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/69A61P35/00A61K41/00
CPCC07D213/69A61P35/00A61K41/0057Y02P20/55
Inventor 谢媛媛袁圣利高变变林玉燕张长俊张雨佳
Owner ZHEJIANG UNIV OF TECH
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