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

A technology of 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: 2021-07-16
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 (4.20g, 25.0mmol), NaHCO 3 (12.60g, 150mmol) and Boc 2 O (6.00g, 27.5mmol), and 75mL of anhydrous methanol was added as a solvent, stirred at room temperature under the protection of argon, the reaction progress was detected by TLC during the reaction, and the color was developed in an iodine jar. After 24h, the reaction was stopped, and the reaction solution was beige, and the unreacted NaHCO 3 The solid was removed by filtration using a Buchner funnel, and rinsed with methanol. The filtrate was distilled under reduced pressure and dissolved in 30 mL of water, then acidified with a 10% potassium bisulfate solution to pH=1-2, and extracted three times with ethyl acetate , the organic layers were combined and washed with saturated brine (3×25mL), dried over anhydrous sodium sulfate for 12h, filtered to remove the solid, evaporated under reduced pressure to remove the solvent, and dried in vacuo to obtain N-Boc-ALA (5.05g, 87%) light yellow Solid, ...

Embodiment 2

[0126] (1) In a 100mL round bottom flask, add the yellow oil (3.30g, 10.0mmol) and pentylamine (5.23g, 60.0mmol) obtained in Example 1 (6), ethanol and water (V:V=1: 1) 20mL was used as a solvent, reacted under reflux conditions for 18h, during which the reaction progress was monitored by TLC, after the reaction was completed, the solvent was distilled off under reduced pressure to obtain a brown oil, dissolved in ethanol and adjusted to pH = 1 with concentrated hydrochloric acid, continued to reflux for 4h, TLC Monitor the progress of the reaction, after the end of the reaction, cool to room temperature, remove the solvent by distillation under reduced pressure, dissolve the residue in water and wash twice with ether, then adjust to pH=9 with 10mol / L sodium hydroxide solution, extract with dichloromethane (3 ×20mL), combined the organic layers, dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure to remove the solvent, and dried in vacuo to obtain a...

Embodiment 3

[0132] (1) In a 100mL round bottom flask, add the yellow oil (3.30g, 10.0mmol) obtained in Example 1 (6) and n-hexylamine (6.07g, 60.0mmol), ethanol and water (V:V=1: 1) 20mL was used as a solvent, reacted under reflux conditions for 18h, during which the reaction progress was monitored by TLC, after the reaction was completed, the solvent was distilled off under reduced pressure to obtain a brown oil, dissolved in ethanol and adjusted to pH = 1 with concentrated hydrochloric acid, continued to reflux for 4h, TLC Monitor the progress of the reaction, after the end of the reaction, cool to room temperature, remove the solvent by distillation under reduced pressure, dissolve the residue in water and wash twice with ether, then adjust to pH=9 with 10mol / L sodium hydroxide solution, extract with dichloromethane (3 ×20mL), combined the organic layers, dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure to remove the solvent, and dried in vacuo to obtain ...

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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. The 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 present invention relates to the fields of organic synthesis and medicinal chemistry, in particular to a class of ALA hybrids that have both iron ion chelating ability and photosensitizing activity 3-hydroxypyridone (HPO) and 5-aminolevulinic acid (ALA) hybrid 3-Hydroxypyridone derivatives and their preparation methods and their applications in photodynamic therapy (Photodynamic therapy, PDT). Background technique [0002] Since the 20th century, with the acceleration of the industrialization process, the pollution of the human living environment has become increasingly serious, and people have become more and more frequently exposed to carcinogens, and the incidence of cancer has also increased year by year. In high-income countries, cancer has surpassed cardiovascular disease as the The number one enemy of human health. The treatment methods for tumors mainly include surgery, chemotherapy and radiotherapy. Although these three commonly used trea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/69A61K41/00A61K31/4412A61P35/00
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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