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10-hydroxyevodiamine type anti-tumor compounds as well as preparation method and application thereof

A technology of hydroxyevodiamine and evodiamine, which is applied in the field of medicine, can solve the problems of poor water solubility and high toxicity, and achieve the effect of enhanced solubility

Active Publication Date: 2016-03-23
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the lactone structure necessary for the activity of this type of compound is hydrolyzed too quickly in the human body into an inactive carboxylate, and has poor water solubility and high toxicity

Method used

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  • 10-hydroxyevodiamine type anti-tumor compounds as well as preparation method and application thereof
  • 10-hydroxyevodiamine type anti-tumor compounds as well as preparation method and application thereof
  • 10-hydroxyevodiamine type anti-tumor compounds as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 110

[0120] The synthesis of embodiment 110-hydroxy evodiamine

[0121] 1. Preparation of N-formyl-5-methoxytryptamine

[0122] In a 50mL three-necked flask, add 4g (21mmol) 5-methoxytryptamine and 13g ethyl formate, and reflux at 80°C for 6 hours. Appeared slowly, 4.5g of the product was obtained by suction filtration, and the yield was 98.3%.

[0123] 2. Preparation of 3,4-dihydro-5-methoxy-β-carboline

[0124] In a 100mL three-necked flask, add 50mL of dichloromethane, under stirring conditions, add 4.0g (18mmol) of N-formyl-5-methoxytryptamine, cool to about 5°C in an ice-water bath, then slowly add 5.0mL Phosphorus oxychloride, reacted under ice bath for 2 hours, and then reacted at room temperature for 2 hours. After the reaction, dichloromethane and unreacted phosphorus oxychloride were recovered by distillation under reduced pressure, and the residual solid was separated with 120mL10% aqueous acetic acid solution. Three extractions. The combined extracts were adjusted t...

Embodiment 210

[0129] Synthesis of Example 210-((3-(tert-butoxy-2-((tert-butoxycarbonyl)amino)propionyl)oxy)evodiamine (L209)

[0130] In a 100mL round bottom flask, add (3-(tert-butoxy-2-((tert-butoxycarbonyl)amino)propionic acid 0.49g, EDC0.36g, DMAP0.23g, dissolve in 40mL DCM, stir at room temperature for 30min , Add 10-hydroxyevodiamine 0.50g (1.57mmol) again, react overnight, point plate monitoring.Reaction completes, directly evaporates to dryness solvent and mixes sample, column chromatography purification, eluent is sherwood oil: ethyl acetate=3: 1. Obtain 0.80 g of 10-((3-(tert-butoxy-2-((tert-butoxycarbonyl)amino)propionyl)oxy)evodiamine with a yield of 90.74%.

Embodiment 310

[0131] Example 31 Synthesis of 0-((1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)oxy)evodiamine (L215)

[0132] Referring to Example 2, N-tert-butoxycarbonylproline was reacted with 10-hydroxyevodiamine to obtain 10-((1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)oxy)evodiamine 0.74 g, the total yield is 92.0%.

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Abstract

The invention relates to 10-hydroxyevodiamine type anti-tumor compounds, a preparation method of the 10-hydroxyevodiamine type anti-tumor compounds and an application of the 10-hydroxyevodiamine type anti-tumor compounds in preparing an anti-tumor drug. The 10-hydroxyevodiamine type anti-tumor compounds have a structure shown in the formula I. The compounds are newly found topoisomerase inhibitors with brand new structures, most of compounds have broad-spectrum antitumor activity, and the IC50 (half maximal inhibitory concentration) of a part of derivatives to tested three tumors is smaller than 0.001 mu g / mL and is superior to that of compounds (10-hydroxyevodiamine) with similar structures and best activity in the prior art.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a 10-hydroxy evodiamine antitumor compound and its preparation method and application. Background technique [0002] DNA topoisomerase, as an enzyme involved in DNA replication and transcription, exists widely in mammals. In the topological transformation of closed-loop double-stranded DNA, one or two strands of DNA are temporarily cut off, and are divided into two types according to the way of isomerization. Cutting a chain to change the topology is called type I topoisomerase (topoisomerase I), and cutting off two chains is called type II topoisomerase (topoisomerase II). [0003] DNA topoisomerase I (topoisomerase I, TopoI) is an essential enzyme for cell DNA replication, transcription, recombination and repair, and the content of TopoI in tumor cells, especially colon cancer, cervical cancer, ovarian cancer, etc. is much higher than that in normal tissues , Drugs that se...

Claims

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Application Information

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IPC IPC(8): C07D471/14A61K31/519A61P35/00
CPCC07D471/14
Inventor 盛春泉张万年董国强陈树强李振钢缪震元姚建忠刘娜武善超方堃
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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