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Substituted-evodiamine anti-tumor and antifungal compounds and preparation method thereof

A technology for evodiamine and compounds, which is applied in the field of substituted evodiamine compounds and their salts and their preparation, can solve problems such as weak enzyme inhibitory activity and the like

Inactive Publication Date: 2010-07-28
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

In the previous study, the inventors carried out a virtual high-throughput screening study on the crystal structure of topoisomerase, and found that evodiamine (Evodiamine) can inhibit the activity of topoisomerase, but the inhibitory activity is weak

Method used

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  • Substituted-evodiamine anti-tumor and antifungal compounds and preparation method thereof
  • Substituted-evodiamine anti-tumor and antifungal compounds and preparation method thereof
  • Substituted-evodiamine anti-tumor and antifungal compounds and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: Preparation of 3-bromopropyl substituted evodiamine compounds (compound 1 in Table 1)

[0039] Take 0.18g (7.5mmol) of NaH and put it in a 50ml distillation bottle, add 15ml of anhydrous DMF and stir at room temperature for 10 minutes, add 0.30g (1mmol) of evodiamine and continue stirring for 30 minutes at room temperature, then add 1,3-di Propane bromide 0.8g (4mmol), slowly warm up to 80°C and react for 24 hours. Stop the reaction, add 40mlH to the reaction solution 2 O, extract with 40ml×3 ethyl acetate, combine the ethyl acetate extracts, dry with an appropriate amount of anhydrous sodium sulfate, filter, and take the filtrate. The solvent was evaporated to dryness, and purified by silica gel column chromatography, the eluent was petroleum ether: ethyl acetate = 4:1, and 0.15 g of white solid was obtained with a yield of 35.4%. 1 H-NMR (500MHz, DMSO) δ: 2.27(m, 2H, C17-2H), 2.39(s, 3H, C15-3H), 2.81(m, 1H, C8-H), 2.98(m, 1H, C8 -H), 3.11(m, 1H, C7-H), ...

Embodiment 2

[0040] Example 2: Preparation of evodiamine-like compounds substituted by acetonitrile (compound 3 in Table 1)

[0041] Take 0.18g (7.5mmol) of NaH and put it in a 50ml distillation bottle, add 15ml of anhydrous DMF and stir at room temperature for 10 minutes, add 0.30g (1mmol) evodiamine and continue stirring at room temperature for 30 minutes, then add bromoacetonitrile 1.2g ( 10 mmol), slowly warming up to 80°C for 24 hours. Stop the reaction, add 40mlH to the reaction solution 2 O, extract with 40ml×3 ethyl acetate, combine the ethyl acetate extracts, dry with an appropriate amount of anhydrous sodium sulfate, filter, and take the filtrate. The solvent was evaporated to dryness, and purified by silica gel column chromatography, the eluent was petroleum ether: ethyl acetate = 4:1, and 0.15 g of white solid was obtained with a yield of 43.9%. 1 H-NMR (500MHz, DMSO) δ: 2.39(s, 3H, C15-3H), 2.82(m, 1H, C8-H), 2.98(m, 1H, C8-H), 3.14(m, 1H, C7 -H), 4.66(m, 1H, C7-H), 5.57(s,...

Embodiment 3

[0042] Example 3: Preparation of ethoxycarbonyl-substituted evodiamine compounds (compound 4 in Table 1)

[0043] Take 0.18g (7.5mmol) of NaH and put it in a 50ml distillation bottle, add 15ml of anhydrous DMF and stir at room temperature for 10 minutes, add 0.30g (1mmol) evodiamine and continue stirring at room temperature for 30 minutes, then add ethyl chloroformate 1.1 g (10 mmol), slowly warming up to 80°C for 24 hours. Stop the reaction, add 40mlH to the reaction solution 2 O, extract with 40ml×3 ethyl acetate, combine the ethyl acetate extracts, dry with an appropriate amount of anhydrous sodium sulfate, filter, and take the filtrate. The solvent was evaporated to dryness, and purified by silica gel column chromatography, the eluent was petroleum ether: ethyl acetate = 4:1, and 0.17 g of white solid was obtained with a yield of 45.3%. 1 H-NMR (500MHz, CDCl 3 )δ: 1.29(t, J=6.7Hz, 3H, C18-3H), 2.45(s, 3H, C15-3H), 2.86(m, 1H, C8-H), 2.99(m, 1H, C8- H), 3.20(m, 1H, C7-H...

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Abstract

The invention discloses substituted-evodiamine anti-tumor and antifungal compounds and a preparation method thereof. The compounds have a general structural formula (I), wherein R represents: (1) benzyl or substituted benzyl; (2) benzoyl or substituted benzoyl; (3) linear or branched alkyl having 2 to 6 carbon atoms; and (4) an ester group. The substituted-evodiamine compounds of the invention have good anti-tumor activities for various tumor cells, provide a new way for deep research and development of new anti-tumor medicaments and can be used for preparing new anti-tumor medicaments.

Description

technical field [0001] The invention relates to the technical field of medicine, and relates to a new alkaloid antitumor and antifungal compound-a substituted evodiamine compound and its salts and a preparation method thereof. Background technique [0002] DNA topoisomerase I (topoisomerase I) is an essential enzyme for cell survival, involved in the whole process of cellular DNA replication, transcription, recombination and repair. Because the TopoI content in tumor cells, especially colon cancer, cervical cancer, ovarian cancer, etc. is much higher than that in normal tissues, they are more sensitive to TopoI inhibitors, so this type of drug has high selectivity for tumor cells. In addition, the enzyme inhibitor has the characteristics of high curative effect and broad anti-tumor spectrum, and the enzyme inhibitor has been listed by the US NCI as one of the six major anti-tumor drugs for key research. Camptothecin (CPT) and its analogs are the most important class of topo...

Claims

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Application Information

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IPC IPC(8): C07D471/14A61K31/519A61P35/00A61P31/10
Inventor 盛春泉张万年王胜正董国强缪震元姚建忠
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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