Benzylisoquinoline alkaloid with human carboxylesterase 2 inhibition effect and application thereof

A technology of benzyl isoquinoline and alkaloids, which is applied in the field of medicine and achieves the effects of high yield, conducive to sustainable industrial production and good research and development prospects

Active Publication Date: 2021-06-11
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The research on the biological activity of alkaloids in Corydalis extract mainly focuses on analgesia and anti-inflammation, and there is no report on the inhibitory effect of benzylisoquinoline alkaloids on carboxylesterase

Method used

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  • Benzylisoquinoline alkaloid with human carboxylesterase 2 inhibition effect and application thereof
  • Benzylisoquinoline alkaloid with human carboxylesterase 2 inhibition effect and application thereof
  • Benzylisoquinoline alkaloid with human carboxylesterase 2 inhibition effect and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] The preparation of Corydalis Corydalis extract, comprises the steps:

[0040] (1) Acetic acid processing: 50 kg of tubers of the traditional Chinese medicine Corydalis yanhusuo W.T.Wang were soaked in 10L of 6% acetic acid solution, and dried at 40°C.

[0041] (2) Extract: The medicinal material prepared with acetic acid was pulverized, soaked in water, and then extracted by ultrasonic for 3 times, each time with 50 L of water for 1 hour, combined the extracts, and concentrated under reduced pressure to obtain the plant extract.

Embodiment 2

[0043] The preparation of benzylisoquinoline alkaloid compound comprises the steps:

[0044] The extract obtained in Example 1 was subjected to macroporous adsorption resin column chromatography, and eluted successively with water, 50% ethanol, and 95% ethanol respectively, and the eluent was concentrated under reduced pressure; the 95% ethanol extract was concentrated to no alcohol, and distilled water was added 2L, extracted 5 times with an equal volume of ethyl acetate to obtain an ethyl acetate phase and an aqueous phase. Ethyl acetate part E was obtained after recovering the organic solvent under reduced pressure. Sample E was eluted by silica gel column chromatography (dichloromethane-methanol 200:1, 150:1, 100:1, 50:1, 25:1, 10:1, 5:1, 3:1, 0:1) , to get component A-I. Component A was selected and then eluted by silica gel column chromatography (petroleum ether-acetone 30:1, 15:1, 10:1, 5:1, 3:1, 2:1, 1:1, acetone) to obtain the component A1-A8. Component A4 was sub...

experiment example 1

[0056] Experimental example 1: Evaluation of the inhibitory effect of the extract on hCE2 activity

[0057] Instruments: metal incubator, vortex shaker, microplate reader

[0058] Reagents: including 0.5mM substrate FD (diacetylfluorescein), 0.1mM phosphate buffer saline PBS (pH7.4), ACN (acetonitrile), HLM human liver microsomes / single enzyme

[0059] Experimental steps:

[0060] 1) The microsome incubation system contains the following components (total volume 200μl):

[0061]

[0062] Table 3. hCE-2 incubation system and dosage

[0063]

[0064] 2) Add HLM+PBS+Inhibitor / DMSO to a black 96-well plate, shake and mix on a vortexer, and pre-incubate at 37°C for 10 minutes;

[0065] 3) After adding FD to start the reaction, perform fluorescence analysis (fluorescence microplate reader);

[0066] 4) set up three control groups simultaneously, one is no inhibitor (add equal volume DMSO) group as the 100% contrast of enzyme activity, the second is no enzyme (add equal vol...

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PUM

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Abstract

The invention discloses a benzylisoquinoline alkaloid compound which has a human carboxylesterase 2(hCE2) inhibiting effect and is shown as a formula (I), a plant extract containing the benzylisoquinoline alkaloid compound, a pharmaceutical composition containing the benzylisoquinoline alkaloid compound, and application of the benzylisoquinoline alkaloid compound in preparation of a human carboxylesterase 2(hCE2) inhibitor.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a benzylisoquinoline alkaloid compound and a plant extract containing the benzylisoquinoline alkaloid compound in the preparation of any carboxylesterase 2 inhibitor. Background technique [0002] Mammalian carboxylesterase is a key enzyme in serine hydrolases, involved in catalyzing the hydrolysis of various esters and amides 1 . Human carboxylesterase 2 (hCE2) is one of the two main carboxylesterases in the human body, mainly distributed in the gastrointestinal tract and less distributed in the liver 2 , which plays a key role in the metabolic activation of many prodrugs, including the anticancer drugs capecitabine and irinotecan, which can hydrolyze their prodrugs into active products to exert their drug effects 3 . In addition, hCE2 is also involved in the hydrolysis of triglycerides. After its activity is inhibited, the intestinal absorption of lipids will sl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/20C07D405/14C07D455/03A61K36/50A61K31/472A61K31/4725A61K31/4375A61P3/06A61P9/12A61P3/04A61P9/00A61P3/10A61P35/00A61P3/00
CPCC07D217/20C07D405/14C07D455/03A61K36/50A61P3/06A61P9/12A61P3/04A61P9/00A61P3/10A61P35/00A61P3/00C07B2200/07Y02P20/55
Inventor 林生王玲燕张景芳夏桂阳夏欢
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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