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Application of natural triterpene-iridoid glycoside dimer heterocomplex in preparation of acetyl-coenzyme A carboxylase 1 inhibitor

A technology of iridoid glycoside dimer and acetyl coenzyme, which is applied in the field of medicine and can solve problems such as low affinity, development limitations, and low cell penetration

Active Publication Date: 2021-11-23
TAIZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Except for GS-0976, the development of other ACC1 inhibitors is limited due to their low cell penetration, low affinity with ACC1, and poor specificity.

Method used

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  • Application of natural triterpene-iridoid glycoside dimer heterocomplex in preparation of acetyl-coenzyme A carboxylase 1 inhibitor
  • Application of natural triterpene-iridoid glycoside dimer heterocomplex in preparation of acetyl-coenzyme A carboxylase 1 inhibitor
  • Application of natural triterpene-iridoid glycoside dimer heterocomplex in preparation of acetyl-coenzyme A carboxylase 1 inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1: the preparation of compound abelifloroside B

[0036] Dry and crush 0.4kg flower buds of A. x grandiflora, extract 5 times with 75% ethanol solution at room temperature, 2L each time for 24 hours. Filter and combine extract, obtain total extract 67g (semi-dry) after concentrating under reduced pressure. After the total extract was dispersed with 1L of water, it was extracted three times with equal volumes of petroleum ether, ethyl acetate and n-butanol. The extract was concentrated under reduced pressure to obtain petroleum ether fraction (17.2 g), ethyl acetate fraction (16.3 g) and n-butanol fraction (20.6 g).

[0037] The ethyl acetate fraction (16.3g) was eluted with ethanol-water (30:70→50:50→70:30→85:15→100:0; v / v) gradient through macroporous resin column chromatography, and collected The resulting lower column solution was color-developed and identified by TLC thin-layer chromatography, and the lower column solution with the same spot was combine...

Embodiment 2

[0045] Example 2: ACC1 inhibitory activity test

[0046] Experimental method: ACC1 is located in the liver and adipocytes and is a key enzyme for fatty acid synthesis. It needs biotin as a coenzyme and relies on the energy provided by ATP to carboxylate acetyl-CoA, catalyzes the production of malonyl-CoA, and then regulates lipid metabolism. This reaction is also accompanied by the consumption of ATP, therefore, the ADP-Glo ​​Kinase Assay Reagent can be used to detect the change of ATP to indirectly reflect the inhibitory effect of the compound on the ACC1 enzyme.

[0047] Specifically, during the preliminary screening, the monomer compound isolated in Example 1 was selected. When the concentration was 20 μg / mL, the percentage inhibition rate of ACC1 enzyme activity was investigated. The test results showed that the inhibition rate of the compound abelifloroside B was 85.3%. .

[0048] Further determination of IC 50 Value: the sample is dissolved in DMSO to make a suitable c...

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Abstract

The invention discloses application of a triterpenoid-iridoid glycoside dimer heterocomplex with a structural formula as shown in a formula (1) in preparation of an acetyl-coenzyme A carboxylase 1 inhibitor. According to the application, it is found that the compound has a remarkable ACC1 inhibition effect in ACC1 inhibition biological experiments, and the heterocomplex can be used for preparing drugs for treating ACC1-mediated diseases or used as a lead compound of the drugs. The heterocomplex has a treatment effect on obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, cancer and other ACC1-mediated diseases, so that the heterocomplex has huge potential application in the field of pharmacy.

Description

technical field [0001] The application belongs to the field of medical technology, and specifically relates to the use of natural triterpene-iridoid glycoside dimer hybrids in the preparation of prevention or control of glycolipids mediated by acetyl-CoA carboxylase 1 (acetyl-CoA carboxylase 1, ACC1). Drugs for diseases related to metabolic disorders (such as obesity, type 2 diabetes, non-alcoholic fatty liver, etc.) or use in lead compounds of such drugs. Background technique [0002] Acetyl-CoA carboxylase 1 (acetyl-CoA carboxylase1, ACC1) has the functions of biotin carboxylase and carboxyltransferase at the same time, plays the role of a rate-limiting enzyme in the synthesis of long-chain fatty acids, and can catalyze the carboxylation of acetyl-CoA Produces malonyl-CoA. The human ACC1 gene is located on chromosome 17q12, and the corresponding protein molecular weight is 165kDa. It is mainly highly expressed in tissues such as liver, adipose tissue and mammary gland whe...

Claims

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Application Information

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IPC IPC(8): A61K31/58C07J71/00A61P35/00A61P3/04A61P3/10A61P1/16
CPCA61K31/58C07J71/0026A61P35/00A61P3/04A61P3/10A61P1/16
Inventor 胡金锋万江熊娟金则新姜春筱
Owner TAIZHOU UNIV