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Natural triterpene-iridoid glycoside dimer heterocomplex, preparation thereof and application of natural triterpene-iridoid glycoside dimer heterocomplex in preparation of ACL inhibitor

A technology of iridoid glycoside dimers and hybrids, which is applied in the field of medicine and can solve problems such as low affinity, limited development, and low specificity

Active Publication Date: 2021-10-29
TAIZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Except for Bempedoic acid, the development of other ACL inhibitors is limited due to their low cell penetration, low affinity with ACL, and poor specificity.

Method used

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  • Natural triterpene-iridoid glycoside dimer heterocomplex, preparation thereof and application of natural triterpene-iridoid glycoside dimer heterocomplex in preparation of ACL inhibitor
  • Natural triterpene-iridoid glycoside dimer heterocomplex, preparation thereof and application of natural triterpene-iridoid glycoside dimer heterocomplex in preparation of ACL inhibitor
  • Natural triterpene-iridoid glycoside dimer heterocomplex, preparation thereof and application of natural triterpene-iridoid glycoside dimer heterocomplex in preparation of ACL inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment 1: the preparation of compound abelifloroside A and abelifloroside B

[0041] Dry and crush 0.4 kg of A. x grandiflora flowers, extract 5 times with 75% ethanol solution at room temperature, 2 L each time for 24 hours. The combined extracts were filtered and concentrated under reduced pressure to obtain 67 g (semi-dry) of the total extract. 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).

[0042] 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 solu...

Embodiment 2

[0055] Example 2: ACL inhibitory activity test

[0056] Experimental method: In this experiment, the ATP-dependent citrate lyase ACL can catalyze the conversion of citric acid into acetyl-CoA, and then produce the precursor molecule of fatty acid synthesis - malonyl-CoA. This reaction is accompanied by the consumption of ATP, so the ADP-Glo ​​kinase detection kit can be used to detect the change of ATP to indirectly reflect the inhibitory effect of the compound on the ACL enzyme activity.

[0057]Specifically, the percentage inhibition rate of ACL enzyme activity was investigated when the concentration of the compound obtained from the separation and purification in Example 1 was selected for primary screening at 20 μg / mL. The test results showed that the inhibition rates of abelifloroside A and abelifloroside B were 96.4% and 84.1% respectively. %.

[0058] Further determination of IC 50 Value: The sample is dissolved in DMSO to make a suitable concentration before use, 3-f...

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Abstract

The invention discloses a natural triterpenoid-iridoid glycoside dimer hybrid, preparation thereof and application of the natural triterpenoid-iridoid glycoside dimer hybrid in preparation of an ACL inhibitor. The structural formula of the triterpenoid-iridoid glycoside dimer hybrid is as shown in a formula (1) or a formula (2). According to the invention, the obtained triterpenoid-iridoid glycoside dimer hybrid abelifloside A and abelifloside B are subjected to ATP-citrate lyase (ATP-citrate lyase, ACL) inhibitory activity experiment, it is shown that the compound has obvious ACL inhibitory activity, can be used for preparing drugs for ACL-mediated diseases or lead compounds of the drugs, and has a treatment effect on hyperlipidemia, atherosclerosis, fatty liver, type II diabetes, cancer and other ACL-mediated diseases, so that the compound has huge potential application in the field of pharmacy.

Description

technical field [0001] The present application relates to the field of medical technology, in particular to a natural triterpene-iridoid glycoside dimer hybrid and its preparation and preparation of ATP-citrate lyase (ATP-citrate lyase, ACL) inhibitors use. Background technique [0002] ATP-citrate lyase (ATP-citrate lyase, ACL) is a key enzyme in sugar metabolism and fatty acid and cholesterol biosynthesis. Its substrate and product are key intermediates in sugar metabolism and can be used as a substrate for fatty acid synthesis . Human ACL enzyme protein is a homotetramer composed of 4 identical 120KDa subunits, each polypeptide chain contains 1101 amino residues (Singh et al, J.Biol.Chem.1976,251, 5254-5250) . ACL is a cytosolic enzyme that catalyzes the conversion of citrate and CoA to acetyl-CoA and oxaloacetate with concomitant hydrolysis of ATP. ACL is highly expressed in adipogenic cells and cholinergic nerve cells such as liver, kidney and pancreas (Beigneux et ...

Claims

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Application Information

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IPC IPC(8): C07J71/00A61P3/06A61P9/10A61P3/10A61P3/04A61P1/16A61P35/00
CPCC07J71/0005A61P3/06A61P9/10A61P3/10A61P3/04A61P1/16A61P35/00
Inventor 胡金锋万江金则新姜春筱
Owner TAIZHOU UNIV