Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

A class of glucuronosyltransferase UGT1A1 inducers and applications thereof

A technology of glucuronic acid and inducer, which is applied in the field of medicine, can solve serious adverse reactions and other problems, and achieve the effects of avoiding the first-pass effect, strong induction ability, and eliminating hyperbilirubinemia

Inactive Publication Date: 2017-02-15
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
View PDF2 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although CPT-11 has achieved satisfactory clinical therapeutic effects, serious adverse reactions caused by it have become an unavoidable problem

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • A class of glucuronosyltransferase UGT1A1 inducers and applications thereof
  • A class of glucuronosyltransferase UGT1A1 inducers and applications thereof
  • A class of glucuronosyltransferase UGT1A1 inducers and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Preparation of 4',7-dihydroxy-3'-prenyl isoflavone diacetyl derivatives

[0028] Weigh 4',7-dihydroxy-3'-prenyl isoflavone ( figure 1 , Compound A) 200 mg was dissolved in 10 mL of dichloromethane, 0.5 mL of triethylamine was added, the reaction solution was cooled to 0° C., and 100 μL of acetyl chloride was slowly added dropwise. After reacting for 1 hour, TLC detected that the reaction was complete, slowly added 20 mL of water, extracted twice with 30 mL of dichloromethane, combined the organic phases, washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a crude product. The crude product 4mL methanol was heated to reflux for 30min, cooled, filtered, and the filter cake was collected and vacuum-dried to obtain 4',7-dihydroxy-3'-prenyl isoflavone diacetyl derivative ( figure 1 , Compound C) 230mg, white solid, yield 91%. Wherein the NMR spectrum of 4,7-dihydroxy-3'-prenyl isoflav...

Embodiment 2

[0032] The ability of this class of drugs to induce the expression of UGT1A1 enzyme mRNA

[0033]Inoculate Caco-2 in a 24-well plate, and after incubation for 24 hours, replace the medium with fresh drug-containing medium containing 4',7-dihydroxy-3'-prenyl isoflavone, and the final concentration of the compound is 25 μM. The fresh medium containing the drug was replaced every day, and the cells were collected with RNA extraction reagent after culturing for 12, 24, 48, and 72 hours, respectively. Total mRNA was extracted according to the procedure attached to the RNA extraction reagent, and the mRNA was reverse-transcribed into cDNA using a reverse transcription kit. Subsequently, the mRNA expression level of UGT1A1 enzyme in the cells was measured with a real-time PCR instrument. By measuring the ability of new psoralen isoflavones to induce the expression of UGT1A1 enzyme over time ( image 3 ) It can be seen that the induction ability of 4',7-dihydroxy-3'-prenyl isoflavo...

Embodiment 3

[0035] Fluorescent probe method to determine the ability of this kind of drugs to induce UGT1A1 enzyme activity

[0036] Caco-2 cells were seeded at 75cm 2 When culturing to 70% confluency, add 25 μM 4',7-dihydroxy-3'-prenyl isoflavone and its acetylated derivatives, and replace the drug-containing fresh medium every day during the culture period until incubation for 3 sky. After incubation, the cells were collected by trypsinization and washed three times with ice-cold PBS. Add PBS containing 1% cocktail protease inhibitor to the cell pellet, place it on ice for sonication, then centrifuge at 9000 g for 20 min, and collect the supernatant as cell S9 component, which is used to determine the activity of UGT1A1 enzyme. The assay procedure of UGT1A1 enzyme activity is as follows:

[0037] (1) 200 microliters of in vitro metabolic reaction system contains 50mM Tris-Hcl buffer (PH=7.4), the protein concentration of cell S9 is 1mg / ml, Mgcl 2 5mM, UGT1A1 probe substrate concentr...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
Protein concentrationaaaaaaaaaa
Login to View More

Abstract

The present invention relates to a class of glucuronosyltransferase UGT1A1 inducers and applications thereof. According to the present invention, the class of the inducers are 4,7-dihydroxy-3'-isopentenyl isoflavone and acetylated derivatives thereof, and can induce the up-regulation of glucuronosyltransferase UGT1A1 so as to alleviate the symptoms of hyperbilirubinemia, Gilbert syndrome, Crigler-Najjar syndrome and other diseases caused by UGT1A1 activity loss and alleviate the toxic-side reactions caused by CPT-11 and other antitumor drugs; the human cell induction experiment results show that the class of the compounds can significantly induce the expression and the activity of UGT1A1 enzyme in Caco-2 cells and provide the strong induction ability for the expression and the activity of the UGT1A1 enzyme compared to the positive control drug chrysin; and the results of the cell experiments and the mouse overall experiments show that the class of the drugs have good safety and good patent medicine prospects.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a class of inducer of glucuronosyltransferase UGT1A1 and application thereof. Background technique [0002] Bilirubin is the main metabolite of iron porphyrin compounds in the body. It is insoluble in water and difficult to be excreted by the kidneys. Excessive accumulation in the body can cause irreversible damage to the brain and nervous system. When the function of liver glucuronyltransferase UGT1A1 is normal, bilirubin is combined with glucuronic acid under the action of liver cell UGT1A1 enzyme, and converted into water-soluble conjugated bilirubin, which is excreted by the kidneys. Genetic factors or acquired factors can cause the decrease of UGT1A1 enzyme activity, thereby affecting the metabolic clearance of bilirubin, leading to clinical hyperbilirubinemia. The pathogenesis of Gilbert (GS) syndrome and Crigler-Najjar (CNS) syndrome are genetic factors leadi...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): A61K31/352A61P1/16A61P39/02
Inventor 杨凌王丹丹葛广波王平宁静李娜
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com