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Pentacyclic triterpenoids and their use as inhibitors of human intestinal carboxylesterase

A technology of pentacyclic triterpenoids and human intestinal carboxylate, applied in the field of biomedicine, can solve the problems of affecting bioavailability, not relieving delayed diarrhea, reducing drug dosage, etc., achieving high safety and simple synthesis process OK, good security effects

Active Publication Date: 2017-10-27
ZHANGJIAGANG IND TECH RES INST CO LTD DALIAN INST OF CHEM PHYSICS CHINESE ACADEMY OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the inhibitory effect of glycyrrhetinic acid and its derivatives on human carboxylesterase has not been reported, nor has there been any report on the use of glycyrrhetinic acid and its derivatives to relieve delayed diarrhea caused by CPT-11
In addition, many oral drugs containing carboxylate bonds are often metabolized by carboxylesterases distributed in the gastrointestinal tract, and are easily hydrolyzed into water-soluble active drugs before being absorbed into the blood, thereby reducing their absorption into the blood. The amount of drug that affects bioavailability

Method used

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  • Pentacyclic triterpenoids and their use as inhibitors of human intestinal carboxylesterase
  • Pentacyclic triterpenoids and their use as inhibitors of human intestinal carboxylesterase
  • Pentacyclic triterpenoids and their use as inhibitors of human intestinal carboxylesterase

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Synthesis of (3-carboxypropionyl)-11-deoxy-glycyrrhetinic acid-30-carboxylate

[0038] (1) Synthesis of compound 1 (11-deoxy-glycyrrhetinic acid)

[0039] At room temperature, add 18β-glycyrrhetinic acid (235.3mg, 0.5mmol) and zinc powder (526.5mg, 16.2mmol) into 1,4-dioxane (9mL) solution, cool the reaction system to 8-12°C, Concentrated hydrochloric acid (1.45 mL) was slowly added dropwise, and the reaction was maintained at 8-12°C after addition, and the reaction was monitored by thin-plate chromatography (TLC). After the reaction was complete, evaporate the solvent under reduced pressure, add water (25mL), extract with dichloromethane three times (30mL×3), combine the organic phases and wash with saturated sodium chloride solution (20mL×1), dry over anhydrous sodium sulfate, and evaporate the solvent , column chromatography of the crude product (petroleum ether / ethyl acetate=20 / 1-5 / 1) gave compound 1 as a white solid with a yield of 65-75%.

[0040] (2) Synthesis ...

Embodiment 2

[0047] Quantitative evaluation of (3-carboxypropionyl)-11-deoxy-glycyrrhetinic acid-30-carboxylate for the inhibition of carboxylesterase 2

[0048] Using the hydrolytic metabolism of fluorescein diacetate as a probe reaction, the IC of inhibition of carboxylesterase 2 by glycyrrhetinic acid and its derivatives was determined by means of human liver microsome in vitro incubation system 50 :

[0049] a. 200 microliters of in vitro metabolic reaction system, containing phosphate buffer solution with a pH of 7.4, the concentration of human liver microsomal protein is 2 μg / ml, and the final concentration of inhibitors is in the range of 0.001 μM-100 μM. Shake pre-incubation at 37°C 10 minutes;

[0050] b. Add the substrate (final concentration 10 μM) to the reaction system to initiate the reaction; after reacting at 37°C for 30 minutes, add 200 μl of acetonitrile, shake vigorously, and terminate the reaction;

[0051] c. Using a high-speed refrigerated centrifuge, under the cond...

Embodiment 3

[0053] Quantitative evaluation of the inhibitory ability of (3-carboxypropionyl)-11-deoxy-glycyrrhetinic acid-30-carboxylate on carboxylesterase 1

[0054] Using the hydrolytic metabolism of fluorescein diacetate as a probe reaction, the IC of inhibition of carboxylesterase 1 by glycyrrhetinic acid and its derivatives was determined by means of human liver microsome incubation system in vitro 50 :

[0055] a. In 200 microliters of in vitro metabolic reaction system, containing phosphate buffer solution with a pH of 7.4, the concentration of human liver microsomal protein is 2 μg / ml, and the final concentration of inhibitors is in the range of 0.001 μM-120 μM. Shake pre-incubation at 37°C 10 minutes;

[0056] b. Add the substrate (final concentration 10 μM) to the reaction system to initiate the reaction; after reacting at 37°C for 30 minutes, add 200 μl of acetonitrile, shake vigorously, and terminate the reaction;

[0057] c. Using a high-speed refrigerated centrifuge, unde...

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Abstract

The invention provides a pentacyclic triterpene compound and its application as an inhibitor of human intestinal carboxylesterase, belonging to the technical field of biomedicine. The pentacyclic triterpenoids have a 11-deoxy-glycyrrhetinic acid skeleton structure, which can potently and selectively inhibit the activity of human intestinal carboxylesterase subtype 2, thereby improving the bioavailability of oral prodrugs , and reduce the intake of intestinal esters. In addition, the inhibitor can also slow down the delayed diarrhea caused by irinotecan. In vitro activity assays found that the IC50 of this type of compound inhibiting human carboxylesterase 2 can reach 0.02 micromolar, and the ratio of the IC50 of inhibiting human carboxylesterase 1 to the IC50 of inhibiting human carboxylesterase 2 can reach 1020, and this type of compound The safety is good, and it also has the advantages of simple preparation process and high yield, suggesting that this type of compound has a good application prospect.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and mainly relates to a pentacyclic triterpenoid compound and its application as a potent inhibitor of human intestinal carboxylate. Background technique [0002] Carboxylesterases (CEs) belong to group B esterases, and the CEs involved in the metabolism of ester drugs in the human body are mainly carboxylesterase 1 (hCE-1) and carboxylesterase 2 (hCE-2). hCE-1 is highly expressed in the liver, and exists in macrophages, lung epithelial cells, heart, testis and other tissues, but little expression in the gastrointestinal tract. hCE-2 is present in small intestine, colon, kidney, liver, heart and brain tissue. CEs participate in the hydrolysis and metabolism of various endogenous and exogenous compounds in the body, and cooperate with other metabolic enzymes or carriers to play an important role in the metabolism and clearance of ester drugs. CEs can hydrolyze a variety of drugs or ester pro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J63/00A61K31/56A61P1/12A61P3/04A61P3/10
CPCA61P1/12A61P3/04A61P3/10C07J63/008
Inventor 杨凌邹立伟葛广波李耀光宁静王平
Owner ZHANGJIAGANG IND TECH RES INST CO LTD DALIAN INST OF CHEM PHYSICS CHINESE ACADEMY OF SCI
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